Digoxin Toxicity in a 14 Days Old Newborn: A Case Report

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İclal Sucaklı

2006-01-01

Full Text Available Digoxin is one of the most commonly used positive inotropic agent. Digitalis toxicity may occur easily because of digoxin has a narrow therapeutic window. Digitalis toxicity may result during treatment with digoxin or from accidental overdose of digoxin. An elevated serum level of digoxin (>2ng/ml is likely to be associated with toxicity, overdose of digoxin (>5ng/ml may lead to life-threatening arrhythmias. A 14-days old newborn with VSD, which had been prescribed the droplet form of digoxin but given the tablet form by the drugstore, was diagnosed as digitalis toxicity and hospitalized to our clinic. His mother expressed that she had given two tablets mashed with spoon and diluted. Bradycardia and grade 3/6 pansystolic murmur was determined in physical examination. Digoxin level in serum was >5 ng/ml and there was third degree atrioventricular block in ECG findings. The case has been presented to emphasize the importance of better evaluation of digoxin indications and making families of the patients conscious of the usage of digoxin.

Pharmacokinetics of a telmisartan, amlodipine and ...

African Journals Online (AJOL)

Conclusion: A formulated FDC tablet containing a telmisartan/amlodipine/HCTZ combination (80/10/25mg) was bioequivalent to a co-administrated commercially available telmisartan/amlodipine combination and HCTZ tablets at equivalent concentrations. Keywords: Fixed-dose combination, Hypertension, Telmisartan, ...

Tissue distribution of tritiated digoxin and quabain in mice

International Nuclear Information System (INIS)

Klopper, J.F.; Atkins, H.L.

1976-01-01

Tissue concentration of tritiated digoxin in human subjects appears to be selective in that after a single dose of the radioactive tracer a myocardial concentration of digoxin on an average 24 to 30 times higher than the serum concentration is reached. In patients studied 3.5 to 84 hours after administration of tritiated digoxin, the dose in the heart was found to vary between 1.95 to 4.83 percent. Should it be possible to label digoxin or another cardiac glycoside with a suitable gamma-emitting tracer, its use as a cardiac imaging agent should thus be feasible. This study was undertaken to determine the tissue distribution in mice of tritiated digoxin at various time intervals post injection; and to determine if these values showed any correlation to the previously determined human data. A preliminary study in mice using 3 H-digitoxin revealed no selective uptake in the heart with high uptakes in the liver and gut. Since ouabain has a more rapid clinical onset of action than digoxin, its tissue distribution was included in the study and compared to that of digoxin

Development of glycoside-bound radiopharmaceuticals; Novel radioiodination method for digoxin

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Takemura, Yasutaka; Dote, Nobuhito; Taniuchi, Hideyuki; Iijima, Naoko; Yokoyama, Akira (Kyoto Univ. (Japan). Faculty of Pharmaceutical Science); Fujibayashi, Yasuhisa; Konishi, Junji

1994-01-01

We combined 2-hydroxy-3-methylbenzoylhydrazide (HMBH) with glycosides as a novel method for the radioiodination of physiologically active glycosides. This method was tested using digoxin, which is one of the cardiac glycosides. A digoxin-HMBH conjugate was synthesized by periodate cleavage of the third sugar ring, and was readily radiolabelled with Na[[sup 125]I] by the chloramine-T method. [sup 125]I labelled digoxin-HMBH conjugate retained Na[sup +], K[sup +]-ATPase binding in vivo and in vitro, and also retained immunoreactivity to an anti-digoxin antibody. Thus, this [sup 125]I labelled digoxin-HMBH conjugate represents a potential radiopharmaceutical for Na[sup +], K[sup +]-ATPase imaging, as well as for the radioimmunoassay of digoxin. (author).

The effects of high-dose amlodipine/benazepril combination therapies on blood pressure reduction in patients not adequately controlled with amlodipine monotherapy.

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Chrysant, Steven G; Sugimoto, Daniel H; Lefkowitz, Marty; Salko, Thomas; Khan, Mahmudul; Arora, Vipin; Shi, Victor

2007-03-01

This study compared the efficacy and safety of amlodipine/benazepril (10/40 mg/day and 10/20 mg/day) with amlodipine 10 mg/day in patients whose blood pressure (BP) was not adequately controlled with amlodipine monotherapy. After a lead-in period with amlodipine monotherapy, 812 non-responder patients (mean sitting diastolic BP > or =95 mmHg) were randomized to one of three treatment groups. Ambulatory BP monitoring was conducted in 276 patients. Treatment with amlodipine/benazepril 10/40 mg/day and 10/20 mg/day resulted in a decrease of mean sitting systolic and mean sitting diastolic BP by 13.3/12.7 mmHg and 12.1/11.6 mmHg, respectively, compared with monotherapy (6.6/8.5 mmHg) (p benazepril 10/40 mg/day and 10/20 mg/day decreased ambulatory systolic and diastolic BP by 9.9/6.7 mmHg and 7.4/5.2 mmHg compared with monotherapy (p benazepril combinations compared with monotherapy (4.5%, 5.5% vs. 9.2%, respectively, p=NS). No significant metabolic side-effects were noted among the combination groups. Amlodipine/benazepril combinations were well tolerated and resulted in significant BP reductions and better BP responder rates than amlodipine monotherapy.

Lack of interaction between digoxin and quinidine in cultured heart cells

International Nuclear Information System (INIS)

Horowitz, J.D.; Barry, W.H.; Smith, T.W.

1982-01-01

Previous investigations have raised the possibility that the digoxin-quinidine interaction is associated with a reduction in the positive inotropic effect of digoxin due to displacement of digoxin from cardiac as well as skeletal muscle. To circumvent some of the complexities presented by intact animal models, this interaction was investigated in cultured chick embryo ventricular cells. Quinidine, even at relatively high concentrations (10(-4)--2 x 10(-3) M), did not significantly affect positive inotropic effects of digoxin and did not protect against cellular contracture induced by toxic digoxin concentrations, despite preincubation of cells with quinidine for 60 min. The effects of digoxin on monovalent cation transport, as judged by active uptake of the K analog 86Rb, were also not altered by 10(-4) M to 2 x 10(-3) M quinidine. These data suggest that quinidine does not displace digoxin from Na, K adenosine triphosphatase binding sites in this preparation. Although these data must be extrapolated to the intact animal with caution, our findings suggest that changes in digoxin clearance are more likely of primary importance in the digoxin-quinidine interaction, and indicate that the approximately 2-fold increase in serum digoxin concentration observed after addition of quinidine would be expected to have direct effects on myocardial cells comparable with those seen with increased digoxin concentration in the absence of quinidine

3H-digoxin distribution in the nervous system in ventricular tachycardia

International Nuclear Information System (INIS)

Frazer, G.; Binnion, P.

1981-01-01

The distribution of 3H-digoxin has been measured in a large number of tissues from the central, autonomic, and peripheral nervous system after the induction of ventricular tachycardia by infusing digoxin into anesthetized dogs. In most parts of the nervous system the tissue digoxin concentration was close to that in the cerebrospinal fluid. Digoxin accumulation in the choroid plexus probably represented a labeling of adenosine triphosphatase. There was a markedly higher concentration of digoxin in the neurohypophysis than in the adenohypophysis, and the very high levels in the neurohypophysis are hard to explain. There may be a relationship between the pituitary and the hypothalamic digoxin levels, although the concentration in the latter was unimpressive. The fornix showed a modest increase in 3H-digoxin concentration and may play a role, as its efferent discharge goes to the hypothalamus. The high concentration of digoxin in the area postrema suggests that this central nervous system structure is responsible, at least in part, for producing digoxin-induced cardiac arrhythmias. It may act as a sensing organ sensitive to blood digoxin concentration. Either it is the only central nervous structure implicated, or it is involved together with the fornix-hypothalamus-hypophysis pathways. Further proof is given for the importance of the autonomic nervous system in cardiac arrhythmias by the high digoxin levels in the superior cervical sympathetic ganglion and adrenal medulla

Digoxigenin-histamine conjugates and their use in digoxin measurement

International Nuclear Information System (INIS)

1979-01-01

A method for measuring the digoxin content of a serum comprises adding to digoxin antibody coated tubes a mixture of a radiolabelled histamine derivative of digoxegenin and a sample, incubating the mixture to bind the antibody, separating the bound, labelled digoxin and measuring the radioactivity. (U.K.)

Amlodipine-induced gingival hyperplasia in chronic renal failure: a ...

African Journals Online (AJOL)

Amlodipine is a dihydropyridine calcium channel blocker that is used in the management of both hypertension and angina. Amlodipine induced side effects are headache, dizziness, edema, flushing, palpitations, and rarely gingival hyperplasia. The exact reason of amlodipine-induced gingival hyperplasia is not known.

Comparative kinetics of serum and vitreous humor digoxin concentrations in a guinea pig model. Part I: Intravenous administration of digoxin

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Donnelly, B.; Balkon, J.; Bidanset, J.H.; Belmonte, A.; Barletta, M.; Manning, T. (Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John' s University, Jamaica, NY (USA))

1991-03-01

The pharmacokinetics of a single intravenous dose of digoxin in the guinea pig was investigated with emphasis on the penetration of digoxin into the vitreous humor. A controlled study was undertaken and data was collected which indicated that digoxin follows an open, two-compartment pharmacokinetic model with a terminal half-life of 318 minutes. The data indicated that the ratio of vitreous concentrations to serum concentrations were determined to be equal following an initial tissue distribution phase.

Comparative kinetics of serum and vitreous humor digoxin concentrations in a guinea pig model. Part I: Intravenous administration of digoxin

International Nuclear Information System (INIS)

Donnelly, B.; Balkon, J.; Bidanset, J.H.; Belmonte, A.; Barletta, M.; Manning, T.

1991-01-01

The pharmacokinetics of a single intravenous dose of digoxin in the guinea pig was investigated with emphasis on the penetration of digoxin into the vitreous humor. A controlled study was undertaken and data was collected which indicated that digoxin follows an open, two-compartment pharmacokinetic model with a terminal half-life of 318 minutes. The data indicated that the ratio of vitreous concentrations to serum concentrations were determined to be equal following an initial tissue distribution phase

Study on the correlation between serum digoxin levels and its therapeutic efficacy and toxicity and pharmacokinetics of digoxin in Thai patients using radionuclide procedures

International Nuclear Information System (INIS)

Poopyruchpong, N.

1984-02-01

The development of a radioimmunoassay procedure for the measurement of serum digoxin, using a locally raised rabbit anti-digoxin serum, tritiated digoxin from a commercial supplier and dextran-coated charcoal for the separation step, is described. Assay optimization included the determination of optimal antiserum dilution, incubation time and charcoal concentration. Assay validation included the evaluation of assay accuracy, precision and specificity. Results of measurements on sera from a preliminary group of patients undergoing digoxin medication are presented

Hypothalamic digoxin, hemispheric chemical dominance, and eating behavior.

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Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-08-01

The isoprenoid pathway produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in eating disorders. The patterns were compared in those with right hemispheric and left hemispheric dominance. The serum HMG CoA reductase activity, RBC membrane Na+-K+ ATPase activity, serum digoxin, magnesium, tryptophan catabolites (serotonin, quinolinic acid, strychnine, and nicotine), and tyrosine catabolites (morphine, dopamine, and noradrenaline) were measured in anorexia nervosa, bulimia nervosa, right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals. Digoxin synthesis was increased with upregulated tryptophan catabolism and downregulated tyrosine catabolism in those with anorexia nervosa and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism and upregulated tyrosine catabolism in those with bulimia nervosa and left hemispheric chemical dominance. The membrane Na+-K+ ATPase activity and serum magnesium were decreased in anorexia nervosa and right hemispheric chemical dominance while they were increased in bulimia nervosa and left hemispheric chemical dominance. Hypothalamic digoxin and hemispheric chemical dominance play a central role in the regulation of eating behavior. Anorexia nervosa represents the right hemispheric chemically dominant/hyperdigoxinemic state and bulimia nervosa the left hemispheric chemically dominant/hypodigoxinemic state.

Importance of Pharmacokinetics and Dosage in digoxin ...

African Journals Online (AJOL)

Patients diagnosed as being digitalis-toxic or as exhibiting refractory cardiac failure on clinical grounds, had digoxin serum levels significantly higher than those found in patients with satisfactorily controlled cardiac failure but without signs of digitalis toxicity. Serum digoxin levels were significantly raised in patients with ...

Study of digoxin use in a public health unit

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Felipe C. Souza

2015-06-01

Full Text Available Digoxin is used for heart failure associated to systolic dysfunction and high ventricular rate. It has a narrow therapeutic range and intoxication may occur due to drug interactions or comorbidities. The aim of this work was to study digoxin use in a public health unit delineating the profile of patients susceptible to digitalis intoxication. Medical records belonging to patients admitted to the cardiomyopathy ward of the health unit (2009-2010 and in use of digoxin were analyzed. Among 647 patients admitted, 185 individuals using digoxin and possessed records available. The registration of plasma digoxin concentration was found in 80 records and it was out of the therapeutic range in 42 patients (52.5%. This group of individuals was constituted mainly by males patients (79%, functional class III of heart failure (65%, exhibiting renal failure (33%. The evaluated sample reflects the epidemiology of heart failure in Brazil and, although pharmacotherapy had been according to Brazilian Guidelines, apparently the monitoring was not performed as recommended. This work highlighs the necessity of plasma digoxin constant monitoring during pharmacotherapy and the development of protocols that enable a safer use, especially in male patients, functional class III and with renal dysfunction.

The effect of age on digoxin pharmacokinetics in Fischer-344 rats

International Nuclear Information System (INIS)

Evans, R.L.; Owens, S.M.; Ruch, S.; Kennedy, R.H.; Seifen, E.

1990-01-01

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 ± 5.3% (means ± SD, n = 15). For pharmacokinetic studies, [ 3 H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [ 3 H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age

Basic evaluation of 67Ga labeled digoxin derivative as a metal-labeled bifunctional radiopharmaceutical

International Nuclear Information System (INIS)

Fujibayashi, Yasuhisa; Konishi, Junji; Takemura, Yasutaka; Taniuchi, Hideyuki; Iijima, Naoko; Yokoyama, Akira.

1993-01-01

To develop metal-labeled digoxin radiopharmaceuticals with affinity with anti-digoxin antibody as well as Na + , K + -ATPase, a digoxin derivative conjugated with deferoxamine was synthesized. The derivative had a high binding affinity with 67 Ga at deferoxamine introduced to the terminal sugar ring of digoxin. The 67 Ga labeled digoxin derivative showed enough in vitro binding affinity and selectivity to anti-digoxin antibody as well as Na + , K + -ATPase. The 67 Ga labeled digoxin derivative is considered to be a potential metal-labeled bifunctional radiopharmaceutical for digoxin RIA as well as myocardial Na + , K + -ATPase imaging. (author)

Hypothalamic digoxin, hemispheric chemical dominance, and spirituality.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-03-01

The isoprenoid pathway was assessed in atheistic and spiritually inclined individuals. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has a correlation with spiritual and atheistic tendency. HMG CoA reductase activity, serum digoxin, RBC membrane Na(+)-K+ ATPase activity, serum magnesium, and tyrosine/tryptophan catabolic patterns were assessed in spiritual/atheistic individuals and in those differing hemispheric dominance. In spiritually-inclined individuals, there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in spiritually-inclined individuals correlated with right hemispheric chemical dominance. In atheistic individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolities (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in atheistic individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to spirituality or atheism.

Personalized Medicine Digoxin Theraphy in Individuals with MDR Gene Polymorphism

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Em Sutrisna

2015-06-01

Full Text Available Digoxin is one of digitalis drugs. Wider applicability to heart failure and arrhythmias (supraventricular requires fairly strict scrutiny because of its narrow therapeutic index. Digoxin is a substrate of P-glycoprotein (P-gp encoded by multi drugs resistance-1 (MDR1. MDR-1 gen located on chromosome 7q21.1. This gene contains 28 exons that encoded a protein of 1280 amino acids. This gene plays an important role in the absorption, distribution and elimination of many drugs. MDR1C3435T polymorphism occurs in exon 26. There are three types of MDR1C3435T gene namely MDR1C3435T CC, MDR1C3435T CT and MDR1C3435T TT. These polymorphisms will affect to the formation of P-gp and consequently to change the kinetic profile of digoxin. The change of kinetic profile causes changes in the digoxin blood levels. The method used in this review is data search based on pubmed, medline, and embase with keywords MDR and digoxin. There are several different studies of the influence of polymorphisms MDR1C3435T on blood digoxin levels. Increased levels of digoxin in the blood due to polymorphism of MDR1C3435T will be at risk of digitalis intoxication. Long-term digoxin treatment or large dose should consider the patient’s genetic profile. Distribution of polymorphism of MDR1C3435T in Javanese population is approximately TT (0,10, CT (0,52, and CC(0, 38.

Digoxin-induced retinal degeneration depends on rhodopsin.

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Landfried, Britta; Samardzija, Marijana; Barben, Maya; Schori, Christian; Klee, Katrin; Storti, Federica; Grimm, Christian

2017-03-16

Na,K-ATPases are energy consuming ion pumps that are required for maintaining ion homeostasis in most cells. In the retina, Na,K-ATPases are especially important to sustain the dark current in photoreceptor cells needed for rapid hyperpolarization of rods and cones in light. Cardiac glycosides like digoxin inhibit the activity of Na,K-ATPases by targeting their catalytic alpha subunits. This leads to a disturbed ion balance, which can affect cellular function and survival. Here we show that the treatment of wild-type mice with digoxin leads to severe retinal degeneration and loss of vision. Digoxin induced cell death specifically in photoreceptor cells with no or only minor effects in other retinal cell types. Photoreceptor-specific cytotoxicity depended on the presence of bleachable rhodopsin. Photoreceptors of Rpe65 knockouts, which have no measurable rhodopsin and photoreceptors of Rpe65 R91W mice that have treatment. Similarly, cones in the all-cone retina of Nrl knockout mice were also not affected. Digoxin induced expression of several genes involved in stress signaling and inflammation. It also activated proteins such as ERK1/2, AKT, STAT1, STAT3 and CASP1 during a period of up to 10 days after treatment. Activation of signaling genes and proteins, as well as the dependency on bleachable rhodopsin resembles mechanisms of light-induced photoreceptor degeneration. Digoxin-mediated photoreceptor cell death may thus be used as an inducible model system to study molecular mechanisms of retinal degeneration.

Evidence Based Digoxin Therapeutic Monitoring - A Lower and Narrower Therapeutic Range

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Amine BENLMOUDEN

2016-06-01

Full Text Available Cardiac glycosides have been used for congestive heart failure and certain cardiac arrhythmias for more than 200 years. Despite the introduction of a variety of new classes of drugs for the management of heart failure, specifically angiotensin-converting enzyme (ACE inhibitors, b-adrenergic antagonists (bblockers, and the aldosterone antagonist spironolactone, digoxin continues to have an important role in long-term outpatient management. However, a narrow margin exists between therapeutic and toxic doses of digoxin, resulting in a high incidence of digoxin toxicity in clinical practice.A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. The clinical relevance of digoxin therapeutic monitoring is also proved but the SDC (Serum Digoxin Conentrations required for optimal clinical efficacy and acceptable toxicity remains controversial. In the last years, international guidelines recommend 1.2 ng/mL as acceptable high level.In this bibliographic synthesis, we aim to collect pertinent informations from MedLine database about exposure-effect relationship in order to assess the evidence level scientific of new digoxin therapeutic monitoring. 

Digoxin serum levels with respect to some biochemical and clinical indicators

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Sedlak, J; Curilla, E [Univerzita P.J. Safarika, Kosice (Czechoslovakia). Lekarska Fakulta

1984-10-01

Digoxin serum levels were examined in 40 patients using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) and correlated with levels of potassium, magnesium, creatinine, urea, glomerular filtration (GF) and with clinical signs of different degrees of digitalis serum concentration. The digoxin level assessed by ELISA and RIA methods correlated fairly closely. An average dependence was found between digoxin levels and levels of creatinine, urea and GF. A correlation was observed between a high level of digoxin and clinical signs of digitalis intoxication.

Digoxin serum levels with respect to some biochemical and clinical indicators

International Nuclear Information System (INIS)

Sedlak, J.; Curilla, E.

1984-01-01

Digoxin serum levels were examined in 40 patients using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) and correlated with levels of potassium, magnesium, creatinine, urea, glomerular filtration (GF) and with clinical signs of different degrees of digitalis serum concentration. The digoxin level assessed by ELISA and RIA methods correlated fairly closely. An average dependence was found between digoxin levels and levels of creatinine, urea and GF. A correlation was observed between a high level of digoxin and clinical signs of digitalis intoxication

Titration of digoxin through radio-immunology in the solid phase

International Nuclear Information System (INIS)

Hersh, L.S.; Yaverbaum, Sidney.

1975-01-01

The invention relates to biological titrations. It refers to a method for determining the digoxin concentration in a solution, characterized in that it comprises the steps of: causing the solution (a known amount of labelled digoxin and a composite substance constituted by anti-digoxin antibodies chemically coupled through the medium of a silane coupling agent) to react with magnetically-sensitive inorganic particles, so as to generate immuno-chemical complex; magnetically separating the composite substance from the reaction solution; measuring the radioactivity of the thus separated composite substance or of the remaining solution; and comparing the measurements of step with a reference curve so as to determine the digoxin concentration [fr

Amlodipine reduces the antimigratory effect of diclofenac in spontaneously hypertensive rats.

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Rodrigues, Stephen Fernandes; Dossantos, Rosangela Aparecida; de Oliveira, Maria Aparecida; Rastelli, Viviani Milan; Nucci, Gilberto de; Tostes, Rita de Cássia; Nigro, Dorothy; Carvalho, Maria Helena; Fortes, Zuleica B

2008-05-01

Amlodipine, an antihypertensive drug, and diclofenac, an antiinflammatory drug, may generally be combined, particularly in elderly patients; therefore, the potential for their interaction is high. We aim to determine if amlodipine interferes with the antimigratory effect of diclofenac. For this, male spontaneously hypertensive rats (SHRs) were treated with either diclofenac (1 mg.kg.d, 15 d) alone or combined with amlodipine (10 mg.kg.d, 15 d). Leukocyte rolling, adherence, and migration were studied by intravital microscopy. Diclofenac did not change (180.0 +/- 2.3), whereas amlodipine combined (163.4 +/- 5.1) or not (156.3 +/- 4.3) with diclofenac reduced the blood pressure (BP) levels in SHR (183.1 +/- 4.4). Diclofenac and amlodipine reduced leukocyte adherence, migration, and ICAM-1 expression, whereas only diclofenac reduced rolling leukocytes as well. Combined with amlodipine, the effect of the diclofenac was reduced. Neither treatment tested increased the venular shear rate or modified the venular diameters, number of circulating leukocytes, P-selectin, PECAM-1, L-selectin, or CD-18 expressions. No difference could be found in plasma concentrations of both drugs given alone or in association. In conclusion, amlodipine reduces leukocyte migration in SHR, reducing endothelial cell ICAM-1 expression. Amlodipine reduces the effect of the diclofenac, possibly by the same mechanism. A pharmacokinetic interaction as well as an effect on the other adhesion molecules tested could be discarded.

Basic evaluation of [sup 67]Ga labeled digoxin derivative as a metal-labeled bifunctional radiopharmaceutical

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Fujibayashi, Yasuhisa; Konishi, Junji (Kyoto Univ. (Japan). Faculty of Medicine); Takemura, Yasutaka; Taniuchi, Hideyuki; Iijima, Naoko; Yokoyama, Akira

1993-11-01

To develop metal-labeled digoxin radiopharmaceuticals with affinity with anti-digoxin antibody as well as Na[sup +], K[sup +]-ATPase, a digoxin derivative conjugated with deferoxamine was synthesized. The derivative had a high binding affinity with [sup 67]Ga at deferoxamine introduced to the terminal sugar ring of digoxin. The [sup 67]Ga labeled digoxin derivative showed enough in vitro binding affinity and selectivity to anti-digoxin antibody as well as Na[sup +], K[sup +]-ATPase. The [sup 67]Ga labeled digoxin derivative is considered to be a potential metal-labeled bifunctional radiopharmaceutical for digoxin RIA as well as myocardial Na[sup +], K[sup +]-ATPase imaging. (author).

Retrospective evaluation of patients with elevated digoxin levels at an emergency department

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Gulsum Limon

2016-03-01

Full Text Available Objectives: We investigated the demographic characteristics, clinical and laboratory findings, treatment strategies and clinical outcomes of patients presenting at emergency department (ED with digoxin levels at or above 1.2 ng/ml. Materials and methods: The demographic and clinical characteristics of patients with serum digoxin levels at or above 1.2 ng/ml admitted to an ED between January 2010 and July 2011 were investigated in this cross-sectional descriptive study. Patients with ECG and clinical findings consistent with digoxin toxicity and no additional explanation of their symptoms were evaluated for digoxin toxicity. Results: In this study 137 patients were included, and 68.6% of patients were women with mean age 76.1 ± 12.2. There was no significant difference between gender and digoxin intoxication. The mean age of intoxicated group was significantly higher than the non-intoxicated group (P = 0.03. The most common comorbidities were congestive heart failure (n = 91 and atrial fibrillation (n = 74. The most common symptoms were nausea, vomiting and abdominal pain. The levels of hospitalization and mortality in this group were significantly higher. Conclusion: Digoxin intoxication must be suspected in patients present in the ED, particularly those with complaints that include nausea and vomiting, as well as new ECG changes; serum digoxin levels must be determined. Keywords: Digoxin, Digoxin level, Intoxication, Emergency department

Hypothalamic digoxin, hemispheric dominance, and neurobiology of love and affection.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-05-01

The human hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neuronal transmission. The digoxin status and neurotransmitter patterns were studied in individuals with a predilection to fall in love. It was also studied in individuals with differing hemispheric dominance to find out the role of cerebral dominance in this respect. In individuals with a predilection to fall in love there was decreased digoxin synthesis, increased membrane Na+-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern correlated with that obtained in left hemispheric chemical dominance. Hemispheric dominance and hypothalamic digoxin could regulate the predisposition to fall in love.

The potential role of amlodipine on experimentally induced bacterial rhinosinusitis

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Arzu Tatar

Full Text Available Abstract Introduction: Antibiotics are frequently used for the treatment of rhinosinusitis. Concerns have been raised regarding the adverse effects of antibiotics and growing resistance. The lack of development of new antibiotic compounds has increased the necessity for exploration of non-antibiotic compounds that have antibacterial activity. Amlodipine is a non-antibiotic compound with anti-inflammatory activity. Objective: In this study we aimed to investigate the potential role of amlodipine in the treatment of rhinosinusitis by evaluating its effects on tissue oxidative status, mucosal histology and inflammation. Methods: Fifteen adult albino guinea pigs were inoculated with Staphylococcus aureus and treated with saline, cefazolin sodium, or amlodipine for 7 days. The control group was composed by five healthy guinea pigs. Animals were sacrificed after the treatment. Histopathological changes were identified using Hematoxylin-Eosin staining. Inflammation was assessed by Polymorphonuclear Leukocyte infiltration density. Tissue levels of antioxidants (superoxide dismutase, glutathione and an oxidative product (malondialdehyde were determined. Results: In rhinosinusitis induced animals, amlodipine reduced loss of cilia, lamina propria edema and collagen deposition compared to placebo (saline and although not superior to cefazolin, amlodipine decreased polymorphonuclear leukocyte infiltration. The superoxide dismutase activity and glutathione levels were reduced, whereas the malondialdehyde levels were increased significantly in all three-treatment groups compared to the control group. Amlodipine treated group showed significantly increased superoxide dismutase and glutathione levels and decreased malondialdehyde levels compared to all treatment groups. Conclusion: The non-antibiotic compound amlodipine may have a role in acute rhinosinusitis treatment through tissue protective, antioxidant and anti-inflammatory mechanisms.

Blood pressure control with amlodipine add-on therapy in patients with hypertension and diabetes: results of the Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial.

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Kloner, Robert A; Neutel, Joel; Roth, Eli M; Weiss, Robert; Weinberger, Myron H; Thakker, Kamlesh M; Schwartz, Brian; Shi, Harry; Gregg, Anne-Marie

2008-11-01

Attainment of blood pressure (BP) goals in patients with diabetes is critical both to reduce the risk of cardiovascular events and to delay the progression of renal disease. While therapeutic guidelines advise initial therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, monotherapy with these agents may not be sufficient to attain target BP. The ADHT (Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial) evaluated the efficacy and safety of adding amlodipine to the treatment regimen of patients with hypertension and diabetes who were already receiving either quinapril or losartan as monotherapy. ADHT was a double-blind, double-dummy, 22-week trial conducted in the US. After a washout period of 7-13 days, patients (aged 30-75 y) with hypertension and diabetes were randomized to receive quinapril 20 mg/day plus placebo or losartan 50 mg/day plus placebo for 4 weeks, titrated to 40 mg or 100 mg (if required), respectively, for an additional 4 weeks to achieve their BP goals (<130/80 mm Hg). At week 8, either amlodipine 5 mg/day or placebo was added for an additional 12 weeks, with titration to 10 mg at week 14 if the BP goal was not achieved. Efficacy of add-on therapy was evaluated in 411 patients (amlodipine 211, placebo 200). BP goal was reached by 27.5% of patients when amlodipine was added to quinapril or losartan monotherapy, compared with 12.5% when placebo was added (OR 2.73; 95% CI 1.61 to 4.64; p < 0.001). When added to quinapril or losartan monotherapy, amlodipine reduced BP by 8.1/5.4 mm Hg, compared with a 1.6/0.7 mm Hg decrease with add-on placebo (p < 0.001). Amlodipine, quinapril, and losartan were well tolerated. Amlodipine is safe and effective when added to quinapril or losartan monotherapy to help lower BP toward therapeutic targets in patients with hypertension and diabetes.

Optimizing Growth Conditions for Digoxin Production in Digitalis lanata Ehrh

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Herman A. van Wietmarschen

2016-08-01

Full Text Available Objective: Digoxin is a therapeutic cardenolide widely used to treat various heart conditions such as atrial flutter, atrial fibrillation and heart failure in both Western as well as Chinese medicine. Digoxin is extracted from cultivated Digitalis lanata Ehrh. plants, known as Mao Hua Yang Di Huang in Chinese medicine. This manuscript presents two studies that were conducted to optimize the cultivation conditions for digoxin production in the TCM Mao Hua Yan Di Huang in a greenhouse under GAP conditions.

Pharmacogenetics-Oriented Therapeutic drug monitoring of Digoxin in critically ill patients

International Nuclear Information System (INIS)

Ebid, Abdel-Hameed I.; Mokhtar, Mohammed Sherif; Abdel-Shafi, Sana'a; El-Feky, Gina Samy

2006-01-01

This study was performed to outline the different MDR-1 (Multi-Drug Resistance-1) genotypes in a sample of 37 Egyptian patients, suffering from atrial fibrillation (AF) and/or congestive heart failure (CHF) and is using digoxin, to assess the role of MDR-1 genotypes polymorphism in affecting steady state serum digoxin therapeutic levels, and studying the consequences on patient's clinical outcome. Two venous blood samples were drawn from each patient; the 1st sample was taken, on admission, for DNA extraction and genotyping and the 2nd was taken, 6 hours post dose after reaching steady state concentration, for serum digoxin assay. Serum digoxin levels were assayed using EMIT 2000 analyzer, and MDR-1 genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Twenty patients (54.1%) showed serum digoxin levels within the therapeutic range, 12 patients (32.4%) showed serum digoxin levels under the minimum effective concentration ( 2 ng/ml), with P value of 0.0001 among three groups. MDR-1 genotyping revealed ten patients (27%) carrying the homozygous mutant TT genotype, 27 patients (73%) carrying the heterozygous mutant CT genotype, with no patient showing the wild CC genotype Allelic distribution showed 42% for the wild type C allele while 58% for the homozygous mutant C allele. Patients carrying the homozygous mutant TT genotype showed significantly lower serum digoxin levels compared with those carrying the heterozygous mutant CT genotype (P value: 0.009). Patients with significant improvement carried the CT genotype and had serum digoxin levels within the therapeutic range. In conclusion, patients with different MDR-1 genotypes had variations in their serum digoxin levels and identification of MDR-1 variations was found useful in predicting therapy outcome. We recommend further extensive work on large samples to study the important role of MDR-1 gene in affecting the disposition of different substrates, to

Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate.

Science.gov (United States)

Kaur, Monika; Ita, Kevin B; Popova, Inna E; Parikh, Sanjai J; Bair, Daniel A

2014-02-01

The aim of this project was to study the effect of stainless steel solid microneedles and microneedle rollers on percutaneous penetration of verapamil hydrochloride and amlodipine besylate. Verapamil, 2-(3,4-dimethooxyphenyl)-5-[2-(3,4 dimethoxyphenyl)ethyl-methyl-amino]-2-propan-2-yl-pentanenitrile is a calcium channel blocker agent that regulates high blood pressure by decreasing myocardial contractilty, heart rate and impulse conduction. Amlodipine, (R, S)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, 4-dihydropyridine, is a calcium channel blocker that is used for the management of hypertension and ischemic heart disease. Passive penetration of verapamil and amlodipine across the skin is low. In vitro studies were performed with microneedle-treated porcine ear skin using vertical static Franz diffusion cells (PermeGear, Hellertown, PA, USA). The receiver chamber contained 5ml of PBS (pH7.4) and was constantly maintained at 37°C temperature with a water circulation jacket. The diffusion area of the skin was 1.77cm(2). The donor compartment was loaded with 1ml of the solution containing 2.5mg/ml of amlodipine besylate. The donor chamber was covered with parafilm to avoid evaporation. Passive diffusion across untreated porcine skin served as control. Aliquots were taken every 2h for 12h and analyzed by liquid chromatography-mass spectrometry. Transcutaneous flux of verapamil increased significantly from 8.75μg/cm(2)/h to 49.96μg/cm(2)/h across microneedle-roller treated porcine skin. Percutaneous flux of amlodipine besylate following the use of stainless steel microneedles was 22.39μg/cm(2)/h. Passive flux for the drug was 1.57μg/cm(2)/h. This enhancement of amlodipine flux was statistically significant. Transdermal flux of amlodipine with microneedle roller was 1.05μg/cm(2)/h in comparison with passive diffusion flux of 0.19μg/cm(2)/h. The difference in flux values was also statistically significant. Stainless

ASSESSMENT OF AMLODIPINE ANTIHYPERTENSIVE EFFECT HOMOGENEITY IN CONTROLLED TRIAL

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V. M. Gorbunov

2016-01-01

Full Text Available Aim. To compare influence of amlodipine and spirapril on ambulatory blood pressure profile, including antihypertensive effect smoothness in patients with arterial hypertension (HT.Methods. 39 patients (aged 53,7±10,0 y.o. with HT were included in the open, randomized, cross-over study, 30 patients completed study. The duration of every therapies was 4 weeks, initial control period and wash-out period between therapies lasted 1 week. The initial daily dose of amlodipine was 5 mg, standard dose of spirapril (6 mg/daily was not changed during the trial. After 1-2 weeks of treatment amlodipine dose was increased up to 10 mg/daily as well as dihydrochlorothiazide was added, if necessary. Ambulatory blood pressure monitoring (ABPM was performed initially and at the end of both therapies.Results. Both drugs demonstrated good antihypertensive effect according to ABPM data. Decrease of systolic/diastolic blood pressure was 11,2±1,8/7,6±1,2 mm Hg in amlodipine therapy and 10,0±1,8/7,1±1,2 in spirapril therapy (p<0,0001. The smoothness indexes (SI were 0,65/0,45 and 0,55/0,45, respectively, differences between two therapies were not significant. However the individual analysis of the SI distribution (with SI=0,5 as a satisfactory criterion, showed that antihypertensive effect smoothness is better in amlodipine therapy than this in spirapril one.Conclusion. Amlodipine has prominent as well as smooth antihypertensive effect, that gives it advantages in the long-term antihypertensive therapy.

Evaluation of the Effectiveness of Sugammadex for Digoxin Intoxication: An Experimental Study.

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Ozbilgin, Sule; Yurtlu, Derya Aslan; Küçükoztaş, Beyza; Kamacı, Gonca; Korkut, Sezen; Yurtlu, Bülent Serhan; Ensari Güneli, M; Hancı, Volkan; Günerli, Ali

2018-03-16

Previous studies have shown that cyclodextrin group medicines bind to various drugs. The hypothesis of our study is to determine whether sugammadex could bind to digoxin and delay the cardiovascular toxicity of that drug. Twenty-eight sedated Wistar rats were infused with digoxin at 3 mg/h (0.25 mg/ml). Five minutes after the start of infusion, animals were treated with a bolus of either 16 mg/kg (Sgdx16), 100 mg/kg (Sgdx100), or 1000 mg/kg (Sgdx1000) sugammadex. The control group infusion did not contain sugammadex. Heart rate, electrocardiography, and respiratory rate were monitored. The primary endpoint was time to asystole. Digoxin infusion continued until the animals arrested. The time to asystole for the Sgdx1000 group was significantly longer compared to that for the control group (p sugammadex 1000 group (p sugammadex delayed digoxin cardiotoxicity in a rat model of digoxin toxicity. We conclude that further research must be conducted on the interaction between digoxin and sugammadex.

Binding of digitoxin and digoxin to normal human β-lipoproteins

International Nuclear Information System (INIS)

Brock, A.

1976-01-01

The binding of digitoxin and digoxin to purified β-lipoprotein, obtained from pooled normal human serum, was studied under equilibrium conditions. Even with as high concentrations of unbound digitoxin or digoxin as 4 μmol/l, the preparations of β-lipoproteins, containing cholesterol 1.98-3.95 mmol/l, showed no signs of saturation. The binding affinity of digitoxin was about ten times as high as that of digoxin. Gel filtration chromatography, performed on native serum after addition of 3 H-digitoxin or 3 H-digoxin, showed a minor fraction of the cardiac glycosides to be associated with te protein fraction of highest molecular weight. This phenomenon disappeared after precipitation of the β-lipoproteins. In clinical relations the contribution of protein-bound digitoxin caused by the lipoprotein interaction is immaterial compared to that caused by the albumin interaction. (author)

Efficiency of individual dosage of digoxin with calculated concentration

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Zhao L

2014-07-01

Full Text Available Li Zhao,1,* Peng Yang,2,* Pengmei Li,1 Xiaoxing Wang,1 Wangjun Qin,1 Xianglin Zhang1 1Department of Pharmacy, 2Department of Cardiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Background: Digoxin is a frequently prescribed drug, particularly in the elderly population, in which there is an increased prevalence of atrial fibrillation and cardiac failure. With its complex pharmacokinetic profile and narrow therapeutic index, use of digoxin requires regular monitoring of blood levels. Recent evidence suggests that a lower concentration range (0.4–1.0 ng/mL is preferable in patients with congestive heart failure and a higher range (0.8–2.0 ng/mL is needed in patients with atrial tachyarrhythmia. The Konishi equation is widely used to predict the serum digoxin concentration (SDC in Japan. This study assessed the correlation between SDC predicted by the Konishi equation and that actually measured in Chinese patients and investigated the impact of renal function on SDC. Methods: The study subjects comprised 72 patients with cardiac failure or/and atrial tachyarrhythmia seen at our hospital from January 2012 to December 2013. The patients were divided into five groups according to Kidney Diseases Outcome Quality Initiative guidelines. SDCs were measured using the Abbott Architect i1000 immunology analyzer. The correlations between measured SDCs and calculated SDCs and between clearance of digoxin and creatinine clearance rate were assessed retrospectively.Results: The correlation between measured and predicted SDC calculated by the Konishi equation was significant (r=0.655, P<0.001 for the 72 patients overall; however, correlations within the different stages of renal function were nonsignificant, with a correlation found only in patients with stage 3 (30 mL per minute < creatinine clearance <60 mL per minute. With regard to the correlation between clearance of

Radioimmunoassay of serum digoxin levels. Clinical exploration

International Nuclear Information System (INIS)

Galland, F.; Geslin, P.; Kerjean, J.; Six, P.; Tadei, A.; Jallet, P.

1982-01-01

This work undertakes, in a second part, the clinical exploration of 947 serum digoxin levels of 281 hospitalized patients on a cardiology ward. Our results, which coincide with those of other researchers, have led us to draw certain practical conclusions: the posology is determined first of all according to kidney function, weight and age of the patient. When the treatment is insufficient or, on the other hand, poorly tolerated, a serum digoxin level is performed permitting thus: in the case of ineffective treatment: to be sure of the patient's cooperation, to increase the posology if the serum digoxin level is not in the toxic zone, to discover an eventual pharmacokinetic problem; to establish the responsability of digitalis (when there are signs of intolerance or of intoxication), in case of arrhythmia, in patients with pacemakers, when associated drugs are capable of causing similar adverse effects; to better manage a digitalis treatment in a high risk patient (unstable renal function, advanced myocardial disease, chronic obstructive disease) [fr

Digoxin therapy in the modern management of cardiovascular disease

African Journals Online (AJOL)

β-blockers for the treatment of heart failure, supports the use of digoxin in patients with left ventricular systolic dysfunction, particularly in those with advanced symptoms.[6] There is, however, no evidence that digoxin improves survival – it may even worsen outcomes. The Digitalis Investigation Group (DIG). Trial, a study of ...

Digoxin use and risk of mortality in hypertensive patients with atrial fibrillation

DEFF Research Database (Denmark)

Okin, Peter M; Hille, Darcy A; Wachtell, Kristian

2015-01-01

, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse...... patients with atrial fibrillation has not been examined. METHODS AND RESULTS: All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (n = 134) or who developed atrial fibrillation during...... fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggest that factors other than digoxin use may...

Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug-Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy.

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Srinivas, Nuggehally R

2016-01-20

Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

Effect of enrofloxacin on digoxin clearance and steady-state serum concentrations in dogs.

OpenAIRE

Novotny, M J; Shaw, D H

1991-01-01

The effect of enrofloxacin on the oral clearance and steady-state concentrations of digoxin in serum was evaluated in dogs. Digoxin was administered orally to six healthy adult Beagle dogs following a multiple-dose regimen of 0.0625 mg every 12 h for 23 days. From days 14 to 23 enrofloxacin was administered orally at a dosage of 2.5 mg/kg every 12 h, with subjects receiving enrofloxacin 2 h prior to digoxin. Trough serum concentrations of digoxin were measured using an immunoassay technique. ...

Digoxin: use pattern in Estonia and bioavailability of the local market leader.

Science.gov (United States)

Pähkla, R; Irs, A; Oselin, K; Rootslane, L

1999-10-01

In comparison with neighbouring Scandinavian countries, the use of digoxin in Estonia is high. The present study was carried out to determine the use pattern of digoxin in Estonia and bioavailability of the local market leader preparation in comparison with Lanoxin. Drug use data were evaluated from the annual reports of wholesale companies. For the bioequivalence study, a single-blind cross-over randomised two-way single-dose comparative bioavailability study was performed using 14 healthy volunteers. Digoxin concentrations in serum samples and urine were measured by chemiluminescent competitive immunoassay. The use of digoxin in Estonia has increased by 35% during the period 1994-97. The steady market leader was the local generic drug. No statistically significant differences were found in any pharmacokinetic parameter between the generic preparation and Lanoxin. All parameters showed considerable variability. The total amount of drug excreted was the parameter with lowest inter- individual variation. The present study indicates that the generic digoxin preparation studied is bioequivalent to Lanoxin. The increasing use of digoxin in Estonia is not caused by low bioavailability of the local market leader but by therapeutic traditions.

Studies on digoxin derivatives in different biological media by radioimmunoassay

International Nuclear Information System (INIS)

Barmasch, Martha; Perez, L.N.; Altschuler, Noe.

1978-05-01

The fundamental aim of this study was to develop a methodology to be applied to pharmacological studies, directed to demonstrate the passage of digitalic compounds through the blood-brain barrier. This study was a comparative one between β methyl digoxin (βMD) and digitoxin (Dt). A methodology of radioimmunoassay was developed for different biological media: serum (S), plasma (P) and cerebro spinal fluid (CSF). In addition, the immunochemical behaviour (affinity, displacement, etc.) of βMD was studied when reacted with digoxin (D) and digoxin-antisera, supplied by the commercial kits utilized in these studies. (author) [es

Isolation of a urinary digitalis-like factor indistinguishable from digoxin

Energy Technology Data Exchange (ETDEWEB)

Goto, A.; Ishiguro, T.; Yamada, K.; Ishii, M.; Yoshioka, M.; Eguchi, C.; Shimora, M.; Sugimoto, T. (Univ. of Tokyo (Japan))

1990-12-31

A digitalis-like factor has been purified to apparent homogeneity from human urine based on the inhibitory effect on ({sup 3}H) ouabain binding to intact human erythrocytes. The purification scheme involved large scale adsorption followed by preparative, semipreparative and analytical high-performance liquid chromatography. The purified material showed a prominent digoxin-like immunoreactivity. The behaviour of the isolated substance was identical to that of authentic digoxin in three high-performance liquid chromatography and three thin-layer chromatography systems. Moreover, fast atom bombardment mass spectrum and proton nuclear magnetic resonance spectrum suggested that the purified material may be indistinguishable from digoxin.

Digoxin affects potassium homeostasis during exercise in patients with heart failure.

Science.gov (United States)

Schmidt, T A; Bundgaard, H; Olesen, H L; Secher, N H; Kjeldsen, K

1995-04-01

The aim was to evaluate whether digitalisation of heart failure patients affects extrarenal potassium handling during and following exercise, and to assess digoxin receptor occupancy in human skeletal muscle in vivo. In a paired study of before versus after digitalisation, 10 patients with congestive heart failure underwent identical exercise sessions consisting of three bouts of increasing work rates, 41-93 W, on a cycle ergometer. The final bouts were followed by exercise to exhaustion. The femoral vessels and brachial artery were catheterised. Arterial blood pressure, heart rate, leg blood flow, cardiac output, plasma potassium, haemoglobin, pH, and skeletal muscle receptor occupancy with digoxin in biopsies were determined. Occupancy of skeletal muscle Na/K-ATPase with digoxin was 9% (P digitalisation femoral venous plasma potassium increased by 0.2-0.3 mmol.litre-1 (P digitalisation the femoral venoarterial difference in plasma potassium increased by 50-100% (P digitalisation on plasma potassium were not the outcome of changes in haemodynamics, because cardiac output and leg blood flow increased by up to 13% and 19% (P < 0.05), nor was it the outcome of changes in haemoconcentration or pH. Extrarenal potassium handling is altered as a result of digoxin treatment. This is likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin, adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se. In heart failure patients, improved haemodynamics induced by digoxin may, however, increase the capacity for physical conditioning. Thus the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by training.

Electrophysiologic similarities of overdose between digoxin and bufadienolides found in a Chinese aphrodisiac

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Maxwell Bressman

2017-02-01

Full Text Available Classically derived from toad venom, bufadienolides are a group of cardioactive steroids with properties similar to digoxin. Some traditional Chinese medications, including several aphrodisiacs, contain bufadienolides. Owing to their physiologic similarities to digoxin, bufadienolides have been shown to produce a toxic profile similar to that of digoxin and there have been multiple case reports of the use of these aphrodisiacs resulting in death. This report will describe a case that illustrates the electrophysiologic similarities between bufadienolide toxicity and digoxin toxicity as well as the treatment of bufadienolide toxicity.

Digoxin Is Associated With Increased Shock Events and Electrical Storms in Patients With Implantable Cardioverter Defibrillators.

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Mina, George S; Acharya, Madan; Shepherd, Taylor; Gobrial, George; Tekeste, Michael; Watti, Hussam; Bhandari, Ruchi; Saini, Aditya; Reddy, Pratap; Dominic, Paari

2018-03-01

Recently, digoxin use has been found to associate with higher mortality. Yet, potential mechanisms by which digoxin use increases mortality remain unclear. Increased arrhythmogenicity from digoxin use is one possibility. Thus, we aimed to evaluate the relation between digoxin and shock events in patients with implantable cardioverter defibrillators (ICDs). We performed a retrospective chart review of all patients with ICDs and at least 1 device interrogation at our institution between January 1, 2012, and January 1, 2015. We aimed to cover 1 year of interrogation period. Patients with heart failure, atrial fibrillation, or both were included in the analysis. Patients were divided into 2 groups based on digoxin use, defined as use of digoxin for any period of time during ICD interrogation period. Incidence of ICD shock events and electrical storms and hospitalizations were compared between the 2 groups. The study included 202 patients. Of those, 55 patients were on digoxin and 147 were not on digoxin. Patients on digoxin were more likely to receive ICD shocks (odds ratio [OR] = 2.5, 95% confidence interval [95% CI] = 1.01-6.18, P = .04) and have increased risk of electrical storms ( P = .02). Moreover, total hospitalizations were higher in digoxin users ( P = .02). Multivariate logistic regression analysis also showed that digoxin use was an independent predictor of shock events (OR = 4.07, 95% CI = 1.43-11.58, P = .009). Digoxin is associated with increased shock events and electrical storms in patients with ICDs; however, large randomized controlled studies are needed to confirm our findings.

Bigeminy: A result of digoxin and St John’s wort interaction

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Anđelić Slađana

2003-01-01

Full Text Available A case of an by digoxin under unusual circumstances is reported. An 80-year-old man, previously on long-term digoxin treatment, started consuming St John’s wort herbal tea (2 000 ml/daily because of frequent episodes of depression. After the cessation of consuming herbal tea containing Hypericum perforatum, digoxin poisoning developed in our patient. Electrocardiography revealed nodal bradicardia 36/min and bigeminy. Manifested symptoms were the consequence of interaction between digoxin and Hypericum perforatum which were consumed simultaneously, and the cessation of consuming St John’s wort herbal tea afterwards. Therapy was the same as in the standard digitalis poisoning. Consumers of St John’s wort combined with medical products are advised not to discontinue tea consumption on their own, without consulting their physician.

Cyclodextrine Screening for the Chiral Separation of Amlodipine Enantiomers by Capillary Electrophoresis

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Gabriel Hancu

2015-03-01

Full Text Available Purpose: Amlodipine is a long acting, dihydropyridine type calcium channel blocker frequently used in the treatment of hypertension and coronary insufficiency. The calcium channel blocking activity resides primarily in the S-amlodipine enantiomer, while R-amlodipine is a potent inhibitor of smooth muscle cell migration. Methods: In this study capillary electrophoresis was applied for the enantiomeric separation of amlodipine using different native and derivatized; neutral and charged cyclodextrines as chiral selectors. The effects of pH and composition of the background electrolyte, concentration and type of chiral selector, capillary temperature, running voltage and injection parameters have been investigated. Results: Stereoselective interactions were observed when using α-CD, β-CD, HP-β-CD, RAMEB, CM-β-CD and SBE-β-CD. Optimized separation conditions consisted on a 50 mM phosphate buffer, pH – 3.0, 20 mM RAMEB as chiral selector, + 25 kV applied voltage, 15°C temperature and UV detection at 238 nm. Using the optimized electrophoretic conditions we succeeded the chiral separation of amlodipine enantiomers in approximately 6 minute, the order of migration being R-amlodipine followed by S-amlodipine. The method was successfully applied for the determination of amlodipine enantiomers from commercially available pharmaceuticals. The linearity range, limits of detection and quantification, precision and accuracy were determined and the results obtained confirmed that the method was suitable for this purpose. Conclusion: It can be concluded that the proposed capillary electrophoresis methods can be useful for routine pharmaceutical applications with benefits of its effectivity, simplicity, short analysis time and low consumption of analytes, solvents and chiral selectors.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

Science.gov (United States)

Okamura, Keisuke; Shirai, Kazuyuki; Totake, Nao; Okuda, Tetsu; Urata, Hidenori

2018-01-01

When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

The influence of intravenous canrenoate on the determination of digoxin in serum by radio- and enzyme-immunoassay

International Nuclear Information System (INIS)

Rietbrock, N.; Lichey, J.; Borner, K.; Freie Univ. Berlin

1979-01-01

Ten patients were kept on a constant maintenance dose of digoxin. During a baseline period of 6 days, blood samples were taken daily for analysis of digoxin in serum. On the 6th day the maintenance dose of digoxin was withheld and a single intravenous dose of 200mg potassium-canrenoate (AldactoneR) was administered to all patients. Digoxin in serum was determined by a classical radioimmunoassay with 125 I-digoxin and solid phase technique (RIA-NEN) and partly by a heterogenous enzyme-immunoassay (EnzymunR-Digoxin, Boehringer, Mannheim). Results of the radioimmunoassay indicated a rise of apparent serum digoxin levels with an average maximum of 201% of the mean baseline value 30 min after injection of canrenoate and a gradual return to the baseline value within 6 to 10 hours. Contrary to the radioimmunoassay there was no interference when using the enzyme-immunoassay in a subgroup of identical serum samples: serum digoxin levels remained constant throughout the test. Interference of determinations of digoxin in serum by spironolactone and its metabolites appear to be related to two factors: 1. The mode of administration and the amount of interfering drug, 2. the specifity of the digoxin antibody used in the kit. (orig.) [de

Comparison of vasodilator drug prazosin with digoxin in aortic regurgitation.

Science.gov (United States)

Hockings, B E; Cope, G D; Clarke, G M; Taylor, R R

1980-01-01

Intravenous administration of the vasodilator sodium nitroprusside has beneficial haemodynamic effects in subjects with severe aortic regurgitation while acute digitalisation can produce unwanted effects associated with an increase in systemic vascular resistance. This study compares the haemodynamic effects of the vasodilator prazosin and digoxin in eight patients with isolated severe aortic regurgitation. Prazosin 5 mg orally resulted in a 12 +/- 3 (SE) per cent increase in cardiac index (thermodilution), maintained over four to six hours, while digoxin 0.75 mg intravenously did not change the cardiac index. Prazosin reduced mean arterial pressure by 9 +/- 3 mmHg and systemic vascular resistance by 18 +/- 4 per cent while digoxin resulted in a 6 +/- 2 per cent increase in the latter. Mean pulmonary capillary wedge pressure fell 3 mmHg with prazosin. In this group of patients with severe aortic regurgitation but without severe cardiac failure, the changes with either drug, studied in doses conventionally used, were small but those with prazosin were directionally more desirable than those resulting from digoxin. PMID:7378215

Studies on cerebral protection of digoxin against hypoxic-ischemic brain damage in neonatal rats.

Science.gov (United States)

Peng, Kaiwei; Tan, Danfeng; He, Miao; Guo, Dandan; Huang, Juan; Wang, Xia; Liu, Chentao; Zheng, Xiangrong

2016-08-17

Hypoxic-ischemic brain damage (HIBD) is a major cause of neonatal acute deaths and chronic nervous system damage. Our present study was designed to investigate the possible neuroprotective effect of digoxin-induced pharmacological preconditioning after hypoxia-ischemia and underlying mechanisms. Neonatal rats were assigned randomly to control, HIBD, or HIBD+digoxin groups. Pharmacological preconditioning was induced by administration of digoxin 72 h before inducing HIBD by carotid occlusion+hypoxia. Behavioral assays, and neuropathological and apoptotic assessments were performed to examine the effects; the expression of Na/K ATPase was also assessed. Rats in the HIBD group showed deficiencies on the T-maze, radial water maze, and postural reflex tests, whereas the HIBD+digoxin group showed significant improvements on all behavioral tests. The rats treated with digoxin showed recovery of pathological conditions, increased number of neural cells and proliferative cells, and decreased number of apoptotic cells. Meanwhile, an increased expression level of Na/K ATPase was observed after digoxin preconditioning treatment. The preconditioning treatment of digoxin contributed toward an improved functional recovery and exerted a marked neuroprotective effect including promotion of cell proliferation and reduction of apoptosis after HIBD, and the neuroprotective action was likely associated with increased expression of Na/K ATPase.

Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein

NARCIS (Netherlands)

Mayer, U; Wagenaar, E; Beijnen, J.H; Smit, J.W; Meijer, D.K F; van Asperen, J.; Borst, P; Schinkel, A.H

1 We have used mice with a disrupted mdrla P-glycoprotein gene (mdrIa (-/-) mice) to study the role of P-glycoprotein in the pharmacokinetics of digoxin, a model P-glycoprotein substrate. 2 [K-3]-digoxin at a dose of 0.2 mg kg(-1) was administered as a single i.v. or oral bolus injection. We

Use of digoxin and risk of death or readmission for heart failure and sinus rhythm

DEFF Research Database (Denmark)

Madelaire, Christian; Schou, Morten; Nelveg-Kristensen, Karl Emil

2016-01-01

BACKGROUND/OBJECTIVES: Digoxin is widely used as symptomatic treatment in heart failure (HF), but the role in contemporary treatment of HF with sinus rhythm (SR) is debatable. We investigated the risk of death and hospital readmission, according to digoxin use, in a nationwide cohort of digoxin...... to primary outcomes of all-cause mortality and HF readmission. RESULTS: The study population comprised 5327 digoxin users and 10,654 matched non-users with a median age of 77. During follow-up 10,643 (66.6%) patients died and 7584 (47.5%) patients were readmitted due to HF. Use of digoxin was associated...... with increased risk of death (hazard ratio (HR): 1.19, 95%-CI: 1.15-1.24) and increased risk of HF readmission (HR: 1.19, 95%-CI: 1.13-1.25). Cumulative incidences of readmission, considering death as a competing risk was 50% for digoxin users and 47% for non-users. The associations applied regardless...

EFFECTS OF AMLODIPINE, FOSINOPRIL AND METOPROLOL ON HEMODYNAMICS IN HYPERTENSIVE PATIENTS

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A. L. Hohlov

2007-01-01

Full Text Available Aim. To assess an efficacy of antihypertensive therapy with calcium antagonist, angiotensin converting enzyme inhibitor and β-blocker in patients with arterial hypertension (AH taking into account influence on central and peripheral hemodynamics.Material and methods. 60 patients with AH of I-II stage, 1-2 grade were studied. They were split in 3 groups. Patients of the first group received amlodipine (Tenox, 5-10 mg/d, the second group – fosinopril (Monopril, 10-20 mg/d and the third group – metoprolol (Metocard, 50-200 mg/d.Diuretics were added when necessary. Ambulatory blood pressure (BP monitoring, echocardiography, ultrasound investigation of brachiocephalic and main cerebral arteries, test on reactive hyperemia and nitroglycerine were conducted before and after 6 months of therapy.Results. Amlodipine, fosinopril and metoprolol had similar antihypertensive effect. Amlodipine was more effective in comparison with fosinopril and metoprolol in reduction of left ventricular (LV myocardial mass and improving of LV diastolic function. Amlodipine and fosinopril had positive effect on vascular remodeling. Metoprolol reduced in BP morning elevation and heart rate, but had no effect on systolic BP variability.Conclusion. Amlodipine, fosinopril and metoprolol have similar antihypertensive effect but different influence on the heart, arteries, BP variability and hemodinamics.

Phototransformation of amlodipine: degradation kinetics and identification of its photoproducts.

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Anna Jakimska

Full Text Available Nowadays, monitoring focuses on the primary compounds and does not include degradation products formed during various biological and chemical processes. Transformation products may have the same effects to human health and the environment or sometimes they can be more toxic than the parent compound. Unfortunately, knowledge about the formation of degradation products is still limited, however, can be very important for the environmental risk assessment. Firstly, the photodegradation kinetic of amlodipine was investigated in two experimental conditions: during the exposure to solar radiation and during the exposure to the light emitted by the xenon lamp. In all cases degradation of amlodipine followed a pseudo-first-order kinetics. In the next step, identification of transformation products of amlodipine formed during the exposure to xenon lamp irradiation was performed using ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS. As a result sixteen photoproducts were identified, their structures were elucidated and ultimately the transformation pathway was proposed. Fifteen compounds (out of 16 photoproducts were newly identified and reported here for the first time; some of those compounds were formed from the first photoproduct, amlodipine pyridine derivative. Several analytes were formed only in acidic or basic conditions. Furthermore, the occurrence of amlodipine and its identified degradation products was investigated in environmental waters. Only one out of 16 compounds was found in wastewater effluent. The possibility of the sorption of examined analytes to sewage sludge particles was discussed based on QSAR.

Cardioprotective effect of amlodipine in oxidative stress induced by experimental myocardial infarction in rats

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Sudhira Begum

2007-12-01

Full Text Available The present study investigated whether the administration of amlodipine ameliorates oxidative stress induced by experimental myocardial infarction in rats. Adrenaline was administered and myocardial damage was evaluated biochemically [significantly increased serum aspertate aminotransferase (AST, lactate dehydrogenase (LDH and malondialdehyde (MDA levels of myocardial tissue] and histologically (morphological changes of myocardium. Amlodipine was administered as pretreatment for 14 days in adrenaline treated rats. Statistically significant amelioration in all the biochemical parameters supported by significantly improved myocardial morphology was observed in amlodipine pretreatment. It was concluded that amlodipine afforded cardioprotection by reducing oxidative stress induced in experimental myocardial infarction of catecholamine assault.

Hypothalamic digoxin, hemispheric chemical dominance and sarcoidosis.

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Ravi Kumar, A; Kurup, Parameswara Achutha

2004-06-01

The isoprenoid pathway produces three key metabolites: endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins) and ubiquinone (free radical scavenger). The role of the isoprenoid pathway in the pathogenesis of sarcoidosis in relation to hemispheric dominance was studied. The isoprenoid pathway-related cascade was assessed in patients with systemic sarcoidosis with pulmonary involvement. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison to find out the role of hemispheric dominance in the pathogenesis of sarcoidosis. In patients with sarcoidosis there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in the cholesterol:phospholipid ratio and a reduction in the glycoconjugate level of red blood cell (RBC) membrane in this group of patients. The same biochemical patterns were obtained in individuals with right hemispheric dominance. In individuals with left hemispheric dominance the patterns were reversed. Endogenous digoxin, by activating the calcineurin signal transduction pathway of T cells, can contribute to immune activation in sarcoidosis. An altered glycoconjugate metabolism can lead to the generation of endogenous self-glycoprotein antigens in the lung as well as other tissues. Increased free radical generation can also lead to immune activation. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of sarcoidosis in relation to right hemispheric chemical dominance is discussed. All the patients with sarcoidosis were right-handed/left hemispheric dominant according to the dichotic listening test, but their biochemical patterns

Comparative effect of fixed dose combination of Amlodipine + Bisoprolol versus Amlodipine and Bisoprolol alone on blood pressure in stage-2 essential hypertensive patients.

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Shirure PA,Tadvi NA, Bajait CS, Baig MS, Gade PR

2012-09-01

Full Text Available Background: Employment of low dose combinations of two antihypertensives, with different mode of action has gained acceptance worldwide for the treatment of mild to moderate hypertension. However, most studies in hypertensive disease have focused on monotherapy. The combination therapy in the treatment of hypertension is largely extrapolated from these monotherapy studies. Objectives: To study and compare the effect of amlodipine, bisoprolol and fixed dose combination of amlodipine + bisoprolol on blood pressure in stage-2 essential hypertensive patients. Methods: The present study was carried out in Department of Pharmacology in collaboration with Department of Medicine at Government Medical College and Hospital, Aurangabad. Results and Conclusion : Amlodipine + bisoprolol in fixed dose combination have showed significant blood pressure control in patients of stage-2 essential hypertension and the antihypertensive effect was greater than individual monotherapy study groups.

Comparison of digoxin concentration in plastic serum tubes with clot activator and heparinized plasma tubes.

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Dukić, Lora; Simundić, Ana-Maria; Malogorski, Davorin

2014-01-01

Sample type recommended by the manufacturer for the digoxin Abbott assay is either serum collected in glass tubes or plasma (sodium heparin, lithium heparin, citrate, EDTA or oxalate as anticoagulant) collected in plastic tubes. In our hospital samples are collected in plastic tubes. Our hypothesis was that the serum sample collected in plastic serum tube can be used interchangeably with plasma sample for measurement of digoxin concentration. Our aim was verification of plastic serum tubes for determination of digoxin concentration. Concentration of digoxin was determined simultaneously in 26 venous blood plasma (plastic Vacuette, LH Lithium heparin) and serum (plastic Vacuette, Z Serum Clot activator; both Greiner Bio-One GmbH, Kremsmünster, Austria) samples, on Abbott AxSYM analyzer using the original Abbott Digoxin III assay (Abbott, Wiesbaden, Germany). Tube comparability was assessed using the Passing Bablok regression and Bland-Altman plot. Serum and plasma digoxin concentrations are comparable. Passing Bablok intercept (0.08 [95% CI = -0.10 to 0.20]) and slope (0.99 [95% CI = 0.92 to 1.11]) showed there is no constant or proportional error. Blood samples drawn in plastic serum tubes and plastic plasma tubes can be interchangeably used for determination of digoxin concentration.

Effects of amlodipine on bone metabolism in male albino Wistar rats

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Iveta Gradošová

2011-01-01

Full Text Available Amlodipine (dihydropyridine-type calcium channel blocker is a widely used agent for the treatment of hypertension in human and veterinary medicine but detailed information about its effects on bone metabolism are missing. Therefore, the aim of our study was to investigate the effect of amlodipine on bone metabolism in male albino Wistar rats. Amlodipine (0.3 mg/100 g body weight; gavage was administered to 8 rats for 8 weeks. Control group (n = 8 received aqua pro inj. (0.2 ml/100 g body weight; gavage. Bone marker concentrations of carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I and aminoterminal propeptide of procollagen type I in serum, and of bone alkaline phosphatase (BALP in both serum and bone homogenate were measured by enzyme immunoassay. We investigated the expression of bone morphogenetic protein 2 (BMP-2 in proximal tibia using Western blotting, and bone mineral density was measured by Dual-energy X-ray Absorptiometry in lumbar and caudal vertebrae and in femoral areas. Mechanical properties of the femurs were measured by three-point bending of the shaft and compression testing of the femoral neck. After 8 weeks of amlodipine administration there was a significant decrease in serum concentrations of BALP (p = 0.0009 and CTX-I (p = 0.003, and the content of BALP in bone homogenate (p = 0.026 compared to the control. In addition, Western blot analysis indicated increased BMP-2 protein concentration after amlodipine administration. Our findings suggest that amlodipine has a retarding influence on bone metabolism in rats by decreasing bone turnover, which probably in consequence increases expression of BMP-2.

Radioimmunoassay of serum digoxin levels in digitalis intoxication

International Nuclear Information System (INIS)

Arendt, G.

1981-01-01

For 101 hospitalized patients where clinical symptoms of a glucosidine intoxication as a consequence of oral digoxin treatment were noted, serum digoxin levels were determined using a RIA kit of the Boehringer company (I-125 tracer, solid phase tube separation technique) on a fasted stomach prior to oral drug administration. An ECG was performed simultaneously and in addition kidney function parameters and electrolyte levels were determined. An anamnesis and clinical examination of the patients were also conducted. Interferences in the RIA method and gastro-intestinal illness resulting in changes in resorption behaviour were excluded. The group of patients showed collectively an average serum digoxin level of 2.9 +- 0.9 ng/ml with a range from 1.8 to 6.8 ng/ml, which was statistically significantly higher than the average value for 101 patients receiving long-term oral medication but without symptoms of glycosidine intoxication. According to the manufacture's specifications for the RIA kit, values > 2.0 ng/ml are considered as toxic, with values between 1.6 and 2.0 ng/mg falling into a ''grey zone''. A correlation was found between toxic serum values with changes in ECG pattern and subjective clinical symptoms of intoxication. A limitation of kidney function was responsible for the high serum glycoside levels in 62% of the patients. It was shown that the differing response of patients towards digitalis medication, above all in the case of long-term therapy, warrants an RIA determination of serum glycoside values in order to adjust the digoxin dose to individual requirements. (orig./MG) [de

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects.

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Kang, Woo Youl; Seong, Sook Jin; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; La, Sookie; Kim, Hyun-Ju; Cho, Seungil; Yoon, Young-Ran; Yang, Dong Heon; Lee, Hae Won

2018-01-01

A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (C max ) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC 0-t ) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean C max and AUC 0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan C max and AUC 0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine C max and AUC 0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the C max for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CKD-828 FDC tablets were shown to

Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats

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Eyer, Florian, E-mail: Florian.Eyer@mac.com [Department of Toxicology, Klinikum rechts der Isar, Munich (Germany); Steimer, Werner [Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Munich (Germany); Nitzsche, Thomas [Munich Center for Integrated Protein Science (CIPS-M), Freising-Weihenstephan (Germany); Lehrstuhl für Biologische Chemie, Technische Universität München, Freising-Weihenstephan (Germany); Jung, Nicole; Neuberger, Heidi [Department of Toxicology, Klinikum rechts der Isar, Munich (Germany); Müller, Christine [Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Munich (Germany); Schlapschy, Martin [Munich Center for Integrated Protein Science (CIPS-M), Freising-Weihenstephan (Germany); Lehrstuhl für Biologische Chemie, Technische Universität München, Freising-Weihenstephan (Germany); Zilker, Thomas [Department of Toxicology, Klinikum rechts der Isar, Munich (Germany); Skerra, Arne [Munich Center for Integrated Protein Science (CIPS-M), Freising-Weihenstephan (Germany); Lehrstuhl für Biologische Chemie, Technische Universität München, Freising-Weihenstephan (Germany)

2012-09-15

Lipocalins tailored with high affinity for prescribed ligands, so-called anticalins, constitute promising candidates as antidotes. Here, we present an animal study to investigate both pharmacokinetic and clinical effects of an anticalin specific for the digitalis compound digoxin. Intravenous digoxin (2.5–50 μg/kg/min) was administered to rats until first changes in the ECG occurred (dose finding study) or a priori for 30 min (kinetic study). The anticalin DigA16(H86N), dubbed DigiCal, was administered intravenously at absolute doses of 1, 5, 10 and 20 mg, while the control group received isotonic saline. Hemodynamic changes, several ECG parameters and digoxin concentration in plasma were monitored at given time intervals. After DigiCal administration free digoxin concentration in plasma ultrafiltrate declined dramatically within 1 min to the presumably non-toxic range. There was also a significant and DigiCal dose-dependent effect on longer survival, less ECG alterations, arrhythmia, and improved hemodynamics. Infusion of a lower digoxin dose (2.5 μg/kg/min) resulted in a more sustained reduction of free digoxin in plasma after DigiCal administration compared to a higher digoxin dose (25 μg/kg/min), whereas ECG and hemodynamic parameters did not markedly differ, reflecting the known relative insensitivity of rats towards digoxin toxicity. Notably, we observed a re-increase of free digoxin in plasma some time after bolus administration of DigiCal, which was presumably due to toxin redistribution from tissue in combination with the relatively fast renal clearance of the rather small protein antidote. We conclude that anticalins with appropriately engineered drug-binding activities and, possibly, prolonged plasma half-life offer prospects for next-generation antidotal therapy. -- Highlights: ► We provide an advanced model of digoxin toxicity in rats. ► We report on binding of digoxin to a novel designed anticalin. ► We report on pharmacokinetics of digoxin

A simplified radioimmunoassay for digoxin determination using a 125-I-labelled solid-phase kit

International Nuclear Information System (INIS)

Doering, W.; Bluemel, E.

1978-01-01

Our experience with a commercially available kit (Radioimmunoassay DIGOXIN, Boehringer, Mannheim) using ( 125 J)-labelled digoxin and antibody-coated tubes is reported. This simplified method requires only two pipetting steps per sample and results can be obtained in 70 min. The intra- and interassay coefficient of variation ranged between 7% and 8%. The specific digoxin antibody antibody gave no clinical relevant cross-reactions with spironolactone or prednisone ( [de

A Rare Case Report of Amlodipine-Induced Gingival Enlargement and Review of Its Pathogenesis

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Sanjeev Joshi

2013-01-01

Full Text Available Gingival enlargement is a common clinical feature of gingival and periodontal diseases. It is an unwanted side effect of certain systemic drugs given for nondental treatment. It is being reported with three main groups of drugs like calcium channel blockers (CCBs, immunosuppressants, and anticonvulsants. Among calcium channel blockers, nifedipine causes gingival hyperplasia in about 10% of patients, whereas the incidence of amlodipine-, a third generation calcium channel blocker, induced gingival hyperplasia is very limited. There are very few reports of amlodipine-induced gingival enlargement at a dose of 5 mg. We report a case of amlodipine-induced gingival enlargement in a 45-year-old hypertensive patient taking amlodipine at a dose of 5 mg.

Studies on cerebral protection of digoxin against ischemia/reperfusion injury in mice.

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Kaur, Shaminder; Rehni, Ashish K; Singh, Nirmal; Jaggi, Amteshwar S

2009-04-01

The present study was designed to investigate the possible neuroprotective effect of digoxin induced pharmacological preconditioning (PP) and its probable mechanism. Bilateral carotid artery occlusion (BCAO) of 17 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion (I/R) induced cerebral injury in male swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using elevated plus maze test. Degree of motor incoordination was evaluated using inclined beam walking test, rota rod test and lateral push test. Digoxin (0.08 mg/kg, i.p.) was administered 24 h before surgery in a separate group of animals to induce PP. BCAO followed by reperfusion, produced significant rise in cerebral infarct size along with impairment of memory and motor coordination. Digoxin treatment produced a significant decrease in cerebral infarct size and reversal of I/R induced impairment of memory and motor incoordination. Digoxin induced neuroprotective effect was abolished significantly by verapamil (15 mg/kg, i.p.), a L-type calcium channel blocker, ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker and 3,4-dichlorobenzamil (Na(+)/Ca(2+) exchanger inhibitor). These findings indicate that digoxin preconditioning exerts a marked neuroprotective effect on the ischemic brain, which is possibly linked to digitalis induced increase in intracellular calcium levels eventually leading to the activation of calcium sensitive signal transduction cascades.

Interference factors in digoxin analysis, especially in the serum of pregnant women, by RIA

International Nuclear Information System (INIS)

Tratz, A.

1981-01-01

The causes of false digoxin concentrations measured in pregnant women by RIA were gone into; 103 sera of healthy women in their last trimester of pregnancy were analyzed by 4 different RIA methods. In 6 cases, falsepositive digoxin levels above 1.0 ng/ml were found; 4 of the measured digoxin levels were above 2.0 ng/ml, i.e. a clinically toxic concentration. No pseudodigoxin was detected post partum; however, the author was only able to make control measurements of 2 of the 3 positive sera between the 6th and 12th week post partum. The causes of this phenomenon remain unclear. It cannot be excluded that these pregnant women may have a still unknown hormone metabolite, resulting from a possible enzymatic defect, which cross-reacts with the digoxin antiserum and thus causes false-positive results. In those rare cases where pregnant women receive digitalis treatment, digoxin serum measurements by RIA must be analyzed very critically due to the possibility of false-positive results. (orig.) [de

Hypothalamic digoxin, hemispheric chemical dominance, and inflammatory bowel disease.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-09-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. It was considered pertinent to assess the pathway in inflammatory bowel disease (ulcerative colitis and regional ileitis). Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. All the patients with inflammatory bowel disease were right-handed/left hemispheric dominant by the dichotic listening test. The following parameters were measured in patients with inflammatory bowel disease and in individuals with differing hemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free-radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition and RBC membrane Na+-K+ ATPase activity. Statistical analysis was done by ANOVA. In patients with inflammatory bowel disease there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Inflammatory bowel disease is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to immune activation, defective glycoprotein bowel antigen presentation, and autoimmunity and a schizophreniform psychosis important in its pathogenesis. The biochemical patterns obtained in inflammatory bowel disease is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with peptic ulcer disease were right

Amlodipine Ameliorates Ischemia-Induced Neovascularization in Diabetic Rats through Endothelial Progenitor Cell Mobilization

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Jiayin Sun

2016-01-01

Full Text Available Objectives. We investigated whether amlodipine could improve angiogenic responses in a diabetic rat model of acute myocardial infarction (AMI through improving bone marrow endothelial progenitor cell (EPC mobilization, in the same way as angiotensin converting enzyme inhibitors. Methods. After induction of AMI by coronary artery ligation, diabetic rats were randomly assigned to receive perindopril (2 mgkg−1 day−1, amlodipine (2.5 mgkg−1 day−1, or vehicle by gavage (n=20 per group. Circulating EPC counts before ligation and on days 1, 3, 5, 7, 14, and 28 after AMI were measured in each group. Microvessel density, cardiac function, and cardiac remodeling were assessed 4 weeks after treatment. The signaling pathway related to EPC mobilization was also measured. Results. Circulating EPC count in amlodipine- and perindopril-treated rats peaked at day 7, to an obvious higher level than the control group peak which was reached earlier (at day 5. Rats treated with amlodipine showed improved postischemia neovascularization and cardiac function, together with reduced cardiac remodeling, decreased interstitial fibrosis, and cardiomyocyte apoptosis. Amlodipine treatment also increased cardiac SDF-1/CXCR4 expression and gave rise to activation of VEGF/Akt/eNOS signaling in bone marrow. Conclusions. Amlodipine promotes neovascularization by improving EPC mobilization from bone marrow in diabetic rats after AMI, and activation of VEGF/Akt/eNOS signaling may in part contribute to this.

INAPPROPRIATE USE OF DIGOXIN IN MEDICAL PRACTICE

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Debasish

2015-08-01

Full Text Available Digoxin, the old golden molecule is one of the commonly prescribed drugs prescribed by general medical practitioners when a patient presents with dyspnea. Inspite of being arrythmogenic and having narrow therapeutic window, physicians do not even hesitate to use even where it could be catastrophic. Most are unaware of the classical indicatio ns where as others use it in myth that it is life saving and miraculous although numerous studies clearly delineates that it does not improve cardiac mortality although delay hospitalization. Our study was a miniature one to improve the cautiousness before digoxin use in medical practice and delineate its irrational use among patients with cardiovascular disease. We studied 4562 patients who were consulted in AIIMS Cardiology and Medicine OPD between October 2014 to June 2015 having digoxin among their ther apeutic armamentarium and delineated their irrational use even in toxic conditions. Rational use was only evident in 2007 (44%cases where as it was advocated wrongly in 2555(56% of cases, most sufferers being rheumatic heart disease (51.27% population, hypertensive heart disease(17.88%, coronary artery disease(5.44%, COPD(12.88% and CKD(0.9% patients being in decreasing order. In RHD scenario mitral stenosis patients suffered most (56% followed by aortic stenosis patients (25% compared to regurgita nt lesions which are better tolerated

A linear graph for digoxin radioimmunoassay

International Nuclear Information System (INIS)

Smith, S.E.; Richter, A.

1975-01-01

The determination of drug or hormone concentrations by radio-immunoassay involves interpolation of values for radioisotope counts within standard curves, a technique which requires some dexterity in curve drawing and which results in some inaccuracy in practice. Most of the procedures designed to overcome these difficulties are complex and time-consuming. In radioimmunoassays involving saturation of the antibody-binding sites a special case exists in that the bound radioactivity is directly proportional to the specific activity of the ligand in the system. Thus a graph of the ratio of radioactivity bound in the absence to that in the presence of added non-radioactive ligand is linear against the concentration of added ligand (Hales,C.N., and Randle, P.J., 1963, Biochem. J., vol. 88, 137). A description is given of a simple and convenient modification of their method, and its application to the routine clinical determination of digoxin using a commercial kit (Lanoxitest β digoxin radioimmunoassay kit, Wellcome Reagents Ltd.). Specially constructed graph paper, which yields linearity with standard solutions, was designed so that it could be used directly without data transmission. The specific activity function appears as the upper arithmetical horizontal scale; corresponding values of the concentration of non-radioactive ligand in the solution added were individually calculated and appear on the lower scale opposite the appropriate values of the upper scale. The linearity of the graphs obtained confirmed that binding of digoxin was approximately constant through the range of clinical concentrations tested (0.5 to 8ng/ml), although binding declined slightly at higher concentrations. (U.K.)

Quantitative model for the blood pressure‐lowering interaction of valsartan and amlodipine

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Heo, Young‐A; Holford, Nick; Kim, Yukyung; Son, Mijeong

2016-01-01

Aims The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. Methods PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3. Results A two‐compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an I max model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1 + D2) +ALPHA×(D1 × D2). D1 and D2 are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were −0.171 (95% CI: −0.218, −0.143) for SBP and −0.0312 (95% CI: −0.07739, −0.00283) for DBP. These infra‐additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes. Conclusion PKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra‐additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified. PMID:27504853

THE ROLE OF S-AMLODIPINE IN ARTERIAL HYPERTENSION THERAPY WITH COMBINATION OF CALCIUM CHANNEL BLOCKERS AND BETA-BLOCKERS

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M. A. Maksimova

2013-01-01

Full Text Available Aim. To study efficacy and safety of calcium channel blocker, S-amlodipine, in combination with β-blocker, atenolol, in patients with arterial hypertension (HT 1-2 degree com- pared to fixed combination of racemic amlodipine and atenolol.Material and methods. Patients (n=31, 7 men and 24 women with HT 1–2 degree were included into the study. The patients were randomized into two groups by the com- binations sequence. Treatment with each combination lasted 4 weeks. Office blood pressure (BP was assessed at baseline and at the end of the treatment periods, possible side effects were registered.Results. All patients completed the study. Both combination of S-amlodipine+atenolol and fixed combination of racemic amlodipine+atenolol reduced systolic (in average, -15.9 and -12.7 mm Hg, respectively and diastolic (in average, -7.3 and -5.3 mmHg, respectively BP significantly. Heart rate also decreased during therapy (in average, -3 and -4 bt/min, respectively. The differences between combinations BP and heart rate effects were not significant. 8 and 16 adverse events were registered during S-amlodipine+atenolol and racemic amlodipine+atenolol therapies, respectively Conclusion. Combination of S-amlodipine+atenolol, as well as combination of racemic amlodipine+atenolol are effective in the treatment of patients with HT 1-2 degree, however combination with S-amlodipine has less number of adverse events.

In-vitro displacement interaction of atenolol and amlodipine on binding with bovine serum albumin when co-administered

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Md. Ashraful Alam, Md. Abdul Awal, Mahbub Mostofa, Md. Kamrul Islam and Nusrat Subhan

2007-06-01

Full Text Available The binding of atenolol (selective β1-blocker and amlodipine (calcium channel blocker to bovine serum albumin (BSA was studied by equilibrium dialysis method in order to have an insight into the binding chemistry of these two to BSA. Free atenolol concentration was increased due to addition of amlodipine which reduced the binding of the compounds to BSA. However, the free fraction was increased to a level as it was expected from direct competitive displacement while the free atenolol concentration was increased according to increasing the amlodipine concentration when only the BSA was present. The result obtained when the binding site was blocked by sufficient amount of amlodipine was that the increment of free concentration of atenolol was prominent. When no amlodipine was added the free concentration of atenolol was only 28% whereas this release was 93 % to 98.01% when amlodipine was added with increasing concentration.

Iodine-125--digoxin radioimmunoassay: comparison of commercial kits

International Nuclear Information System (INIS)

Battaglia, D.J.; Cianci, M.L.

1976-01-01

Iodine-125-digoxin radioimmunoassay kits available from Abbott Diagnostics (AD), Dade Division (D), Schwarz/Mann (SM), and Clinical Assays (CA) were evaluated with respect to assay quality. The kit accuracies did not differ significantly at 2.0 ng/ml and the interassay coefficients of variation ranged from 9 percent (AD) to 21.4 percent (CA). The accuracy for all kits above 4 ng/ml is questionable, and since serum-dilution values correlated well with undiluted serum values, the dilution method of dose quantitation is preferable for levels above 4 ng/ml. Although all the kits were adequate for evaluating digoxin at the 2 ng/ml level, the Abbott kit seems to be of slightly better quality

Original Research Monotherapy with amlodipine or ...

African Journals Online (AJOL)

hypertension is the most common cardiovascular disease ... on the electrolyte profile of Nigerians with mild to moderate hypertension. Methods ... sphygmomanometer. ... Figure 1: Systolic blood pressure measurements following treatment with amlodipine and ..... above, the age of the subjects may be a contributing factor;.

Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

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Alexander Zhyvoloup

2017-07-01

Full Text Available HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

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Zhyvoloup, Alexander; Melamed, Anat; Anderson, Ian; Planas, Delphine; Lee, Chen-Hsuin; Kriston-Vizi, Janos; Ketteler, Robin; Merritt, Andy; Routy, Jean-Pierre; Ancuta, Petronela; Bangham, Charles R M; Fassati, Ariberto

2017-07-01

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

Antihypertensive treatment with telmisartan in a cat with amlodipine-induced gingival hyperplasia

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Lien Desmet

2017-12-01

Full Text Available Case summary Systemic arterial hypertension is commonly reported in middle-aged-to-older cats. Amlodipine is recommended as the initial antihypertensive drug in cats. In this case report, gingival hyperplasia secondary to the use of amlodipine in a cat is described. Benazepril as a monotherapy was unsuccessful in reducing blood pressure in this cat. After replacement of benazepril by telmisartan, gingival hyperplasia disappeared and blood pressure was well controlled. Relevance and novel information This case report describes the first reported case of reversible gingival hyperplasia as a result of the treatment with amlodipine. It also contains the first published data on the effect of telmisartan in a hypertensive cat.

Is digoxin an independent risk factor for long-term mortality after acute myocardial infarction?

DEFF Research Database (Denmark)

Køber, L; Torp-Pedersen, C; Gadsbøll, N

1994-01-01

age, LVEF, diabetes mellitus, heart failure, atrial fibrillation or flutter, ventricular fibrillation, gender, dose of furosemide at discharge and calcium antagonists and digoxin treatment as covariates, digoxin was independently associated with an increased risk of death (relative risk 1.8 (95...

An optical sensor for the determination of digoxin in serum samples based on a molecularly imprinted polymer membrane

International Nuclear Information System (INIS)

Paniagua Gonzalez, Gema; Fernandez Hernando, Pilar; Durand Alegria, J. S.

2009-01-01

This paper reports the synthesis and testing of a molecularly imprinted polymer membrane for digoxin analysis. Digoxin-specific bulk polymer was obtained by the UV initiated co-polymerisation of methacrylic acid and ethylene glycol dimethacrylate in acetonitrile as porogen. After extracting the template analyte, the ground polymer particles were mixed with plasticizer polyvinyl chloride to form a MIP membrane. A reference polymer membrane was prepared from the same mixture of monomers but with no template. The resultant membrane morphologies were examined by scanning electron microscopy. The imprinted membrane was tested as the recognition element in a digoxin-sensitive fluorescence sensor; sensor response was measured using standard solutions of digoxin at concentrations of up to 4 x 10 -3 mg L -1 . The detection limit was 3.17 x 10 -5 mg L -1 . Within- and between-day relative standard deviations RSD (n = 5) were in the range 4.5-5.5% and 5.5-6.5% respectively for 0 and 1 x 10 -3 mg L -1 digoxin concentrations. A selectivity study showed that compounds of similar structure to digoxin did not significantly interfere with detection for interferent concentrations at 10, 30 and 100 times higher than the digoxin concentration. This simply manufactured MIP membrane showed good recognition characteristics, a high affinity for digoxin, and provided satisfactory results in analyses of this analyte in human serum.

Noncardiogenic Pulmonary Edema after Amlodipine Overdose without Refractory Hypotension and Bradycardia

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M. Hedaiaty

2015-01-01

Full Text Available Amlodipine overdose can be life-threatening when manifesting as noncardiogenic pulmonary edema. Treatment remains challenging. We describe a case of noncardiogenic pulmonary edema without refractory hypotension and bradycardia after ingestion of 500 milligram amlodipine with suicidal intent. Mechanical ventilation, dexamethasone, atrovent HFA (ipratropium, pulmicort inhalation, and antibiotic therapy were used for the management. Length of hospital stay was 11 days. The patient was discharged with full recovery.

VERIFICATION HPLC METHOD OF QUANTITATIVE DETERMINATION OF AMLODIPINE IN TABLETS

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Khanin V. A

2014-10-01

Full Text Available Introduction. Amlodipine ((±-2-[(2-aminoetoksimethyl]-4-(2-chlorophenyl-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl 5-methyl ester as besylate and small tally belongs to the group of selective long-acting calcium channel blockers, dihydropyridine derivatives. In clinical practice, as antianginal and antihypertensive agent for the treatment of cardiovascular diseases. It is produced in powder form, substance and finished dosage forms (tablets of 2.5, 5 and 10 mg. The scientific literature describes methods of quantitative determination of the drug by spectrophotometry – by his own light absorption and by reaction product with aloksan, chromatography techniques, kinetic-spectrophotometric method in substances and preparations and methods chromatomass spectrometry and stripping voltammetry. For the quantitative determination of amlodipine besylate British Pharmacopoeia and European Pharmacopoeia recommend the use of liquid chromatography method. In connection with the establishment of the second edition of SPhU and when it is comprised of articles on the finished product, we set out to analyze the characteristics of the validation of chromatographic quantitative determination of amlodipine besylate tablets and to verify the analytical procedure. Material & methods. In conducting research using substance amlodipine besylate series number AB0401013. Analysis subject pill “Amlodipine” series number 20113 manufacturer of “Pharmaceutical company “Zdorovye”. Analytical equipment used is: 2695 chromatograph with diode array detector 2996 firms Waters Corp. USA using column Nova-Pak C18 300 x 3,9 mm with a particle size of 4 μm, weight ER-182 company AND Japan, measuring vessel class A. Preparation of the test solution. To accurately sample powder tablets equivalent to 50 mg amlodipine, add 30 ml of methanol, shake for 30 minutes, dilute the solution to 50.0 ml with methanol and filtered. 5 ml of methanol solution adjusted to

Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.

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Jamerson, Kenneth; Weber, Michael A; Bakris, George L; Dahlöf, Björn; Pitt, Bertram; Shi, Victor; Hester, Allen; Gupte, Jitendra; Gatlin, Marjorie; Velazquez, Eric J

2008-12-04

The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic. In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; Pbenazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.) 2008 Massachusetts Medical Society

Amlodipine-induced gingival hyperplasia in chronic renal

African Journals Online (AJOL)

Administrator

Keywords: Amlodipine, gingival hyperplasia, chronic renal failure. African Health ... for the treatment of hypertension and angina. Pharmacokinetic ... patient appealed to the dentist at first. ... Am Heart J. 1989 Nov; 118(5 Pt 2):. 1100-1103. 2.

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828 formulation and coadministered telmisartan and S-amlodipine in healthy subjects

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Kang WY

2018-03-01

Full Text Available Woo Youl Kang,1,2,* Sook Jin Seong,1,* Boram Ohk,1,2 Mi-Ri Gwon,1,3 Bo Kyung Kim,1,2 Sookie La,4 Hyun-Ju Kim,3 Seungil Cho,1 Young-Ran Yoon,1,2 Dong Heon Yang,5 Hae Won Lee1 1Clinical Trial Center, Kyungpook National University Hospital, Daegu, Republic of Korea; 2Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, Daegu, Republic of Korea; 3Department of Molecular Medicine, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea; 4Analytical Research Division, Biocore Co Ltd, Seoul, Republic of Korea; 5Division of Cardiology, Department of Internal Medicine, Kyungpook National University School of Medicine & Hospital, Daegu, Republic of Korea *These authors contributed equally to this work Purpose: A new fixed-dose combination (FDC formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828 has been developed to increase convenience (as only one tablet is required per day and improve treatment compliance.Methods: The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography–tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period.Results: Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax and the area under the plasma concentration–time curve from time 0 to the last measurement (AUC0–t values of telmisartan were 522.29 ng/mL and 2,475.16 ng⋅h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng⋅h/mL for the individual agents

The effect of captopriland amlodipine on C-reactive protein concentrations in type 2 diabetic hypertensive patients

International Nuclear Information System (INIS)

Mahmood, I.H.

2008-01-01

To compare the effects of the ACE inhibitor captopril with the calcium channel blocker amlodipine on serum CRP concentrations in hypertensive type 2 diabetic patients. This is a case control study conducted in Al-Wafa Diabetic Center in Mosul. Serum CRP concentrations were measured in two groups of hypertensive type 2 diabetic patients before and after drug administration (group 1 on captopril therapy, group two on amlodipine therapy). A significant reduction of serum CRP level was demonstrated after treatment with captopril but not with amlodipine. Mean CRP concentration of the control group was statistically lower than those of captopril and amlodipine groups. The present study showed that hypertensive type 2 diabetic patients are associated with increased level of CRP and therapy with captopril but not amlodipine significantly reduced CRP, suggesting a possible anti-inflammatory action of captopril in addition to its BP lowering effects thus captopril may be regarded as the drug of choice in the treatment of BP in diabetic hypertensive patients. (author)

An optical sensor for the determination of digoxin in serum samples based on a molecularly imprinted polymer membrane

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Paniagua Gonzalez, Gema [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), 28040 Madrid (Spain); Fernandez Hernando, Pilar, E-mail: pfhernando@ccia.uned.es [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), 28040 Madrid (Spain); Durand Alegria, J. S. [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), 28040 Madrid (Spain)

2009-04-13

This paper reports the synthesis and testing of a molecularly imprinted polymer membrane for digoxin analysis. Digoxin-specific bulk polymer was obtained by the UV initiated co-polymerisation of methacrylic acid and ethylene glycol dimethacrylate in acetonitrile as porogen. After extracting the template analyte, the ground polymer particles were mixed with plasticizer polyvinyl chloride to form a MIP membrane. A reference polymer membrane was prepared from the same mixture of monomers but with no template. The resultant membrane morphologies were examined by scanning electron microscopy. The imprinted membrane was tested as the recognition element in a digoxin-sensitive fluorescence sensor; sensor response was measured using standard solutions of digoxin at concentrations of up to 4 x 10{sup -3} mg L{sup -1}. The detection limit was 3.17 x 10{sup -5} mg L{sup -1}. Within- and between-day relative standard deviations RSD (n = 5) were in the range 4.5-5.5% and 5.5-6.5% respectively for 0 and 1 x 10{sup -3} mg L{sup -1} digoxin concentrations. A selectivity study showed that compounds of similar structure to digoxin did not significantly interfere with detection for interferent concentrations at 10, 30 and 100 times higher than the digoxin concentration. This simply manufactured MIP membrane showed good recognition characteristics, a high affinity for digoxin, and provided satisfactory results in analyses of this analyte in human serum.

Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal.

Science.gov (United States)

Sevilla, María A; Voces, Felipe; Carrón, Rosalía; Guerrero, Estela I; Ardanaz, Noelia; San Román, Luis; Arévalo, Miguel A; Montero, María J

2004-07-02

Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal. Copyright 2004 Elsevier Inc.

Unmasking the Role of Uptake Transporters for Digoxin Uptake Across the Barriers of the Central Nervous System in Rat

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Kunal S Taskar

2017-03-01

Full Text Available The role of uptake transporter (organic anion–transporting polypeptide [Oatp] in the disposition of a P-glycoprotein (P-gp substrate (digoxin at the barriers of central nervous system, namely, the blood-brain barrier (BBB, blood-spinal cord barrier (BSCB, and brain-cerebrospinal fluid barrier (BCSFB, was studied using rat as a preclinical species. In vivo chemical inhibition of P-gp and Oatp was achieved using elacridar and rifampicin, respectively. Our findings show that (1 digoxin had a low brain-to-plasma concentration ratio (B/P (0.07 in rat; (2 in the presence of elacridar, the B/P of digoxin increased by about 12-fold; (3 rifampicin administration alone did not change the digoxin B/P significantly when compared with digoxin B/P alone; (4 rifampicin administration along with elacridar resulted only in 6-fold increase in the B/P of digoxin; (5 similar fold changes and trends were seen with the spinal cord-to-plasma concentration ratio of digoxin, indicating the similarity between BBB and the BSCB; and (6 unlike BBB and BSCB, the presence of rifampicin further increased the cerebrospinal fluid-to-plasma concentration ratio (CSF/P for digoxin, suggesting a differential orientation of the uptake transporters at the BCSFB (CSF to blood compared with the BBB (blood to brain. The observations for digoxin uptake, at least at the BBB and the BSCB, advocate the importance of uptake transporters (Oatps. However, the activity of such uptake transporters became evident only after inhibition of the efflux transporter (P-gp.

Investigation of forced and total degradation products of amlodipine besylate by liquid chromatography and liquid chromatography-mass spectrometry

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Stoiljković Zora Ž.

2014-01-01

Full Text Available An isocratic, reversed-phase liquid chromatographic method was applied for the investigation of the degradation products of amlodipine besylate under the stressed conditions in solution. Amlodipine besylate stock solutions were subjected to acid and alkali hydrolysis, chemical oxidation and photodegradation as well as to the electrochemical degradation by cyclic voltammetry in 0.05 mol/L NaHCO3 on gold electrode. The total degradation of amlodipine besylate was achieved in 5 mol/L NaOH at 80°C for 6 h and the compound with molecular formula C15H16NOCl was identified as a main degradation product. Under acidic (5 mol/L HCl at 80°C for 6 h stress conditions 75.2% of amlodipine besylate degradation was recorded. Oxidative degradation in the solution of 3% H2O2-methanol 80:20 at 80°C for 6 h showed that amlodipine besylate degraded to 80.1%. After 14 days of expose in photostability chamber amlodipine besylate solution showed degradation of 32.2%. In electrochemical degradation after 9 hours of cyclization the beginning of amlodipine oxidation was shifted for 200 mV to more negative potentials, with the degradation of 66.5%. Mass spectrometry analysis confirmed the presence of dehydro amlodipine derivate with molecular formula C20H23N2O5Cl in oxidative and acidic conditions while in electrochemical degradation was detected in traces. [Projekat Ministarsva nauke Republike Srbije, br. 172013

Amlodipine and Atorvastatin Improved Hypertensive Cardiac Remodeling through Regulation of MMPs/TIMPs in SHR Rats

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Jingchao Lu

2016-06-01

Full Text Available Background: MMPs/TIMPs system is well known to play important roles in pressure overload-induced cardiac remodeling, and Amlodipine and Atorvastatin have been showed to exert favourable protective effects on cardiovascular disease, however, it is not clear whether Amlodipine and Atorvastatin can improve hypertensive cardiac remodeling and whether the MMPs/TIMPs system is involved. The present study aims to answer these questions. Methods: 36 weeks old male spontaneous hypertension (SHR rats were randomly divided into four groups: 1. SHR control group, 2. Amlodipine alone (10 mg/kg/d group, 3. Atorvastatin alone (10 mg/kg/d group, 4.Combination of Amlodipine and Atorvastatin (10 mg/kg/d for each group. Same gender, weight and age of Wistar-Kyoto (WKY rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The blood pressure and left ventricle mass index were measured. Enzyme activity of MMP-2 and MMP-9 was assessed with Gelatin zymography. MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA and protein expression was studied by RT-PCR and Western blot. Single factor ANOVA and LSD-t test were used in statistical analysis. Results: Treatment with Amlodipine alone or combination with atorvastatin significantly decreased blood pressure, left ventricle mass index in SHR rats (P Conclusion: Amlodipine and Atorvastatin could improve ventricular remodeling in SHR rats through intervention with the imbalance of MMP-2/TIMP-2 and MMP-9/TIMP-1 system.

Comparative effects of amlodipine and benazepril on left atrial pressure in dogs with experimentally-induced mitral valve regurgitation.

Science.gov (United States)

Suzuki, Shuji; Fukushima, Ryuji; Ishikawa, Taisuke; Yamamoto, Yuta; Hamabe, Lina; Kim, Soomin; Yoshiyuki, Rieko; Machida, Noboru; Tanaka, Ryou

2012-09-18

One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine's effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS.

Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

Science.gov (United States)

Kadow, Brian T; Lyon, Timothy D; Zhang, Zhaocun; Lamm, Vladimir; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

2016-07-01

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition. Copyright © 2016 the American Physiological Society.

Design and stability study of an oral solution of amlodipine besylate for pediatric patients.

Science.gov (United States)

van der Vossen, A C; van der Velde, I; Smeets, O S N M; Postma, D J; Vermes, A; Koch, B C P; Vulto, A G; Hanff, L M

2016-09-20

Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production. The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4°C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks. Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of digoxin and. beta. -methyldigoxin on the heart rate of decompensated patients with atrial fibrillation

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Andersson, K E; Johansson, B W; Ledermann, H; von Schenck, H; Thorell, J I [Lund Univ. (Sweden). Clinical Pharmacological Lab.; Allmaenna Sjukhuset, Malmoe (Sweden). Heat Lab.; Allmaenna Sjukhuset, Malmoe (Sweden). Dept. of Clinical Chemistry)

1977-02-01

Eighteen patients with atrial fibrillation were given digoxin 0.13 mg twice daily for 3 weeks and ..beta..-methyldigoxin 0.10 mg twice daily for another 3 weeks. At the end of each 3 week period an exercise test was performed and the effects on the heart rate of the two drugs were compared. No difference in heart rate was obtained at rest, wheareas the heart rate after 6 min of exercise was higher during treatment with digoxin (131 beats/min) than when the patients were taking ..beta..-methyldigoxin (124 beats/min). There were no significant differences between digoxin and ..beta..-methyldigoxin in their effects on the ECT (R-R intervals, T-wave, Q-T duration). The plasma concentrations of the two glycosides were determined by radioimmunoassay and by /sup 86/Rb-uptake inhibition assay. Comparable plasma concentration values (1.0 ng/ml for digoxin, 1.1 ng/ml for ..beta..-methyldigoxin, mean values) were obtained by radioimmunoassay, but the /sup 86/Rb-technique gave significantly higher values (mean 1.5 ng/ml) for ..beta..-methyldigoxin. It is concluded that ..beta..-methyldigoxin is equal to digoxin for producing slowing of the heart rate in patients with atrial fibrillation.

Comparison of efficacy and tolerability of different brands of amlodipine in patients with mild to moderate hypertension

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Molouk Hadjibabaie

2015-10-01

Full Text Available Background: The efficacy of amlodipine, a calcium channel blocker, in treating systemic hypertension is well established but the most efficacious brand of this drug is still uncertain. The cost of different brands of amlodipine is tremendously different which may affect decision-making in hypertension treatment. The purpose of this study was to compare the efficacy and safety of different brands of amlodipine (Amlodipine, Amlopress, and Norvasc in the treatment of hypertension in adult patients.Methods: This was a double-blind, randomized, three-sequence crossover study. Ambulatory patients with hypertension who had the inclusion criteria were enrolled. Patients were randomized and entered into three groups to receive either brand of amlodipine in a crossover method. After every four weeks of treatment completed, the other brand of drug was prescribed. The total period of the study was 12 weeks for all three drugs including four weeks for each brand.Results: A total of 20 patients entered to the study, 15 completed the 12-week treatment schedule. The absolute reductions in seated and supine systolic blood pressure (SBP and diastolic blood pressure (DBP were similar with all three brands during the 4 weeks of treatment. Headache, malaise and weakness were the most common reported adverse effects (AE with all three drugs. Generic amlodipine had the most AE as compared with other brands. These AE were mild and did not require withdrawal of the drug. Conclusion: There is no statistical difference in lowering blood pressure by three different brands of amlodipine thus everyone which has the lowest price can be the first choice.

Solid phase tube radioimmunoassay for digoxin detection

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Stellner, K.; Glatz, C.; Linke, R.

1975-01-01

A solid phase radioimmunoassay with 125 I is described for cardiac patients. The test for the digoxin determination and the poisoning due to cardiac glycosides can be measured very accurately and carried out easily. In addition, the test determination can be automatically performed in connection with other tests. (GSE/LH) [de

Functional Vascular Study in Hypertensive Subjects with Type 2 Diabetes Using Losartan or Amlodipine

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Cesar Romaro Pozzobon

2014-07-01

Full Text Available Background: Antihypertensive drugs are used to control blood pressure (BP and reduce macro- and microvascular complications in hypertensive patients with diabetes. Objectives: The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan. Methods: Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day or losartan (100 mg/day. Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV, and flow-mediated dilation (FMD of the brachial artery. Results: A total of 42 patients were evaluated (21 in each group, with a predominance of women (71% in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9 years, with no significant difference in the mean BP [amlodipine group: 145 ± 14 mmHg (systolic and 84 ± 8 mmHg (diastolic; losartan group: 153 ± 19 mmHg (systolic and 90 ± 9 mmHg (diastolic]. The augmentation index (30% ± 9% and 36% ± 8%, p = 0.025 and augmentation pressure (16 ± 6 mmHg and 20 ± 8 mmHg, p = 0.045 were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups. Conclusions: Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect.

Beneficial effects of combined benazepril-amlodipine on cardiac nitric oxide, cGMP, and TNF-alpha production after cardiac ischemia.

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Siragy, Helmy M; Xue, Chun; Webb, Randy L

2006-05-01

The aim of this study was to determine if myocardial inflammation is increased after myocardial ischemia and whether angiotensin-converting enzyme inhibitors, calcium channel blockers, or diuretics decrease mediators of inflammation in rats with induced myocardial ischemia. Changes in cardiac interstitial fluid (CIF) levels of nitric oxide metabolites (NOX), cyclic guanosine 3',5'-monophosphate (cGMP), angiotensin II (Ang II), and tumor necrosis factor-alpha (TNF-alpha) were monitored with/without oral administration of benazepril, amlodipine, combined benazepril-amlodipine, or hydrochlorothiazide. Using a microdialysis technique, levels of several mediators of inflammation were measured after sham operation or 30-minute occlusion of the left anterior descending coronary artery. Compared with sham animals, levels of CIF NOX and cGMP were decreased in animals with ischemia (P Benazepril or amlodipine significantly increased NOX levels (P benazepril significantly increased cGMP (P benazepril-amlodipine further increased CIF NOX and cGMP (P benazepril alone, or combined benazepril-amlodipine significantly reduced TNF-alpha (P benazepril-amlodipine may be beneficial for managing cardiac ischemia.

An HPLC method for the determination of digoxin in dissolution samples

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Milenković Miroslav Ž.

2010-01-01

Full Text Available An HPLC method for digoxin quantification in dissolution samples obtained as per the official British Pharmacopeia (BP method is presented in this paper. The chromatography was performed at 20 °C on a Symmetry C18; 3.5 ìm, 75 x 4.6 mm column with water - acetonitrile (72 : 28, v/v, as the mobile phase and UV detection at 220 nm. The method was found to be selective, linear, accurate and precise in the specified ranges. The LOD and LOQ were 0.015 μg mL-1 and 0.050 μg mL-1, respectively. Robustness testing was conducted to evaluate the impact of minor changes in the chromatographic parameters (i.e., acetonitrile fraction, flow rate of the mobile phase, column temperature and column length on the characteristics of the digoxin peak. A. full factorial design (24 was used to investigate the influence of the four variables The presented HPLC method was applied in quality and stability testing of Digoxin tablets 0.25 mg.

Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation

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Suzuki Shuji

2012-09-01

Full Text Available Abstract Background One of the purposes of treatment for dogs with mitral regurgitation (MR is lowering left atrial pressure (LAP. There has been few study of the amlodipine in dogs with MR and amlodipine’s effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h vs benazepril (0.5 mg/kg PO q12h, on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. Results Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p  .05. LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA of the amlodipine treatment was significantly lower (p  Conclusions LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS.

Digoxin Use and Lower 30-day All-cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure

NARCIS (Netherlands)

Ahmed, Ali; Bourge, Robert C.; Fonarow, Gregg C.; Patel, Kanan; Morgan, Charity J.; Fleg, Jerome L.; Aban, Inmaculada B.; Love, Thomas E.; Yancy, Clyde W.; Deedwania, Prakash; van Veldhuisen, Dirk J.; Filippatos, Gerasimos S.; Anker, Stefan D.; Allman, Richard M.

BACKGROUND: Heart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after

Blood pressure effects of high-dose amlodipine-benazepril combination in Black and White hypertensive patients not controlled on monotherapy.

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Chrysant, Steven G

2012-06-01

Black hypertensive patients are more resistant to angiotensin-converting enzyme (ACE) inhibitor monotherapy than White patients. This resistance can be overcome with the combination of ACE inhibitors with diuretics or calcium-channel blockers (CCBs). The objective of this clinical investigation was to evaluate the antihypertensive effectiveness of monotherapy with the ACE inhibitor benazepril or the CCB amlodipine and their combination in Black and White hypertensive patients in two separate studies. This was a post hoc analysis of data from two separate studies, pooled because of their similarities, to increase the sample size. Outpatient Black and White hypertensive patients were selected for these studies. In study H2303, 201 patients of both sexes and races, whose mean seated diastolic blood pressure (MSDBP) was ≥95 mmHg after 4 weeks of single-blind treatment with benazepril 40 mg/day, were randomized into two groups. Group 1 received benazepril 40 mg/day and group 2 received amlodipine/benazepril 5/40 mg/day, which was uptitrated to amlodipine/benazepril 10/40 mg/day at week 4 of the study. In study H2304, 812 similar patients, whose MSDBP was ≥95 mmHg after 4 weeks of single-blind treatment with amlodipine 10 mg/day, were randomized into three groups. Group 1 received amlodipine/benazepril 10/20 mg/day, uptitrated to amlodipine/benazepril 10/40 mg/day after 2 weeks. Group 2 received amlodipine/benazepril 10/20 mg/day. Group 3 received amlodipine 10 mg/day. All three groups were followed up for 6 additional weeks. This report presents the results of post hoc analysis of pooled data from two separate but similar studies. Combination therapy resulted in greater lowering of MSDBP and mean seated systolic blood pressure (MSSBP) than monotherapy with either benazepril or amlodipine (p benazepril 10/20 mg/day resulted in greater blood pressure (BP) reductions in White patients than in Black patients (p benazepril 10/40�

Less adrenergic response to mental task during verapamil compared to amlodipine treatment in hypertensive subjects

NARCIS (Netherlands)

Sevre, K; Lefrandt, JD; Eide, [No Value; Smit, AJ; Rostrup, M

2001-01-01

We compared the effects of amlodipine and verapamil slow release on autonomic responses to a 5-min mental arithmetic test (MST) in patients with mild to moderate hypertension. Twenty subjects received 8 weeks of verapamil slow release 240 mg or amlodipine 10 mg in a double-blind crossover design,

Nociceptor-Enriched Genes Required for Normal Thermal Nociception

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Ken Honjo

2016-07-01

Full Text Available Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil. Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals.

The effects of digoxin and β-methyldigoxin on the heart rate of decompensated patients with atrial fibrillation

International Nuclear Information System (INIS)

Andersson, K.E.; Johansson, B.W.; Ledermann, H.; Schenck, H. von; Thorell, J.I.; Allmaenna Sjukhuset, Malmoe; Allmaenna Sjukhuset, Malmoe

1977-01-01

Eighteen patients with atrial fibrillation were given digoxin 0.13 mg twice daily for 3 weeks and β-methyldigoxin 0.10 mg twice daily for another 3 weeks. At the end of each 3 week period an exercise test was performed and the effects on the heart rate of the two drugs were compared. No difference in heart rate was obtained at rest, wheareas the heart rate after 6 min of exercise was higher during treatment with digoxin (131 beats/min) than when the patients were taking β-methyldigoxin (124 beats/min). There were no significant differences between digoxin and β-methyldigoxin in their effects on the ECT (R-R intervals, T-wave, Q-T duration). The plasma concentrations of the two glycosides were determined by radioimmunoassay and by 86 Rb-uptake inhibition assay. Comparable plasma concentration values (1.0 ng/ml for digoxin, 1.1 ng/ml for β-methyldigoxin, mean values) were obtained by radioimmunoassay, but the 86 Rb-technique gave significantly higher values (mean 1.5 ng/ml) for β-methyldigoxin. It is concluded that β-methyldigoxin is equal to digoxin for producing slowing of the heart rate in patients with atrial fibrillation. (orig.) [de

[Simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma by LC-HESI/MS/MS method].

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Pan, Hua-Ling; Lin, Li-Shan; Ding, Jue-Fang; Chen, Xiao-Yan; Zhong, Da-Fang

2014-01-01

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.

Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp.

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Annie Albin Lumen

Full Text Available We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918 to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health, Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown. These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1 bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2 partition into the basolateral membrane and directly reduce membrane permeability; (3 aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while

Shielding cognition from nociception with working memory.

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Legrain, Valéry; Crombez, Geert; Plaghki, Léon; Mouraux, André

2013-01-01

Because pain often signals the occurrence of potential tissue damage, nociceptive stimuli have the capacity to capture attention and interfere with ongoing cognitive activities. Working memory is known to guide the orientation of attention by maintaining goal priorities active during the achievement of a task. This study investigated whether the cortical processing of nociceptive stimuli and their ability to capture attention are under the control of working memory. Event-related brain potentials (ERPs) were recorded while participants performed primary tasks on visual targets that required or did not require rehearsal in working memory (1-back vs 0-back conditions). The visual targets were shortly preceded by task-irrelevant tactile stimuli. Occasionally, in order to distract the participants, the tactile stimuli were replaced by novel nociceptive stimuli. In the 0-back conditions, task performance was disrupted by the occurrence of the nociceptive distracters, as reflected by the increased reaction times in trials with novel nociceptive distracters as compared to trials with standard tactile distracters. In the 1-back conditions, such a difference disappeared suggesting that attentional capture and task disruption induced by nociceptive distracters were suppressed by working memory, regardless of task demands. Most importantly, in the conditions involving working memory, the magnitude of nociceptive ERPs, including ERP components at early latency, were significantly reduced. This indicates that working memory is able to modulate the cortical processing of nociceptive input already at its earliest stages, and could explain why working memory reduces consequently ability of nociceptive stimuli to capture attention and disrupt performance of the primary task. It is concluded that protecting cognitive processing against pain interference is best guaranteed by keeping out of working memory pain-related information. Copyright © 2012 Elsevier Ltd. All rights reserved.

Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two-period crossover study in healthy Korean male volunteers.

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Noh, Yook-Hwan; Lim, Hyeong-Seok; Kim, Mi Jo; Kim, Yo Han; Choi, Hee Youn; Sung, Hye Ryoung; Jin, Seok-Joon; Lim, Jonglae; Bae, Kyun-Seop

2012-07-01

Telmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy. To investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug-drug interaction study required before developing the fixed-dose combination agent. This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(τ,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0

Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

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Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S. (Medical Center for Postgraduate Education, Warsaw (Poland))

1990-01-01

Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly.

Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

International Nuclear Information System (INIS)

Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S.

1990-01-01

Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly

Effects of haemolysis, urea and bilirubin on the precision of digoxin and insulin radioimmunoassays

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Dwenger, A.; Trautschold, I.

1982-01-01

The influence of haemolysis, uraemia and hyperbilirubinaemia on the radioimmunoassay for both digoxin and insulin has been investigated for five separation techniques (dextran/charcoal; coated tube; polyethyleneglycol 4000; sodium sulphite; double antibody). Recoveries, and intra- and interassay precision were calculated. It was demonstrated that even in serum samples with a rather high degree of haemolysis (haemoglobin up to 50 g/l) digoxin can be measured by using each of the five separation techniques without any significant interference. Visible haemolysis (haemoglobin above 200 mg/l) leads either to disturbance or to a complete failure of insulin radioimmunoassays with all separation techniques. This effect can be largely neutralized, and precision improved, by using N-ethyl-maleimide. With the exception of the coated tube separation technique the intraassay precision has a CV of < 10%, and the interassay CV is between 10 and 20%. Elevated urea concentrations interfered in the digoxin radioimmuno-assay only when the coated tube technique was used. The insulin radioimmunoassay, however was affected by high urea when either the double antibody or the coated tube technique was used. Here the intraassay precision also has a coefficient of variation < 10%, the interassay CV lying between 10 and 20%. Bilirubin influenced the digoxin test when the sodium sulphite separation was used, and it affected the insulin determinations with polyethyleneglycol 4000 and sodium sulphite. The intra- and interassay precision were however also around 10% and between 10 and 20% respectively. Compared with the interassay precision of 15% CV for digoxin and 13% for insulin for a pool-serum from blood donors, the decrease of interassay precision caused by haemolysis, uraemia and hyperbilirubin-aemia was insignificant.

Zero crossing and ratio spectra derivative spectrophotometry for the dissolution tests of amlodipine and perindopril in their fixed dose formulations

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Maczka Paulina

2014-06-01

Full Text Available Dissolution tests of amlodipine and perindopril from their fixed dose formulations were performed in 900 mL of phosphate buffer of pH 5.5 at 37°C using the paddle apparatus. Then, two simple and rapid derivative spectrophotometric methods were used for the quantitative measurements of amlodipine and perindopril. The first method was zero crossing first derivative spectrophotometry in which measuring of amplitudes at 253 nm for amlodipine and 229 nm for perindopril were used. The second method was ratio derivative spectrophotometry in which spectra of amlodipine over the linearity range were divided by one selected standard spectrum of perindopril and then amplitudes at 242 nm were measured. Similarly, spectra of perindopril were divided by one selected standard spectrum of amlodipine and then amplitudes at 298 nm were measured. Both of the methods were validated to meet official requirements and were demonstrated to be selective, precise and accurate. Since there is no official monograph for these drugs in binary formulations, the dissolution tests and quantification procedure presented here can be used as a quality control test for amlodipine and perindopril in respective dosage forms.

A critical appraisal of a further three new commercial digoxin radioimmunoassay kits with reference to cross-reacting substances

International Nuclear Information System (INIS)

Wood, W.G.; Wachter, C.

1979-01-01

A further 3 digoxin radioimmunoassay (RIA) kits have been evaluated for performance and cross-reaction with digitoxin, spironolactone, canrenone and furosemide (Lasix-Hoechst). Effects of serum protein concentrations have also been tested. The kits tested were from the following manufacturers: A) Diagnostic Products Corporation Digoxin RIA Kit. B) Byk-Mallinckrodt SPAC Digoxin Kit. C) Boehringer-Mannheim Digoxin RIA Kit. All kits used a 125 I-labelled tracer. Kit A used a conventional liquid phase system using double-antibody separation for bound and free drug. Kits B and C used a solid-phase antibody coated tube method. All kits showed a lower cross-reaction to digitoxin than quoted by the manufacturer. Cross-reaction to spironolactone (Aldactone - Boehringer-Mannheim) was less than 1.50 nmol/l at a serum concentration of 125 mg/l Aldactone in all 3 kits. The cross-reaction to canrenone was somewhat higher, 5.2 nmol/l 'digoxin' being measured in one kit at a serum canrenone concentration of 125 mg/l. There was no cross-reaction with furosemide in any kit, even at a serum concentration of 5 g/l. The coated-tube assays were affected by serum albumin and globulin concentration changes, one kit showing a difference of over 50% binding in the range 1-20% albumin. The double-antibody kit did not show dependence on the concentration of these proteins. All kits measured digoxin with good reproducibility in the range 0.40-10.0 nmol/l. (orig.) [de

Hypothalamic digoxin, hemispheric chemical dominance, and chronic bronchitis emphysema.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-09-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator, and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger). This was assessed in patients with chronic bronchitis emphysema. The pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find the role of hemispheric dominance in the pathogenesis of chronic bronchitis emphysema. All the 15 patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. In patients with chronic bronchitis emphysema there was elevated digoxin synthesis, increased dolichol, and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate levels of RBC membrane in patients with chronic bronchitis emphysema. The same biochemical patterns were obtained in individuals with right hemispheric dominance. Endogenous digoxin by activating the calcineurin signal transduction pathway of T-cell can contribute to immune activation in chronic bronchitis emphysema. Increased free radical generation can also lead to immune activation. Endogenous synthesis of nicotine can contribute to the pathogenesis of the disease. Altered glycoconjugate metabolism and membranogenesis can lead to defective lysosomal stability contributing to the disease process by increased release of lysosomal proteases. The role of an endogenous digoxin and hemispheric dominance in the pathogenesis of chronic bronchitis emphysema and in the regulation of lung structure/function is discussed. The biochemical patterns obtained in chronic bronchitis emphysema is similar to those obtained in left

Controlling attention to nociceptive stimuli with working memory.

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Valéry Legrain

Full Text Available BACKGROUND: Because pain often signals the occurrence of potential tissue damage, a nociceptive stimulus has the capacity to involuntarily capture attention and take priority over other sensory inputs. Whether distraction by nociception actually occurs may depend upon the cognitive characteristics of the ongoing activities. The present study tested the role of working memory in controlling the attentional capture by nociception. METHODOLOGY AND PRINCIPAL FINDINGS: Participants performed visual discrimination and matching tasks in which visual targets were shortly preceded by a tactile distracter. The two tasks were chosen because of the different effects the involvement of working memory produces on performance, in order to dissociate the specific role of working memory in the control of attention from the effect of general resource demands. Occasionally (i.e. 17% of the trials, tactile distracters were replaced by a novel nociceptive stimulus in order to distract participants from the visual tasks. Indeed, in the control conditions (no working memory, reaction times to visual targets were increased when the target was preceded by a novel nociceptive distracter as compared to the target preceded by a frequent tactile distracter, suggesting attentional capture by the novel nociceptive stimulus. However, when the task required an active rehearsal of the visual target in working memory, the novel nociceptive stimulus no longer induced a lengthening of reaction times to visual targets, indicating a reduction of the distraction produced by the novel nociceptive stimulus. This effect was independent of the overall task demands. CONCLUSION AND SIGNIFICANCE: Loading working memory with pain-unrelated information may reduce the ability of nociceptive input to involuntarily capture attention, and shields cognitive processing from nociceptive distraction. An efficient control of attention over pain is best guaranteed by the ability to maintain active goal

Evidence for Enhanced Intestinal Absorption of Digoxin by P ...

African Journals Online (AJOL)

Purpose: To investigate the influence of macrolides as P-glycoprotein inhibitors on the level of intestinal ... The effective permeability of the drug was calculated after analyzing the ... associated with oral formulation factors such ... high performance liquid chromatography ..... pharmacokinetics of intravenous digoxin in.

Role of NHE1 in Nociception

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Jorge Elías Torres-López

2013-01-01

Full Text Available Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na+/H+ exchangers (NHEs are electroneutral Na+-dependent proteins that exchange extracellular Na+ for intracellular H+. To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn’s disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.

Lectins Labelled with Digoxin as a Novel Tool to Study Glycoconjugates

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Jerka Dumić

2002-01-01

Full Text Available In recent years it has become clear that carbohydrate portions of glycoconjugates are performing numerous vital physiological functions in higher organisms. However, since glycobiology is a relatively new science, and carbohydrate structures are highly complex, the continuous development of novel analytical techniques is necessary to support the process of understanding the intricate nature of glycoconjugate structure and function. The introduction of digoxin as a novel tag for labelling of lectins that are being used to analyse glycoconjugates in immunoassay-like techniques is described. Lectins labelled with digoxin have significant advantages over biotin- or digoxigenin-labelled lectins and will hopefully prove to be a useful addition to the repertoire of glycobiological tools.

Hypothalamic digoxin, hemispheric chemical dominance, and interstitial lung disease.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-10-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. This was assessed in patients with idiopathic pulmonary fibrosis and in individuals of differing hemispheric dominance to find out the role of hemispheric dominance in the pathogenesis of idiopathic pulmonary fibrosis. All 15 cases of interstitial lung disease were right-handed/left hemispheric dominant by the dichotic listening test. The isoprenoidal metabolites--digoxin, dolichol, and ubiquinone, RBC membrane Na(+)-K+ ATPase activity, serum magnesium, tyrosine/tryptophan catabolic patterns, free radical metabolism, glycoconjugate metabolism, and RBC membrane composition--were assessed in idiopathic pulmonary fibrosis as well as in individuals with differing hemispheric dominance. In patients with idiopathic pulmonary fibrosis there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in patients with idiopathic pulmonary fibrosis. Isoprenoid pathway dysfunction con tributes to the pathogenesis of idiopathic pulmonary fibrosis. The biochemical patterns obtained in interstitial lung disease are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. However, all the patients with interstitial lung disease were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Interstitial lung disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

Performance of radioimmunoassays for digoxin as evaluated by a group experiment

International Nuclear Information System (INIS)

Dwenger, A.; Friedel, R.; Trautschold, I.

1977-01-01

In order to gather informations on the performance of routinely employed test system for the radioimmunological determination of digoxin in serum a group experiment was set up in which 36 laboratories in the Federal Republic of Germany took part. They were asked to determine the digoxin content in 25 specimens including a recovery curve, sera with pathologic composition and known concentrations of digoxin, sera from a pharmacokinetic study and commercial control sera. This identity of the specimens was withheld from the participants. As far as accuracy and precision are concerned the results reported for a total of 54 assays were better than those obtained in group experiments on radioimmunological determination of hormones. Recovery ranged from 90% to 110% in 57%, from 80% to 120% in 85% of the assays. Reproducibility in the series expressed as coefficient of variation was better than 5% in 54%, better than 10% in 85% of the assays. Considerable differences were found for the cross-reactivities of antibodies with digitoxin and metabolites of spironolactone. Dysproteinemia seems to be an unsolved problem whereas moderate hemolysis and hyperlipemia did not lead to severe errors. Improvements, especially with respect to inter-laboratory variances can be expected mainly from a further standardization of standard preparations. (orig.) [de

Studying structurally-mechanical characteristics suppositories with amlodipine

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Fadi Al Zedan

2013-02-01

Full Text Available Rheological behaviour suppositories with amlodipine on lypofiles to a basis are studied and character of temperature effect on their structurally-mechanical properties is positioned. It is revealed that the temperature of carrying out of technological operations of homogenization and overflow suppositories 50-55ºС is optimum, providing necessary fluidity suppositories masses at hypodispersion in it reacting and aids.

Hypothalamic digoxin and hemispheric chemical dominance: relation to speech and language dysfunction.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-06-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. Since endogenous digoxin can regulate neurotransmitter transport and dolichols can modulate glycoconjugate synthesis important in synaptic connectivity, the pathway was assessed in patients with dyslexia, delayed recovery from global aphasia consequent to a dominant hemispheric thrombotic infarct, and developmental delay of speech milestone. The pathway was also studied in right hemispheric, left hemispheric, and bihemispheric dominance to find out the role of hemispheric dominance in the pathogenesis of speech disorders. The plasma/serum--activity of HMG CoA reductase, magnesium, digoxin, dolichol, ubiquinone--and tryptophan/tyrosine catabolic patterns, as well as RBC (Na+)-K+ ATPase activity, were measured in the above mentioned groups. The glycoconjugate metabolism and membrane composition was also studied. The study showed that in dyslexia, developmental delay of speech milestone, and delayed recovery from global aphasia there was an upregulated isoprenoidal pathway with increased digoxin and dolichol levels. The membrane (Na+)-K+ ATPase activity, serum magnesium and ubiquinone levels were low. The tryptophan catabolites were increased and the tyrosine catabolites including dopamine decreased in the serum contributing to a speech dysfunction. There was an increase in carbohydrate residues of glycoproteins, glycosaminoglycans, and glycolipids levels as well as an increased activity of GAG degrading enzymes and glyco hydrolases in the serum. The cholesterol:phospholipid ratio of RBC membrane increased and membrane glycoconjugates showed a decrease. All of these could contribute to altered synaptic inactivity in these disorders. The patterns correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance may play a role in the genesis of these disorders. Hemispheric chemical dominance has no correlation with handedness

Efficacy and safety of olmesartan medoxomil and hydrochlorothiazide compared with benazepril and amlodipine besylate.

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Kereiakes, Dean J; Neutel, Joel M; Punzi, Henry A; Xu, Jianbo; Lipka, Leslie J; Dubiel, Robert

2007-01-01

Most patients with stage 2 hypertension require two or more antihypertensive agents in order to achieve the BP goals recommended in current treatment guidelines. Accordingly, combinations of two drugs with different mechanisms of antihypertensive action are widely used. The aim of this randomized, double-blind, multicenter 12-week study was to compare the efficacy, safety, and tolerability of a combination of olmesartan medoxomil/hydrochlorothiazide (HCTZ) with that of benazepril plus amlodipine besylate in patients with stage 2 hypertension. Patients were eligible for randomization following a 3- to 4-week placebo run-in period if they had either (i) mean seated DBP>or=90 mm Hg butor=160 mm Hg but or=100 mm Hg butor=95 mm Hg and145 mm Hg andbenazepril (10 mg/day for 2 weeks; then 20 mg/day for 2 weeks; then benazepril 20 mg/day plus amlodipine besylate 5 mg/day for 4 weeks; then benazepril 20 mg/day plus amlodipine besylate 10 mg/day for 4 weeks). The primary endpoint was change from baseline in mean SBP at the end of week 12 (end of study). Secondary endpoints included DBP after completion of monotherapy and combination therapy at the end of weeks 4 and 12, SBP at the end of week 4, and percentage of patients attaining BP goals ofbenazepril plus amlodipine besylate (least square [LS] mean change: -32.5 vs -26.5 mm Hg, p=0.024; LS mean treatment difference -6.0 mm Hg; 95% CI -11.1, -0.8 mm Hg). The LS mean change for reduction in DBP approached statistical significance with olmesartan medoxomil/HCTZ compared with the benazepril-based regimen (p=0.056) at week 12 (end of study). BP reductions showed statistically significant differences between treatment groups favoring olmesartan medoxomil/HCTZ in both SBP and DBP at week 8. The percentage of patients achieving goal rates at the end of the study for olmesartan medoxomil/HCTZ and benazepril plus amlodipine besylate, respectively, were 66.3% versus 44.7% (p=0.006) forbenazepril plus amlodipine besylate 20/5 and 20

Therapeutic drug monitoring of digoxin in cardiac heart failure outpatients: comparisons of two analytical methods

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Isabel Cristina Medeiros Barros

2014-01-01

Full Text Available Objective: To compare two analytical techniques used in the determination of plasma digoxin (LC-MS/MS and immunoassay and to verify which one better answer the need of the clinical monitoring routine of patients with cardiac heart failure. Method: The clinical findings in 15 cardiac heart failure (CHF outpatients of the Cardiac Heart Service of the Goias Federal University Clinical Hospital were investigated. Blood samples of the patients were collected and analysed by Immunoassay and by Liquid Chromatography coupled to Mass Spectrometry (LC-MS/MS. Results: The results of the statistic test (Student p = 0,05 showed a significant difference between the analytical methods: immunoassay concentrations were higher than the concentrations determined by LCMS/ MS. The explanation may be because immunoassay method measures digoxin plus other metabolites and endogenous substances, while the LC-MS/MS method measures only the digoxin molecule. None of the patients, showed relevant clinical data suggestive of digitalis intoxication, even several drugs with potential interaction were associated with treatment. Conclusion: It was concluded, therefore, that LC-MS/MS me thod is safer, more selective and specific than immunoassay, being an option for therapeutic drug monitoring of digoxin, since the reference values would be obtain for digoxinemia by LC-MS/MS.

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC

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Fadi Kayali

2011-02-01

Full Text Available Fadi Kayali, Muhamad A Janjua, Damian A Laber, Donald Miller, Goetz H KloeckerUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY, USABackground: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC, with a response rate (RR of 10%. This study's hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP in NSCLC.Methods: Patients with progressive disease (PD after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group score from 0 to 2 and good organ function. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred.Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78, 14 were female, 17 had prior radiation (not involving the target lesions, 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were

Influence of the cardiac glycoside digoxin on cardiac troponin I, acid-base and electrolyte balance, and haematobiochemical profiles in healthy donkeys (Equus asinus).

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Tharwat, Mohamed; Al-Sobayil, Fahd

2014-03-12

The effect of digoxin administration on the serum concentration of the cardiac troponin I (cTnI) has not been reported to date in equidae. This study was therefore designed to evaluate the effect of digoxin on cardiac cell damage in donkeys (Equus asinus) as assessed by cTnI, acid-base and electrolyte balance and haematobiochemical profiles. Ten clinically healthy donkeys were given an IV infusion of digoxin at a dose of 14 μg/kg. Blood samples were collected from the donkeys up through 72 h post-injection. Three of the donkeys exhibited increased heart and respiratory rates post-injection. In the other seven animals, the heart and respiratory rates were lower 4 h post-injection. The serum digoxin concentration increased significantly at many time points after injection. The serum concentration of cTnI did not differ significantly between pre- and post-injection. An increase in blood pH was noted at 3 h after digoxin injection. There were also increases in PO2 and in oxygen saturation. Decreases in PCO2 at 2 to 48 h post-injection as well as a decrease in blood lactate at 4 h post-injection were observed. The serum concentration of glucose remained significantly elevated at all-time points after digoxin injection. It is concluded that administration of digoxin to healthy donkeys (14 μg/kg) did not result in elevations of serum cTnI concentration, signs of digoxin intoxication, ECG abnormalities and did not increase serum concentrations of blood urea nitrogen and creatinine.

Expression of nociceptive ligands in canine osteosarcoma.

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Shor, S; Fadl-Alla, B A; Pondenis, H C; Zhang, X; Wycislo, K L; Lezmi, S; Fan, T M

2015-01-01

Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities. Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment. Ten dogs with appendicular OS. Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies. Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples. Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

The Use of Digoxin in Patients With Worsening Chronic Heart Failure Reconsidering an Old Drug to Reduce Hospital Admissions

NARCIS (Netherlands)

Ambrosy, Andrew P.; Butler, Javed; Ahmed, Ali; Vaduganathan, Muthiah; van Veldhuisen, Dirk J.; Colucci, Wilson S.; Gheorghiade, Mihai

2014-01-01

Digoxin is the oldest cardiac drug still in contemporary use, yet its role in the management of patients with heart failure (HF) remains controversial. A purified cardiac glycoside derived from the foxglove plant, digoxin increases ejection fraction, augments cardiac output, and reduces pulmonary

Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice.

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Ikarashi, Nobutomo; Kagami, Mai; Kobayashi, Yasushi; Ishii, Makoto; Toda, Takahiro; Ochiai, Wataru; Sugiyama, Kiyoshi

2011-06-01

In humans, digoxin is mainly eliminated through the kidneys unchanged, and renal clearance represents approximately 70% of the total clearance. In this study, we used the mouse models to examine digoxin pharmacokinetics in polyuria induced by diabetes mellitus and lithium carbonate (Li(2)CO(3)) administration, including mechanistic evaluation of the contribution of glomerular filtration, tubular secretion, and tubular reabsorption. After digoxin administration to streptozotocin (STZ)-induced diabetic mice, digoxin CL/F increased to approximately 2.2 times that in normal mice. After treatment with Li(2)CO(3) (0.2%) for 10 days, the CL/F increased approximately 1.1 times for normal mice and 1.6 times for STZ mice. Creatinine clearance (CLcr) and the renal mRNA expression levels of mdr1a did not differ significantly between the normal, STZ, and Li(2)CO(3)-treated mice. The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li(2)CO(3)-treated mice increased approximately 7.3 times for normal mice and 2.3 times for STZ mice. These results suggest that the therapeutic effect of digoxin may be significantly reduced in the presence of polyuria either induced by diabetes mellitus or manifested as an adverse effect of Li(2)CO(3) in diabetic patients, along with increased urine volume.

The early and late effects of digoxin treatment on the sodium transport, sodium content and Na+K+- ATPase or erythrocytes.

Science.gov (United States)

Cumberbatch, M; Zareian, K; Davidson, C; Morgan, D B; Swaminathan, R

1981-01-01

1 Erythrocyte sodium content, sodium transport (ouabain sensitive sodium flux Eos, and ouabain sensitive efflux rate constant ERCos) sodium, potassium activated ouabain sensitive adenosine triphosphatase (Na+K+ATPase) and plasma digoxin were measured in patients during acute digitalisation and in patients who were on long-term digoxin treatment. 2 In the six patients who were studied during digitalisation, the ERCos and Na+K+ATPase activity decreased and erythrocyte sodium content increased during days 2-4 treatment, but there was no change in Eos. 3 In 39 patients on long term digoxin therapy (2-119 months) the erythrocyte sodium content was normal, but the erythrocyte Na+K+ATPase activity was higher than the control group. When the results from these 39 patients were divided according to the duration of treatment it was found that the erythrocyte sodium content was higher in patients treated for 2-4 months than in patients treated for longer periods and the erythrocyte Na+K+ATPase activity increased with duration of treatment. In eight patients (duration of treatment greater than 29 months) in whom ERCos and Eos were measured, ERCos and Eos were higher than the control group. 4 The results suggest that the effects of digoxin on erythrocytes which occur during acute digoxin treatment do not persist in the long term. 5 The possible explanation for the higher ERCos, Eos and Na+K+ATPase activity in patients treated with digoxin for more than 2 months is discussed. PMID:6268133

Determination of digoxin by enzyme immunoassay and radioimmunoassay

International Nuclear Information System (INIS)

Mueller, H.; Braeuer, H.; Foerster, G.; Reinhardt, M.

1978-01-01

The results of parallel determinations of digoxin in the sera of non selected patients (n=104) by enzyme immunoassay (EMIT.EIA) and radioimmunoassay (J-125 labeled RIA) were compared with each other. The determinations revealed considerably different concentrations; the values determined by EIA were statistical lower (for EIA 1,09+'0,99ng/ml, for RIA 1,34+'1,01ng/ml, p [de

Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

Science.gov (United States)

Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

2017-08-01

Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

Targeting Hypertension with Valsartan: Lessons Learned from the Valsartan/HCTZ Versus Amlodipine in Stage II Hypertensive Patients (VAST Trial

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Luis M Ruilope

2006-03-01

Full Text Available Many patients with hypertension, especially those at increased risk because of additional cardiovascular risk factors, require treatment with more than one antihypertensive agent to achieve target blood pressure (BP goals. Many different classes of antihypertensive agents are available: a renin-angiotensin-aldosterone system (RAAS blocker and a diuretic are widely used in combination.Here we report the results of the recently completed Valsartan/HCTZ versus Amlodipine in STage II hypertensive patients (VAST trial. In this 24-week study, patients with moderate hypertension and at least one other cardiovascular risk factor were treated with a combination of valsartan 160 mg and hydrochlorothiazide (HCTZ 12.5 or 25 mg once daily (o.d., or with amlodipine monotherapy (10 mg o.d.. Overall, valsartan plus HCTZ 25 mg reduced systolic BP significantly more than amlodipine monotherapy, and with fewer adverse events. In addition, combination therapy resulted in a trend towards more favourable outcomes with respect to pro-thrombotic and proinflammatory markers than amlodipine alone.

Targeting Hypertension with Valsartan: Lessons Learned from the Valsartan/HCTZ Versus Amlodipine in Stage II Hypertensive Patients (VAST Trial

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Luis M Ruilope

2006-03-01

Full Text Available Many patients with hypertension, especially those at increased risk because of additional cardiovascular risk factors, require treatment with more than one antihypertensive agent to achieve target blood pressure (BP goals. Many different classes of antihypertensive agents are available: a renin-angiotensin-aldosterone system (RAAS blocker and a diuretic are widely used in combination. Here we report the results of the recently completed Valsartan/HCTZ versus Amlodipine in STage II hypertensive patients (VAST trial. In this 24-week study, patients with moderate hypertension and at least one other cardiovascular risk factor were treated with a combination of valsartan 160 mg and hydrochlorothiazide (HCTZ 12.5 or 25 mg once daily (o.d., or with amlodipine monotherapy (10 mg o.d.. Overall, valsartan plus HCTZ 25 mg reduced systolic BP significantly more than amlodipine monotherapy, and with fewer adverse events. In addition, combination therapy resulted in a trend towards more favourable outcomes with respect to pro-thrombotic and pro-inflammatory markers than amlodipine alone.

Digoxin Downregulates NDRG1 and VEGF through the Inhibition of HIF-1α under Hypoxic Conditions in Human Lung Adenocarcinoma A549 Cells

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Dong Wei

2013-04-01

Full Text Available Digoxin, an inhibitor of Na+/K+ ATPase, has been used in the treatment of heart-related diseases (such as congestive heart failure and atrial arrhythmia for decades. Recently, it was reported that digoxin is also an effective HIF-1α inhibitor. We investigated whether digoxin could suppress tumor cell growth through HIF-1α in non-small cell lung cancer cells (A549 cells under hypoxic conditions. An MTT assay was used to measure cell viability. RT-PCR and western blotting were performed to analyze the mRNA and protein expression of VEGF, NDRG1, and HIF-1α. HIF-1α nuclear translocation was then determined by EMSA. Digoxin was found to inhibit the proliferation of A549 cells under hypoxic conditions. Our results showed that hypoxia led to the upregulation of VEGF, NDRG1, and HIF-1α both at the mRNA and protein levels. We also found that the hypoxia-induced overexpression of VEGF, NDRG1, and HIF-1α was suppressed by digoxin in a concentration-dependent manner. As expected, our EMSA results demonstrated that under hypoxic conditions HIF-1α nuclear translocation was also markedly reduced by digoxin in a concentration-dependent manner. Our results suggest that digoxin downregulated hypoxia-induced overexpression of VEGF and NDRG1 at the transcriptional level probably through the inhibition of HIF-1α synthesis in A549 cells.

Clinical Utility of Amlodipine/Valsartan Fixed-Dose Combination in the Management of Hypertension in Chinese Patients

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Wenbo He, MD

2017-02-01

Full Text Available Amlodipine/valsartan (Aml/Val single-pill combination (SPC therapy has been widely used and studied in clinical practice in recent years. This article reviews the Chinese and English literature on the clinical use of Aml/Val SPC therapy in Chinese hypertensive patients. According to five studies concerning the efficacy and safety of this treatment, Aml/Val SPC therapy was more efficacious than monotherapy with valsartan, amlodipine, or the nifedipine gastrointestinal therapeutic system. This treatment showed greater blood pressure-lowering effects, a higher blood pressure control rate, and a higher response rate. Aml/Val SPC treatment was well tolerated, with adverse event rates similar to those of monotherapy with valsartan or amlodipine and significantly rarer adverse events compared with the nifedipine gastrointestinal therapeutic system. Aml/Val SPC is a highly efficacious and well-tolerated antihypertensive treatment in Chinese hypertensive patients.

[Blood pressure lowering efficacy of telmisartan and amlodipine taking on the morning or at bedtime: ABPM results].

Science.gov (United States)

Peng, Gui-cheng; Wang, Yi-fang; Xiao, Yong; Chen, Jian-fu; Yang, Yu; Ye, Yu-liang; Sai, Shuang-qiao; Huang, Jin-xiang

2013-06-01

To observe the blood lowering effect of telmisartan and amlodipine taking on the morning or at bedtime in hypertensive patients. A total of 108 individuals with hypertension (grade 2 or above) were randomized to receive telmisartan and amlodipine in one of the following four therapeutic schemes: Group A (26 cases): both medications taken on the morning; Group B (28 cases): both medication taken at bedtime; Group C (27 cases): telmisartan on the morning and amlodipine at bedtime; or Group D (27 cases): amlodipine on the morning and telmisartan at bedtime. ABPM was performed before and after 8 weeks treatment. BP was significantly reduced in 4 groups and the value of 24 hours SBP/DBP decline for each group after treatment was 29.94/16.32, 31.37/18.35, 29.49/17.30 and 25.80/15.51 mm Hg (1 mm Hg = 0.133 kPa) respectively (P 0.05). The night-time BP decline and the distributive difference of dipper, non-dipper, extreme dipper and reverse dipper pattern were similar among groups at both baseline and after various treatment regimens (all P > 0.05) . Morning blood pressure surge (MBPS) after treatment in group B declined more significantly than other groups (P < 0.05). Telmisartan/amlodipine administered either on the morning or at bedtime can effectively reduce blood pressure. The efficacy of BP lowering is independent of the drug taking time. There is a trend both in better BP lowering and less BP variability when two medications are administered at bedtime.

Changing characteristics of the TDx digoxin II assay in detecting bufadienolides in a traditional Chinese medicine: for better or worse?

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Panesar, Nirmal S; Chan, Kam W; Law, Lap K

2005-10-01

In 1992, apparent digoxin concentrations determined by the Abbott TDx II assay 5 hours after the ingestion of 10 pills of traditional Chinese medicine containing toad secretions (chan su) by 7 volunteers, yielded results that were equimolar to bufalin measured by 2 in-house bufalin radioimmunoassays (RIAs). Recently, a 17-year-old Chinese female unintentionally took 100 (instead of 10) of these pills for a sore throat but suffered no ill effects. The blood bufalin concentration at 3 hours by 1 of the 2 RIAs was 10.93 nmol/L, which was commensurate with the dose. However, the apparent digoxin measured by a TDx II assay produced in 2004 was only 3.08 nmol/L, which probably reflects the change in the specificity of the polyclonal digoxin antisera used in the assay over the years. In 1989, the TDx assay was commended for its ability to detect poisoning from plant and animal cardenolides, a property that seems to be waning and, thus, bad news for those wishing to use the assay to detect alternative cardenolides. But, on the other hand, it possibly eliminates the "specter" of digoxin-like immunoreactive substance (DLIS) that has afflicted some digoxin assays, which can only be good news.

4-Aminopyridine (fampridine) effectively treats amlodipine poisoning: A case report

NARCIS (Netherlands)

Wilffert, B.; Boskma, R.J.; Van Der Voort, P.H.J.; Uges, D.R.A.; Van Roon, E.N.; Brouwers, J.R.B.J.

2007-01-01

A case of a serious poisoning with the calcium entry blocker amlodipine is described, which was treated effectively with 4-aminopyridine. Calcium is suggested as general treatment of poisoning with calcium entry blockers in many guidelines. The use of intravenous 4-aminopyridine is theoretically

4-Aminopyridine (fampridine) effectively treats amlodipine poisoning : a case report

NARCIS (Netherlands)

Wilffert, B.; Boskma, R. J.; van der Voort, P. H. J.; Uges, D. R. A.; van Roon, E. N.; Brouwers, J. R. B. J.

2007-01-01

A case of a serious poisoning with the calcium entry blocker amlodipine is described, which was treated effectively with 4-aminopyridine. Calcium is suggested as general treatment of poisoning with calcium entry blockers in many guidelines. The use of intravenous 4-aminopyridine is theoretically

Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure.

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Katz, Adriana; Tal, Daniel M; Heller, Dan; Habeck, Michael; Ben Zeev, Efrat; Rabah, Bilal; Bar Kana, Yaniv; Marcovich, Arie L; Karlish, Steven J D

2015-11-03

The ciliary epithelium in the eye consists of pigmented epithelial cells that express the α1β1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the α2β3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for α2β3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R-NH2 substituents and identified derivatives with significant selectivity for human α2β1 over α1β1 (up to 7.5-fold). When applied topically, the most α2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the β1 subunit, Gln84, suggesting a role for β in digoxin binding. Gln84 in β1 is replaced by Val88 in β3. Assuming that alkyl substituents might interact with β3Val88, we synthesized perhydro-1,4-oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for α2β3 over α1β1 (22-33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that α2β3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy.

Atorvastatin calcium plus amlodipine for the treatment of hypertension.

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Delgado-Montero, Antonia; Zamorano, Jose L

2012-12-01

Hypertension (HTN) and dyslipemia (DYL) are two of the major modifiable cardiovascular (CV) risk factors, determinants in the development of cerebrovascular and coronary heart disease (CHD). Many patients have both risk factors which increase their total CV risk compared with patients with only one risk factor. Treatment guideline recommendations are poorly implemented in real practice, in part due to numerous and complicated drug regimes which hamper patient´s adherence. In this article the authors describe the first combined fixed-dose pill of an antihypertensive and a lipid-lowering agent, the single-pill combination of amlodipine besylate and atorvastatin calcium (SPAA). They summarize the pharmacokinetic and pharmacodynamic properties of both compounds and the main randomized clinical studies, as well as real-world observational studies, made with the new combined formulation. The use of the single-pill amlodipine and atorvastatin is an adequate option for the clinician to treat hypertensive patients with DYL or high CV risk burden, with proven efficacy, tolerability, cost-effectiveness, and the advantage of improving patient treatment compliance.

Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

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Nesreen E.M. Mohammed

2016-11-01

Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

Amlodipine and valsartan as components of a rational and effective fixed-dose combination

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Bernard Waeber

2009-03-01

Full Text Available Bernard Waeber1, Luis M Ruilope21Division of Clinical Pathophysiology, University Hospital, Faculty of Biology and Medicine, University of Lausanne, Switzerland; 2Hypertension Unit, Hospital 12 de Octubre, Madrid, SpainAbstract: Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists and blockers of the renin-angiotensin system are widely used today to initiate antihypertensive therapy but, when given as monotherapy, do not suffice in most patients to normalize blood pressure. Combining the two types of agents considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. This is exemplified by the experience accumulated with the recently developed fixed dose combination containing the AT1-receptor blocker valsartan (160 mg and the dihydropyridine amlodipine (5 or 10 mg. In a randomized trial, an 8-week treatment normalized blood pressure (<140/90 mmHg within 8 weeks in a large fraction of hypertensive patients (78.4% and 85.2% using the 5/160 [n = 371] and 10/160 mg [n = 377] dosage, respectively. Like all AT1-receptor blockers valsartan has a placebo-like tolerability. Valsartan prevents to a large extent the occurrence amlodipine-induced peripheral edema. Both amlodipine and valsartan have beneficial effects on cardiovascular morbidity and mortality, as well as protective effects on renal function. The co-administration of these two agents is therefore very attractive, as it enables a rapid and sustained blood pressure control in hypertensive patients. The availability of a fixed-dose combination based on amlodipine and valsartan is expected therefore to facilitate the management of hypertension, to improve long-term adherence with antihypertensive therapy and, ultimately, to have a positive impact on cardiovascular and renal outcomes.Keywords: antihypertensive therapy, fixed-dose combination, calcium antagonists

Beneficial effect of low dose Amlodipine vs Nifedipine on serum cholesterol profile of rabbits receiving standard diet.

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Bavane DS, Rajesh CS, Gurudatta Moharir, Bharatha Ambadasu

2013-01-01

Full Text Available To investigate the effect of low dose amlodipine v/s nifedipine on serum cholesterol profile of rabbits receiving standard diet. Methods: Fourty Newzealand rabbits were selected for the study. Their cholesterol profile was estimated at the beginning of the study. Rabbits were grouped into 4 groups receiving standard diet (control group, standard diet + vehicle propylene glycol, standard diet + nifedipine dissolved in propylene glycol and standard diet + amlodipine dissolved in propylene glycol. Along with standard diet they were treated with respective drugs for ten weeks. At the end of ten weeks serum cholesterol profile was estimated. Results: The cholesterol profile was estimated at the beginning and at the end of ten weeks. Total cholesterol in the amlodipine group decreased from 97±4.06 mg/dl to 90±4.2 mg/dl and HDL-Cholesterol increased from 32.01±4.40 mg/dl to 37±4.60 mg/dl after 10 week treatment but these changes were not significant. LDL cholesterol decreased significantly in rabbits with low dose of amlodipine from 55.42±3.32 mg/dl to 32.40±3.22 mg/dl and. In the nifedipine group there was a slight increase in total cholesterol from 102.49±5.16 mg/dl to 106±5.39 mg/dl, HDL cholesterol from 34.10±2.80 to 35.16±2.82 mg/dl and LDL cholesterol also increased from 56.20±2.20 mg/dl to 59.00±2.20 mg/dl after 10 week treatment. Conclusion: The study shows amlodipine produces favorable alterations in serum cholesterol profile

Successful use of digoxin-specific immune Fab in the treatment of severe Nerium oleander toxicosis in a dog.

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Pao-Franco, Amaris; Hammond, Tara N; Weatherton, Linda K; DeClementi, Camille; Forney, Scott D

2017-09-01

To describe a case in which digoxin-specific immune Fab was used successfully in a dog with severe oleander toxicosis secondary to ingesting plant material. A 6-year-old intact female Rhodesian Ridgeback mixed breed dog was presented for severe oleander toxicosis and was refractory to all antiarrhythmic therapies and supportive care. Digoxin-specific immune Fab was successful in treating this dog. The dog recovered but suffered ischemic injuries, the long-term effects of which are unknown. This report describes the successful use of digoxin-specific immune Fab in the treatment of oleander toxicosis in a dog, which has not previously been published in veterinary literature. Oleander poisoning can be associated with permanent cardiac arrhythmias due to the ischemic damage. © Veterinary Emergency and Critical Care Society 2017.

The significance of amlodipine on autonomic nervous system adjustment (ANSA method: A new approach in the treatment of hypertension

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Milovanović Branislav

2009-01-01

Full Text Available Introduction. Cardiovascular autonomic modulation is altered in patients with essential hypertension. Objective To evaluate acute and long-term effects of amlodipine on cardiovascular autonomic function and haemodynamic status in patients with mild essential hypertension. Methods. Ninety patients (43 male, mean age 52.12 ±10.7 years with mild hypertension were tested before, 30 minutes after the first 5 mg oral dose of amlodipine and three weeks after monotherapy with amlodipine. A comprehensive study protocol was done including finger blood pressure variability (BPV and heart rate variability (HRV beat-to-beat analysis with impedance cardiography, ECG with software short-term HRV and nonlinear analysis, 24-hour Holter ECG monitoring with QT and HRV analysis, 24-hour blood pressure (BP monitoring with systolic and diastolic BPV analysis, cardiovascular autonomic reflex tests, cold pressure test, mental stress test. The patients were also divided into sympathetic and parasympathetic groups, depending on predominance in short time spectral analysis of sympathovagal balance according to low frequency and high frequency values. Results. We confirmed a significant systolic and diastolic BP reduction, and a reduction of pulse pressure during day, night and early morning hours. The reduction of supraventricular and ventricular ectopic beats during the night was also achieved with therapy, but without statistical significance. The increment of sympathetic activity in early phase of amlodipine therapy was without statistical significance and persistence of sympathetic predominance after a few weeks of therapy detected based on the results of short-term spectral HRV analysis. All time domain parameters of long-term HRV analysis were decreased and low frequency amongst spectral parameters. Amlodipne reduced baroreflex sensitivity after three weeks of therapy, but increased it immediately after the administration of the first dose. Conclusion. The results

Simultaneous determination of telmisartan and amlodipine in dog plasma by LC-MS-MS.

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Wang, Baolian; Sheng, Li; Li, Yan

2015-01-01

A simple, rapid and sensitive method was established for the simultaneous determination of telmisartan and amlodipine in dog plasma by a HPLC-MS-MS analysis. The plasma sample preparation was a simple deproteinization by the addition of three volumes of methanol/acetonitrile mixture followed by centrifugation. The analytes and internal standard diphenhydramine were separated on a Zorbax SB-C18 column with a mobile phase of acetonitrile : water (45 : 55, v/v) at a flow rate of 0.2 mL/min with an operating temperature of 25°C. Detection was carried out by electrospray ionization in positive-ion multiple reaction monitoring mode. The calibration plots in dog plasma were linear over the ranges of 0.5-2,000 ng/mL for telmisartan and 0.5-500 ng/mL for amlodipine. The lower limit of quantification was 0.5 ng/mL for two analytes. The intra- and interday precisions (RSD%) were within 9.0%. The average recoveries of analytes were >85.0%. The method was successfully applied to the pharmacokinetic study of the two compounds after oral administration of telmisartan-amlodipine combination preparation to dogs. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Is Time an Important Problem in Management of Hypertension and Hypercholesterolemia by Using an Amlodipine-Atorvastatin Single Pill Combination?

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Zeng, Rui; Wang, Mian; Zhang, Li

2016-07-26

BACKGROUND Is the timing of dosing for amlodipine and atorvastatin important with regard to therapeutic efficacy? To answer this question, we designed an outpatient, practice-based, case-control study lasting 8 weeks. MATERIAL AND METHODS Two hundred patients were divided into 2 groups: in Group I, patients were provided with a single pill containing amlodipine/atorvastatin (5/20 mg) to be taken each night at 10 pm, and in Group II, patients were taking amlodipine (5 mg) and atorvastatin (20 mg) each morning at 7 am. RESULTS Our results indicated no obvious difference in blood pressure control between the 2 groups. Taking amlodipine at night not only lowered blood pressure, but it also provided better control during the peak blood pressure in the morning. Hypercholesterolemia control in the 2 groups was also not significantly different, taking atorvastatin in the morning was as effective as dosing at night in patients with hypercholesterolemia. While the carotid IMT, hs-CRP, and LVMI were significantly lower after treatment, no differences were found between the 2 groups. Although no obvious difference was found in adverse drug reactions between the 2 groups, compliance was much better in the single-pill group than in patients taking the 2 medications separately. CONCLUSIONS In conclusion, single-pill amlodipine-atorvastatin taken at night can lower blood pressure and reduce the morning peak blood pressure levels the next day. Additionally, this dosing method could improve patient adherence to the therapy.

Hypothalamic digoxin and hemispheric chemical dominance--relation to the pathogenesis of senile osteoporosis, degenerative osteoarthritis, and spondylosis.

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Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-03-01

The isoprenoid pathway produces three key metabolites: i) digoxin (a membrane sodium-potassium ATPase inhibitor which can regulate intracellular calcium/magnesium ratios), ii) dolichol (which regulates N-glycosylation of proteins), and iii) ubiquinone (a free radical scavenger), all of which are important in bone and joint metabolism. The pathway was assessed in senile osteoporosis, spondylosis, and osteoarthritis. Digoxin could possibly play a role in the genesis of cerebral dominance because it can regulate multiple neurotransmitter systems. The pathway was also assessed in individuals of differing hemispheric dominance for comparison and to find out the role of cerebral dominance in the pathogenesis of these diseases. The plasma/serum-activity of HMG CoA reductase, magnesium, digoxin, dolichol, ubiquinone, and tryptophan/tyrosine catabolic patterns, as well as RBC Na(+)-K+ ATPase activity, were measured in the above mentioned groups. The glycoconjugate metabolism, free radical metabolism, and membrane composition were also studied. The pathway was upregulated with increased digoxin synthesis in patients with spondylosis and osteoarthritis. In this group of patients, the glycoconjugate levels and dolichol levels were increased and lysosomal stability reduced. The ubiquinone levels were low and free radicals increased in spondylosis and osteoarthritis. On the other hand, in senile osteoporosis, the isoprenoid pathway was downregulated and digoxin synthesis reduced. The glycoconjugate and dolichol levels were low and lysosomal stability increased. The ubiquinone levels were increased and free radical production increased in senile osteoporosis. The significance of these changes in the pathogenesis of osteoarthritis, spondylosis, and osteoporosis is discussed. The hyperdigoxinemic state is seen in osteoarthritis and spondylosis and in right hemispheric dominance. The hypodigoxinemic state is seen in left hemispheric dominance and senile osteoporosis. Hemispheric

Efficacy and duration of benazepril plus amlodipine or hydrochlorothiazide on 24-hour ambulatory systolic blood pressure control.

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Jamerson, Kenneth A; Devereux, Richard; Bakris, George L; Dahlöf, Björn; Pitt, Bertram; Velazquez, Eric J; Weir, Matthew; Kelly, Roxzana Y; Hua, Tsushung A; Hester, Allen; Weber, Michael A

2011-02-01

The combination of benazepril plus amlodipine was shown to be more effective than benazepril plus hydrochlorothiazide in reducing cardiovascular events in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. There was a small difference in clinic systolic blood pressure between the treatment arms favoring benazepril plus amlodipine. Ambulatory blood pressure monitoring provides a more rigorous estimate of blood pressure effects. A subset of 573 subjects underwent ambulatory blood pressure monitoring during year 2. Readings were obtained every 20 minutes during a 24-hour period. Between-treatment differences (benazepril plus amlodipine versus benazepril plus hydrochlorothiazide) in mean values were analyzed using ANOVA. Treatment comparisons with respect to categorical variables were made using Pearson's χ². At year 2, the treatment groups did not differ significantly in 24-hour mean daytime or nighttime blood pressures (values of 123.9, 125.9, and 118.1 mm Hg for benazepril plus amlodipine group versus 122.3, 124.1, and 116.9 for the benazepril plus hydrochlorothiazide group), with mean between-group differences of 1.6, 1.8, and 1.2 mm Hg, respectively. Blood pressure control rates (24-hour mean systolic blood pressure <130 mm Hg on ambulatory blood pressure monitoring) were greater than 80% in both groups. Nighttime systolic blood pressure provided additional risk prediction after adjusting for the effects of drugs. The 24-hour blood pressure control was similar in both treatment arms, supporting the interpretation that the difference in cardiovascular outcomes favoring a renin angiotensin system blocker combined with amlodipine rather than hydrochlorothiazide shown in the ACCOMPLISH trial was not caused by differences in blood pressure, but instead intrinsic properties (metabolic or hemodynamic) of the combination therapies.

21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions

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Rocha, Sayonarah C.; Pessoa, Marco T. C.; Neves, Luiza D. R.; Alves, Silmara L. G.; Silva, Luciana M.; Santos, Herica L.; Oliveira, Soraya M. F.; Taranto, Alex G.; Comar, Moacyr; Gomes, Isabella V.; Santos, Fabio V.; Paixão, Natasha; Quintas, Luis E. M.; Noël, François; Pereira, Antonio F.; Tessis, Ana C. S. C.; Gomes, Natalia L. S.; Moreira, Otacilio C.; Rincon-Heredia, Ruth; Varotti, Fernando P.; Blanco, Gustavo; Villar, Jose A. F. P.; Contreras, Rubén G.; Barbosa, Leandro A.

2014-01-01

Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions. PMID:25290152

Reduction of cerebral injury in stroke-prone spontaneously hypertensive rats by amlodipine

NARCIS (Netherlands)

Blezer, E.L.A.; Nicolaij, K.; Goldschmeding, R.C.; Koomans, H.A.; Joles, Jaap

2002-01-01

Dihydropyridine Ca2+ channel antagonists, initiated together with high salt intake, prevent the development of hypertension and subsequent cerebral damage in stroke-prone spontaneously hypertensive rats (SHRSP). We hypothesized that the dihydropyridine Ca2+ channel antagonist amlodipine

Plasma digoxin concentrations and urinary excretion during a 'simpler' regimen of infant digitalization.

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Savage, M O; Hibble, A G; Pickering, D

1975-01-01

We have measured the plasma concentrations in sick neonates and infants being administered digoxin by a safer regimen. In the presence of normal renal function the plasma concentrations appear to be satisfactory. PMID:1103751

Therapeutic drug monitoring of amlodipine and the Z-FHL/HHL ratio ...

African Journals Online (AJOL)

Globally, high blood pressure (BP) is the leading single risk factor for ... concentrations and clinical effect or toxicity and those with a narrow therapeutic ..... The pharmacokinetics of amlodipine in healthy volunteers after. 120 ... revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS).

Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats.

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Nascimento, G C; Bariotto-Dos-Santos, K; Leite-Panissi, C R A; Del-Bel, E A; Bortolanza, M

2018-04-02

Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation. Further, the effect of L-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by L-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non-lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. L-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of L-DOPA-induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition.

Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

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Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, Li; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

2014-01-01

Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na+, and T-type Ca2+ channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron. PMID:25168672

Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure

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Monica Doménech

2010-04-01

Full Text Available Monica Doménech, Antonio CocaHypertension Unit, Department of Internal Medicine, Institute of Internal Medicine and Dermatology, Hospital Clinic (IDIBAPS, University of Barcelona, SpainAbstract: Hypertension is one of the main risk factors for the development of cardiovascular diseases and the search for new therapeutic strategies aimed at optimizing its control remains an ongoing research and clinical challenge. In recent years, there has been a marked increase in the use of combinations of antihypertensive drugs with complementary mechanisms of action, with the aims of reducing blood pressure levels more rapidly and vigorously than strategies employing monotherapy and improving treatment compliance and adhesion. Therefore, as recommended by the 2009 reappraisal of the European Society of Hypertension/European Society of Cardiology Guidelines, the use of a triple combination that combines a calcium channel blocker, an angiotensin II receptor blocker and a thiazide diuretic seems a reasonable and efficacious combination for the management of hypertensive patients with moderate, high or very high risk. This article reviews the clinical trials carried out with the fixed combination of amlodipine/valsartan/hydrochlorothiazide at the doses recommended for each drug in monotherapy. The data show that this combination achieved greater reductions in mean sitting diastolic and systolic blood pressure than amlodipine, valsartan or hydrochlorothiazide in monotherapy, with favorable pharmacodynamic and pharmacokinetic profiles. The triple combination at high single doses should be used with caution in elderly patients and those with renal or liver failure. Although the tolerability and safety of the triple combination are good, the mostfrequently reported adverse effects were peripheral edema, headache and dizziness. Analytical alterations were consistent with the already-known biochemical effects of amlodipine, valsartan or hydrochlorothiazide in

A novel method for radioimmunoassay and its application to the assay of digoxin

International Nuclear Information System (INIS)

Lader, S.R.

1977-01-01

A novel radioimmunoassay method has been developed for digoxin which eliminates the need for centrifugation while retaining a short incubation time at ambient temperature. The apparatus used consists of a plastic reaction chamber containing a pad of absorbent material impregnated with solid phase antibody. A mixture of tracer and standard (or tracer and sample) is pipetted onto the antibody-containing pad and at the end of the thirty minute incubation period radioactivity remaining unbound to antibody is drawn through the pad into an absorbent filter by capillary attraction. The specificity, sensitivity, precision and accuracy of the method are described. Clinical evaluation of the method has been carried out in two laboratories in the United Kingdom and four in the United States of America. The consistency of performance of the new digoxin method as judged by precision and accuracy were quite striking compared with the wide variation in performance of routine in-house methods. Thus, results for between assay reproducibility show that C.V.'s for the novel method ranged from 9.6% to 15.5% while those for the routine assays ranged from 7% to 27,8%. The recovery of digoxin added to serum varied from 85% to 117% for the new method and from 88% to 164% with in-house methods. In a total of 640 clinical samples the results compared well with those obtained with established in-house procedures. (orig.) [de

Comparative biology of pain: What invertebrates can tell us about how nociception works.

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Burrell, Brian D

2017-04-01

The inability to adequately treat chronic pain is a worldwide health care crisis. Pain has both an emotional and a sensory component, and this latter component, nociception, refers specifically to the detection of damaging or potentially damaging stimuli. Nociception represents a critical interaction between an animal and its environment and exhibits considerable evolutionary conservation across species. Using comparative approaches to understand the basic biology of nociception could promote the development of novel therapeutic strategies to treat pain, and studies of nociception in invertebrates can provide especially useful insights toward this goal. Both vertebrates and invertebrates exhibit segregated sensory pathways for nociceptive and nonnociceptive information, injury-induced sensitization to nociceptive and nonnociceptive stimuli, and even similar antinociceptive modulatory processes. In a number of invertebrate species, the central nervous system is understood in considerable detail, and it is often possible to record from and/or manipulate single identifiable neurons through either molecular genetic or physiological approaches. Invertebrates also provide an opportunity to study nociception in an ethologically relevant context that can provide novel insights into the nature of how injury-inducing stimuli produce persistent changes in behavior. Despite these advantages, invertebrates have been underutilized in nociception research. In this review, findings from invertebrate nociception studies are summarized, and proposals for how research using invertebrates can address questions about the fundamental mechanisms of nociception are presented. Copyright © 2017 the American Physiological Society.

Effects of hypertension and ovariectomy on rat hepatocytes. Are amlodipine and lacidipine protective? (A stereological and histological study).

Science.gov (United States)

Dursun, Hakan; Albayrak, Fatih; Uyanik, Abdullah; Keleş, Nuri Osman; Beyzagül, Polat; Bayram, Ednan; Halici, Zekai; Altunkaynak, Zuhal Berrin; Süleyman, Halis; Okçu, Nihat; Ünal, Bünyamin

2010-12-01

Calcium channel blockers are increasingly used for the treatment of hypertension. Menopause and hypertension are both important risk factors for liver damage and several other circulatory abnormalities. The aim of this study was to determine the effects of amlodipine and lacidipine in an ovariectomy-induced postmenopausal period model and a deoxycorticosterone acetate-salt-induced hypertensive model in rats. In this study, animals were divided into six groups as follows: control (Group 1), hypertension (Group 2), ovariectomy (Group 3), ovariectomy and hypertension (Group 4), ovariectomy, hypertension and amlodipine-treated (Group 5), and ovariectomy, hypertension and lacidipine-treated (Group 6). At the end of the experiment, the livers were removed and tissue samples were histologically and stereologically examined. The numerical densities of the hepatocytes according to group were 0.000422, 0.00329, 0.000272, 0.00259, 0.00374 and 0.000346 μm3, respectively. Significant differences were found between values of all groups (phypertension in Groups 5 and 6. Our experimental results show that both hypertension and the postmenopausal period have negative effects on the number of hepatocytes and histological structure of the liver. Both amlodipine and lacidipine appear to ameliorate the hypertension and/or postmenopausal period-related decrease in hepatocyte number. We thus suggest that lacidipine and particularly amlodipine have important protective and recovering effects on the liver.

[Successful treatment of fetal supraventricular tachycardia with a combination of digoxin and amiodarone].

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Hajdú, J; Szabó, I; Német, J

1996-10-06

The supraventricular tachycardia is a life threatening state in the intrauterine life. It can cause non-immune hydrops fetalis, intrauterine death or complications during the delivery. The unexplained tachycardia can cause fetal distress and premature delivery. Usually the digoxin is the first drug of choice for transplacental cardioversion. If digitalisation does not achieve cardioversion, the second line antiarrhythmic drugs should be instituted. Amiodarone has been suggested as a therapeutic alternative after failure of digoxin-verapamil combination. We give a drug in standard therapeutic doses for four-five days and after it we determine whether it is effective or not. We should determine the newer therapy or termination of pregnancy. The transplacental administration of amiodarone may be dangerous because of fetal cretinism. Our case is the first in Hungary-in our best knowledge- and we suggest the amiodarone for transplacental therapy.

Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma.

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Kurup, Ravi Kumar; Kurup, Paramesware Achutha

2003-12-01

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with

Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

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Wang Ying-Wei

2010-01-01

Full Text Available Abstract Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist and parecoxib (a selective cyclooxygenase-2 inhibitor on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity, while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.

Hypothalamic digoxin and hemispheric chemical dominance: relation to alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration.

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Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-08-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin (modulate tryptophan/tyrosine transport), dolichol (important in N -glycosylation of proteins), and ubiquinone (free radical scavenger). It was considered pertinent to assess the pathway in alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Since endogenous digoxin can regulate neurotransmitter transport, the pathway was also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. In the patient group there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites as reduced endogenous morphine synthesis from tyrosine. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. The same patterns were obtained in individuals with right hemispheric chemical dominance. Alcoholic cirrhosis, alcoholic addiction, and acquired hepatocerebral degeneration are associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to NMDA excitotoxicity and altered connective tissue/lipid metabolism important in its pathogenesis. Endogenous morphine deficiency plays a role in alcoholic addiction. Alcoholic cirrhosis, addiction, and acquired hepato -cerebral degeneration occur in right hemispheric chemically dominant individuals. Ninety percent of the patients with alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration were right-handed and left hemispheric dominant by the dichotic listening test. However, their biochemical patterns were similar to those obtained in right hemispheric chemical dominance. Hemispheric chemical dominance is a different entity and has no correlation

Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization

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Patel, Atit A.

2018-01-01

ABSTRACT Diabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi-expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity. PMID:29752280

p-Cymene reduces orofacial nociceptive response in mice

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Michele F. Santana

2011-12-01

Full Text Available This study investigated the possible antinociceptive effect of p-cymene in different tests of orofacial nociception. The animals (mice were pretreated (i.p. with p-cymene (25, 50, 100 mg/kg, morphine (5 mg/kg, or vehicle (0.2% Tween 80+saline, and were then subsequently administered, subcutaneously into their upper lip: formalin, capsaicin, and glutamate. The nociceptive behavior response was characterized by the time in s that the mice remained rubbing the orofacial region, for a period of 40 min in the formalin test (first phase, 0-6 min; and second phase, 21-40 min, and for 42 and 15 min in the capsaicin and glutamate tests, respectively. To verify the possible opioid involvement in the antinociceptive effects, naloxone (i.p. was administered into the mice 15 min prior to the pretreatment with p-cymene (100 mg/kg. Finally, whether or not the p-cymene evoked any change in motor performance in the Rota-rod test was evaluated. The results showed that the treatment with p-cymene, at all doses, reduced (p<0.001 the nociceptive behavior in all nociception tests. The antinociceptive effect of p-cymene was antagonized by naloxone (1.5 mg/kg. Additionally, mice treated with p-cymene did not show any change in motor performance. In conclusion, p-cymene attenuated orofacial nociception, suggesting an involvement of the opioid system in this effect. Thus, p-cymene might represent an important biomolecule for management and/or treatment of orofacial pain.

Effects of haemolysis, urea and bilirubin on the precision of digoxin and insulin radioimmunoassays

International Nuclear Information System (INIS)

Dwenger, A.; Trautschold, I.

1982-01-01

The influence of haemolysis, uraemia and hyperbilirubinaemia on the radioimmunoassay for both digoxin and insulin has been investigated for five separation techniques (dextran/charcoal; coated tube; polyethyleneglycol 4000; sodium sulphite; double antibody). Recoveries, and intra- and interassay precision were calculated. It was demonstrated that even in serum samples with a rather high degree of haemolysis (haemoglobin up to 50 g/l) digoxin can be measured by using each of the five separation techniques without any significant interference. Visible haemolysis (haemoglobin above 200 mg/l) leads either to disturbance or to a complete failure of insulin radioimmunoassays with all separation techniques. This effect can be largely neutralized, and precision improved, by using N-ethyl-maleimide. With the exception of the coated tube separation technique the intraassay precision has a CV of [de

Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers

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Oh M

2017-12-01

Full Text Available Minkyung Oh,1,2,* Sung-Eun Park,3,* Jong-Lyul Ghim,1–3 Young-Kyung Choi,1 Eon-Jeong Shim,1–3 Jae-Gook Shin,1–3 Eun-Young Kim1–3 1Department of Pharmacology, 2PharmacoGenomics Research Center, Inje University College of Medicine, Busan, 3Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea *These authors contributed equally to this work Objective: This study compared the pharmacokinetic (PK and safety profiles of a fixed-dose combination (FDC formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.Materials and methods: This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration–time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.Results: The geometric mean ratios and 90% CIs for the maximum plasma concentration (Cmax and area under the curve from time zero to the last sampling time (AUCt were 0.8782 (0.8167–0.9444 and 0.9662 (0.9210–1.0136 for telmisartan and 1.0069 (0.9723–1.0427 and 1.0324 (0.9969–1.0690 for S-amlodipine, respectively. A total of 36 adverse events (AEs were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.Conclusion: For both telmisartan and S-amlodipine, the Cmax and AUCt 90% CIs

Amlodipine and the Successful Management of Post-Electroconvulsive Therapy Agitation.

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Shahriari, Ali; Khooshideh, Maryam; Sheikh, Mahdi

2016-01-01

Electroconvulsive therapy (ECT) is a highly effective nonpharmacologic treatment for the management of depression and some other psychiatric disorders. Post-ECT agitation occurs in up to 12% of ECT treatments and is characterized by motor restlessness, irritability, disorientation, and panic-like behaviors. The severity of post-ECT agitation ranges from mild and self-limited to serious and severe forms requiring prompt medical intervention to protect the patient and the medical staff. In severe agitation medical management may be necessary which consists of using sedative agents, either benzodiazepines or propofol. The side-effects of these sedative agents, especially in the elderly population, necessitate finding ways that could help the prevention of the occurrence of agitation after ECT treatments. We report a 68-year-old female with major depression who was referred for ECT. She experienced severe post-ECT agitation requiring medical intervention after all ECT treatments. Administering of oral amlodipine (5 mg) one hour before ECT treatment successfully prevented the occurrence of post-ECT agitation in this patient. We briefly discuss the possible underlying mechanisms and pathophysiology of amlodipine in the prevention of post-ECT agitation.

Amlodipine and the Successful Management of Post-Electroconvulsive Therapy Agitation

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Ali Shahriari

2016-01-01

Full Text Available Electroconvulsive therapy (ECT is a highly effective nonpharmacologic treatment for the management of depression and some other psychiatric disorders. Post-ECT agitation occurs in up to 12% of ECT treatments and is characterized by motor restlessness, irritability, disorientation, and panic-like behaviors. The severity of post-ECT agitation ranges from mild and self-limited to serious and severe forms requiring prompt medical intervention to protect the patient and the medical staff. In severe agitation medical management may be necessary which consists of using sedative agents, either benzodiazepines or propofol. The side-effects of these sedative agents, especially in the elderly population, necessitate finding ways that could help the prevention of the occurrence of agitation after ECT treatments. We report a 68-year-old female with major depression who was referred for ECT. She experienced severe post-ECT agitation requiring medical intervention after all ECT treatments. Administering of oral amlodipine (5 mg one hour before ECT treatment successfully prevented the occurrence of post-ECT agitation in this patient. We briefly discuss the possible underlying mechanisms and pathophysiology of amlodipine in the prevention of post-ECT agitation.

Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension

DEFF Research Database (Denmark)

de Courten, Maximilian; Ferrari, P; Schneider, M

1993-01-01

Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients......To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model...... [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg...

Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

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Oh, Minkyung; Park, Sung-Eun; Ghim, Jong-Lyul; Choi, Young-Kyung; Shim, Eon-Jeong; Shin, Jae-Gook; Kim, Eun-Young

2017-01-01

This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs. This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews. The geometric mean ratios and 90% CIs for the maximum plasma concentration (C max ) and area under the curve from time zero to the last sampling time (AUC t ) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting. For both telmisartan and S-amlodipine, the C max and AUC t 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway.

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Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L; McParland, Aidan L; Longhurst, Colin A; Galko, Michael J; Ganter, Geoffrey K

2017-08-30

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a

Treatment with triple combination of atorvastatin, perindopril, and amlodipine in patients with stable coronary artery disease: A subgroup analysis from the PAPA-CAD study.

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Dézsi, Csaba András

2018-01-01

Background In patients with stable coronary artery disease, aspirin, a statin, and an angiotensin-converting enzyme inhibitor are recommended as first-line agents for secondary prevention. Subgroup analyses of the previously published Hungarian Perindopril plus Amlodipine in PAtients with Coronary Artery Disease (PAPA-CAD) non-interventional trial demonstrated that the addition of the metabolically beneficial, fixed combination of perindopril + amlodipine to atorvastatin further improves the patient's lipid profile. Methods The PAPA-CAD study, a 6-month open-label, prospective, multicenter, observational/non-interventional survey evaluated data accumulated from patients with hypertensive patients with stable coronary artery disease. The herein-reported subgroup analysis was conducted using the findings from those 1130 patients, who were taking atorvastatin in addition to the fixed combination of perindopril + amlodipine at the time of all four study visits (i.e., at baseline and 1, 3, and 6 months later). Results In the subgroup of patients taking atorvastatin as an add-on agent, 82.5% reached the target blood pressure of 140/90 mmHg compared with 78.8% of those not taking a statin. The addition of atorvastatin to the fixed combination of perindopril + amlodipine resulted in further significant improvements of key metabolic parameters. Conclusion This subgroup analysis confirmed that favorable synergism exists among perindopril, amlodipine, and atorvastatin.

EFFECTS OF AMLODIPIN AND METOPROLOL ON AUTONOMIC SYSTEM IN EMOTIONAL AND COLD TESTS IN HYPERTENSIVE PATIENTS WITH DIFFERENT PSYCHOLOGICAL PROFILE

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M. P. Rubanova

2006-01-01

Full Text Available Aim. To asses effects of amlodipin and metoprolol on autonomic system in emotional and cold tests in hypertensive patients with different psychological profile (PP Material and methods. 61 patients with arterial hypertension of II grade were observed. Therapy with amlodipin or metoprolol was prescribed and allowed to reach target blood pressure (BP level in all the patients. Patients were divided into 2 groups: 1-st one – patients with normal PP, 2-nd group – patients with subclinical depression. Patients were examined before and 30 days after therapy. Examination included ambulatory BP monitoring, assessment of autonomic status by variational intervalometry and spectral analysis of heart rate variability (HRV in cold and emotional tests. Depression and anxiety levels were determined with Bek’s and HADS scales.  Results. Treatment with amlodipin  and metoprolol can result in improvement, worsening or unchanging of PP.  In hypertensive patients with subclinical depression improving their PP resulted in autonomic reaction change: sympathetic activity increases and reaction on stress becomes more adequate. If subclinical depression occurred in hypertensive patients because of amlodipin and metoprolol therapy, sympathetic system stress-reaction decreased and parasympathetic influence increased. Conclusion. The study results show necessity of psychometric examination of hypertensive patients in order to reveal subclinical depression and anxiety.  

The efficacy and safety of fixed-dose combination of amlodipine/benazepril in Chinese essential hypertensive patients not adequately controlled with benazepril monotherapy: a multicenter, randomized, double-blind, double-dummy, parallel-group clinical trial.

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Yan, Pingping; Fan, Weihu

2014-01-01

This double-blind, double-dummy clinical trial evaluated the efficacy and safety of two strengths of fixed-dose combination of amlodipine/benazepril in Chinese hypertensive patients not adequately controlled with benazepril. Of 442 patients who received treatment with benazepril 10 mg for 4 weeks, 341 patients failed to achieve to diastolic blood pressure (DBP) benazepril 2.5/10 mg, or amlodipine/benazepril 5/10 mg, or benazepril 10 mg for 8 weeks. BP reductions with amodipinel/benazepril 2.5/10 mg (15.2/11.8 mmHg) or amlodipine/benazepril 5/10 mg (15.4/12.4 mmHg) were significantly greater than that with benazepril 10 mg (9.88/9.46 mmHg) at study end (p benazepril). BP control rate was 83.8% with amlodipine/benazepril 2.5/10 mg, 80.2% with amlodipine/benazepril 5/10 mg, 64.9% with benazepril 10 mg at study end (p benazepril). Three groups were generally well tolerated. Our study indicated that amlodipine/benazepril fixed-dose combination offered significant additional BP reductions and BP control rate compared with the continuation of benazepril monotherapy. No significant differences were observed in both BP reductions and BP control rate between amlodipine/benazepril 2.5/10 mg and amlodipine/benazepril 5/10 mg.

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach.

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Pessôa, Marco T C; Alves, Silmara L G; Taranto, Alex G; Villar, José A F P; Blanco, Gustavo; Barbosa, Leandro A

2018-12-01

Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner.

Digoxin-like immunoreactivity, endogeneous cardiac glycoside-like factors (s) and natriuretic hormone

International Nuclear Information System (INIS)

Clerico, A.

1987-01-01

Endogenous factors crossreacting with antidigoxin antibodies (digoxin-like immunoreactive substances=DLIS) have been found in several tissues and body fluids of animals and humans, using commercially avaiable digoxin RIA or EIA methods. Detectable DLIS concentration were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at present, unknown, although it has been suggested that DLIS could be a substance with low molecular weight. Experimental studies and theoretical consideration suggest that DLIS, in addition to reacting with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na + /K + ATPase (sodium pump). Therefore, it has been suggested that DLSI is an endogeneous modulator of the membrane sodium-potassium pump and it could play a role in the regulation of fluid and electrolytes muscular tone of myocardial and also in pathogenesis of hypertension

Effect of a nitric oxide donor (glyceryl trinitrate) on nociceptive thresholds in man

DEFF Research Database (Denmark)

Thomsen, L L; Brennum, J; Iversen, Helle Klingenberg

1996-01-01

Several animal studies suggest that nitric oxide (NO) plays a role in central and peripheral modulation of nociception. Glyceryl trinitrate (GTN) exerts its physiological actions via donation of NO. The purpose of the present study was to examine the effect of this NO donor on nociceptive...... central facilitation of nociception by NO. However, we regard convergence of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO as a more likely explanation of our findings....

Nociceptive flexion reflexes during analgesic neurostimulation in man.

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García-Larrea, L; Sindou, M; Mauguière, F

1989-11-01

Nociceptive flexion reflexes of the lower limbs (RIII responses) have been studied in 21 patients undergoing either epidural (DCS, n = 16) or transcutaneous (TENS, n = 5) analgesic neurostimulation (AN) for chronic intractable pain. Flexion reflex RIII was depressed or suppressed by AN in 11 patients (52.4%), while no modification was observed in 9 cases and a paradoxical increase during AN was evidenced in 1 case. In all but 2 patients, RIII changes were rapidly reversible after AN interruption. RIII depression was significantly associated with subjective pain relief, as assessed by conventional self-rating; moreover, in 2 patients it was possible to ameliorate the pain-suppressing effects of AN by selecting those stimulation parameters (intensity and frequency) that maximally depressed nociceptive reflex RIII. We recorded 2 cases of RIII attenuation after contralateral neurostimulation. AN appeared to affect nociceptive reflexes rather selectively, with no or very little effect on other cutaneous, non-nociceptive responses. Recording of RIII reflexes is relatively simple to implement as a routine paraclinical procedure. It facilitates the objective assessment of AN efficacy and may help to choose the most appropriate parameters of neurostimulation. In addition, RIII behavior in patients could be relevant to the understanding of some of the mechanisms involved in AN-induced pain relief.

Hypothalamic digoxin, hemispheric chemical dominance, and mesenteric artery occlusion.

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Kurup, Ravi Kumar; Kurup, Paramesware Achutha

2003-12-01

The role of the isoprenoid pathway in vascular thrombosis, especially mesenteric artery occlusion and its relation to hemispheric dominance, was assessed in this study. The following parameters were measured in patients with mesenteric artery occlusion and individuals with right hemispheric, left hemispheric, and bihemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition. In patients with mesenteric artery occlusion there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, low ubiquinone, and elevated free radical levels. The RBC membrane Na(+)-K+ ATPase activity and serum magnesium were decreased. There was also an increase in tryptophan catabolites and reduction in tyrosine catabolites in the serum. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these patients. The biochemical patterns obtained in mesenteric artery occlusion is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with mesenteric artery occlusion were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Mesenteric artery occlusion occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance may thus control the risk for developing vascular thrombosis in individuals.

Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

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Nahman-Averbuch, Hadas; Martucci, Katherine T; Granovsky, Yelena; Weissman-Fogel, Irit; Yarnitsky, David; Coghill, Robert C

2014-12-01

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Evaluation of palatability of 10 commercial amlodipine orally disintegrating tablets by gustatory sensation testing, OD-mate as a new disintegration apparatus and the artificial taste sensor.

Science.gov (United States)

Uchida, Takahiro; Yoshida, Miyako; Hazekawa, Mai; Haraguchi, Tamami; Furuno, Hiroyuki; Teraoka, Makoto; Ikezaki, Hidekazu

2013-09-01

The purpose of this study was to evaluate and compare the palatability of 10 formulations (the original manufacturer's formulation and nine generics) of amlodipine orally disintegrating tablets (ODTs) by means of human gustatory sensation testing, disintegration/dissolution testing and the evaluation of bitterness intensity using a taste sensor. Initially, the palatability, dissolution and bitterness intensity of the ODTs were evaluated in gustatory sensation tests. Second, the disintegration times of the ODTs were measured using the OD-mate, a newly developed apparatus for measuring the disintegration of ODTs, and lastly, the bitterness intensities were evaluated using an artificial taste sensor. Using factor analysis, the factors most affecting the palatability of amlodipine ODTs were found to be disintegration and taste. There was high correlation between the disintegration times of the 10 amlodipine ODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of amlodipine ODTs 10, 20 and 30 s after starting the conventional brief dissolution test and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. The OD-mate and the taste sensor may be useful for predicting the disintegration and bitterness intensity of amlodipine ODTs in the mouth. © 2013 Royal Pharmaceutical Society.

Benazepril combined with either amlodipine or hydrochlorothiazide is more effective than monotherapy for blood pressure control and prevention of end-organ injury in hypertensive Dahl rats.

Science.gov (United States)

Zhou, Ming-Sheng; Jaimes, Edgar A; Raij, Leopoldo

2006-07-01

We studied the effect of hydrochlorothiazide (HCTZ), the angiotensin-converting enzyme inhibitor benazepril, the calcium channel blocker amlodipine, or a combination of benazepril/amlodipine or benazepril/HCTZ on systolic blood pressure (BP) and end-organ injury (left ventricular hypertrophy, proteinuria, and endothelium-dependent relaxation to acetylcholine) in hypertensive Dahl salt-sensitive rats fed either a normal-salt (0.5% NaCl) or high-salt (4% NaCl) diet for 6 weeks. Rats fed a high-salt diet developed hypertension and significant end-organ injury. Monotherapy with HCTZ (75 mg/L in drinking water) or amlodipine (10 mg/kg/day by gavage) reduced systolic BP and proteinuria; benazepril (40 mg/kg/day by gavage) decreased proteinuria without significantly lowering systolic BP. In rats receiving a high-salt diet, only HCTZ reduced left ventricular hypertrophy, whereas endothelium-dependent relaxation was improved by amlodipine and benazepril but not by HCTZ. Combining benazepril with either amlodipine or HCTZ dramatically reduced systolic BP and end-organ injury. These data clearly support clinical studies suggesting that combination therapy is more effective than monotherapy for systolic BP control and prevention of end-organ injury. Complementary mechanisms of action of agents from different antihypertensive classes appear to facilitate the greater benefit on BP and end-organ injury.

Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

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Onozawa Kitaro

2011-11-01

Full Text Available Abstract Background We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC. The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS delivered to the BLA on nociceptive responses in the rat PFC. Results HFS induced long lasting suppression (LLS of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA receptor antagonists (2-amino-5-phosphonovaleric acid (APV, dizocilpine (MK-801 and also metabotropic glutamate receptor (mGluR group antagonists (α-methyl-4-carboxyphenylglycine (MCPG, and 2-[(1S,2S-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl-D-alanine (LY341495, prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride and D4 (3-{[4-(4-chlorophenyl piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870, microinjected into the PFC, inhibited LLS of nociceptive responses. Conclusions Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

Analysis of Digoxin and Metildigoxin in Whole Blood Using Solid-Phase Extraction and Liquid Chromatography Tandem Mass Spectrometry

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Paula Melo

2012-01-01

Full Text Available A simple and rapid UPLC/MS/MS method has been developed and validated for the analysis of digoxin and metildigoxin in whole blood. Samples were prepared by SPE extraction with Oasis HLB columns. Separation was achieved with an ACQUITY UPLC HSS T3 column (2.1×100; 1.8 μm, at 35°C. The mobile phase consisted of acetonitrile (70% and ammonium formate 5 mM (30%. Total run time was 1.5 min operating at isocratic mode with a flow rate of 0.3 mL/min. Mass spectrometry detection was performed by positive mode electrospray, on the ammonium adducts with two transitions for each analyte and one for the IS (d3-digoxin. The method proved to be specific and linear over the range (0.3–10 ng/mL. This technique also showed high sensitivity with a 0.09 ng/mL LOD and a 0.28 ng/mL LOQ, for both substances. Percentage recovery ranged from 83 to 100% for digoxin and from 62 to 94% for metildigoxin. The intra- and interday precision CV were ≤10%.

Determination of the Effects of Digoxin on the Right Ventricular Function in Patients Undergoing Pneumonectomy

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Alireza Sharifian Attar

2014-02-01

Full Text Available Introduction: Pneumonectomy is the standard treatment of lung cancer, even though patients should undergo several evaluations before surgery; deterioration of cardiopulmonary function after pulmonary resection is inevitable. We have evaluated the effects of digoxin on the improvement of right ventricular function and prevention of probable complications after lung resection surgery. Materials and Methods: All patients who were candidate for pneumonectomy or extensive lobectomy in Ghaem hospital from 2010 to 2012 were enrolled into this study and were divided into two groups randomly. The first group (group D received digoxin during surgery and in the second group (group C normal saline was administered as placebo. Echocardiographic evaluation of the patients was accomplished the day before and the day after surgery. Results: Among 20 patients in each group, male to female ratio was almost 2:1 and mean age was 63.8 (ranged 46-83 years. The most common cause of pneumonectomy was lung cancer. Comparison of the preoperative demographic variables, blood biochemistry, pulmonary function tests, echocardiographic and blood gas indexes showed no statistically significant differences between two groups. ,But postoperative evaluations showed a significant improvement in left ventricular ejection fraction in group D. Right ventricular systolic and diastolic diameters and pulmonary artery pressure were decreased significantly  as well. Conclusion: According to our results, we suggest a single dose of digoxin during lung resection surgery to improve cardiac performance after pneumonectomy.

Scottish immunoassay support service quality control scheme for thyroxine, triiodothyronine, and digoxin assays: analysis of first 18 months' experience

International Nuclear Information System (INIS)

Ratcliffe, W.A.; Logue, F.C.; Ratcliffe, J.G.

1978-01-01

Initial experience of the Scottish Immunoassay Support Service Quality Control scheme for thyroxin(T4), triiodothyronine (T3), and digoxin is analysed. For T4, radioimmunoassay (RIA) methods gave values close to the all-method mean. Competitive protein binding (CPB) kits gave values significantly higher (by 12%) in one and lower (by 10%) in another, probably due to the extraction of interfering substances such as non-esterified fatty acids or thyroid hormone binding proteins. The range of between-batch precision of individual laboratories was 10.8-47.5% (mean 17.8%) over the clinically relevant range. It was particularly poor at levels below the lower limit of the normal range. For T3 RIA, kit methods gave significantly higher values than independent methods although recovery of exogenous T3 was approximately quantitative with both. Cross reaction of T4 in T3 assays was insignificant. The range of between-batch precision for individual laboratories was 11.4-35.5% (mean 21.9%), and was poorest at levels of 1 nmol/l or less. For digoxin RIA, Lanoxitest γ gave significantly higher values than other methods, and over-recovered exogenous digoxin. The range of between-batch precision was 13.8-35.2% (mean 21.6%), and was poorest at levels of 1 nmol/l or less. The distribution of liquid human serum specimens at ambient temperature was satisfactory for quality control of T4, T3, and digoxin RIA but not for T4 by the Thyopac 4 method. Ox serum was unsuitable for certain T4 RIA methods. (author)

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-04-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-06-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats

NARCIS (Netherlands)

Liang, Wei; Chen, Cheng; Shi, Jing; Ren, Zhilong; Hu, Fengqi; van Goor, Harry; Singhal, Pravin C.; Ding, Guohua

Background. Several studies in patients with primary aldosteronism (PA) have suggested that aldosterone (ALD) is directly contributing to albuminuria. However, there are limited data pertaining to the direct role of ALD in (EPL), telmisartan (TEL) and amlodipine (AML) on ALD-induced renal structural

Assessment of anti-nociceptive efficacy of costus speciosus rhizome in swiss albino mice.

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Bhattacharya, Sanjib; Nagaich, Upendra

2010-01-01

Present study attempts to evaluate the anti-nociceptive activity of the aqueous and ethanol extracts of Costus speciosus rhizome (CPA and CPE) in Swiss albino mice. The maceration extracts were evaluated for anti-nociceptive activity by acetic acid-induced writhing and tail flick method in mice. The anti-nociceptive screening revealed significant peripheral anti-nociceptive actions of both extracts against acetic acid induced writhing in mice. Aqueous extract (CPA) significantly inhibited writhes at the dose of 75 and 150 mg/kg body weight, while ethanol extract (CPE) produced significant protection at the dose of 150 mg/kg body weight. However, in tail flick method only the ethanol extract (CPE) showed significant central analgesic action, while aqueous extract was totally ineffective. The present investigation demonstrates that the rhizome extracts of C. speciosus exhibited significant anti-nociceptive effects in Swiss albino mice.

Assessment of anti-nociceptive efficacy of Costus Speciosus rhizome in swiss albino mice

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Sanjib Bhattacharya

2010-01-01

Full Text Available Present study attempts to evaluate the anti-nociceptive activity of the aqueous and ethanol extracts of Costus speciosus rhizome (CPA and CPE in Swiss albino mice. The maceration extracts were evaluated for anti-nociceptive activity by acetic acid-induced writhing and tail flick method in mice. The anti-nociceptive screening revealed significant peripheral anti-nociceptive actions of both extracts against acetic acid induced writhing in mice. Aqueous extract (CPA significantly inhibited writhes at the dose of 75 and 150 mg/kg body weight, while ethanol extract (CPE produced significant protection at the dose of 150 mg/kg body weight. However, in tail flick method only the ethanol extract (CPE showed significant central analgesic action, while aqueous extract was totally ineffective. The present investigation demonstrates that the rhizome extracts of C. speciosus exhibited significant anti-nociceptive effects in Swiss albino mice.

Intraplantar injection of tetrahydrobiopterin induces nociception in mice

DEFF Research Database (Denmark)

Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe

2015-01-01

was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral......Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models...

Anti-nociceptive activity of Pereskia bleo Kunth. (Cactaceae) leaves extracts.

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Abdul-Wahab, Ikarastika Rahayu; Guilhon, Carolina Carvalho; Fernandes, Patricia Dias; Boylan, Fabio

2012-12-18

Local communities in Malaysia consume Pereskia bleo Kunth. (Cactaceae) leaves as raw vegetables or as a concoction and drink as a tea to treat diabetes, hypertension, rheumatism, cancer-related diseases, inflammation, gastric pain, ulcers, and for revitalizing the body. To evaluate anti-nociceptive activity of the extracts and vitexin, isolated for the first time in this species, in two analgesic models; formalin-induced licking and acetic acid-induced abdominal writhing. Three and a half kilos of P. bleo leaves were extracted using Soxhlet apparatus with ethanol for 72 h. The crude ethanol extract was treated with activated charcoal overnight and subjected to a liquid-liquid partition yielding hexane, dichloromethane, ethyl acetate and butanol extracts. All extracts, including the crude ethanol and vitexin isolated from the ethyl acetate partition were tested for peripheral anti-nociceptive activity using formalin test and acetic acid-induced abdominal writhing, besides having their acute toxicity assays performed. The phytochemical analyses resulted in the isolation of vitexin (1), β-sitosterol glucoside (2) and β-sitosterol (3) isolated from the ethyl acetate, dichloromethane and hexane extracts, respectively. This is the first time vitexin and β-sitosterol glucoside are isolated from this species. The anti-nociceptive activities for all extracts were only moderate. Vitexin, which was isolated from the ethyl acetate extract did not show any activity in all models tested when used alone at the same concentration as it appears in the extract. This study showed that all the extracts possess moderate anti-nociceptive activity. Vitexin is not the compound responsible for the anti-nociceptive effect in the ethyl acetate extract. Further investigations are needed to identify the compound(s) that might be responsible for the anti-nociceptive activity in this plant. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Nociception at the diabetic foot, an uncharted territory

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Chantelau, Ernst A

2015-01-01

The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy. PMID:25897350

Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial.

Science.gov (United States)

Ambrosy, Andrew P; Bhatt, Ankeet S; Stebbins, Amanda L; Wruck, Lisa M; Fudim, Marat; Greene, Stephen J; Kraus, William E; O'Connor, Christopher M; Piña, Ileana L; Whellan, David J; Mentz, Robert J

2018-05-01

Despite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). HF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF ≤35% between April 2003 and February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to prevalent digoxin status at baseline. The association between digoxin therapy and outcomes was assessed using Cox proportional hazard and inverse-probability weighted (IPW) regression models adjusted for demographics, medical history, medications, laboratory values, quality of life, and exercise parameters. The prevalence of digoxin therapy decreased from 52% during the first 6 months of enrollment to 35% at the end of the HF-ACTION trial (P <0.0001). Study participants were 59± 13 years of age, 72% were male, and approximately half had an ischemic etiology of HF. Patients receiving digoxin at baseline tended to be younger and were more likely to report New York Heart Association functional class III/IV symptoms (rather than class II) compared to those not receiving digoxin. Patients taking digoxin had worse baseline exercise capacity as measured by peak VO 2 and 6-min walk test and greater impairments in health status as reflected by the Kansas City Cardiomyopathy Questionnaire. The association between digoxin and the risk of death or hospitalization differed depending on whether Cox proportional hazard (Hazard Ratio 1.03, 95% Confidence Interval 0.92-1.16; P = .62) or IPW regression models (HR 1.08, 95% CI 1.00-1.17; P = .057) were used to adjust for potential confounders. Although digoxin use was associated with high-risk clinical features, the association between digoxin therapy and outcomes was dependent on the statistical methods used for multivariable adjustment. Clinical equipoise exists and additional prospective research is

Impact of Statin Therapy on the Blood Pressure-Lowering Efficacy of a Single-Pill Perindopril/Amlodipine Combination in Hypertensive Patients with Hypercholesterolemia.

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Sirenko, Yuriy; Radchenko, Ganna

2017-03-01

Several lines of research indicate that statins can lower blood pressure (BP) independently of their lipid-lowering effects when used as monotherapy and in combination with antihypertensive agents. This short-term, open-label study examined whether statin therapy had a synergistic effect on the BP-lowering efficacy of perindopril/amlodipine in a subgroup of patients in the PERSPECTIVA study with concomitant hypertension and hypercholesterolemia, with or without statin at baseline. The PERSPECTIVA study recruited 732 adults with untreated or uncontrolled hypertension. This subgroup analysis of PERSPECTIVA included 587 patients with concomitant hypertension and hypercholesterolemia (mean age 56.7 years) of whom 226 were receiving a statin at baseline (statin [+] group) and 361 were not (statin [-] group). All patients received treatment with single-pill combination perindopril/amlodipine at a dose of 5/5, 10/5 or 10/10 mg/day. The study duration was 60 days with follow-up visits for BP monitoring at 7, 15, 30 and 60 days. At day 60, BP control (statin [+] vs statin [-] group: 73 vs 64% respectively (+14%, P statin [+] group, the single-pill perindopril/amlodipine combination significantly reduced BP in patients previously untreated (n = 18), or treated with monotherapy (n = 97), dual therapy (n = 93), or triple therapy (n = 18): -38.8/-20.0, -39.1/-20.1, -38.0/-19.4, -39.9/-18.3 mmHg respectively (P statin [+] group (0.9%) vs the statin [-] group (2.5%). BP control rates in patients with uncontrolled hypertension and concomitant hypercholesterolemia are significantly improved with a treatment regimen that combines perindopril/amlodipine with statin therapy, regardless of previous antihypertensive therapy. This subanalysis of the PERSPECTIVA study supports the synergistic BP-lowering effect of statins and perindopril/amlodipine.

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

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Aaron D. Mickle

2016-11-01

Full Text Available Specialized receptors belonging to the transient receptor potential (TRP family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.

Amlodipine induced plasma cell granuloma of the gingiva: A novel case report.

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Vishnudas, Bhandari; Sameer, Zope; Shriram, Bansode; Rekha, Kardile

2014-07-01

Drug-induced gingival overgrowth (DIGO) can be a serious concern for both patients and clinicians. DIGO is a well-documented side-effect of some pharmacologic agents, including, but not limited to, calcium channel blockers, phenytoin, and cyclosporine. Plasma cell granulomas (pseudotumors) are exceedingly rare, non-neoplastic, reactive tumor-like proliferation, primarily composed of plasma cells that manifest primarily in the lungs, but may occur in various anatomic locations. Intraoral plasma cell granulomas involving the lip, oral mucosa, tongue, and gingiva have been reported in the past. This is the first case report of amlodipine induced plasma cell granuloma of the gingiva in the medical literature presenting a 54 year-old female patient with hypertension, who received amlodipine (10 mg/day, single dose orally) for 2 years, sought medical attention because of developing maxillary anterior massive gingival overgrowth causing functional and esthetic problem, which was treated by excisional biopsy. Histologically, these lesions were composed of mature plasma cells, showing polyclonality for both lambda and kappa light chains and fibrovascular connective tissue stroma confirming a diagnosis of plasma cell granuloma. This case also highlights the need to biopsy for unusual lesions to rule out potential neoplasms.

Nanomagnet-based removal of lead and digoxin from living rats

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Herrmann, Inge K.; Schlegel, Andrea; Graf, Rolf; Schumacher, Christoph M.; Senn, Nico; Hasler, Melanie; Gschwind, Sabrina; Hirt, Ann-Marie; Günther, Detlef; Clavien, Pierre-Alain; Stark, Wendelin J.; Beck-Schimmer, Beatrice

2013-08-01

In a number of clinical conditions such as intoxication, bacteraemia or autoimmune diseases the removal of the disease-causing factor from blood would be the most direct cure. However, physicochemical characteristics of the target compounds limit the applicability of classical filtration and diffusion-based processes. In this work, we present a first in vivo magnetic blood purification rodent animal model and demonstrate its ability to rapidly clear toxins from blood circulation using two model toxins with stable plasma levels (lead (Pb2+) and digoxin). Ultra-strong functionalized metal nanomagnets are employed to eliminate the toxin from whole blood in an extracorporeal circuit. In the present experimental demonstration over 40% of the toxin (i.e. lead or digoxin) was removed within the first 10 minutes and over 75% within 40 minutes. After capturing the target substance, a magnetic trap prevents the toxin-loaded nanoparticles from entering the blood circulation. Elemental analysis and magnetic hysteresis measurements confirm full particle recovery by simple magnetic separation (residual particle concentration below 1 μg mL-1 (detection limit)). We demonstrate that magnetic separation-based blood purification offers rapid blood cleaning from noxious agents, germs or other deleterious materials with relevance to a number of clinical conditions. Based on this new approach, current blood purification technologies can be extended to efficiently remove disease-causing factors, e.g. overdosed drugs, bacteria or cancer cells without being limited by filter cut-offs or column surface saturation.

Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain.

Science.gov (United States)

Shelukhina, Irina; Mikhailov, Nikita; Abushik, Polina; Nurullin, Leniz; Nikolsky, Evgeny E; Giniatullin, Rashid

2017-01-01

Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown. Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca 2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which

PATHOGENESIS OF IMMUNE ALTERATIONS AND CORRECTIVE ROLE OF AMLODIPINE IN EXPERIMENTAL CHRONIC RENAL FAILURE

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M. V. Osikov

2016-01-01

Full Text Available The purpose of this study was to assess some mechanisms of changes in immune state, and to evaluate a role of amlodipine, a known calcium channel blocker, as a potential corrective drug in experimental chronic renal failure (CRF. An animal CRF model was produced in rats by a two-stage operative resection of 5/6 of the renal tissue. Amlodipine is used per os at a daily dose of 0.25 mg/kg for 7 days. Flow cytofluorimetric approach was used to discern peripheral blood lymphocytes: CD3+ (mainly, T lymphocytes, CD45RA+ (mainly, B cells, as well as the following cell markers: Annexin 5-FITC+/7-AAD- (early apoptosis, Annexin 5-FITC+/7-AAD+ (late apoptosis and, in part, necrotic cells. Moreover, we have measured serum concentrations of urea, creatinine, phosphate, total calcium, parathyroid hormone (PTH, IL-1β, IL-4, interferon-γ, superoxide dismutase (SOD and catalase activities. Evaluation of Th1- and Th2-dependent immune response was carried out, respectively, by detection of delayed-type hypersensitivity, and scoring the antibody-forming cells in rat spleen induced by immunization with allogeneic erythrocytes. Primary, secondary and final products of lipid peroxidation were evaluated in lipid extracts from peripheral blood lymphocytes. Changes of immune state in CRF included depression of Th1 and Th2 dependent immune response, reduced number of lymphocytes bearing T and В cell markers, increased IL-1β concentrations in blood, along with decreased amounts of IFNγ and IL-4. Probable pathogenesis of the altered immune state may be associated with increased number of peripheral lymphocytes being at early and late stages of apoptosis/necrosis, elevated blood levels of IL-1β, total calcium, parathyroid hormone, reduced concentrations of IFNγ, and increased contents of primary, secondary and final peroxidation products in peripheral blood lymphocytes, being accompanied by inhibition of the SOD and catalase activity in blood plasma

The effect on serum enzymes of intramuscular injections of digoxin, bumetanide, pentazocine and isotonic sodium chloride

DEFF Research Database (Denmark)

Andersen, Klaus Ejner; Damsgaard, T

1976-01-01

Intramuscular injections of digoxin, bumetanide, pentazocine or isotonic sodium chloride have been given to 39 patients. We followed the serum concentrations of creatine kinase (CK), aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH) and LDH isoenzymes for 4 days. Ten patients receiving...

Treatment of Aluminium Phosphide Poisoning with a Combination of Intravenous Glucagon, Digoxin and Antioxidant Agents

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Zohreh Oghabian

2016-08-01

Full Text Available Aluminium phosphide (AlP is used to protect stored grains from rodents. It produces phosphine gas (PH3, a mitochondrial poison thought to cause toxicity by blocking the cytochrome c oxidase enzyme and inhibiting oxidative phosphorylation, which results in cell death. AlP poisoning has a high mortality rate among humans due to the rapid onset of cardiogenic shock and metabolic acidosis, despite aggressive treatment. We report a 21-yearold male who was referred to the Afzalipour Hospital, Kerman, Iran, in 2015 after having intentionally ingested a 3 g AlP tablet. He was successfully treated with crystalloid fluids, vasopressors, sodium bicarbonate, digoxin, glucagon and antioxidant agents and was discharged from the hospital six days after admission in good clinical condition. For the treatment of AlP poisoning, the combination of glucagon and digoxin with antioxidant agents should be considered. However, evaluation of further cases is necessary to optimise treatment protocols.

Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice.

Science.gov (United States)

Bonjardim, L R; Silva, A M; Oliveira, M G B; Guimarães, A G; Antoniolli, A R; Santana, M F; Serafini, M R; Santos, R C; Araújo, A A S; Estevam, C S; Santos, M R V; Lyra, A; Carvalho, R; Quintans-Júnior, L J; Azevedo, E G; Botelho, M A

2011-08-01

In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia. Copyright © 2011 John Wiley & Sons, Ltd.

Nociceptive sensations evoked from 'spots' in the skin by mild cooling and heating.

Science.gov (United States)

Green, Barry G; Roman, Carolyn; Schoen, Kate; Collins, Hannah

2008-03-01

It was recently found that nociceptive sensations (stinging, pricking, or burning) can be evoked by cooling or heating the skin to innocuous temperatures (e.g., 29 and 37 degrees C). Here, we show that this low-threshold thermal nociception (LTN) can be traced to sensitive 'spots' in the skin equivalent to classically defined warm spots and cold spots. Because earlier work had shown that LTN is inhibited by simply touching a thermode to the skin, a spatial search procedure was devised that minimized tactile stimulation by sliding small thermodes (16 and 1mm(2)) set to 28 or 36 degrees C slowly across the lubricated skin of the forearm. The procedure uncovered three types of temperature-sensitive sites (thermal, bimodal, and nociceptive) that contained one or more thermal, nociceptive, or (rarely) bimodal spots. Repeated testing indicated that bimodal and nociceptive sites were less stable over time than thermal sites, and that mechanical contact differentially inhibited nociceptive sensations. Intensity ratings collected over a range of temperatures showed that LTN increased monotonically on heat-sensitive sites but not on cold-sensitive sites. These results provide psychophysical evidence that stimulation from primary afferent fibers with thresholds in the range of warm fibers and cold fibers is relayed to the pain pathway. However, the labile nature of LTN implies that these low-threshold nociceptive inputs are subject to inhibitory controls. The implications of these findings for the roles of putative temperature receptors and nociceptors in innocuous thermoreception and thermal pain are discussed.

Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

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Mamoru Takeda

2016-10-01

Full Text Available Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM.

Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactionss

NARCIS (Netherlands)

Ellens, H.; Deng, S.; Coleman, J.; Bentz, J.; Taub, M.E.; Ragueneau-Majlessi, I.; Chung, S.P.; Herédi-Szabó, K.; Neuhoff, S.; Palm, J.; Balimane, P.; Zhang, L.; Jamei, M.; Hanna, I.; O'connor, M.; Bednarczyk, D.; Forsgard, M.; Chu, X.; Funk, C.; Guo, A.; Hillgren, K.M.; Li, L.; Pak, A.Y.; Perloff, E.S.; Rajaraman, G.; Salphati, L.; Taur, J.-S.; Weitz, D.; Wortelboer, H.M.; Xia, C.Q.; Xiao, G.; Yamagata, T.; Lee, C.A.

2013-01-01

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits Pglycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when themaximumconcentration of inhibitor at steady state divided by IC50

Value of digoxin in heart failure and sinus rhythm : New features of an old drug?

NARCIS (Netherlands)

vanVeldhuisen, DJ; deGraeff, PA; Remme, WJ

1996-01-01

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

Science.gov (United States)

Hausner, Helene; Derving Karsbøl, Julie; Holst, Anders G; Jacobsen, Jacob B; Wagner, Frank-Dietrich; Golor, Georg; Anderson, Thomas W

2017-11-01

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Learned control over spinal nociception in patients with chronic back pain.

Science.gov (United States)

Krafft, S; Göhmann, H-D; Sommer, J; Straube, A; Ruscheweyh, R

2017-10-01

Descending pain inhibition suppresses spinal nociception, reducing nociceptive input to the brain. It is modulated by cognitive and emotional processes. In subjects with chronic pain, it is impaired, possibly contributing to pain persistence. A previously developed feedback method trains subjects to activate their descending inhibition. Participants are trained to use cognitive-emotional strategies to reduce their spinal nociception, as quantified by the nociceptive flexor reflex (RIII reflex), under visual feedback about their RIII reflex size. The aim of the present study was to test whether also subjects with chronic back pain can achieve a modulation of their descending pain inhibition under RIII feedback. In total, 33 subjects with chronic back pain received either true (n = 18) or sham RIII feedback (n = 15), 15 healthy control subjects received true RIII feedback. All three groups achieved significant RIII suppression, largest in controls (to 76 ± 26% of baseline), intermediate in chronic back pain subjects receiving true feedback (to 82 ± 13%) and smallest in chronic back pain subjects receiving sham feedback (to 89 ± 14%, all p chronic pain subjects receiving true feedback significantly improved their descending inhibition over the feedback training, quantified by the conditioned pain modulation effect (test pain reduction of baseline before training: to 98 ± 26%, after: to 80 ± 21%, p chronic back pain can achieve a reduction of their spinal nociception and improve their descending pain inhibition under RIII feedback training. Subjects with chronic back pain can learn to control their spinal nociception, quantified by the RIII reflex, when they receive feedback about the RIII reflex. © 2017 European Pain Federation - EFIC®.

Changes in cardiac glycoside receptor sites /sup 86/ rubidium uptake and intracellular sodium concentrations in the erythrocytes of patients receiving digoxin during the early phases of treatment of cardiac failure in regular rhythm and of atrial fibrillation

Energy Technology Data Exchange (ETDEWEB)

Ford, A R; Aronson, J K; Grahame-Smith, D G; Carver, J G [Medical Research Council, Oxford (UK)

1979-08-01

Measurements of the binding of 12-..cap alpha..-(/sup 3/H)-digoxin to the membranes of intact erythrocytes, erythrocytic /sup 86/Rb uptake and intraerythrocytic sodium concentrations have been made in the red cells of patients receiving digoxin in the short-term for atrial fibrillation or cardiac failure in regular rhythm. During the first few days of treatment (/sup 3/H)-digoxin binding and /sup 86/Rb uptake fall and intraerythrocytic sodium concentrations rise. Subsequently parallel fluctuations occur in (/sup 3/H)-digoxin binding and /sup 86/Rb uptake but not in intraerythrocytic sodium concentrations and the significance of the fluctuations is discussed. The values of all three measurements correlate significantly with the response of the heart in sinus rhythm as measured by QS/sub 2/I. Plasma digoxin concentrations do not correlate with QS/sub 2/I.

Changes in thermal nociceptive responses in dairy cows following experimentally induced Esherichia coli mastitis

DEFF Research Database (Denmark)

Rasmussen, Ditte B.; Fogsgaard, Katrine; Røntved, Christine Maria

2011-01-01

Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS......) in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables....

CORTICAL RESPONSES TO SALIENT NOCICEPTIVE AND NOT NOCICEPTIVE STIMULI IN VEGETATIVE AND MINIMAL CONSCIOUS STATE

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MARINA eDE TOMMASO

2015-01-01

Full Text Available Aims Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient multimodal visual, acoustic, somatosensory electric non nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation.Methods: Five Vegetative State (VS, 4 Minimally Conscious State (MCS patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 sec. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2 vertex complex in the 500 msec post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R and Coma Recovery Scale (CRS-R for clinical evaluation of pain perception and consciousness impairment.Results: The laser evoked potentials (LEPs were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the

[Fixed drug combinations in hypertension: a budget impact analysis for the Spanish Health System on the marketing of a fixed combination of olmesartan/amlodipine].

Science.gov (United States)

Belén Ferro-Rey, M; Roca-Cusachs, Alex; Sicras-Mainar, Antoni; Alvarez-Martín, Carlos; de Salas-Cansado, Marina

2011-07-01

To carry out a budget impact analysis (BIA) of olmesartan/amlodipine (20/5, 40/5 and 40/10mg) marketed as a fixed combination (FC) in its approved indication for the National Health System (NHS). We developed a decision tree model in order to estimate usual hypertension treatment algorithm in Spanish clinical practice. The BIA has been developed from the perspective of the NHS for a period of 3 years (years 2010-2012). Spanish hypertensive population ≥ 35 years old. Introduction into the market of a fixed combination (FC) olmesartan/amlodipine in Spain. Expected costs to be assumed by the Spanish NHS (RRP-VAT) for hypertensive population able to be treated with the FC versus currently assumed costs by the NHS with free combination olmesartan and amlodipine. Estimated pharmaceutical costs in hypertensive population treated with olmesartan and amlodipine (2 pills) would be €25.2M (1(st) year), €26.4M (2011), €27.6M (2012), with a total 3-year period of €79.2M. According to patient tree model, the population able to be treated with FC would be 71,283 patients (2010), with a growth rate of 4.8% in the successive years, which supposes an annual cost of €21.2M (2010), €21.8M (2011) and €22.4M (2012), with a total 3-year period of €65.4M. The BIA shows savings of €13.8M in a total 3-year period. The BIA of FC olmesartan/amlodipine could generate net savings of €13.8M for the NHS in the period ranging from years 2010 to 2012. Copyright © 2010 Elsevier España, S.L. All rights reserved.

A Comparative Study of the Management of Stage 2 hypertension by Combined therapy with Losartan, Amlodipine and Hydrochlorothiazide

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Reza Jafarzadeh Esfehani

2012-09-01

Full Text Available Background: The most effective and accurate treatment of hypertensive patients reduces cardiovascular events and improves the quality of life. Objective: This study compared the efficacy and safety of combined (combination therapy with an angiotensin-receptor blocker (ARB a calcium-channel blocker (CCB (Losartan / Amloidipine 50/10mg vs maximal combination doses of ARB with hydrochlorothiazide (Losartan /HCTZ 100/25 mg and maximal combination doses of CCB with HCTZ (Amlodipine /HCTZ 10/25 mg in the management of stage 2 hypertension. Methods: This randomized clinical trial (RTC comprised 478 hypertensive patients with mean age 50.5±5.21 years, and took place between January 2010 and December 2011 in Vasei Hospital clinic in Sabzevar. Antihypertensive drugs were washed out after 5 days of discontinuation of drugs and the patients with mean blood pressure in sitting position ≥ 160 and <200 mmHg in systole and ≥ 100 and <110 mmHg in diastole were randomized into three groups: Losartan / Amlodipine 50/10 mg (n =164 , Losartan / HCTZ 100/25 mg (n =155 and Amlodipine / HCTZ 10/25 mg (n =159. The end point was reaching the blood pressure below 140/90 within 56 days of treatment in each group. Results: There was a significant difference in systolic blood pressure reductions between treatment groups (P<0.001 and also there was a significant difference between groups in reducing diastolic blood pressure (P<0.01. The highest systolic and diastolic blood pressure reduction respectively was found in Amlodipine/losartane and losartane/HTCZ group. The ANCOVA analysis revealed that only treatment regimen had a significant effect (P=0.01 and other factor including Age, Gender, Diabetes Mellitus, Smoking and High serum cholesterol didn’t have significant effect on blood pressure reduction. Conclusion: ARB/CCB combination therapy reduced blood pressure more effectively than the maximal doses of ARB or CCB with HCTZ in stage 2 hypertensive patients within

Impact of behavioral control on the processing of nociceptive stimulation

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James W Grau

2012-08-01

Full Text Available How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation, it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation. These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: Controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit. Uncontrollable stimulation also enhances mechanical reactivity (allodynia. We review evidence that training with controllable stimulation engages a BDNF-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin. A model is proposed that assumes nociceptive input is gated at an early stage, within the dorsal horn. his gate is sensitive to current environmental relations (between proprioceptive and nociceptive input, allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain.

Impact of Behavioral Control on the Processing of Nociceptive Stimulation

Science.gov (United States)

Grau, James W.; Huie, J. Russell; Garraway, Sandra M.; Hook, Michelle A.; Crown, Eric D.; Baumbauer, Kyle M.; Lee, Kuan H.; Hoy, Kevin C.; Ferguson, Adam R.

2012-01-01

How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID:22934018

(-)-α-Bisabolol reduces orofacial nociceptive behavior in rodents.

Science.gov (United States)

Melo, Luana Torres; Duailibe, Mariana Araújo Braz; Pessoa, Luciana Moura; da Costa, Flávio Nogueira; Vieira-Neto, Antonio Eufrásio; de Vasconcellos Abdon, Ana Paula; Campos, Adriana Rolim

2017-02-01

The purposes of this study were to evaluate the anti-nociceptive effect of oral and topical administration of (-)-α-bisabolol (BISA) in rodent models of formalin- or cinnamaldehyde-induced orofacial pain and to explore the inhibitory mechanisms involved. Orofacial pain was induced by injecting 1.5% formalin into the upper lip of mice (20 μL) or into the temporomandibular joint (TMJ) of rats (50 μL). In another experiment, orofacial pain was induced with cinnamaldehyde (13.2 μg/lip). Nociceptive behavior was proxied by time (s) spent rubbing the injected area and by the incidence of head flinching. BISA (100, 200, or 400 mg/kg p.o. or 50, 100, or 200 mg/mL topical) or vehicle was administered 60 min before pain induction. The two formulations (lotion and syrup) were compared with regard to efficacy. The effect of BISA remained after incorporation into the formulations, and nociceptive behavior decreased significantly in all tests. The high binding affinity observed for BISA and TRPA1 in the molecular docking study was supported by in vivo experiments in which HC-030031 (a TRPA1 receptor antagonist) attenuated pain in a manner qualitatively and quantitatively similar to that of BISA. Blockers of opioid receptors, NO synthesis, and K + ATP channels did not affect orofacial pain, nor inhibit the effect of BISA. In conclusion, BISA had a significant anti-nociceptive effect on orofacial pain. The effect may in part be due to TRPA1 antagonism. The fact that the effect of BISA remained after incorporation into oral and topical formulations suggests that the compound may be a useful adjuvant in the treatment of orofacial pain.

Studies on the comparability of the results from different methods for the radioimmunological determination of digoxin

International Nuclear Information System (INIS)

Dwenger, A.; Trautschold, I.

1978-01-01

Three iodine-125-digoxin radioimmunoassay kits (A Amersham Buchler; B Boehringer Mannheim; C Schwarz Mann/Becton Dickinson) were evaluated with respect to assay quality and comparability of the results. Intra- and interassay variances were calculated for the following types of samples: Three media (a pool serum; b artificial human serum; c buffer solution with albumin and globulin) containing pure digoxin, sera from a pharmacokinetic study, sera with different concentrations of proteins, a hemolytic serum and sera with digitoxin and metabolites of spironolactone. The intra-assay precision depended on the medium of the sample and was higher for samples with identical digoxin concentrations in an identical medium (e.g. CV for 2 μg/l in medium a for kit A: 4.3% for kit B: 7.0%; for kit C: 2.2%) than for samples with identical antigen concentrations in different media (CV for 2 μg/l in media a, b and c for kit A: 6.4%; for kit B: 9.1%; for kit C: 4.3%). The mean recovery in the range 0.5-4 μg/l depended on the kind of medium (a, b or c) and varied for kit A from 84.4% to 100.8%, for kit B from 112.0% to 119.6%, and for kit C from 98.0% to 104.5%. Decreasing serum protein concentrations to less than one half of the physiological concentration gave false negative results for kit A and fals positive results for kit C; for kit B this dependency was not be observed, but there was a decrease of reproducibility. (orig./AJ) [de

A study of the reliability of the Nociception Coma Scale.

Science.gov (United States)

Riganello, F; Cortese, M D; Arcuri, F; Candelieri, A; Guglielmino, F; Dolce, G; Sannita, W G; Schnakers, C

2015-04-01

In this study, we investigated the reliability of the Nociception Coma Scale which has recently been developed to assess nociception in non-communicative, severely brain-injured patients. Prospective cross-sequential study. Semi-intensive care unit and long-term brain injury care. Forty-four patients diagnosed as being in a vegetative state (n=26) or in a minimally conscious state (n=18). Patients were assessed by two experts (rater A and rater B) on two consecutive weeks to measure inter-rater agreement and test-retest reliability. Total scores and subscores of the Nociception Coma Scale. We performed a total of 176 assessments. The inter-rater agreement was moderate for the total scores (k = 0.57) and fair to substantial for the subscores (0.33 ≤ k ≤ 0.62) on week 2. The test-retest reliability was substantial for the total scores (k = 0.66) and moderate to almost perfect for the subscores (0.53 ≤ k ≤ 0.96) for rater A. The inter-rater agreement was weaker on week 1, whereas the test-retest reliability was lower for the least experienced rater (rater B). This study provides further evidence of the psychometric qualities of the Nociception Coma Scale. Future studies should assess the impact of practical experience and background on administration and scoring of the scale. © The Author(s) 2014.

Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats.

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Luiz Fabio Dimov

Full Text Available Transcranial direct current stimulation (tDCS is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG and the dorsal horn of the spinal cord (DHSC in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1, which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.

Measuring cutaneous thermal nociception in group-housed pigs using laser technique - effects of laser power output

DEFF Research Database (Denmark)

Herskin, Mette S.; Ladevig, Jan; Arendt-Nielsen, Lars

2009-01-01

Nociceptive testing is a valuable tool in the development of pharmaceutical products, for basic nociceptive research, and for studying changes in pain sensitivity is investigated after inflammatory states or nerve injury. However, in pigs only very limited knowledge about nociceptive processes...... nociceptive stimulation from a computer-controlled CO2-laser beam applied to either the caudal part of the metatarsus on the hind legs or the shoulder region of gilts. In Exp. 1, effects of laser power output (0, 0.5, 1, 1.5 and 2 W) on nociceptive responses toward stimulation on the caudal aspects...... of the metatarsus were examined using 15 gilts kept in one group and tested in individual feeding stalls after feeding. Increasing the power output led to gradually decreasing latency to respond (P 

Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state

Science.gov (United States)

de Tommaso, Marina; Navarro, Jorge; Lanzillotti, Crocifissa; Ricci, Katia; Buonocunto, Francesca; Livrea, Paolo; Lancioni, Giulio E.

2015-01-01

Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor

Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex

DEFF Research Database (Denmark)

Laursen, Mette; Gregersen, Jonas Lindholt; Yatime, Laure

2015-01-01

. These functionalities have specific influence on the binding properties. We report crystal structures of the Na+,K+-ATPase in the E2P form in complex with bufalin (a nonglycosylated CTS with a six-membered lactone) and digoxin (a trisaccharide-conjugated CTS with a five-membered lactone) and compare......Cardiotonic steroids (CTSs) are specific and potent inhibitors of the Na+,K+-ATPase, with highest affinity to the phosphoenzyme (E2P) forms. CTSs are comprised of a steroid core, which can be glycosylated, and a varying number of substituents, including a five- or six-membered lactone...... in site II of the digoxin and ouabain complexes, whereas both sites are occupied by K+ in the E2P–bufalin complex. In all complexes, αM4 adopts a wound form, characteristic for the E2P state and favorable for high-affinity CTS binding. We conclude that the occupants of the cation-binding site and the type...

Can combining different risk interventions into a single formulation contribute to improved cardiovascular disease risk reduction? The single pill of amlodipine/atorvastatin

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FD Richard Hobbs

2007-11-01

Full Text Available FD Richard HobbsUniversity of Birmingham, Edgbaston, Birmingham B15 2TT, UK.Abstract: In order to prevent cardiovascular events, it is essential to effectively manage overall risk of cardiovascular disease. However, despite guideline recommendations to this effect, current management of the major, modifiable cardiovascular risk factors such as hypertension and dyslipidemia is disconnected and patient adherence to therapy is poor. This is particularly important for patients with multiple cardiovascular risk factors, who are often prescribed multiple medications. The JEWEL study program investigated the use of single-pill amlodipine/atorvastatin as a strategy to improve management of these patients. The JEWEL program consisted of two 16-week, international, openlabel, multicenter, titration-to-goal studies in patients with hypertension and dyslipidemia. The two studies differed based on country of enrollment and certain tertiary endpoints, but the overall designs were very similar. Patients were enrolled from 255 centers across Canada and 13 European countries. The study was designed to assess the efficacy, safety, and utility of amlodipine/atorvastatin single pill therapy in a real-world setting. Patients were initiated at a dose of amlodipine 5 mg/atorvastatin 10 mg, unless previously treated, and were uptitrated as necessary. The primary efficacy parameter was the percentage of patients, at different levels of cardiovascular risk, achieving country-specific guideline-recommended target levels for blood pressure and lipids. A secondary analysis of efficacy measured attainment of the same single goal for blood pressure across all study participants (JEWEL I and II and the same single goal for LDL-C across all study participants (JEWEL I and II. The program utilized a newly developed questionnaire to gain better understanding of participants’ beliefs and behaviors towards medical treatment of their multiple risk factors. Approximately 2850

Comparative efficacy of amlodipine and hydrochlorthiazide-amiloride in cases of mild essential hypertension in outdoor patients at Combined Military Hospital Multan

International Nuclear Information System (INIS)

Ullah, M.U.; Khan, M.B.; Tahir, M.; Alamgir, W.; Yousif, M.A.

2010-01-01

To compare antihypertensive effect of fixed dose combination Hydrochlorothiazide-Amiloride and Amlodipine in patients of mild essential hypertension. After fulfilling the inclusion criteria of mild essential hypertension, defined as per recommendations of Seventh Joint National Committee (JNC 7) for treatment of Hypertension as stage 1 hypertension, systolic blood pressure (SBP) amlodipine and hydrochlorthiazide-amiloride 140-159-mmHg and Diastolic blood pressure(DBP) greater or equal to 90-99-mmHg, 100 patients were randomized into two study groups using a table of random numbers. Group 1 received tab amlodipine (5 mg) and Group 2 received tab hydrocholrthiazide-amiloride (25 mg-2.5mg). Informed written consent was taken. The patients were followed on subsequent visits (6 in total) for five months and systolic and diastolic blood pressure was recorded carefully. All the data thus obtained were processed and analyzed using SPSS version 10.0. Mean and standard deviation (SD) were calculated for age, diastolic and systolic blood pressure. In group 1 the drop in mean SBP between first and last visit was 15.42 mm Hg. In group 2 the drop in mean SBP between first and last visit was 18.34 mm Hg. In group 1, the drop in mean DBP between first and last visit was 10.08 mm Hg. In group 2 the drop in mean DBP between first and last visit was 14.65 mmHg. Mean drop in SBP of both the groups were compared with each other and found to be significantly different (P=0.003). Similarly mean drop in DBP of both the groups were compared with each other and found to be significant statistically (P=0.001). Hydrochlorothiazide-Amiloride had significantly better antihypertensive effect than Amlodipine in patients of mild essential hypertension at the end of five months therapy. (author)

CGRPα within the Trpv1-Cre population contributes to visceral nociception.

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Spencer, Nick J; Magnúsdóttir, Elín I; Jakobsson, Jon E T; Kestell, Garreth; Chen, Bao Nan; Morris, David; Brookes, Simon J; Lagerström, Malin C

2018-02-01

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherry lx/lx ;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherry lx/lx ;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherry lx/lx ;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor

Synaptic Plasticity and Nociception

Institute of Scientific and Technical Information of China (English)

ChenJianguo

2004-01-01

Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.

Development and validation of an rp-hplc method for simultaneous determination of Ramipril and Amlodipine in tablets

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Shi-Ying Dai

2013-12-01

Full Text Available An rp-hplc method for the simultaneous determination of Ramipril (RP and Amlodipine (AL in tablets was developed and validated by Chinese Pharmacopoeia 2010. The linearity of the proposed method was investigated in the range of 0.01–0.25 mg/mL (r2=0.9998 for RP and 0.014–0.36 mg/mL (r2=0.9997 for AL. The limits of detection (LOD were 0.06 μg/mL and 0.02 μg/mL for RP and AL, and the limits of quantitation (LOQ were 0.2 μg/mL and 0.07 μg/mL, respectively. Some major impurities and degradation products did not disturb the detection of RP and AL and the assay can thus be considered stability-indicating. Keywords: Ramipril, Amlodipine, RP-HPLC, Stability-indicating

Separation of digoxin by luiquid-luiquid extraction from extracts of foxglove secondary glycosides

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Novković Vesna V.

2014-01-01

Full Text Available The present study deals with the extraction of digoxin (Dgx from chloroform and trichloroethylene extracts of the secondary glycosides of fermented foxglove (Digitalis lanata Ehrh. foliage by liquid-liquid extraction. The extraction degree (ED of Dgx achieved by maceration and percolation using 10% vol. aqueous ethanol solutions were higher than 95%. Using trichlorethylene and chloroform, the ED of Dgx of about 100% and 96%, respectively from the liquid ethanolic extracts (macerate or percolate were achieved by the four-cycle extraction. Fifteen separating funnels were employed for the liquid-liquid extraction. Three different four-component two-phase systems (ethanol:water - chloroform:ethyl acetate, ethanol:water - chloroform:trichloroethylene and ethanol:water - trichloroethylene:ethyl acetate were tested as an extracting solvent to get the final product having more than 98% of Dgx. The initial amount of the chloroform or trichloroethylene extract in the light phase was varied between 5 and 25 g/L, while the volume ratio of light and heavy phases was in the range of 1:1 to 1:2. The best Dgx yield of 98% was achieved with the system ethanol:water - chloroform:trichloroethylene 35:15:20:30 at the volume ratio of the phases of 1:1.1 and at the initial amount of the extract of 15 g/L. Purity of the separated digoxin was 99.8 %. [Projekat Ministarstva nauke Republike Srbije, br. TR-34012

Comparative digoxin determination in serum by means of a radioimmuno- and an enzyme immunoassay

International Nuclear Information System (INIS)

Reinhard, M.

1981-01-01

Two immunologic measuring methods for the quantitative digoxin determination in serum were compared. One method bases on the principle of radioisotope dilution, the second one on the principle of enzyme inhibition. The radioimmunoassay served as reference method. The limit of detection for RIA is 0.23 ng/ml, for EIA 0.40 ng/ml. For both methods the measuring range extends up to approx. 5.5 ng/ml. The degree of precision in series is 8.2% for RIA, 10.8% for EIA. Day-to-day precision is 4.4% for RIA, 15.2% for EIA. On comparison, the 59 serum samples of patients who received digoxin did not show any systematic difference. The results obtained can be transformed by means of the equations Csub(EIA) = 0.041 ng/ml + 0.936 Csub(RIA). In pathologic sera, however, there are significant differences disfavoring EIA, because due to high color concentrations or turbidities these sera do not permit any or any exact extinction measurements. The enzyme immunoassay should not be used with such sera. With regard to practicability the EIA corresponds more or less to RIA. The EIA can essentially be economized by using semi-microcuvettes and applying only the half of the recommended enzyme and antibody volume. (orig.) [de

Multiway analysis methods applied to the fluorescence excitation-emission dataset for the simultaneous quantification of valsartan and amlodipine in tablets

Science.gov (United States)

Dinç, Erdal; Ertekin, Zehra Ceren; Büker, Eda

2017-09-01

In this study, excitation-emission matrix datasets, which have strong overlapping bands, were processed by using four different chemometric calibration algorithms consisting of parallel factor analysis, Tucker3, three-way partial least squares and unfolded partial least squares for the simultaneous quantitative estimation of valsartan and amlodipine besylate in tablets. In analyses, preliminary separation step was not used before the application of parallel factor analysis Tucker3, three-way partial least squares and unfolded partial least squares approaches for the analysis of the related drug substances in samples. Three-way excitation-emission matrix data array was obtained by concatenating excitation-emission matrices of the calibration set, validation set, and commercial tablet samples. The excitation-emission matrix data array was used to get parallel factor analysis, Tucker3, three-way partial least squares and unfolded partial least squares calibrations and to predict the amounts of valsartan and amlodipine besylate in samples. For all the methods, calibration and prediction of valsartan and amlodipine besylate were performed in the working concentration ranges of 0.25-4.50 μg/mL. The validity and the performance of all the proposed methods were checked by using the validation parameters. From the analysis results, it was concluded that the described two-way and three-way algorithmic methods were very useful for the simultaneous quantitative resolution and routine analysis of the related drug substances in marketed samples.

Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial

NARCIS (Netherlands)

Adams, Kirkwood F.; Butler, Javed; Patterson, J. Herbert; Stough, Wendy Gattis; Bauman, Jerry L.; van Veldhuisen, Dirk J.; Schwartz, Todd A.; Sabbah, Hani; Mackowiak, John I.; Ventura, Hector O.; Ghali, Jalal K.

AimsMany patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose

Innocuous cooling can produce nociceptive sensations that are inhibited during dynamic mechanical contact.

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Green, Barry G; Pope, Jennifer V

2003-02-01

In a previous study of the heat grill illusion, sensations of burning and stinging were sometimes reported when the skin was cooled by as little as 2 degrees C. Informal tests subsequently indicated that these nociceptive sensations were experienced if cooling occurred when the stimulating thermode rested on the skin, but not when the thermode was cooled and then touched to the skin. In experiment 1 subjects judged the intensity of thermal (cold/warm) and nociceptive (burning/stinging) sensations when the volar surface of the forearm was cooled to 25 degrees C (1) via a static thermode (Static condition), or (2) via a cold thermode touched to the skin (Dynamic condition). The total area of stimulation was varied from 2.6 to 10.4 cm(2) to determine if the occurrence of nociceptive sensations depended upon stimulus size. Burning/stinging was rated 10.3 times stronger in the Static condition than in the Dynamic condition, and this difference did not vary significantly with stimulus size. In experiment 2, thermal and nociceptive sensations were measured during cooling to just 31 degrees, 29 degrees or 27 degrees C, and data were obtained on the frequency at which different sensation qualities were experienced. Stinging was the most frequently reported nociceptive quality in the Static condition, and stinging and burning were both markedly reduced in the Dynamic condition. In experiment 3 we tested the possibility that dynamic contact might have inhibited burning and stinging not because of mechanical contact per se, but rather because dynamic contact caused higher rates of cooling. However, varying cooling rate over a tenfold range (-0.5 degrees to -5.0 degrees /s) had no appreciable effect on the frequency of stinging and burning. Overall, the data show that mild cooling can produce nociceptive sensations that are suppressed under conditions of dynamic mechanical contact. The latter observation suggests that cold is perceived differently during active contact with

Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

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Yelena Nersesyan

2017-11-01

Full Text Available Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.

Sequential Spectrophotometric Method for the Simultaneous Determination of Amlodipine, Valsartan, and Hydrochlorothiazide in Coformulated Tablets

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Hany W. Darwish

2013-01-01

Full Text Available A new, simple and specific spectrophotometric method was developed and validated in accordance with ICH guidelines for the simultaneous estimation of Amlodipine (AML, Valsartan (VAL, and Hydrochlorothiazide (HCT in their ternary mixture. In this method three techniques were used, namely, direct spectrophotometry, ratio subtraction, and isoabsorptive point. Amlodipine (AML was first determined by direct spectrophotometry and then ratio subtraction was applied to remove the AML spectrum from the mixture spectrum. Hydrochlorothiazide (HCT could then be determined directly without interference from Valsartan (VAL which could be determined using the isoabsorptive point theory. The calibration curve is linear over the concentration ranges of 4–32, 4–44 and 6–20 μg/mL for AML, VAL, and HCT, respectively. This method was tested by analyzing synthetic mixtures of the above drugs and was successfully applied to commercial pharmaceutical preparation of the drugs, where the standard deviation is <2 in the assay of raw materials and tablets. The method was validated according to the ICH guidelines and accuracy, precision, repeatability, and robustness were found to be within the acceptable limits.

Preparation and preclinical evaluation of 68Ga-DOTA-amlodipine for L-type calcium channel imaging

Science.gov (United States)

Firuzyar, Tahereh; Jalilian, Amir Reza; Aboudzadeh, Mohammad Reza; Sadeghpour, Hossein; Shafiee-Ardestani, Mahdi; Khalaj, Ali

2016-01-01

Aim: In order to develop a possible tracer for L-type calcium channel imaging, we here report the development of a Ga-68 amlodipine derivative for possible PET imaging. Materials and Methods: Amlodipine DOTA conjugate was synthesized, characterized and went through calcium channel blockade, toxicity, apoptosis/necrosis tests. [68Ga] DOTA AMLO was prepared at optimized conditions followed by stability tests, partition coefficient determination and biodistribution studies using tissue counting and co incidence imaging up to 2 h. Results: [68Ga] DOTA AMLO was prepared at pH 4–5 in 7–10 min at 95°C in high radiochemical purity (>99%, radio thin layer chromatography; specific activity: 1.9–2.1 GBq/mmol) and was stable up to 4 h with a log P of −0.94. Calcium channel rich tissues including myocardium, and tissues with smooth muscle cells such as colon, intestine, and lungs demonstrated significant uptake. Co incidence images supported the biodistribution data up to 2 h. Conclusions: The complex can be a candidate for further positron emission tomography imaging for L type calcium channels. PMID:27833311

Changes in thermal nociceptive responses in dairy cows following experimentally induced Escherichia coli mastitis

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Klaas Ilka C

2011-05-01

Full Text Available Abstract Background Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables. Methods Seven Danish Holstein-Friesian cows were kept in tie-stalls, where the E. coli associated mastitis was induced and laser stimulations were conducted. Measurements of rectal temperature, somatic cell counts, white blood cell counts and E. coli counts were conducted. Furthermore, scores were given for anorexia, local udder inflammation and milk appearance to quantify the local and systemic disease response. In order to quantify the nociceptive threshold, behavioral responses toward cutaneous NLS applied to six skin areas at the tarsus/metatarsus and udder hind quarters were registered at evening milking on day 0 (control and days 1, 2, 3, 6 and 10 after experimental induction of mastitis. Results All clinical and paraclinical variables were affected by the induced mastitis. All cows were clinically ill on days 1 and 2. The cows responded behaviorally toward the NLS. For hind leg stimulation, the proportion of cows responding by stepping was higher on day 0 than days 3 and 6, and the frequency of leg movements after laser stimulation tended to decrease on day 1 compared to the other days. After udder stimulation, the proportion of cows responding by stepping was higher on day 1 than on all other days of testing. Significant correlations between the clinical and paraclinical variables of disease and the behavioral responses toward nociceptive stimulation were found. Conclusions Changes in behavioral responses coincide with peaks in local and systemic signs of E

Extracorporeal life support and digoxin-specific Fab fragments for successful management of Taxus baccata intoxication with low output and ventricular arrhythmia.

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Farag, Mina; Badowski, Dominika; Koschny, Ronald; Skopp, Gisela; Brcic, Andreas; Szabo, Gabor B

2017-12-01

Yew plants are evergreen shrubs which are widely spread throughout the northern hemisphere. Taxane alkaloid derivatives, mainly taxine B, represent the main toxins of Taxus baccata and are highly cardiotoxic. Due to the lack of randomized clinical trials, case reports on accidental or suicidal yew intoxications build the only source of knowledge of clinical treatment options. We report the case of a suicidal yew ingestion admitted to our hospital under prolonged cardiopulmonary resuscitation due to pulseless electrical activity. Extra-corporeal life support (ECLS) was established to maintain adequate organ perfusion. Repeated administration of digoxin-specific Fab antibody fragments, which cross-react with taxine, was associated with an immediate conversion from asystole to broad-complex bradycardia and a gradual normalization of the electrocardiogram (ECG). This was paralleled by a recovery of the cardiac function and weaning from the ECLS. The taxine metabolite 3,5-dimethoxyphenol could be detected by mass spectrometry before but not after the first Fab-fragment treatment. In contrast, the total amount of taxine (including the neutralized, Fab fragment-bound fraction) was increased after each Fab fragment administration, suggesting an accumulation of neutralized, since antibody-bound taxine in the blood by anti-digoxin Fab fragments. In conclusion, the successful clinical course of this case suggests a benefit of an early anti-digoxin Fab-fragment administration for the treatment of yew intoxication. Copyright © 2017 Elsevier Inc. All rights reserved.

Combined Treatment with Amlodipine and Atorvastatin Calcium Reduces Circulating Levels of Intercellular Adhesion Molecule-1 and Tumor Necrosis Factor-α in Hypertensive Patients with Prediabetes.

Science.gov (United States)

Huang, Zhouqing; Chen, Chen; Li, Sheng; Kong, Fanqi; Shan, Peiren; Huang, Weijian

2016-01-01

To assess the effect of amlodipine and atorvastatin on intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α expression, as endothelial function and inflammation indicators, respectively, in hypertensive patients with and without prediabetes. Forty-five consecutive patients with hypertension, diagnosed according to JNC7, were divided into two groups based on the presence (HD group, n = 23) or absence (H group, n = 22) of prediabetes, diagnosed according to 2010 ADA criteria, including impaired glucose tolerance (IGT) and fasting glucose tests. All patients simultaneously underwent 12-week treatment with daily single-pill amlodipine besylate/atorvastatin calcium combination (5/10 mg; Hisun-Pfizer Pharmaceuticals Co. Ltd). Serum isolated before and after treatment from overnight fasting blood samples was analyzed by ELISA. In the HD and H groups after vs. before 12-week amlodipine/atorvastatin treatment, there were significantly (all P atorvastatin improved endothelial function and inflammation, as reflected by lower circulating levels of ICAM-1 and TNF-α, more prominently in hypertensives with than without prediabetes. Starting statin treatment before overt diabetes in hypertensives might thus improve cardiovascular outcomes.

Development and validation of different methods manipulating zero order and first order spectra for determination of the partially overlapped mixture benazepril and amlodipine: A comparative study

Science.gov (United States)

Hemdan, A.

2016-07-01

Three simple, selective, and accurate spectrophotometric methods have been developed and then validated for the analysis of Benazepril (BENZ) and Amlodipine (AML) in bulk powder and pharmaceutical dosage form. The first method is the absorption factor (AF) for zero order and amplitude factor (P-F) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 238 nm or from their first order spectra at 253 nm. The second method is the constant multiplication coupled with constant subtraction (CM-CS) for zero order and successive derivative subtraction-constant multiplication (SDS-CM) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 240 nm and 238 nm, respectively, or from their first order spectra at 214 nm and 253 nm for Benazepril and Amlodipine respectively. The third method is the novel constant multiplication coupled with derivative zero crossing (CM-DZC) which is a stability indicating assay method for determination of Benazepril and Amlodipine in presence of the main degradation product of Benazepril which is Benazeprilate (BENZT). The three methods were validated as per the ICH guidelines and the standard curves were found to be linear in the range of 5-60 μg/mL for Benazepril and 5-30 for Amlodipine, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits.

[Comparison of benazepril monotherapy to amlodipine plus benazepril in the treatment of patients with mild and moderate hypertension: a multicentre, randomized, double-blind, parallel-controlled study].

Science.gov (United States)

Fan, Chao-mei; Yan, Li-rong; Tao, Yong-kang; Wang, Li; Li, Yu-qing; Gao, Ming-ming; Wang, Yan-ni; Li, Cheng-xiang; Wang, Xiao-wan; Lu, Xiao-lei; Pang, Hui-min; Li, Yi-shi

2011-01-01

To evaluate the efficacy and tolerability of the fixed combination of amlodipine 5 mg/benazepril 10 mg once-daily therapy, compared with benazepril, 10 mg, monotherapy in patients with mild and moderate hypertension, and to evaluate the 24 h antihypertensive efficacy and the duration of action by ambulatory blood pressure monitoring. In a multicenter, randomized, double-blind, parallel controlled trial, 356 cases of hypertensive patients after 2 weeks wash-out, and then given 4 weeks of benazepril 10 mg monotherapy, 220 patients with mean seated diastolic blood pressure (SeDBP) remained ≥ 90 mm Hg (1 mm Hg = 0.133 kPa) were randomly divided into benazepril 10 mg/amlodipine 5 mg (BZ10/AML5) fixed-dose combination therapy group (once a day, n = 113), and benazepril monotherapy group (daily 20 mg, n = 107). In the two groups the patients with SeDBP ≥ 90 mm Hg were doubled the dosage of the initial regimen at the end of 4-week treatment for additional 4 weeks, and the patients with SeDBP benazepril/amlodipine (10 mg/5 mg) and benazepril (20 mg) alone were 83.1%/76.0% and 85.8%/79.5%, respectively. Adverse events rates were 16.8% in the combination therapy group and 35.5% in the monotherapy group (P benazepril/amlodipine was superior to benazepril monotherapy and was well tolerated in patients with essential hypertension and allowing a satisfactory BP control for 24 hours.

Predictors of systolic BP benazepril plus amlodipine or hydrochlorothiazide) in the ACCOMPLISH Study.

Science.gov (United States)

Kjeldsen, Sverre E; Jamerson, Kenneth A; Bakris, George L; Pitt, Bertram; Dahlöf, Björn; Velazquez, Eric J; Hua, Tsushung A; Kelly, Roxzana Y; Zappe, Dion; Hester, Allen; Tuomilehto, Jaakko; Ostergren, Jan; Ibsen, Hans; Weber, Michael

2012-04-01

The ACCOMPLISH Trial investigated intensive antihypertensive combination treatment with benazepril + amlodipine (B+A) or benazepril + hydrochlorothiazide (B+H) on cardiovascular outcomes in patients with systolic hypertension. We analyzed the baseline predictors of achieving a systolic blood pressure (SBP) Nordic region) and Caucasian ethnicity in both randomization arms. A higher diastolic BP and the use of lipid lowering agents indicated favorable effects in the B+H arm only. The predictors of uncontrolled SBP were: (i) higher baseline SBP values, (ii) higher number of previous antihypertensive medications in both arms, (iii) the previous use of insulin in the B+A arm, and (iv) pre-trial calcium channel blocker (CCB) use in the B+H arm. Additionally, pre-trial use of thiazides and electrocardiogram (ECG)-left ventricular hypertrophy (LVH) at baseline predicted higher, and smoking lower absolute SBP in the B+A arm and the use of thiazides and proteinuria a higher SBP in the B+H arm. Irrespective of treatment, patients in the USA and Caucasians achieved better SBP control, whereas higher baseline SBP and more previous antihypertensive medications indicated less control. Concomitant use of lipid lowering treatment indicated a better SBP control in the benazepril + hydrochlorothiazide arm. Lastly, insulin use and ECG-LVH in the benazepril + amlodipine arm and proteinuria in the benazepril + hydrochlorothiazide arm indicated poor control.

Chronic intrathecal cannulation enhances nociceptive responses in rats

Directory of Open Access Journals (Sweden)

Almeida F.R.C.

2000-01-01

Full Text Available The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2 was significantly increased in cannulated (Cn rats, compared with naive (Nv or sham-operated (Sh rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%. The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

Efficacy of fix dose combination (atorvastatin and amlodipine) in treatment of uncontrolled hypertension and dyslipidemia

International Nuclear Information System (INIS)

Bashir, S.; Sherwani, M.U.K.; Batool, A.

2012-01-01

The fixed-dose combination containing the antihypertensive agent amlodipine and the statin, atorvastatin, is the first combination of its kind designed to treat two risk factors for cardiovascular disease (CVD), i.e., hypertension and dyslipidemia. in this study, blood pressure and lipid lowering effects of combination of amlodipine and atorvastatin were evaluated in uncontrolled hypertensive patients. Methods: Thirty patients both male and female in the age group 35-60 years attending the hypertensive clinic of PMRC FJMC suffering from uncontrolled hypertension were selected. baseline blood pressure was checked after half hour rest in sitting and standing position using mercury sphygmomanometer. Blood sample was collected from all patients after overnight fasting for assessment of serum cholesterol, triglycerides, LDL and HDL cholesterol levels. they were prescribed with fixed dose combination of 5 mg amlodipine and 10 mg atorvastatin. Patients were followed for their blood pressure measurement after every 4 weeks up to 12 weeks. At the end of 12 weeks their fasting blood sample was taken again for determination of serum cholesterol, triglyceride, IDL and HDL cholesterol levels. Results: Systolic blood pressure after 4, 8 and 12 weeks was significantly lower at all intervals from baseline. when systolic blood pressure after 8 and 12 weeks was compared with 4 weeks, the effect was again significant (p=0.024, p=0.002 respectively). There was no significant reduction seen in 8 versus 12 weeks (p=0.493). Diastolic blood pressure at 4, 8 and 12 weeks was significantly lower from baseline. Diastolic blood pressure after 4 and 8 weeks when compared with 8 and 12 weeks was not significantly low (p=0.99 and 0.91 respectively). Lipid profile of the patients was significantly reduced from baseline after twelve weeks of fixed dose combination of treatment (p<0.000). Conclusion: Combination therapy proved to be effective in controlling hypertension and dyslipidemia than single

Efficacy of fix dose combination (atorvastatin and amlodipine) in treatment of uncontrolled hypertension and dyslipidemia

Energy Technology Data Exchange (ETDEWEB)

Bashir, S; Sherwani, M U.K.; Batool, A [Fatima Jinnah Medical College, Lahore (Pakistan)

2012-07-15

The fixed-dose combination containing the antihypertensive agent amlodipine and the statin, atorvastatin, is the first combination of its kind designed to treat two risk factors for cardiovascular disease (CVD), i.e., hypertension and dyslipidemia. in this study, blood pressure and lipid lowering effects of combination of amlodipine and atorvastatin were evaluated in uncontrolled hypertensive patients. Methods: Thirty patients both male and female in the age group 35-60 years attending the hypertensive clinic of PMRC FJMC suffering from uncontrolled hypertension were selected. baseline blood pressure was checked after half hour rest in sitting and standing position using mercury sphygmomanometer. Blood sample was collected from all patients after overnight fasting for assessment of serum cholesterol, triglycerides, LDL and HDL cholesterol levels. they were prescribed with fixed dose combination of 5 mg amlodipine and 10 mg atorvastatin. Patients were followed for their blood pressure measurement after every 4 weeks up to 12 weeks. At the end of 12 weeks their fasting blood sample was taken again for determination of serum cholesterol, triglyceride, IDL and HDL cholesterol levels. Results: Systolic blood pressure after 4, 8 and 12 weeks was significantly lower at all intervals from baseline. when systolic blood pressure after 8 and 12 weeks was compared with 4 weeks, the effect was again significant (p=0.024, p=0.002 respectively). There was no significant reduction seen in 8 versus 12 weeks (p=0.493). Diastolic blood pressure at 4, 8 and 12 weeks was significantly lower from baseline. Diastolic blood pressure after 4 and 8 weeks when compared with 8 and 12 weeks was not significantly low (p=0.99 and 0.91 respectively). Lipid profile of the patients was significantly reduced from baseline after twelve weeks of fixed dose combination of treatment (p<0.000). Conclusion: Combination therapy proved to be effective in controlling hypertension and dyslipidemia than single

[Pharmacogenetic approaches to predicting the efficiency and safety of amlodipine in patients with arterial hypertension].

Science.gov (United States)

Sychev, D A; Shih, N V; Kalle, E G; Ryzhikova, K A; Morozova, T E

2017-10-01

An open, non-comparative, prospective clinical study was conducted to evaluate the antihypertensive efficacy and tolerability of amlodipine, a calcium antagonist, in patients with arterial hypertension (AH) I-II stages, depending on the genotype for the polymorphic marker C3435T of the ABCB1 gene. The study included 100 patients with AH I-II stages, aged from 45 to 58 years. The initial dose of amlodipine was 5 mg, duration of treatment was 12 weeks. General clinical examination methods, office measurement and daily blood pressure monitoring, tolerance evaluation, and genotyping using the ABCB1 polymorphic marker C3435T by the PCR-RFLP method (polymerase chain reaction and restriction fragment length polymorphism) were used. The statistical analysis of results was carried out using the Mann-Whitney U test for quantitative variables, Kruskal-Wallis one-way analysis of variance (ANOVA) for three independent groups of quantitative data. Excellent antihypertensive efficacy with the CC genotype was found in 11.8% patients, with CT - 33.9%, with TT - 43.3%; good - 35.3%, 32.1%, and 33.3% respectively, satisfactory - 52.9%, 34,0% and 23.4% respectively. Six patients with the CT genotype and nine patients with the CC genotype required the increase in the dose to 10 mg. The number of patients with Adverse drug reactions (ADR) were found in 35.3% of patients with the CC genotype, 6.7% with the TT genotype and 11.3% with the CT genotype. The Kruskal-Wallis test revealed significant differences between CC and TT genotypes in the degree of decrease in SBP (p=0.02), antihypertensive efficacy parameter (p=0.02), an increase in dose requirements (p = 0.04) and the incidence of ADR(p=0.05). In AH patients (I-II stage) with the TT genotype of the C3435T gene polymorphism one can expect higher rates of antihypertensive efficacy of amlodipine in combination with a good safety profile and the lowest ADR percentage, while patients with the CC genotype more likely to develop ADR and

Cost Minimization Analysis of Antihypertensive Therapy with Captopril-Hydrochlorothiazide and Amlodipine-Hydrochlorothiazide in One of Hospitals in Bandung

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Andini Faramitha

2017-09-01

Full Text Available The successful therapy of stage 2 hypertension can be supported by the administration of antihypertensive. Existence of various antihypertensive alternative, making pharmacoeconomics study is needed in order to have an effective and efficient therapy. Purpose of this study is to find the antihypertensive group therapy which is more efficient in cost (cost minimization which used in the treatment of stage 2 hypertension in patients at one hospital in Bandung from 2011 until 2013. This study is an observational reserach with retrospective data collection. Data retrieval is done by taking the medical records of hospitalized patients who received therapy of stage 2 hypertension antihypertensive, captopril-hydrochlorothiazide or amlodipin-hydrochlorothiazide. Components that are collected include the cost of antihypertensive, supportive therapy costs, the cost of action, administrative expenses and cost of hospitalization. The result of the study cost minimization analysis showed that the total cost of treatment with the antihypertensive captopril-hydrochlorothiazide is lower compared to amlodipin- hydrochlorothiazide, with the difference amounting to Rp126,798.

Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study

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Ariadne M. Brondi

2017-01-01

Full Text Available A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40°C under 75% relative humidity and dry conditions. For this study, a method based on high-performance liquid chromatography (HPLC was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD and charged aerosol detector (CAD. The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 μg mL−1 for amlodipine and from 25 to 500 μg mL−1 for olmesartan with coefficient of determination (R2 ≥ 0.9908 while repeatability and reproducibility (expressed as relative standard deviation were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing.

A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.

Science.gov (United States)

Eghbali, Aziz; Kazemi, Hamideh; Taherahmadi, Hassan; Ghandi, Yazdan; Rafiei, Mohammad; Bagheri, Bahador

2017-12-01

Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hypothalamic digoxin and hemispheric chemical dominance in relation to the pathogenesis of bronchial asthma.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-08-01

The isoprenoid pathway produces three key metabolites--digoxin (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter transport), dolichol (regulator of N-glycosylation of proteins), and ubiquinone (free radical scavenger). The isoprenoid pathway was assessed in patients with bronchial asthma. The pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find out the role of hemispheric dominance in the pathogenesis of bronchial asthma. The pathway was upregulated with increase in digoxin synthesis in bronchial asthma. There was an increase in tryptophan catabolites and a reduction in tyrosine catabolites in patients with bronchial asthma. The ubiquinone levels were low and lipid peroxidation increased in these patients. There was increase in dolichol and glycoconjugate levels and reduction in lysosomal stability in these patients. The cholesterol:phospholipid ratio was increased and glycoconjugate levels were reduced in the membranes of these patients. The patterns noticed in bronchial asthma were similar to those in patients with right hemispheric chemical dominance. Bronchial asthma occurs in right hemispheric chemically dominant individuals. Ninety percent of the patients with bronchial asthma were right-handed and left hemispheric dominant by the dichotic listening test. But their biochemical patterns were similar to those obtained in right hemispheric chemical dominance. Hemispheric chemical dominance is a different entity and has no correlation with handedness or the dichotic listening test.

Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

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Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

2017-07-01

Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Factors affecting mechanical (nociceptive) thresholds in piglets.

Science.gov (United States)

Janczak, Andrew M; Ranheim, Birgit; Fosse, Torunn K; Hild, Sophie; Nordgreen, Janicke; Moe, Randi O; Zanella, Adroaldo J

2012-11-01

To evaluate the stability and repeatability of measures of mechanical (nociceptive) thresholds in piglets and to examine potentially confounding factors when using a hand held algometer. Descriptive, prospective cohort. Forty-four piglets from four litters, weighing 4.6 ± 1.0 kg (mean ± SD) at 2 weeks of age. Mechanical thresholds were measured twice on each of 2 days during the first and second week of life. Data were analyzed using a repeated measures design to test the effects of behavior prior to testing, sex, week, day within week, and repetition within day. The effect of body weight and the interaction between piglet weight and behaviour were also tested. Piglet was entered into the model as a random effect as an additional test of repeatability. The effect of repeated testing was used to test the stability of measures. Pearson correlations between repeated measures were used to test the repeatability of measures. Variance component analysis was used to describe the variability in the data. Variance component analysis indicated that piglet explained only 17% of the variance in the data. All variables in the model (behaviour prior to testing, sex, week, day within week, repetition within day, body weight, the interaction between body weight and behaviour, piglet identity) except sex had a significant effect (p testing and measures changed with repeated testing and increased with increasing piglet weight, indicating that time (age) and animal body weight should be taken into account when measuring mechanical (nociceptive) thresholds in piglets. Mechanical (nociceptive) thresholds can be used both for testing the efficacy of anaesthetics and analgesics, and for assessing hyperalgesia in chronic pain states in research and clinical settings. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Has central sensitization become independent of nociceptive input in chronic pancreatitis patients who fail thoracoscopic splanchnicectomy?

NARCIS (Netherlands)

Bouwense, S.A.W.; Buscher, H.C.J.L.; Goor, H. van; Wilder-Smith, O.H.G.

2011-01-01

BACKGROUND AND OBJECTIVES: : Central sensitization due to visceral pancreatic nociceptive input may be important in chronic pancreatitis pain. We investigated whether bilateral thoracoscopic splanchnicectomy (BTS) to reduce nociceptive input in chronic pancreatitis patients (CPP) with poor pain

Cellular mechanisms of nociception in the frog

Czech Academy of Sciences Publication Activity Database

Kuffler, D. P.; Lyfenko, Alla; Vyklický st., Ladislav; Vlachová, Viktorie

2002-01-01

Roč. 88, č. 4 (2002), s. 1843-1850 ISSN 0022-3077 R&D Projects: GA ČR GA305/00/1639; GA MŠk LN00B122 Grant - others:NATO(XX) Grant 977062 Institutional research plan: CEZ:AV0Z5011922 Keywords : cellular mechanisms of nociception * frog Subject RIV: FH - Neurology Impact factor: 3.743, year: 2002

Possible effects of mobilisation on acute post-operative pain and nociceptive function after total knee arthroplasty

DEFF Research Database (Denmark)

Lunn, T H; Kristensen, B B; Gaarn-Larsen, L

2012-01-01

anaesthesia and analgesia underwent an exercise (mobilisation) strategy on the first post-operative morning consisting of 25-m walking twice, with a 20-min interval. Pain was assessed at rest and during passive hip and knee flexion before, and 5 and 20 min after walk, as well as during walk. Nociceptive......BACKGROUND: Experimental studies in animals, healthy volunteers, and patients with chronic pain suggest exercise to provide analgesia in several types of pain conditions and after various nociceptive stimuli. To our knowledge, there is no data on the effects of exercise on pain and nociceptive...... function in surgical patients despite early mobilisation being an important factor to enhance recovery. We therefore investigated possible effects of mobilisation on post-operative pain and nociceptive function after total knee arthroplasty (TKA). METHODS: Thirty patients undergoing TKA under standardised...

Mechanisms of G Protein-Coupled Estrogen Receptor-Mediated Spinal Nociception

DEFF Research Database (Denmark)

Deliu, Elena; Brailoiu, G. Cristina; Arterburn, Jeffrey B.

2012-01-01

. Cytosolic calcium concentration elevates faster and with higher amplitude following G-1 intracellular microinjections compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium......Human and animal studies suggest that estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pronociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER......) activation. Membrane depolarization and increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological, and fluorescent imaging studies, we evaluated GPER involvement...

Digoxin-like immunoreactivity, endogeneous cardiac glycoside-like factors (s) and natriuretic hormone. More than a hypothesis. Review article

Energy Technology Data Exchange (ETDEWEB)

Clerico, A

1987-01-01

Endogenous factors crossreacting with antidigoxin antibodies (digoxin-like immunoreactive substances=DLIS) have been found in several tissues and body fluids of animals and humans, using commercially avaiable digoxin RIA or EIA methods. Detectable DLIS concentration were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at present, unknown, although it has been suggested that DLIS could be a substance with low molecular weight. Experimental studies and theoretical consideration suggest that DLIS, in addition to reacting with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na/sup +//K/sup +/ ATPase (sodium pump). Therefore, it has been suggested that DLSI is an endogeneous modulator of the membrane sodium-potassium pump and it could play a role in the regulation of fluid and electrolytes muscular tone of myocardial and also in pathogenesis of hypertension. 91 refs.

Hypothalamic digoxin, hemispheric chemical dominance, and the tridosha theory.

Science.gov (United States)

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-05-01

Ayurveda, the traditional Indian System of Medicine, deals with the theory of the three tridosha states (both physical and psychological): Vata, Pitta, and Kapha. They are the three major human constitutional types that both depend on psychological and physical characteristics. The Pitta state is described as a critical, discriminative, and rational psychological state of mind, while the Kapha state is described as being dominant for emotional stimuli. The Vata state is an intermediate unstable shifting state. The Pitta types are of average height and built with well developed musculature. The Vata types are thin individuals with low body mass index. The Kapha types are short stocky individuals that tend toward obesity, and who are sedentary. The study assessed the biochemical differences between right hemispheric dominant, bihemispheric dominant, and left hemispheric dominant individuals, and then compared this with the patterns obtained in the Vata, Pitta, and Kapha states. The isoprenoid metabolites (digoxin, dolichol, and ubiquinone), glycoconjugate metabolism, free radical metabolism, and the RBC membrane composition were studied. The hemispheric chemical dominance in various systemic diseases and psychological states was also investigated. The results showed that right hemispheric chemically dominant/Kapha state had elevated digoxin levels, increased free radical production and reduced scavenging, increased tryptophan catabolites and reduced tyrosine catabolites, increased glycoconjugate levels and increased cholesterol: phospholipid ratio of RBC membranes. Left hemispheric chemically dominant/Pitta states had the opposite biochemical patterns. The patterns were normal or intermediate in the bihemispheric chemically dominant/Vata state. This pattern could be correlated with various systemic and neuropsychiatric diseases and personality traits. Right hemispheric chemical dominance/Kapha state represents a hyperdigoxinemic state with membrane sodium

Preparation and preliminary biological evaluation of radiogallium-labeled DTPA-amlodipine complex for possible L-type calcium channel imaging

Energy Technology Data Exchange (ETDEWEB)

Firuzyar, Tahereh; Shafiee-Ardestani, Mehdi; Khalaj, Ali [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Faculty of Pharmacy; Jalilian, Amir R.; Fazaeli, Yousef; Aboudzadeh, Mohammad Reza [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of). Radiopharmacy Research Group

2014-07-01

A DTPA-conjugated amlodipine analog (DTPA-AMLO) 3, was prepared for possible voltage gated calcium channel imaging after radiolabeling with Ga-67. [{sup 67}Ga]-DTPA-AMLO complex was prepared starting [{sup 67}Ga]gallium chloride and DTPA-AMLO in 60-90 min at 50-60 C in phosphate buffer. The partition co-efficient and stability of the tracer was determined in final solution (25 C) and presence of human serum (37 C) up to 24 h. The biodistribution of the labeled compound in wild-type rats were determined up to 72 h using organ counting and SPECT. The radiolabled complex was prepared in high radiochemical purity (>96%, RTLC and >98% HPLC) and significant specific activity (7-10 GBq/mmol). The log P for the complex was calculated as -0.594, consistent with a water soluble complex. The tracer is mostly washed out through kidneys which were in full compliance with the amlodipine metabolism and imaging studies demonstrated the same behavior. The tracer uptake in organs with smooth muscles was observed in stomach, colon as well as intestine.

Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses.

Science.gov (United States)

Elfenbein, Johanna R; Sanchez, L Chris; Robertson, Sheilah A; Cole, Cynthia A; Sams, Richard

2009-03-01

To evaluate the effects of detomidine on visceral and somatic nociception, heart and respiratory rates, sedation, and duodenal motility and to correlate these effects with serum detomidine concentrations. Nonrandomized, experimental trial. Five adult horses, each with a permanent gastric cannula weighing 534 +/- 46 kg. Visceral nociception was evaluated by colorectal (CRD) and duodenal distension (DD). The duodenal balloon was used to assess motility. Somatic nociception was assessed via thermal threshold (TT). Nose-to-ground (NTG) height was used as a measure of sedation. Serum was collected for pharmacokinetic analysis. Detomidine (10 or 20 microg kg(-1)) was administered intravenously. Data were analyzed by means of a three-factor anova with fixed factors of treatment and time and random factor of horse. When a significant time x treatment interaction was detected, differences were compared with a simple t-test or Bonferroni t-test. Significance was set at p Detomidine produced a significant, dose-dependent decrease in NTG height, heart rate, and skin temperature and a significant, nondose-dependent decrease in respiratory rate. Colorectal distension threshold was significantly increased with 10 microg kg(-1) for 15 minutes and for at least 165 minutes with 20 microg kg(-1). Duodenal distension threshold was significantly increased at 15 minutes for the 20 microg kg(-1) dose. A significant change in TT was not observed at either dose. A marked, immediate decrease in amplitude of duodenal contractions followed detomidine administration at both doses for 50 minutes. Detomidine caused a longer period of visceral anti-nociception as determined by CRD but a shorter period of anti-nociception as determined by DD than has been previously reported. The lack of somatic anti-nociception as determined by TT testing may be related to the marked decrease in skin temperature, likely caused by peripheral vasoconstriction and the low temperature cut-off of the testing device.

Effect of ouabain, digoxin and digitoxigenin on potassium uptake and histamine release from rat peritoneal mast cells

DEFF Research Database (Denmark)

Knudsen, T; Ferjan, I; Johansen, Torben

1993-01-01

Rat peritoneal mast cells were used to study the effects of digitalis glycosides on potassium uptake and histamine release induced by compound 48/80, substance P and egg-albumin (immunological release). In the absence of calcium all glycosides inhibited potassium uptake. Ouabain and digoxin....... Hydrophilic digitalis glycosides seem to enhance histamine release secondary to an increase in intracellular sodium. Lipophilic glycosides have no effect on the release....

Linkage between increased nociception and olfaction via a SCN9A haplotype.

Directory of Open Access Journals (Sweden)

Dirk Heimann

Full Text Available BACKGROUND AND AIMS: Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity. METHODS: SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14 or rs6746030C>T (R1150W; n = 21 were compared with non-carriers (n = 40. Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli. RESULTS: The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1, 1 allele: 10.6±2.6 (n = 34, 2 alleles: 9.5±2.1 (n = 40. The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m(2, 1 allele: 29.8±10.4 N/m(2, 2 alleles: 33.5±10.2 N/m(2. CONCLUSIONS: The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level.

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

Science.gov (United States)

Saitoh, Chikashi; Yokoyama, Hitoshi; Chancellor, Michael B.; de Groat, William C.; Yoshimura, Naoki

2009-01-01

Aims Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (ip) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats. Methods Female Sprague-Dawley rats were used. Cystitis was induced by ip injection of CYP (100 and 200mg/kg) or intravesical instillation of acetone (10, 30 and 50%) via a polyethylene catheter temporarily inserted into the bladder through the urethra. Then the incidence of nociceptive behavior (immobility with decreased breathing rates) was scored. Voided urine was collected simultaneously and continuously to measure bladder capacity. The plasma extravasation in the bladder was quantified by an evans blue (EB) dye leakage technique. Results CYP (100mg/kg, ip) induced nociceptive behavior without affecting bladder capacity or EB concentration in the bladder. A higher dose of CYP (200mg/kg, ip) decreased bladder capacity and increased EB levels as well as nociceptive behavior. In contrast, intravesical instillation of acetone (30%) decreased bladder capacity and increased EB levels, but evoked nociceptive behavior less frequently compared with CYP-treated animals. In capsaicin pretreated rats, nociceptive behavior induced by CYP or acetone was reduced; however, the overall effects of CYP or acetone on bladder capacity and bladder EB levels were unaffected. Conclusions These results suggest that there is a difference in the induction process of nociceptive behavior and small bladder capacity after two different types of bladder irritation and that C-fiber sensitization is more directly involved in pain sensation than reduced bladder capacity. PMID:19618450

Nociceptive Effects of Locally Treated Metoprolol

Directory of Open Access Journals (Sweden)

Nursima Cukadar

2015-06-01

Results: Metoprolol, an antagonist, significantly decreased the thermal latency and mechanical thresholds with dose and time dependent manner. However, dobutamine, an agonist, enhanced the latency and thresholds dose and time dependent. Conclusions: This results suggest that in contrast to dobutamine, locally treated metoprolol may cause hyperalgesic and allodynic actions. In addition, our results can demonstrate that peripheral beta-adrenergic receptors can play important roles in nociceptive process. [Cukurova Med J 2015; 40(2.000: 258-266

Differential effects of amlodipine and atorvastatin treatment and their combination on atherosclerosis in ApoE*3-Leiden transgenic mice

NARCIS (Netherlands)

Delsing, D.J.; Jukema, J.W.; van de Wiel, M.A.; Emeis, J.; van der Laarse, A.; Havekes, L.M.; Princen, H.M.G.

2003-01-01

This study was designed to investigate the potential antiatherosclerotic effects of the calcium antagonist amlodipine as compared with the HMG-CoA reductase inhibitor atorvastatin and the combination of both in ApoE*3-Leiden transgenic mice. Four groups of 15 ApoE*3-Leiden mice were put on a

Antioxidant and orofacial anti-nociceptive activities of the stem bark aqueous extract of Anadenanthera colubrina (Velloso) Brenan (Fabaceae).

Science.gov (United States)

Damascena, N P; Souza, M T S; Almeida, A F; Cunha, R S; Damascena, N P; Curvello, R L; Lima, A C B; Almeida, E C V; Santos, C C S; Dias, A S; Paixão, M S; Souza, L M A; Quintans Júnior, L J; Estevam, C S; Araujo, B S

2014-01-01

The anti-nociceptive and antioxidant activities of the Anadenantheracolubrina stem bark aqueous extract (AEAC) were investigated. AEAC (30 μg/mL) reduced 94.8% of 2,2-diphenyl-1-picrylhydrazyl radical and prevented 64% (200 μg/mL) of lipid peroxidation caused by 2,2'-azobis(2-methylpropionamidine) dihydrochloride-induced peroxyl radicals. AEAC treatment (200 and 400 mg/kg) significantly (p < 0.001) reduced mice orofacial nociception in the first (61.4% and 62.6%, respectively) and second (48.9% and 61.9%, respectively) phases of the formalin test. Nociception caused by glutamate was significantly (p < 0.001) reduced by up to 79% at 400 mg/kg, while 56-60% of the nociceptive behaviour induced by capsaicin was significantly inhibited by AEAC (100-400 mg/kg). Mice treated with AEAC did not show changes in motor performance in the Rota-rod apparatus. It appears that AEAC is of pharmacological importance in treating pain due to its anti-nociceptive effects, which were shown to be mediated by central and peripheral mechanisms.

Anti-inflammatory and anti-nociceptive activities of methanol extract from aerial part of Phlomis younghusbandii Mukerjee.

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Qiu-Shi Wang

Full Text Available This study was designed to investigate the anti-inflammatory and anti-nociceptive activity of the methanol extract from the aerial part of Phlomis younghusbandii (MEAP and to explore the possible related mechanisms. Anti-inflammatory effects of MEAP were evaluated by using the ear edema test induced by dimethylbenzene and vascular permeability test induced by acetic acid. Anti-nociceptive activities of MEAP were evaluated by the chemical nociception in models of acetic acid-induced writhing and formalin-induced hind paw licking, and by the thermal nociception in hot plate tests. Mechanisms of MEAP activities also were explored by evaluating expression levels of TNF-α, IL-6 and iNOS induced by LPS using real-time fluorogenic PCR and expression of COX-2 using Western blotting and an open-field test. The results indicated that the MEAP administered orally could significantly decrease ear edema induced by dimethylbenzene and increase vascular permeability induced by acetic acid. Additionally, the nociceptions induced by acetic acid and formalin were significantly inhibited. The anti-nociceptive effect could not be decreased by naloxone in the formalin test, and MEAP did not affect the normal autonomic activities of mice. Expression levels of pro-inflammatory cytokines (TNF-α, IL-6, iNOS induced by LPS were decreased obviously by treatment with MEAP. Furthermore, COX-2 expression in the spinal dorsal horns of the pain model mice induced by formalin was significantly down-regulated by MEAP. In conclusion, MEAP has significant anti-inflammatory and antinociceptive activities, and the mechanisms may be related to the down-regulated expression of TNF-α, IL-6, iNOS and COX-2.

Design and monitoring of photostability systems for amlodipine dosage forms.

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Ragno, G; Cione, E; Garofalo, A; Genchi, G; Ioele, G; Risoli, A; Spagnoletta, A

2003-10-20

Photostability of amlodipine (AML) has been monitored in several pharmaceutical inclusion systems characterized by plurimolecular aggregation of the drug and excipients with high molecular weight. Several formulations including cyclodextrins, liposomes and microspheres have been prepared and characterized. The photodegradation process has been monitored according to the conditions suggested by the ICH Guideline for photostability testing, by using a light cabinet equipped with a Xenon lamp and monitored by spectrophotometry. The formulations herein tested have been found to be able to considerably increase drug stability, when compared with usual pharmaceutical forms. The residual concentration detected in the inclusion complexes with cyclodextrins and liposomes was 90 and 77%, respectively, while a very good value of 97% was found for microspheres, after a radiant exposure of 11,340 kJm(-2).

Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis.

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Schwartz, Erica S; Xie, Amy; La, Jun-Ho; Gebhart, G F

2015-08-01

Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue) from the prostate revealed that thoracolumbar and lumbosacral DRG are the principal sources of somata of prostate afferents. Nociceptive markers (eg, transient receptor potential, TREK, and P2X channels) were upregulated in fast blue-labeled thoracolumbar and lumbosacral somata for up to four weeks after inflaming the prostate (intraprostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21, and 28 days after zymosan injection. Interleukin 10 and NGF were also significantly upregulated in the prostate throughout the 4 weeks of inflammation. Open-field pain-related behaviors (eg, rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase, and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for the study of mechanisms underlying pain in chronic prostatitis.

Borneol, a Bicyclic Monoterpene Alcohol, Reduces Nociceptive Behavior and Inflammatory Response in Mice

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Jackson Roberto Guedes da Silva Almeida

2013-01-01

Full Text Available Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P<0.01 reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.. When the hot plate test was conducted, borneol (in higher dose produced an inhibition (P<0.05 of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

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Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

2011-07-01

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation. Copyright © 2010 Wiley-Liss, Inc.

Trigeminal nociception-induced, cerebral Fos expression in the conscious rat

NARCIS (Netherlands)

Ter Horst, GJ; Meijler, WJ; Korf, J; Kemper, RHA

2001-01-01

Little is known about trigeminal nociception-induced cerebral activity and involvement of cerebral structures in pathogenesis of trigeminovascular headaches such as migraine. Neuroimaging has demonstrated cortical, hypothalamic and brainstem activation during the attack and after abolition with

Application of a handheld Pressure Application Measurement device for the characterisation of mechanical nociceptive thresholds in intact pig tails

DEFF Research Database (Denmark)

Di Giminiani, Pierpaolo; Sandercock, Dale A.; Malcolm, Emma M.

2016-01-01

The assessment of nociceptive thresholds is employed in animals and humans to evaluate changes in sensitivity potentially arising from tissue damage. Its application on the intact pig tail might represent a suitable method to assess changes in nociceptive thresholds arising from tail injury...... to the body was observed (P knowledge, no other...... nociceptive threshold in pig tails. This methodological approach is possibly suitable for assessing changes in tail stump MNTs after tail injury caused by tail docking and biting....

Comparison of the efficacy and safety profiles of two fixed-dose combinations of antihypertensive agents, amlodipine/benazepril versus valsartan/hydrochlorothiazide, in patients with type 2 diabetes mellitus and hypertension: a 16-week, multicenter, randomized, double-blind, noninferiority study.

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Lee, I-Te; Hung, Yi-Jen; Chen, Jung-Fu; Wang, Chih-Yuan; Lee, Wen-Jane; Sheu, Wayne Huey-Herng

2012-08-01

Hypertension is a prevalent condition that is closely associated with chronic complications in patients with diabetes. Fixed-dose combination therapy is currently recommended for the treatment of hypertension due to the advantage of reducing the pill burden. However, the effects of combination therapy may be diverse because of the different components. We examined blood pressure reduction and metabolic alterations after amlodipine/benazepril and valsartan/hydrochlorothiazide treatment in patients with type 2 diabetes mellitus and hypertension and microalbuminuria. This randomized, double-blind, parallel comparison, noninferiority clinical trial included patients with type 2 diabetes mellitus and hypertension and microalbuminuria detected within the past year. After a 2-week, placebo run-in period, patients were assigned to treatment with amlodipine/benazepril or valsartan/hydrochlorothiazide for 16 weeks. The primary end point was mean change in diastolic blood pressure. The prespecified boundary for noninferiority was 3.5 mm Hg of the mean change in diastolic blood pressure between treatments (amlodipine/benazepril minus valsartan/hydrochlorothiazide). If the upper limit of the 95% CI fell within 3.5 mm Hg, amlodipine/benazepril would be considered noninferior to valsartan/hydrochlorothiazide. Of the 226 patients assessed for eligibility, 169 satisfied the inclusion/exclusion criteria and were assigned to a treatment group; 83 patients (54.2% male, mean age of 60.5 [10.0] years) in the amlodipine/benazepril group and 84 patients (64.3% male, mean age of 59.0 [10.6] years) in the valsartan/hydrochlorothiazide group received at least 1 dose of study medication and were included in the intention-to-treat population. In the per-protocol population, amlodipine/benazepril (n = 74) was noninferior to valsartan/hydrochlorothiazide (n = 78) with regard to the mean change in diastolic blood pressure (difference, -0.9 mm Hg; 95% CI, -3.5 to 1.6). The mean change in systolic

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF-TIMI 48 Trial

DEFF Research Database (Denmark)

Eisen, Alon; Ruff, Christian T; Braunwald, Eugene

2017-01-01

BACKGROUND: Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). METHO...

Local anesthetic effect of docosahexaenoic acid on the nociceptive jaw-opening reflex in rats.

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Mitome, Kazuki; Takehana, Shiori; Oshima, Katsuo; Shimazu, Yoshihito; Takeda, Mamoru

2018-02-23

Although docosahexaenoic acid (DHA) administration suppresses sodium channels in primary afferent sensory neurons, the acute local effect of DHA on the trigeminal nociceptive reflex remains to be elucidated, in vivo. Therefore, the aim of the present study was to investigate whether local administration of DHA attenuates the nociceptive jaw-opening reflex (JOR) in vivo in the rat. The JOR evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1-5 x threshold). At 3 x threshold, local administration of DHA (0.1, 10 and 25 mM) dose-dependently inhibited the dEMG response, and lasted 40 min. Maximum inhibition of the dEMG signal amplitude was seen within approximately 10 min. The mean magnitude of inhibition of the dEMG signal amplitude by DHA (25 mM) was almost equal to the local anesthetic, 1% lidocaine (37 mM), a sodium channel blocker. These findings suggest that DHA attenuates the nociceptive JOR via possibly blocking sodium channels, and strongly support the idea that DHA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception. Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

Comparison of valsartan and amlodipine on ambulatory blood pressure variability in hypertensive patients.

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Eguchi, Kazuo; Imaizumi, Yuki; Kaihara, Toshiki; Hoshide, Satoshi; Kario, Kazuomi

We tested the hypothesis that calcium channel blockers (CCBs: amlodipine group, n = 38)) are superior to angiotensin receptor blockers (ARBs: valsartan group, n = 38) against ambulatory blood pressure variability (BPV) in untreated Japanese hypertensive patients. Both drugs significantly reduced ambulatory systolic and diastolic BP values. With regard to BPV, standard deviation (SD) in SBP did not change with the administration of either drug, but the ARB significantly increased SD in awake DBP (12 ± 4-14 ± 4 mmHg). The ARB also significantly increased the coefficients of variation (CVs)in awake and 24-h SBP/DBP (all P valsartan, especially in reducing maximum BP levels.

Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology.

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Legrain, V; Mancini, F; Sambo, C F; Torta, D M; Ronga, I; Valentini, E

2012-10-01

The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Anti-nociceptive effect of total alkaloids isolated from the seeds of ...

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pretreatment of the animals with naloxone (2 mg/kg) was performed to investigate whether the anti- nociceptive effect .... detecting the absorbance at 618 nm. Arecoline ..... attenuates food allergic responses in ovalbumin- sensitized mice.

Anti-nociceptive and anti-inflammatory properties of the ethanolic ...

African Journals Online (AJOL)

Anti-nociceptive and anti-inflammatory properties of the ethanolic extract of Lagenaria breviflora whole fruit in rat and mice. ... Its effect was comparable especially at 200mg/kg body weight to those of diclofenac, indomethacin and ibuprofen. It could be suggested from the findings of this experiment that the extract may be ...

A qualitative study of amlodipine and its related compounds by electrospray ionization tandem mass spectrometry.

Science.gov (United States)

Gibbons, John; Pugh, Jonathan; Dimopoulos-Italiano, Gina; Pike, Richard

2006-01-01

A comprehensive structural analysis of amlodipine and certain related compounds was performed by electrospray ionization tandem mass spectrometry. Triple quadrupole and quadrupole time-of-flight instruments were used to provide collision-induced dissociation and accurate mass measurement for selected product and second-generation product ions. A unique ion rearrangement was observed, which was found to be characteristic of certain dihydropyridines. This study provides a fundamental understanding of the fragmentation of these compounds. The structural elucidation of an unknown impurity is presented as an example. Copyright (c) 2006 John Wiley & Sons, Ltd.

Substrate-Dependent Inhibition of P-glycoprotein Mediated Efflux Transport of Digoxin

DEFF Research Database (Denmark)

Saaby, Lasse; Ozgür, Burak; Brodin, Birger

, distribution and excretion of a wide range of structurally diverse drug compounds and P-gp therefore constitutes a potential site for drug-drug interactions. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend that all new investigational drugs be screened...... for interactions with P-gp among other transporters in vitro. This includes an evaluation of new drug compounds as inhibitors of P-gp, preferably in competition with a clinically relevant probe substrate such as digoxin. However, increasing evidence indicates that the binding pocket of P-gp contains several...... overlapping binding sites for substrates. This suggests that drug-drug interactions may be pairwise specific and observations of interaction from a single drug-drug combination may therefore not apply to a second drug combination. At present, it is not known which drug combinations should be considered...

The role of Drosophila Piezo in mechanical nociception.

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Kim, Sung Eun; Coste, Bertrand; Chadha, Abhishek; Cook, Boaz; Patapoutian, Ardem

2012-02-19

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo

Identifying brain nociceptive information transmission in patients with chronic somatic pain

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Don A. Davis

2016-10-01

Conclusion:. Collectively, the results suggest that, across 2 types of chronic pain, nociceptive-specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pronociceptive descending modulation, and interrupting cortical cognitive processes.

Sensory processing of deep tissue nociception in the rat spinal cord and thalamic ventrobasal complex.

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Sikandar, Shafaq; West, Steven J; McMahon, Stephen B; Bennett, David L; Dickenson, Anthony H

2017-07-01

Sensory processing of deep somatic tissue constitutes an important component of the nociceptive system, yet associated central processing pathways remain poorly understood. Here, we provide a novel electrophysiological characterization and immunohistochemical analysis of neural activation in the lateral spinal nucleus (LSN). These neurons show evoked activity to deep, but not cutaneous, stimulation. The evoked responses of neurons in the LSN can be sensitized to somatosensory stimulation following intramuscular hypertonic saline, an acute model of muscle pain, suggesting this is an important spinal relay site for the processing of deep tissue nociceptive inputs. Neurons of the thalamic ventrobasal complex (VBC) mediate both cutaneous and deep tissue sensory processing, but in contrast to the lateral spinal nucleus our electrophysiological studies do not suggest the existence of a subgroup of cells that selectively process deep tissue inputs. The sensitization of polymodal and thermospecific VBC neurons to mechanical somatosensory stimulation following acute muscle stimulation with hypertonic saline suggests differential roles of thalamic subpopulations in mediating cutaneous and deep tissue nociception in pathological states. Overall, our studies at both the spinal (lateral spinal nucleus) and supraspinal (thalamic ventrobasal complex) levels suggest a convergence of cutaneous and deep somatosensory inputs onto spinothalamic pathways, which are unmasked by activation of muscle nociceptive afferents to produce consequent phenotypic alterations in spinal and thalamic neural coding of somatosensory stimulation. A better understanding of the sensory pathways involved in deep tissue nociception, as well as the degree of labeled line and convergent pathways for cutaneous and deep somatosensory inputs, is fundamental to developing targeted analgesic therapies for deep pain syndromes. © 2017 University College London. Physiological Reports published by Wiley Periodicals

Suppression of thermal and chemical nociception in rats by methanol extract and its sub-fraction from lantana camara

International Nuclear Information System (INIS)

Simjee, S.U.; Perveen, H.; Zehra, S.Q.

2016-01-01

The traditional use of Lantana camara (Verbenaceae) is reported to include anti-nociceptive, antimicrobial, and immunosuppressant activity. To our knowledge no systematic study has been carried out on the anti-nociceptive activity of L. camara. The present study was designed to delineate the analgesic activity of L. camara extract and its fractions to elucidate the traditional belief in the painkilling effects. Experimental models employed were thermal and chemical-induced nociception assays. After initial screening of the methanol extract and its fractions prepared from the aerial parts of the plant, the dose of 50,100 and 200 mg/kg were selected and route of administration was i.p. The test samples were tested against a reference drug indomethacine (i.p. 5 mg/kg). The observations were made at 15, 30, 60, and 120 seconds following the administration of the samples or reference drug. Experiments on naloxone antagonism were conducted to determine involvement of opioid receptors. Compared to concurrent controls, a significant anti-nociceptive activity was observed in methanol extract LC (ED50 50 mg/kg, P < 0.002) and its sub-fractions LCEA-AQ (ED50 50 mg/kg, P < 0.004), LCEA (ED50 100 mg/kg, P < 0.004) and LCEA-PEI (ED50 100 mg/kg, P < 0.005). No apparent acute toxicity was observed in any test groups. The anti-nociceptive activity was not precipitated by naloxone antagonism indicating that these fractions do not act through opioid receptors. The methanol extract and active fractions of Lantana camara possess anti-nociceptive activity. Further investigations are needed to elucidate the mechanism of its action. (author)

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions.

Science.gov (United States)

Yegutkin, Gennady G; Guerrero-Toro, Cindy; Kilinc, Erkan; Koroleva, Kseniya; Ishchenko, Yevheniia; Abushik, Polina; Giniatullina, Raisa; Fayuk, Dmitriy; Giniatullin, Rashid

2016-09-01

Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

DYNAMICS OF STRUCTURAL AND FUNCTIONAL STATUS OF MYOCARDIUM DUE TO COMBINATION THERAPY WITH AMLODIPINE AND BISOPROLOL IN PATIENTS WITH ARTERIAL HYPERTENSION

Directory of Open Access Journals (Sweden)

I. L. Zapesochnaya

2015-09-01

Full Text Available Aim. To evaluate the effect of 6-month therapy with combination of amlodipine and bisoprolol on the structural and functional status of the myocardium in hypertensive patients who work in the Far North.Material and methods. 140 hypertensive patients who live in the Khanty-Mansiysk Autonomous District - Yugra were divided into two groups depending on arrangement of working time. The first group included 72 patients who work only day shift; the second group – 68 patients who work alternate (day/night shifts. Combination therapy with amlodipine and bisoprolol assigned to all patients. Echocardiography was performed at baseline, after 12 weeks, and after 6 months of therapy.Results. The target blood pressure (BP level in group 1 was achieved in 92.9%. A share of patients with normal left ventricular (LV geometry increased from 37.5 to 44.8%; a share of patients with concentric and eccentric LV hypertrophy (LVH decreased from 30.6 to 23.9% and 19.4 to 19.2%, respectively. Target BP level in group 2 was achieved in 87.9%. A share of patients with normal LV geometry increased from 23.5 to 33.3%; while share of patients with concentric and eccentric LVH decreased from 45.6 to 38.1% and from 19.1 to 17.4%, respectively. A positive correlation between LV myocardial index and average daily systolic and diastolic BP was found.Conclusion. Revealed changes in BP and in LV structure and function due to treatment with amlodipine and bisoprolol can be considered as cardioprotective effect of this combination in hypertensive patients who work in the Far North. This effect was more pronounced in hypertensive patients working alternate (day/night shifts.

DYNAMICS OF STRUCTURAL AND FUNCTIONAL STATUS OF MYOCARDIUM DUE TO COMBINATION THERAPY WITH AMLODIPINE AND BISOPROLOL IN PATIENTS WITH ARTERIAL HYPERTENSION

Directory of Open Access Journals (Sweden)

I. L. Zapesochnaya

2014-01-01

Full Text Available Aim. To evaluate the effect of 6-month therapy with combination of amlodipine and bisoprolol on the structural and functional status of the myocardium in hypertensive patients who work in the Far North.Material and methods. 140 hypertensive patients who live in the Khanty-Mansiysk Autonomous District - Yugra were divided into two groups depending on arrangement of working time. The first group included 72 patients who work only day shift; the second group – 68 patients who work alternate (day/night shifts. Combination therapy with amlodipine and bisoprolol assigned to all patients. Echocardiography was performed at baseline, after 12 weeks, and after 6 months of therapy.Results. The target blood pressure (BP level in group 1 was achieved in 92.9%. A share of patients with normal left ventricular (LV geometry increased from 37.5 to 44.8%; a share of patients with concentric and eccentric LV hypertrophy (LVH decreased from 30.6 to 23.9% and 19.4 to 19.2%, respectively. Target BP level in group 2 was achieved in 87.9%. A share of patients with normal LV geometry increased from 23.5 to 33.3%; while share of patients with concentric and eccentric LVH decreased from 45.6 to 38.1% and from 19.1 to 17.4%, respectively. A positive correlation between LV myocardial index and average daily systolic and diastolic BP was found.Conclusion. Revealed changes in BP and in LV structure and function due to treatment with amlodipine and bisoprolol can be considered as cardioprotective effect of this combination in hypertensive patients who work in the Far North. This effect was more pronounced in hypertensive patients working alternate (day/night shifts.

Citral reduces nociceptive and inflammatory response in rodents

OpenAIRE

Quintans-Júnior, Lucindo J.; Guimarães, Adriana G.; Santana, Marilia T. de; Araújo, Bruno E.S.; Moreira, Flávia V.; Bonjardim, Leonardo R.; Araújo, Adriano A. S.; Siqueira, Jullyana S.; Antoniolli, Ângelo R.; Botelho, Marco A.; Almeida, Jackson R. G. S.; Santos, Márcio R. V.

2011-01-01

Citral (CIT), which contains the chiral enantiomers, neral (cis) and geranial (trans), is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT...

The Role of PPK26 in Drosophila Larval Mechanical Nociception

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Yanmeng Guo

2014-11-01

Full Text Available In Drosophila larvae, the class IV dendritic arborization (da neurons are polymodal nociceptors. Here, we show that ppk26 (CG8546 plays an important role in mechanical nociception in class IV da neurons. Our immunohistochemical and functional results demonstrate that ppk26 is specifically expressed in class IV da neurons. Larvae with mutant ppk26 showed severe behavioral defects in a mechanical nociception behavioral test but responded to noxious heat stimuli comparably to wild-type larvae. In addition, functional studies suggest that ppk26 and ppk (also called ppk1 function in the same pathway, whereas piezo functions in a parallel pathway. Consistent with these functional results, we found that PPK and PPK26 are interdependent on each other for their cell surface localization. Our work indicates that PPK26 and PPK might form heteromeric DEG/ENaC channels that are essential for mechanotransduction in class IV da neurons.

Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

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Reese, Jeremy N; Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

2015-04-15

This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex. Copyright © 2015 the American Physiological Society.

Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

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Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

2003-01-01

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

Effect of Gmelina arborea Roxb in experimentally induced inflammation and nociception

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Yogesh A Kulkarni

2013-01-01

Full Text Available Background: Gmelina arborea Roxb (Verbenaceae, also known as "Gambhari", is an important medicinal plant in the Ayurveda. There are no meticulous scientific reports on effect of the plant on inflammation and pain. Objective: To study the anti-inflammatory and anti-nociceptive properties of aqueous extracts (AE and methanol extracts (ME of G. arborea. Materials and Methods: The AE and ME of stembark of G. arborea was prepared by cold maceration and Soxhlet extraction technique respectively. Anti-inflammatory activity was determined in Wistar albino rats in a model of acute plantar inflammation induced by carrageenan. The anti-nociceptive activity was evaluated by using hot plate test and writhing test in Swiss albino mice. Significant differences between the experimental groups were assessed by analysis of variance. Results: AE and ME at dose of 500 mg/kg showed maximum inhibition in carrageenan induced inflammation up to 30.15 and 31.21% respectively. In hot plate test, the AE and ME showed the maximum response of 8.8 ± 0.97 (P < 0.01 and 8.2 ± 1.24 (P < 0.01 respectively at dose of 500 mg/kg when compared with control. AE showed maximum inhibition of writhing response (84.3% as compared to ME (77.9% in writhing test at a dose of 500 mg/kg. Conclusion: The findings suggested that G. arborea possess significant anti-inflammatory and anti-nociceptive activities.

Effects of magnetic field exposure on open field behaviour and nociceptive responses in mice.

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Del Seppia, Cristina; Mezzasalma, Lorena; Choleris, Elena; Luschi, Paolo; Ghione, Sergio

2003-09-15

Results of previous studies have shown that nociceptive sensitivity in male C57 mice is enhanced by exposure to a regular 37 Hz or an irregularly varying (field. In order to test whether these fields affect more generally mouse behaviour, we placed Swiss CD-1 mice in a novel environment (open field test) and exposed them for 2 h to these two different magnetic field conditions. Hence, we analysed how duration and time course of various behavioural patterns (i.e. exploration, rear, edge chew, self-groom, sit, walk and sleep) and nociceptive sensitivity had been affected by such exposure. Nociceptive sensitivity was significantly greater in magnetically treated mice than in controls. The overall time spent in exploratory activities was significantly shorter in both magnetically treated groups (time), than in controls (42%). Conversely, the time spent in sleeping was markedly longer in the treated groups (both 27% of total time) than in controls (11%). These results suggest that exposure to altered magnetic fields induce a more rapid habituation to a novel environment.

Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

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Mark S. Cooper

2011-01-01

Full Text Available Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical scaling factor, electrophysiological symbols are developed to represent the magnitude of synaptic conversion within nociceptive circuits. When inserted into a nociceptive circuit diagram, these symbols assist in understanding the generation of neuropathic pain associated with the collapse of transmembrane chloride gradients. A more generalized scaling factor is also derived to represent the interplay of chloride and bicarbonate driving potentials on the function of GABAergic and glycinergic synapses. These mathematical and symbolic representations of synaptic conversion help illustrate the critical role that anion driving potentials play in the transduction of pain. Using these representations, we discuss ramifications of glial-mediated synaptic conversion in the genesis, and treatment, of neuropathic pain.

Role of valsartan, amlodipine and hydrochlorothiazide fixed combination in blood pressure control: an update

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Maurizio Destro

2010-04-01

Full Text Available Maurizio Destro1, Francesca Cagnoni1, Antonio D’Ospina1, Alessandra Rossi Ricci1, Elena Demichele1, Emmanouil Peros1, Augusto Zaninelli2, Paola Preti31Internal Medicine, Ospedale Unificato Broni-Stradella, Stradella (PV, Italy; 2General Medicine, School of Medicine, University of Florence, Florence, Italy; 3Internal Medicine, University of Pavia, Pavia, ItalyAbstract: The treatment of moderate or severe hypertension in most cases requires the contemporaneous use of multiple antihypertensive agents. The most available two-drug combinations have an agent that addresses renin secretion and another one that is statistically more effective in renin-independent hypertension. The practice of combining agents that counteract different mechanisms is the most likely explanation for the fact that most available two-drug combinations have an agent that addresses renin secretion (beta-blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker or direct renin inhibitor and another one that is more effective in renin-independent hypertension (diuretic, dihydropyridine or non-dihydropyridine calcium channel blocker. Based on these considerations, addition of hydrochlorothiazide to the combination of an antagonist of the renin-angiotensin system with a calcium channel blocker would constitute a logical approach. Inclusion of a diuretic in the triple combination is based on the evidence that these agents are effective and cheap, enhance the effect of other antihypertensive agents, and add a specific effect to individuals with salt-sensitivity of blood pressure. The benefit of triple combination therapy with amlodipine, valsartan and hydrochlorothiazide over its dual component therapies has been demonstrated, and the use of a single pill will simplify therapy resulting in better blood pressure control.Keywords: valsartan, amlodipine, hydrochlorothiazide, HCTZ, blood pressure, hypertension

Neonatal morphine enhances nociception and decreases analgesia in young rats.

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Zhang, Guo Hua; Sweitzer, Sarah M

2008-03-14

The recognition of the impact of neonatal pain experience on subsequent sensory processing has led to the increased advocacy for the use of opioids for pain relief in infants. However, following long-term opioid exposure in intensive care units more than 48% of infants exhibited behaviors indicative of opioid abstinence syndrome, a developmentally equivalent set of behaviors to opioid withdrawal as seen in adults. Little is known about the long-term influence of repeated neonatal morphine exposure on nociception and analgesia. To investigate this, we examined mechanical and thermal nociception on postnatal days 11, 13, 15, 19, 24, 29, 39 and 48 following subcutaneous administration of morphine (3 mg/kg) once daily on postnatal days 1-9. The cumulative morphine dose-response was assessed on postnatal days 20 and 49, and stress-induced analgesia was assessed on postnatal days 29 and 49. Both basal mechanical and thermal nociception in neonatal, morphine-exposed rats were significantly lower than those in saline-exposed, handled-control rats and naive rats until P29. A rightward-shift of cumulative dose-response curves for morphine analgesia upon chronic neonatal morphine was observed both on P20 and P49. The swim stress-induced analgesia was significantly decreased in neonatal morphine-exposed rats on P29, but not on P49. These data indicate that morphine exposure equivalent to the third trimester of gestation produced prolonged pain hypersensitivity, decreased morphine antinociception, and decreased stress-induced analgesia. The present study illustrates the need to examine the long-term influence of prenatal morphine exposure on pain and analgesia in the human pediatric population.

Validation of a thermal threshold nociceptive model in bearded dragons (Pogona vitticeps).

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Couture, Émilie L; Monteiro, Beatriz P; Aymen, Jessica; Troncy, Eric; Steagall, Paulo V

2017-05-01

To validate a thermal threshold (TT) nociceptive model in bearded dragons (Pogona vitticeps) and to document TT changes after administration of morphine. A two-part randomized, blinded, controlled, experimental study. Five adult bearded dragons (242-396 g). A TT device delivered a ramped nociceptive stimulus (0.6 °C second -1 ) to the medial thigh until a response (leg kick/escape behavior) was observed or maximum (cut-off) temperature of 62 °C was reached. In phase I, period 1, six TT readings were determined at 20 minute intervals for evaluation of repeatability. Two of these readings were randomly assigned to be sham to assess specificity of the behavioral response. The same experiment was repeated 2 weeks later (period 2) to test reproducibility. In phase II, animals were administered either intramuscular morphine (10 mg kg -1 ) or saline 0.9%. TTs (maximum 68 °C) were determined before and 2, 4, 8, 12 and 24 hours after treatment administration. Data were analyzed using one-way anova (temporal changes and repeatability) and paired t tests (reproducibility and treatment comparisons) using Bonferroni correction (p dragons. TT nociceptive testing detected morphine administration and may be suitable for studying opioid regimens in bearded dragons. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Ambulatory blood pressure monitoring after 1 year on valsartan or amlodipine-based treatment: a VALUE substudy

DEFF Research Database (Denmark)

Pedersen, Ole Lederballe; Mancia, Giuseppe; Pickering, Thomas

2007-01-01

OBJECTIVE: The ambulatory blood pressure (ABP) monitoring substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was carried out in a subset of patients from USA, Italy and Denmark. ABP was measured after 1 year in the trial, with the aim of evaluating comparability...... of ABP levels on valsartan (VAL) and amlodipine (AML)-based regimens. METHODS: ABP was measured every 20 min during a 25-h period after morning administration of medicine; 659 patients were available for intention-to-treat analysis. RESULTS: Office blood pressure (BP) differences were smaller than...

Validation of an HPLC–UV method for the determination of digoxin residues on the surface of manufacturing equipment

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ZORAN B. TODOROVIĆ

2009-09-01

Full Text Available In the pharmaceutical industry, an important step consists in the removal of possible drug residues from the involved equipments and areas. The cleaning procedures must be validated and methods to determine trace amounts of drugs have, therefore, to be considered with special attention. An HPLC–UV method for the determination of digoxin residues on stainless steel surfaces was developed and validated in order to control a cleaning procedure. Cotton swabs, moistened with methanol were used to remove any residues of drugs from stainless steel surfaces, and give recoveries of 85.9, 85.2 and 78.7 % for three concentration levels. The precision of the results, reported as the relative standard deviation (RSD, were below 6.3 %. The method was validated over a concentration range of 0.05–12.5 µg mL-1. Low quantities of drug residues were determined by HPLC–UV using a Symmetry C18 column (150´4.6 mm, 5 µm at 20 °C with an acetonitrile–water (28:72, v/v mobile phase at a flow rate of 1.1 mL min-1, an injection volume of 100 µL and were detected at 220 nm. A simple, selective and sensitive HPLC–UV assay for the determination of digoxin residues on stainless steel was developed, validated and applied.

Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates.

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Sessle, B J

2000-01-01

This paper reviews the recent advances in knowledge of brainstem mechanisms related to craniofacial pain. It also draws attention to their clinical implications, and concludes with a brief overview and suggestions for future research directions. It first describes the general organizational features of the trigeminal brainstem sensory nuclear complex (VBSNC), including its input and output properties and intrinsic characteristics that are commensurate with its strategic role as the major brainstem relay of many types of somatosensory information derived from the face and mouth. The VBSNC plays a crucial role in craniofacial nociceptive transmission, as evidenced by clinical, behavioral, morphological, and electrophysiological data that have been especially derived from studies of the relay of cutaneous nociceptive afferent inputs through the subnucleus caudalis of the VBSNC. The recent literature, however, indicates that some fundamental differences exist in the processing of cutaneous vs. other craniofacial nociceptive inputs to the VBSNC, and that rostral components of the VBSNC may also play important roles in some of these processes. Modulatory mechanisms are also highlighted, including the neurochemical substrate by which nociceptive transmission in the VBSNC can be modulated. In addition, the long-term consequences of peripheral injury and inflammation and, in particular, the neuroplastic changes that can be induced in the VBSNC are emphasized in view of the likely role that central sensitization, as well as peripheral sensitization, can play in acute and chronic pain. The recent findings also provide new insights into craniofacial pain behavior and are particularly relevant to many approaches currently in use for the management of pain and to the development of new diagnostic and therapeutic procedures aimed at manipulating peripheral inputs and central processes underlying nociceptive transmission and its control within the VBSNC.

Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli.

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Michael Schütz

Full Text Available BACKGROUND: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity. METHODS: Olfactory function and nociception was compared between carriers (n = 38 and non-carriers (n = 43 of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2. RESULTS: Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2 were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049. Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006, which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced. CONCLUSIONS: The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.

Assessment of Glomerular Filtration Rate Based on Alterations of Serum Brain-Derived Neurotrophic Factor in Type 2 Diabetic Subjects Treated with Amlodipine/Benazepril or Valsartan/Hydrochlorothiazide

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I-Te Lee

2015-01-01

Full Text Available Background. Brain-derived neurotrophic factor (BDNF is associated with sympathetic activation. However, the effects of BDNF on diabetic nephropathy are unknown. The aim of this study was to assess the estimated glomerular filtration rates (eGFRs and changes in serum BDNF levels in type 2 diabetic subjects treated with antihypertensive medications. Methods. In this randomized, double-blind clinical trial, type 2 diabetic subjects with hypertension were assigned to either the benazepril/amlodipine or valsartan/hydrochlorothiazide treatment groups for a 16-week period. The post hoc analyses were based on increased or decreased serum BDNF levels. Results. Of the 153 enrolled subjects, the changes in eGFR were significantly and inversely correlated with those in BDNF in the 76 subjects treated with valsartan/hydrochlorothiazide (r=-0.264, P=0.021 but not in the 77 subjects treated with benazepril/amlodipine (r=-0.025, P=0.862. The 45 subjects with increased BDNF following valsartan/hydrochlorothiazide treatment exhibited a significantly reduced eGFR (-8.8±14.9 mL/min/1.73 m2; P<0.001. Multivariate regression analysis revealed that increased serum BDNF represents an independent factor for reduced eGFR (95% confidence interval between −0.887 and −0.076, P=0.020. Conclusions. Increased serum BDNF is associated with reduced eGFR in type 2 diabetic subjects treated with valsartan/hydrochlorothiazide but not with amlodipine/benazepril.

Effect of butorphanol on thermal nociceptive threshold in healthy pony foals.

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McGowan, K T; Elfenbein, J R; Robertson, S A; Sanchez, L C

2013-07-01

Pain management is an important component of foal nursing care, and no objective data currently exist regarding the analgesic efficacy of opioids in foals. To evaluate the somatic antinociceptive effects of 2 commonly used doses of intravenous (i.v.) butorphanol in healthy foals. Our hypothesis was that thermal nociceptive threshold would increase following i.v. butorphanol in a dose-dependent manner in both neonatal and older pony foals. Seven healthy neonatal pony foals (age 1-2 weeks), and 11 healthy older pony foals (age 4-8 weeks). Five foals were used during both age periods. Treatments, which included saline (0.5 ml), butorphanol (0.05 mg/kg bwt) and butorphanol (0.1 mg/kg bwt), were administered i.v. in a randomised crossover design with at least 2 days between treatments. Response variables included thermal nociceptive threshold, skin temperature and behaviour score. Data within each age period were analysed using a 2-way repeated measures ANOVA, followed by a Holm-Sidak multiple comparison procedure if warranted. There was a significant (P<0.05) increase in thermal threshold, relative to Time 0, following butorphanol (0.1 mg/kg bwt) administration in both age groups. No significant time or treatment effects were apparent for skin temperature. Significant time, but not treatment, effects were evident for behaviour score in both age groups. Butorphanol (0.1 mg/kg bwt, but not 0.05 mg/kg bwt) significantly increased thermal nociceptive threshold in neonatal and older foals without apparent adverse behavioural effects. Butorphanol shows analgesic potential in foals for management of somatic painful conditions. © 2012 EVJ Ltd.

Pruritic and Nociceptive Sensations and Dysesthesias From a Spicule of Cowhage

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LaMotte, R. H.; Shimada, S. G.; Green, B. G.; Zelterman, D.

2009-01-01

Although the trichomes (spicules) of a pod of cowhage (Mucuna pruriens) are known to evoke a histamine-independent itch that is mediated by a cysteine protease, little is known of the itch and accompanying nociceptive sensations evoked by a single spicule and the enhanced itch and pain that can occur in the surrounding skin. The tip of a single spicule applied to the forearm of 45 subjects typically evoked 1) itch accompanied by nociceptive sensations (NS) of pricking/stinging and, to a lesser extent, burning, and 2) one or more areas of cutaneous dysesthesia characterized by hyperknesis (enhanced itch to pricking) with or without alloknesis (itch to stroking) and/or hyperalgesia (enhanced pricking pain). Itch could occur in the absence of NS or one or more dysesthesias but very rarely the reverse. The peak magnitude of sensation was positively correlated for itch and NS and increased (exhibited spatial summation) as the number of spicules was increased within a spatial extent of 6 cm but not 1 cm. The areas of dysesthesia did not exhibit spatial summation. We conclude that itch evoked by a punctate chemical stimulus can co-exist with NS and cutaneous dysesthesias as may occur in clinical pruritus. However, cowhage itch was not always accompanied by NS or dysesthesia nor was a momentary change in itch necessarily accompanied by a similar change in NS or vice versa. Thus there may be separate neural coding mechanisms for itch, nociceptive sensations, and each type of dysesthesia. PMID:19144738

DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF IBOPAMINE AND DIGOXIN IN PATIENTS WITH MILD-TO-MODERATE HEART-FAILURE - RESULTS OF THE DUTCH IBOPAMINE MULTICENTER TRIAL (DIMT)

NARCIS (Netherlands)

VANVELDHUISEN, DJ; MANINTVELD, AJ; DUNSELMAN, PHJM; LOK, DJA; DOHMEN, HJM; POORTERMANS, JC; WITHAGEN, AJAM; PASTEUNING, WH; BROUWER, J; LIE, KI

1993-01-01

Objectives. This study was conducted to determine the efficacy and safety of long-term treatment with the orally active dopamine agonist ibopamine in patients with mild to moderate chronic congestive heart failure and to compare the results with those of treatment with digoxin and placebo.

Ovariectomy results in variable changes in nociception, mood and depression in adult female rats.

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Li-Hong Li

Full Text Available Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing. The present study investigated whether hormonal depletion alters the nociceptive, depressive-like and learning behaviors in experimental rats after ovariectomy (OVX, a common method to deplete animals of their gonadal hormones. OVX rats developed thermal hyperalgesia in proximal and distal tail that was established 2 weeks after OVX and lasted the 7 weeks of the experiment. A robust mechanical allodynia was also occurred at 5 weeks after OVX. In the 5th week after OVX, dilute formalin (5%-induced nociceptive responses (such as elevating and licking or biting during the second phase were significantly increased as compared to intact and sham-OVX females. However, chronic constriction injury (CCI of the sciatic nerve-induced mechanical allodynia did not differ as hormonal status (e.g. OVX and ovarian intact. Using formalin-induced conditioned place avoidance (F-CPA, which is believed to reflect the pain-related negative emotion, we further found that OVX significantly attenuated F-CPA scores but did not alter electric foot-shock-induced CPA (S-CPA. In the open field and forced swimming test, there was an increase in depressive-like behaviors in OVX rats. There was no detectable impairment of spatial performance by Morris water maze task in OVX rats up to 5 weeks after surgery. Estrogen replacement retrieved OVX-induced nociceptive hypersensitivity and depressive-like behaviors. This is the first study to investigate the impacts of ovarian removal on nociceptive perception, negative emotion, depressive-like behaviors and spatial learning in adult female rats in a uniform and standard way.

Sex-dependent effects of restraint on nociception and pituitary-adrenal hormones in the rat.

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Aloisi, A M; Steenbergen, H L; van de Poll, N E; Farabollini, F

1994-05-01

The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.

Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

Science.gov (United States)

Hilleman, D E; Reyes, A P; Wurdeman, R L; Faulkner, M

2001-08-01

Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination

Changes in the nitric oxide system in the shore crab Hemigrapsus sanguineus (Crustacea, Decapoda) CNS induced by a nociceptive stimulus.

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Dyuizen, Inessa V; Kotsyuba, Elena P; Lamash, Nina E

2012-08-01

Using NADPH-diaphorase (NADPH-d) histochemistry, inducible nitric oxide synthase (iNOS)-immunohistochemistry and immunoblotting, we characterized the nitric oxide (NO)-producing neurons in the brain and thoracic ganglion of a shore crab subjected to a nociceptive chemical stimulus. Formalin injection into the cheliped evoked specific nociceptive behavior and neurochemical responses in the brain and thoracic ganglion of experimental animals. Within 5-10 min of injury, the NADPH-d activity increased mainly in the neuropils of the olfactory lobes and the lateral antenna I neuropil on the side of injury. Later, the noxious-induced expression of NADPH-d and iNOS was detected in neurons of the brain, as well as in segmental motoneurons and interneurons of the thoracic ganglion. Western blotting analysis showed that an iNOS antiserum recognized a band at 120 kDa, in agreement with the expected molecular mass of the protein. The increase in nitrergic activity induced by nociceptive stimulation suggests that the NO signaling system may modulate nociceptive behavior in crabs.

Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone.

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Huang, Y; Brodda-Jansen, G; Lundeberg, T; Yu, L C

2000-08-04

The present study investigated the role of calcitonin gene-related peptide (CGRP) on nociception in nucleus raphe magnus (NRM) and the interaction between CGRP and opioid peptides in NRM of rats. CGRP-like immunoreactivity was found at a concentration of 6.0+/-0. 77 pmol/g in NRM tissue of ten samples of rats, suggesting that it may contribute to physiological responses orchestrated by the NRM. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation increased significantly after intra-NRM administration of 0.5 or 1 nmol of CGRP in rats, but not 0.25 nmol. The anti-nociceptive effect induced by CGRP was antagonized by following intra-NRM injection of 1 nmol of the CGRP receptor antagonist CGRP8-37. Furthermore, the CGRP-induced anti-nociceptive effect was attenuated by following intra-NRM administration of 6 nmol of naloxone. The results indicate that CGRP and its receptors play an important role in anti-nociception, and there is a possible interaction between CGRP and opioid peptides in NRM of rats.

Neonatal bee venom exposure induces sensory modality-specific enhancement of nociceptive response in adult rats.

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Li, Mengmeng; Chen, Huisheng; Tang, Jiaguang; Chen, Jun

2014-06-01

Previous studies have shown that inflammatory pain at the neonatal stage can produce long-term structural and functional changes in nociceptive pathways, resulting in altered pain perception in adulthood. However, the exact pattern of altered nociceptive response and associated neurochemical changes in the spinal cord in this process is unclear. In this study, we used an experimental paradigm in which each rat first received intraplantar bee venom (BV) or saline injection on postnatal day 1, 4, 7, 14, 21, or 28. This was followed 2 months later by a second intraplantar bee venom injection in the same rats to examine the difference in nociceptive responses. We found that neonatal inflammatory pain induced by the first BV injection significantly reduced baseline paw withdrawal mechanical threshold, but not baseline paw withdrawal thermal latency, when rats were examined 2 months from the first BV injection. Neonatal inflammatory pain also exacerbated mechanical, but not thermal, hyperalgesia in response to the second BV injection in these same rats. Rats exposed to neonatal inflammation also showed up-regulation of spinal NGF, TrkA receptor, BDNF, TrkB receptor, IL-1β, and COX-2 expression following the second BV injection, especially with prior BV exposure on postnatal day 21 or 28. These results indicate that neonatal inflammation produces sensory modality-specific changes in nociceptive behavior and alters neurochemistry in the spinal cord of adult rats. These results also suggest that a prior history of inflammatory pain during the developmental period might have an impact on clinical pain in highly susceptible adult patients. Wiley Periodicals, Inc.

Simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by LC–ESI-MS/MS and its application to pharmacokinetics in rats

Directory of Open Access Journals (Sweden)

Shankar Ganesh Gadepalli

2014-12-01

Full Text Available Polypill is a fixed-dose combination that contains three or more active ingredients used as a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. A novel and accurate liquid chromatography tandem mass spectrometry method using electrospray ionization mode has been developed and validated for the simultaneous determination of amlodipine (AMD, valsartan (VAL using losartan (LOS as an internal standard (IS, and hydrochlorothiazide (HCT using furosemide (FSD as an IS. The separation was carried on Aquasil C18 (50 mm×2.1 mm, 5 µm reversed phase column using acetonitrile and water containing 0.1% formic acid (50:50, v/v as the mobile phase. The method was validated in terms of linearity, accuracy and precision over the concentration range of 1–1000 ng/mL. The intra and inter-day precision and accuracy, stability and extraction recoveries of all the analytes were in the acceptable range. This method can be successfully applied to the pharmacokinetic study of AMD, VAL and HCT when given as a polypill. Keywords: Amlodipine, Valsartan, Hydrochlorothiazide, Exforge HCT, Polypill

Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine

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Jordan L. Hawkins

2017-12-01

Conclusion:. Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.

Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning.

Science.gov (United States)

Stock, M L; Barth, L A; Van Engen, N K; Millman, S T; Gehring, R; Wang, C; Voris, E A; Wulf, L W; Labeur, Léa; Hsu, W H; Coetzee, J F

2016-02-01

The objective of this study was to investigate the effects of carprofen administered immediately before cautery dehorning on nociception and stress. Forty Holstein calves aged approximately 6 to 8 wk old were either placebo treated and sham dehorned ( = 10) or cautery dehorned following administration of carprofen (1.4 mg/kg) subcutaneously ( = 10) or orally ( = 10) or a subcutaneous and oral placebo ( = 10) in a randomized, controlled trial. All animals were given a cornual nerve block using lidocaine before dehorning. Response variables including mechanical nociception threshold, ocular temperature, heart rate, and respiratory rate were measured before and following cautery dehorning for 96 h. Blood samples were also collected over 96 h following dehorning and analyzed for plasma cortisol and substance P concentrations by RIA. Plasma carprofen concentration and ex vivo PGE concentrations were also determined for this time period. Average daily gain was calculated for 7 d after dehorning. Data were analyzed using a linear mixed effects model with repeated measures, controlling for baseline values by their inclusion as a covariate in addition to planned contrasts. Dehorning was associated with decreased nociception thresholds throughout the study and a stress response immediately after dehorning, following the loss of local anesthesia, and 48 h after dehorning compared with sham-dehorned calves. Carprofen was well absorbed after administration and reached concentrations that inhibited ex vivo PGE concentrations for 72 h (subcutaneous) and 96 h (oral) compared with placebo-treated calves ( Carprofen-treated calves tended to be less sensitive ( = 0.097) to nociceptive threshold tests. Overall, at the dosing regimen studied, the effect of carprofen on sensitivity and stress following cautery dehorning was minimal. Consideration of route of administration and dose determination studies may be warranted.

Efficacy and safety of long-term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension.

Science.gov (United States)

Chrysant, Steven G; Oparil, Suzanne; Melino, Michael; Karki, Sulekha; Lee, James; Heyrman, Reinilde

2009-09-01

J Clin Hypertens (Greenwich). 2009;11:475-482. (c) 2009 Wiley Periodicals, Inc.The authors report on the 44-week open-label extension of the 8-week, double-blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up-titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM+/-HTCZ, up-titrated as necessary, allowed a majority of patients to achieve BP goal.

Are patients reliable when self-reporting medication use? Validation of structured drug interviews and home visits by drug analysis and prescription data in acutely hospitalized patients

DEFF Research Database (Denmark)

Glintborg, Bente; Hillestrøm, Peter René; Olsen, Lenette Holm

2007-01-01

were compared to the patients' self-reported medication history. Information on prescribed drugs dispensed from any Danish pharmacy was collected from nationwide real-time pharmacy records. The authors performed home visits in a subgroup of 115 patients 4 weeks after their discharge. Stored drugs were......The medication history among hospitalized patients often relies on patients' self-reports due to insufficient communication between health care professionals. The aim of the present study was to estimate the reliability of patients' self-reported medication use. Five hundred patients admitted...... to an acute medical department at a Danish university hospital were interviewed on the day of admission about their recent medication use. Blood samples drawn immediately after admission were screened for contents of 5 drugs (digoxin, bendroflumethiazide, amlodipine, simvastatin, glimepiride), and the results...

New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input

NARCIS (Netherlands)

Henssen, D.J.H.A.; Kurt, E.; Kozicz, L.T.; Dongen, R.T.M. van; Bartels, R.H.M.A.; Cappellen van Walsum, A.M. van

2016-01-01

Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called

The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

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Li Li

2014-01-01

Full Text Available The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG evoked by bee venom (BV. The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat

NARCIS (Netherlands)

N.A. Jansen (Nico A.); G.J. Giesler (Glenn J.)

2015-01-01

textabstractWe tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek

Pain sensation and nociceptive reflex excitability in surgical patients and human volunteers

DEFF Research Database (Denmark)

Dahl, J B; Erichsen, C J; Fuglsang-Frederiksen, A

1992-01-01

Pain threshold, nociceptive flexion reflex (NFR) threshold and responses to suprathreshold stimulation were investigated in 15 female patients (mean age 32 yr (range 22-48 yr)) before and 68 (range 48-96) h after gynaecological laparotomy. Control measurements were performed in 17 healthy human v...

Calcitonin gene-related peptide modulates heat nociception in the human brain - An fMRI study in healthy volunteers

DEFF Research Database (Denmark)

Asghar, Mohammad Sohail; Becerra, Lino; Larsson, Henrik B.W.

2016-01-01

Background: Intravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded...... cortex. Sumatriptan injection reversed these changes. Conclusion: The changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli....

Electrophysiological assessment of nociception in patients with Parkinson's disease : A multi-methods approach

NARCIS (Netherlands)

Priebe, Janosch A.; Kunz, Miriam; Morcinek, Christian; Rieckmann, Peter; Lautenbacher, Stefan

2016-01-01

Objective: Nociceptive abnormalities indicating increased pain sensitivity have been reported in patients with Parkinson's disease (PD). The disturbances are mostly responsive to dopaminergic (DA) treatment; yet, there are conflicting results. The objective of the present study was to investigate

Hydro-ethanolic leaf extract of Ziziphus abyssinica Hochst Ex A. Rich (Rhamnaceae) exhibits anti-nociceptive effects in murine models.

Science.gov (United States)

Boakye-Gyasi, Eric; Henneh, Isaac Tabiri; Abotsi, Wonder Kofi Mensah; Ameyaw, Elvis Ofori; Woode, Eric

2017-04-26

Despite substantial advances in pain research and treatment, millions of people continue to suffer from pain and this has been attributed mainly to the unavailability of effective and safer analgesics. The use of plants as medicines is still widespread and plants constitute a large source of novel phytocompounds that might become leads for the discovery of newer, effective and safer alternatives. Various parts of Ziziphus abyssinica have been used in folk medicine in several African countries as painkillers. However, there is no report on the possible anti-nociceptive effects of this plant especially the leaves, hence the need for this current study. The possible anti-nociceptive activity of hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) was assessed in rodents using chemical (acetic acid, formalin and glutamate), thermal (tail-immersion test) and mechanical/inflammatory (carrageenan) models of nociception. EthE (30-300 mg/kg, p.o.) dose-dependently and significantly inhibited chemical-induced nociception with a maximum inhibition of 86.29 ± 2.27%, 76.34 ± 5.67%, 84.97 ± 5.35%, and 82.81 ± 5.97% respectively for acetic acid, formalin (phase 1), formalin (phase 2) and glutamate tests at its highest dose. EthE also dose-dependently and significantly increased reaction times in both tail-immersion and carrageenan-induced hypernociceptive tests. The activities of the extract in the various models were comparable with the effect of morphine hydrochloride and diclofenac sodium used as standard analgesic drugs. Oral administration of hydro-ethanolic leaf extract of Ziziphus abyssinica ameliorates nocifensive behaviours associated with chemical-, thermal- and mechanical/inflammatory - induced nociceptive pain.

Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex.

Science.gov (United States)

Laursen, Mette; Gregersen, Jonas Lindholt; Yatime, Laure; Nissen, Poul; Fedosova, Natalya U

2015-02-10

Cardiotonic steroids (CTSs) are specific and potent inhibitors of the Na(+),K(+)-ATPase, with highest affinity to the phosphoenzyme (E2P) forms. CTSs are comprised of a steroid core, which can be glycosylated, and a varying number of substituents, including a five- or six-membered lactone. These functionalities have specific influence on the binding properties. We report crystal structures of the Na(+),K(+)-ATPase in the E2P form in complex with bufalin (a nonglycosylated CTS with a six-membered lactone) and digoxin (a trisaccharide-conjugated CTS with a five-membered lactone) and compare their characteristics and binding kinetics with the previously described E2P-ouabain complex to derive specific details and the general mechanism of CTS binding and inhibition. CTSs block the extracellular cation exchange pathway, and cation-binding sites I and II are differently occupied: A single Mg(2+) is bound in site II of the digoxin and ouabain complexes, whereas both sites are occupied by K(+) in the E2P-bufalin complex. In all complexes, αM4 adopts a wound form, characteristic for the E2P state and favorable for high-affinity CTS binding. We conclude that the occupants of the cation-binding site and the type of the lactone substituent determine the arrangement of αM4 and hypothesize that winding/unwinding of αM4 represents a trigger for high-affinity CTS binding. We find that the level of glycosylation affects the depth of CTS binding and that the steroid core substituents fine tune the configuration of transmembrane helices αM1-2.

Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers.

Science.gov (United States)

Nilsson, H J; Schouenborg, J

1999-03-01

It is known that stimulation of thin cutaneous nerve fibers can induce long lasting analgesia through both supraspinal and segmental mechanisms, the latter often exhibiting restricted receptive fields. On this basis, we recently developed a new method, termed cutaneous field stimulation (CFS), for localized stimulation of A delta and C fibers in the superficial part of the skin. In the present study, we have evaluated the effects of CFS on non-nociceptive and nociceptive skin senses. We compared the effects of CFS with those of conventional transcutaneous electrical nerve stimulation (TENS), known to preferentially activate coarse myelinated fibers. A battery of sensory tests were made on the right volar forearm of 20 healthy subjects. CFS (16 electrodes, 4 Hz per electrode, 1 ms, up to 0.8 mA) and TENS (100 Hz, 0.2 ms, up to 26 mA) applied either on the right volar forearm (homotopically), or on the lower right leg (heterotopically) were used as conditioning stimulation for 25 min. The tactile threshold was not affected by either homo- or heterotopical CFS or TENS. The mean thresholds for detecting warming or cooling of the skin were increased by 0.4-0.9 degrees C after homo- but not heterotopical CFS and TENS. Regarding nociceptive skin senses, homo- but not heterotopical CFS, markedly reduced CO2-laser evoked A delta- and C fiber mediated heat pain to 75 and 48% of control, respectively, and mechanically evoked pain to 73% of control. Fabric evoked prickle, was not affected by CFS. Neither homo- nor heterotopical TENS induced any marked analgesic effects. It is concluded that different qualities of nociception can be differentially controlled by CFS.

Role of the thalamic parafascicular nucleus cholinergic system in the modulation of acute corneal nociception in rats

Directory of Open Access Journals (Sweden)

Esmaeal Tamaddonfard

2011-11-01

Full Text Available The present study investigated the effects of microinjections of acetylcholine (a cholinergic agonist, physostigmine (a cholinesterase inhibitor, atropine (an antagonist of muscarinic cholinergic receptors and hexamethonium (an antagonist of nicotinic cholinergic receptors into the parafascicular nucleus of thalamus on the acute corneal nociception in rats. Acute corneal nociception was induced by putting a drop of 5 M NaCl solution onto the corneal surface of the eye and the number of eye wipes was counted during the first 30s. Both acetylcholine and physostigmine at the same doses of 0.5, 1 and 2 μg significantly (P < 0.05 reduced the number of eye wipes. The intensity of corneal nociception was not changed when atropine and hexamethonium were used alone. Atropine (4 μg, but not hexamethonium (4 μg significantly (P < 0.05 prevented acetylcholine (2 μg- and physostigmine (2 μg-induced antinociceptive effects. The results indicated that at the level of the parafascicular nucleus of thalamus, the muscarinic cholinergic receptors might be involved in the antinociceptive effects of acetylcholine and physostigmine.

Nurses assessing pain with the Nociception Coma Scale: interrater reliability and validity

NARCIS (Netherlands)

Vink, Peter; Eskes, Anne Maria; Lindeboom, Robert; van den Munckhof, Pepijn; Vermeulen, Hester

2014-01-01

The Nociception Coma Scale (NCS) is a pain observation tool, developed for patients with disorders of consciousness (DOC) due to acquired brain injury (ABI). The aim of this study was to assess the interrater reliability of the NCS and NCS-R among nurses for the assessment of pain in ABI patients

Clinical utility of fixed-combination telmisartan–amlodipine in the treatment of hypertension

Directory of Open Access Journals (Sweden)

Segura J

2011-05-01

Full Text Available Julian Segura, Luis M RuilopeHypertension Unit, Hospital 12 de Octubre, Madrid, SpainAbstract: The majority of hypertensive patients, especially those with target organ damage, are likely to require multiple-drug therapy in order to reach blood pressure (BP targets and reduce their risk of adverse vascular outcomes. The rationale for combination therapy with agents that block the renin–angiotensin system (RAS and a calcium channel blocker (CCB or diuretic is well founded in growing evidence. Recent published trials have shown that the combination of an RAS suppressor and a dihydropiridinic CCB would offer additional benefits independently of BP reduction. A telmisartan–amlodipine combination has demonstrated significantly greater BP reductions compared with each monotherapy component in the overall population, and in particular in patients with moderate to severe hypertension and high-risk patients. This combination is well tolerated with a safety profile similar to placebo and is consistent with the known safety profile of its monotherapy components.Keywords: hypertensive patients, monotherapy, stroke, antihypertensive

Nociceptive DRG neurons express muscle lim protein upon axonal injury.

Science.gov (United States)

Levin, Evgeny; Andreadaki, Anastasia; Gobrecht, Philipp; Bosse, Frank; Fischer, Dietmar

2017-04-04

Muscle lim protein (MLP) has long been regarded as a cytosolic and nuclear muscular protein. Here, we show that MLP is also expressed in a subpopulation of adult rat dorsal root ganglia (DRG) neurons in response to axonal injury, while the protein was not detectable in naïve cells. Detailed immunohistochemical analysis of L4/L5 DRG revealed ~3% of MLP-positive neurons 2 days after complete sciatic nerve crush and maximum ~10% after 4-14 days. Similarly, in mixed cultures from cervical, thoracic, lumbar and sacral DRG ~6% of neurons were MLP-positive after 2 days and maximal 17% after 3 days. In both, histological sections and cell cultures, the protein was detected in the cytosol and axons of small diameter cells, while the nucleus remained devoid. Moreover, the vast majority could not be assigned to any of the well characterized canonical DRG subpopulations at 7 days after nerve injury. However, further analysis in cell culture revealed that the largest population of MLP expressing cells originated from non-peptidergic IB4-positive nociceptive neurons, which lose their ability to bind the lectin upon axotomy. Thus, MLP is mostly expressed in a subset of axotomized nociceptive neurons and can be used as a novel marker for this population of cells.

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats

OpenAIRE

Birol Muhammet Er; İsmail Serhat Kocamanoğlu; Ayhan Bozkurt; Sırrı Bilge; Erhan Çetin Çetinoğlu

2016-01-01

Background: Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. Aims: The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Study Design: Animal experimentation. ...

[Changes in ingestive behavior during growth affects the functional maturation of temporomandibular joint nociceptive neurons of rats].

Science.gov (United States)

Hiranuma, Maya

2013-03-01

Temporomandibular joint (TMJ) loading during development promotes its growth and maintains normal structure/function. Continuous change in diet consistency is related to development and maturation of the peripheral nervous system, including the nociceptive system. However, the functional modulation of TMJ-nociceptive neurons under different ingestive behavior is unclear. We fed growing rats a liquid diet to investigate the effects of low TMJ loading on the response properties of neurons in the trigeminal spinal tract subnucleus caudalis (Sp5C). Forty 2-week-old male rats were used. They were fed chow pellets (n = 20, C group) or a liquid diet (n = 20, LD group) soon after weaning. Firing activities of single sensory units in response to TMJ pressure stimuli were recorded at 4, 5, 7 and 9 weeks. In TMJ-nociceptive neurons, the firing threshold (FT) in the LD group was significantly lower than that in the C group at each recording age. The FT in the C group remained unchanged throughout the recording period, whereas that in the LD group was the highest at 4 weeks, and gradually decreased. On the other hand, the initial firing frequency (IFF) was significantly higher in the LD group than in the C group at each recording age. The IFF in the C group remained unchanged throughout the experimental period, whereas that in the LD group was at its lowest at 4 weeks, and gradually increased. Based on these findings, ingestive behavior that results from continuous changes in the physical consistency of the diet during growth may affect the functional maturation of TMJ-nociceptive neurons.

Are patients reliable when self-reporting medication use? Validation of structured drug interviews and home visits by drug analysis and prescription data in acutely hospitalized patients

DEFF Research Database (Denmark)

Glintborg, Bente; Hillestrøm, Peter René; Olsen, Lenette Holm

2007-01-01

inspected, and patients were interviewed about their drug use. Additional blood samples were drawn for drug analysis. The median age of included patients was 72 years, and 298 patients (60%) were women. Patients reported use of 3 (median) prescription-only medications (range, 0-14) during the structured...... interview. The congruence between self-report and drug analysis was high for all 5 drugs measured (all kappa >0.8). However, 9 patients (2%) reported use of drugs that were not detected in their blood samples. In 29 patients (6%), the blood samples contained drugs not reported during the structured...... to an acute medical department at a Danish university hospital were interviewed on the day of admission about their recent medication use. Blood samples drawn immediately after admission were screened for contents of 5 drugs (digoxin, bendroflumethiazide, amlodipine, simvastatin, glimepiride), and the results...

Prediction of immediate postoperative pain using the analgesia/nociception index: a prospective observational study.

Science.gov (United States)

Boselli, E; Bouvet, L; Bégou, G; Dabouz, R; Davidson, J; Deloste, J-Y; Rahali, N; Zadam, A; Allaouchiche, B

2014-04-01

The analgesia/nociception index (ANI) is derived from heart rate variability, ranging from 0 (maximal nociception) to 100 (maximal analgesia), to reflect the analgesia/nociception balance during general anaesthesia. This should be correlated with immediate postoperative pain in the post-anaesthesia care unit (PACU). The aim of this study was to evaluate the performance of ANI measured at arousal from general anaesthesia to predict immediate postoperative pain on arrival in PACU. Two hundred patients undergoing ear, nose, and throat or lower limb orthopaedic surgery with general anaesthesia using an inhalational agent and remifentanil were included in this prospective observational study. The ANI was measured immediately before tracheal extubation and pain intensity was assessed within 10 min of arrival in PACU using a 0-10 numerical rating scale (NRS). The relationship between ANI and NRS was assessed using linear regression. A receiver-operating characteristic (ROC) curve was used to evaluate the performance of ANI to predict NRS>3. A negative linear relationship was observed between ANI immediately before extubation and NRS on arrival in PACU. Using a threshold of 3 were both 86% with 92% negative predictive value, corresponding to an area under the ROC curve of 0.89. The measurement of ANI immediately before extubation after inhalation-remifentanil anaesthesia was significantly associated with pain intensity on arrival in PACU. The performance of ANI for the prediction of immediate postoperative pain is good and may assist physicians in optimizing acute pain management. ClinicalTrials.gov NCT01796249.

Assessment of glomerular filtration rate based on alterations of serum brain-derived neurotrophic factor in type 2 diabetic subjects treated with amlodipine/benazepril or valsartan/hydrochlorothiazide.

Science.gov (United States)

Lee, I-Te; Sheu, Wayne Huey-Herng; Hung, Yi-Jen; Chen, Jung-Fu; Wang, Chih-Yuan; Lee, Wen-Jane

2015-01-01

Brain-derived neurotrophic factor (BDNF) is associated with sympathetic activation. However, the effects of BDNF on diabetic nephropathy are unknown. The aim of this study was to assess the estimated glomerular filtration rates (eGFRs) and changes in serum BDNF levels in type 2 diabetic subjects treated with antihypertensive medications. In this randomized, double-blind clinical trial, type 2 diabetic subjects with hypertension were assigned to either the benazepril/amlodipine or valsartan/hydrochlorothiazide treatment groups for a 16-week period. The post hoc analyses were based on increased or decreased serum BDNF levels. Of the 153 enrolled subjects, the changes in eGFR were significantly and inversely correlated with those in BDNF in the 76 subjects treated with valsartan/hydrochlorothiazide (r = -0.264, P = 0.021) but not in the 77 subjects treated with benazepril/amlodipine (r = -0.025, P = 0.862). The 45 subjects with increased BDNF following valsartan/hydrochlorothiazide treatment exhibited a significantly reduced eGFR (-8.8 ± 14.9 mL/min/1.73 m(2); P benazepril.

Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

Czech Academy of Sciences Publication Activity Database

Kádková, Anna; Synytsya, Viktor; Krůšek, Jan; Zímová, Lucie; Vlachová, Viktorie

2017-01-01

Roč. 66, č. 3 (2017), s. 425-439 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA15-15839S; GA MZd(CZ) NV16-28784A Institutional support: RVO:67985823 Keywords : transient receptor potential ankyrin 1 * bradykinin * structure- function * nociception * post-translational modifications * signaling pathways Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 1.461, year: 2016

A comparison of automated and manual radioimmunoassays for the estimation of serum digoxin

International Nuclear Information System (INIS)

Tuttlebee, J.W.

1984-01-01

Digoxin was assayed manually (SPAC kit) and by an automated radioimmunoassay instrument (ARIA II). There was good correlation between the methods (r=0.964; n=120). Carryover by the automated method was marginally significant from low to high level samples (5.2%), but insignificant from high to low level samples (1.4%). The precision on the ARIA II was far better in spite of the fact that assays were performed only in singlets compared with duplicates on the manual procedure. Best precision was obtained at the high level (3.76 nmol/l; between-batch CV: 2.4% ARIA; 5.5% SPAC). All values for control samples (manual and automated) fell within 6% of the all-method means. Using the ARIA II is marginally quicker and significantly cheaper. However, some back-up procedure is required for 'down time' with the machine, for what can be an urgent investigation. Patient results correlated well with clinical data. (orig.) [de

Phytochemical Screening and Anti-nociceptive Properties of the Ethanolic Leaf Extract of Trema Cannabina Lour

Directory of Open Access Journals (Sweden)

Hira Arpona

2013-02-01

Full Text Available Purpose: The present study was designed to investigate the anti-nociceptive activity of ethanolic leaf extract of Trema cannabina Lour (family: Cannabaceae in experimental animal models. Methods: The anti-nociceptive action was carried out against two types of noxious stimuli, thermal (hot plate and tail immersion tests and chemical (acetic acid-induced writhing in mice. Results: Phytochemical analysis of crude extract indicated the presence of reducing sugar, tannins, steroid and alkaloid types of secondary metabolites. Crude extract of T. cannabina (500 mg/kg dose showed maximum time needed for the response against thermal stimuli (6.79±0.15 seconds which is comparable to diclofenac sodium (8.26±0.14 seconds in the hot plate test. Hot tail immersion test also showed similar results as in hot plate test. At the dose of 250 and 500 mg/kg body weight, the extract showed significantly and in a dose-dependent (p<0.001 reduction in acetic acid induced writhing in mice with a maximum effect of 47.56% reduction at 500 mg/kg dose comparable to that of diclofenac sodium (67.07% at 25 mg/kg. Conclusion: The obtained results tend to suggest the Anti-nociceptive activity of ethanolic leaf extract of Trema cannabina and thus provide the scientific basis for the traditional uses of this plant part as a remedy for pain.

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

Science.gov (United States)

de la Peña, Amparo; Cui, Xuewei; Geiser, Jeanne; Loghin, Corina

2017-11-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Slack KNa Channels Influence Dorsal Horn Synapses and Nociceptive Behavior.

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Evely, Katherine M; Pryce, Kerri D; Bausch, Anne E; Lukowski, Robert; Ruth, Peter; Haj-Dahmane, Samir; Bhattacharjee, Arin

2017-01-01

The sodium-activated potassium channel Slack (Kcnt1, Slo2.2) is highly expressed in dorsal root ganglion neurons where it regulates neuronal firing. Several studies have implicated the Slack channel in pain processing, but the precise mechanism or the levels within the sensory pathway where channels are involved remain unclear. Here, we furthered the behavioral characterization of Slack channel knockout mice and for the first time examined the role of Slack channels in the superficial, pain-processing lamina of the dorsal horn. We performed whole-cell recordings from spinal cord slices to examine the intrinsic and synaptic properties of putative inhibitory and excitatory lamina II interneurons. Slack channel deletion altered intrinsic properties and synaptic drive to favor an overall enhanced excitatory tone. We measured the amplitudes and paired pulse ratio of paired excitatory post-synaptic currents at primary afferent synapses evoked by electrical stimulation of the dorsal root entry zone. We found a substantial decrease in the paired pulse ratio at synapses in Slack deleted neurons compared to wildtype, indicating increased presynaptic release from primary afferents. Corroborating these data, plantar test showed Slack knockout mice have an enhanced nociceptive responsiveness to localized thermal stimuli compared to wildtype mice. Our findings suggest that Slack channels regulate synaptic transmission within the spinal cord dorsal horn and by doing so establishes the threshold for thermal nociception.

Reliability and validity of a brief method to assess nociceptive flexion reflex (NFR) threshold.

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Rhudy, Jamie L; France, Christopher R

2011-07-01

The nociceptive flexion reflex (NFR) is a physiological tool to study spinal nociception. However, NFR assessment can take several minutes and expose participants to repeated suprathreshold stimulations. The 4 studies reported here assessed the reliability and validity of a brief method to assess NFR threshold that uses a single ascending series of stimulations (Peak 1 NFR), by comparing it to a well-validated method that uses 3 ascending/descending staircases of stimulations (Staircase NFR). Correlations between the NFR definitions were high, were on par with test-retest correlations of Staircase NFR, and were not affected by participant sex or chronic pain status. Results also indicated the test-retest reliabilities for the 2 definitions were similar. Using larger stimulus increments (4 mAs) to assess Peak 1 NFR tended to result in higher NFR threshold estimates than using the Staircase NFR definition, whereas smaller stimulus increments (2 mAs) tended to result in lower NFR threshold estimates than the Staircase NFR definition. Neither NFR definition was correlated with anxiety, pain catastrophizing, or anxiety sensitivity. In sum, a single ascending series of electrical stimulations results in a reliable and valid estimate of NFR threshold. However, caution may be warranted when comparing NFR thresholds across studies that differ in the ascending stimulus increments. This brief method to assess NFR threshold is reliable and valid; therefore, it should be useful to clinical pain researchers interested in quickly assessing inter- and intra-individual differences in spinal nociceptive processes. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Phototransformation of Amlodipine in Aqueous Solution: Toxicity of the Drug and Its Photoproduct on Aquatic Organisms

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Marina DellaGreca

2007-01-01

Full Text Available The phototransformation of amlodipine in water was investigated under various conditions. A quantum yield ΦS2.2×10−4 and a half-life time t1/2 0.419 days were calculated when the drug in water (10−4 M was exposed to sunlight. The only photoproduct found was its pyridine derivative. Formation of this product was explained on the basis of a radical cation intermediate. The acute and chronic toxicity of the drug and its photoproduct were evaluated on different organisms of the freshwater chain (Brachionus calyciflorus, Thamnocephalus platyurus, Daphnia magna, Ceriodaphnia dubia. The photoproduct exhibited a stronger toxic potential than the parent drug on the long time for C. dubia.

Sensitization of the nociceptive system in patients with low back pain and sickness absence: Disc degeneration disease or pain syndrome

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Jensen, Ole Kudsk; Nielsen, Claus Vinther; Stengaard-Pedersen, Kristian

SENSITIZATION OF THE NOCICEPTIVE SYSTEM IN PATIENTS WITH LOW BACK PAIN AND SICKNESS ABSENCE O.K. Jensen1, C.V. Nielsen2, K. Stengaard-Pedersen3 1The Spine Center, Department of Internal Medicine, Region Hospital Silkeborg, 2Department of Clinical Social Medicine, University of Aarhus, and 3...... characterized by sensitization of the nociceptive system. Purpose: To assess sensitization of the nociceptive system in low back pain (LBP) patients by means of TP examination and measure of Pressure Pain Threshold (PPT) on the thumb nails. To search for associations between the number of TPs and structural...... = 1.35, p = 0.017) and mental distress (anxiety) in men (OR = 1.39, p = 0.003). After adjustment for age and sex, a positive association between LBP score and DDS was found only in patients with less than six TPs (OR = 1.21 (1.0-1.47), p = 0.043). Low PPT on the thumb nails was associated with DDS...

Sertraline inhibits formalin-induced nociception and cardiovascular responses

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Santuzzi, C.H. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Futuro Neto, H.A. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Escola de Medicina da Empresa Brasileira de Ensino, Pesquisa e Extensão, Vitória, ES (Brazil); Escola Superior de Ciências da Saúde, Santa Casa de Misericórdia de Vitória, Vitória, ES (Brazil); Pires, J.G.P. [Escola de Medicina da Empresa Brasileira de Ensino, Pesquisa e Extensão, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Gonçalves, W.L.S. [Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Tiradentes, R.V.; Gouvea, S.A.; Abreu, G.R. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil)

2011-11-18

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8 per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg{sup −1}·day{sup −1}, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5% (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7%), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9%, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

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Passmore, Gayle M.; Reilly, Joanne M.; Thakur, Matthew; Keasberry, Vanessa N.; Marsh, Stephen J.; Dickenson, Anthony H.; Brown, David A.

2012-01-01

M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 μM XE991 sensitized Aδ- but not C-fibers to noxious heat stimulation and induced spontaneous, ongoing activity at 32°C in many Aδ-fibers. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn (DH) neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Aδ-fiber peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Aδ-fiber responses and provide a rationale for the nocifensive behaviors that arise following intraplantar injection of the M-channel blocker XE991. PMID:22593734

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

Directory of Open Access Journals (Sweden)

Gayle M. Passmore

2012-05-01

Full Text Available M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 µM XE991 sensitised Adelta- but not C-fibres to noxious heat stimulation and induced spontaneous, ongoing activity at 32ºC in many Adelta-fibres. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Adelta-fibre peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Adelta-fibre responses and provide a rationale for the nocifensive behaviours that arise following intraplantar injection of the M-channel blocker XE991.

Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception.

Directory of Open Access Journals (Sweden)

G Gregory Neely

Full Text Available The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Science.gov (United States)

Mair, Norbert; Racz, Ildiko; Milinkeviciute, Giedre; Meixner, Arabella; Nayanala, Swetha; Griffin, Robert S.; Belfer, Inna; Dai, Feng; Smith, Shad; Diatchenko, Luda; Marengo, Stefano; Haubner, Bernhard J.; Novatchkova, Maria; Gibson, Dustin; Maixner, William; Pospisilik, J. Andrew; Hirsch, Emilio; Whishaw, Ian Q.; Zimmer, Andreas; Gupta, Vaijayanti; Sasaki, Junko; Kanaho, Yasunori; Sasaki, Takehiko; Kress, Michaela; Woolf, Clifford J.; Penninger, Josef M.

2012-01-01

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. PMID:23236288

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex

DEFF Research Database (Denmark)

Fischer, I W; Gram, M; Hansen, T M

2017-01-01

solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty...

17β-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception.

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Qu, Zu-Wei; Liu, Ting-Ting; Ren, Cuixia; Gan, Xiong; Qiu, Chun-Yu; Ren, Ping; Rao, Zhiguo; Hu, Wang-Ping

2015-12-01

Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17β-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.

Comparison of effects of valsartan and amlodipine on cognitive functions and auditory p300 event-related potentials in elderly hypertensive patients.

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Katada, Eiichi; Uematsu, Norihiko; Takuma, Yuko; Matsukawa, Noriyuki

2014-01-01

We compared the antihypertensive effect of valsartan (VAL) and amlodipine (AML) treatments in elderly hypertensive patients by examining the long-term changes in cognitive function and auditory P300 event-related potentials. We enrolled 20 outpatients, including 12 men and 8 women in the age group of 56 to 81 years who had mild to moderate essential hypertension. The subjects were randomly allocated to receive either 80 mg VAL once a day (10 patients) or 5 mg AML once a day (10 patients). Neuropsychological assessment and auditory P300 event-related potentials were obtained before initiation of VAL or AML treatment and after 6 months of the treatment with VAL or AML. Neuropsychological assessment was evaluated by conducting the Mini-Mental State Examination, the verbal fluency, word-list memory, word-list recall test, word-list recognition, and Trails B tests. Both the groups showed significantly reduced-blood pressure after 6 months of treatment, and the intergroup difference was not significant. The mean baseline Mini-Mental State Examination scores of the VAL and AML groups were not significantly different. Amlodipine treatment did not significantly affect any test score, but VAL treatment significantly increased the word-list memory and word-list recall test scores. Valsartan, and not AML, significantly reduced the mean P300 latency after 6 months. These results suggest that VAL exerts a positive effect on cognitive functions, independent of its antihypertensive effect.

Effects of awareness and nociception on heart rate variability during general anaesthesia

International Nuclear Information System (INIS)

Huhle, R; Zaunseder, S; Malberg, H; Burghardt, M; Koch, T; Heller, A R; Wessel, N

2012-01-01

During anaesthesia awareness and nociception are serious complications that may further lead to haemodynamic instability. Specific monitoring of depth of hypnosis and depth of analgesia based on heart rate variability (HRV) analysis is eligible to improve patient safety and reduce efforts in post-operative care. Consequently, in this analysis we assess the applicability of HRV parameters during surgical interventions with standardized intravenous propofol-remifentanil-anaesthesia. Peri-operative electrocardiograms were recorded from cardiovascular stable patients (ASA Score I/II, N = 32, age: 36.4 ± 11.23 a, BMI: 25.2 ± 3.16) scheduled for trauma and dentofacial surgery. HRV time- and frequency-domain parameters, measures of complexity and nonlinear dynamics were compared by analysing longitudinally distributed 300 s intervals preceding/following induction of anaesthesia (BL–I1), intubation (I1–I2) and extubation (E1–E2). Mean value (meanNN) and standard deviation (sdNN) of the heart rate are influenced in BL–I1 (p < 0.001), I1–I2 (p < 0.05) and E1–E2 (p < 0.001). The number of forbidden words of symbolic dynamics changes significantly for BL–I1 (p < 0.001) and not for I1–I2 and E1–E2 (p > 0.05). Probability of low-variability POLVAR10 is significantly altered in all comparisons (BL–I1: Δ = 0.032, p < 0.01, I1–I2: Δ = 0.12, p < 0.05, E1–E2: Δ = 0.169, p < 0.01) but especially during nociception. While standard time-domain parameters lacked selectivity, parameters of symbolic dynamics appear to be specifically influenced by changes in depth of hypnosis and nociception, respectively. However, the lack of steady-state ventilation/breathing in this study needs to be considered in future research. To be used for clinical anaesthesia monitoring our results have to be prospectively validated in clinical studies. (paper)

Fish oil concentrate delays sensitivity to thermal nociception in mice

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Veigas, Jyothi M.; Williams, Paul J.; Halade, Ganesh; Rahman, Mizanur M.; Yoneda, Toshiyuki; Fernandes, Gabriel

2011-01-01

Fish oil has been used to alleviate pain associated with inflammatory conditions such as rheumatoid arthritis. The anti-inflammatory property of fish oil is attributed to the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid. Contrarily, vegetable oils such as safflower oil are rich in n-6 fatty acids which are considered to be mediators of inflammation. This study investigates the effect of n-3 and n-6 fatty acids rich oils as dietary supplements on the thermally induced pain sensitivity in healthy mice. C57Bl/6J mice were fed diet containing regular fish oil, concentrated fish oil formulation (CFO) and safflower oil (SO) for 6 months. Pain sensitivity was measured by plantar test and was correlated to the expression of acid sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1) and c-fos in dorsal root ganglion cells. Significant delay in sensitivity to thermal nociception was observed in mice fed CFO compared to mice fed SO (p<0.05). A significant diminution in expression of ion channels such as ASIC1a (64%), ASIC13 (37%) and TRPV1 (56%) coupled with reduced expression of c-fos, a marker of neuronal activation, was observed in the dorsal root ganglion cells of mice fed CFO compared to that fed SO. In conclusion, we describe here the potential of fish oil supplement in reducing sensitivity to thermal nociception in normal mice. PMID:21345372

Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

Science.gov (United States)

Casey, Kenneth L.

1999-07-01

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Pre-test habituation improves the reliability of a handheld test of mechanical nociceptive threshold in dairy cows

DEFF Research Database (Denmark)

Raundal, P. M.; Andersen, P. H.; Toft, Nils

2015-01-01

Mechanical nociceptive threshold (MNT) testing has been used to investigate aspects of painful states in bovine claws. We investigated a handheld tool, where the applied stimulation force was monitored continuously relative to a pre-encoded based target force. The effect on MNT of two pre-testing...... habituation procedures was performed in two different experiments comprising a total of 88 sound Holsteins dairy cows kept either inside or outside their home environment. MNT testing was performed using five consecutive mechanical nociceptive stimulations per cow per test at a fixed pre-encoded target rate...... of 2.1 N/s. The habituation procedure performed in dairy cows kept in their home environment led to lowered intra-individual coefficient of variation of MNT (P test...

Occlusal splint versus modified nociceptive trigeminal inhibition splint in bruxism therapy: a randomized, controlled trial using surface electromyography.

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Dalewski, B; Chruściel-Nogalska, M; Frączak, B

2015-12-01

An occlusal splint and a modified nociceptive trigeminal inhibition splint (AMPS, anterior deprogrammer, Kois deprogrammer, Lucia jig, etc.) are commonly and quite frequently used in the treatment of masticatory muscle disorders, although their sustainable and long-lasting effect on these muscles' function is still not very well known. Results of scant surface electromyography studies in patients with temporomandibular disorders have been contradictory. The aim of this study was to evaluate both devices in bruxism therapy; EMG activity levels during postural activity and maximum voluntary contraction of the superficial temporal and masseter muscles were compared before and after 30 days of treatment. Surface electromyography of the examined muscles was performed in two groups of bruxers (15 patients each). Patients in the first group used occlusal splints, while those in the second used modified nociceptive trigeminal inhibition splints. The trial was randomized, controlled and semi-blind. Neither device affected the asymmetry index or postural activity/maximum voluntary contraction ratio after 1 month of treatment. Neither the occlusal nor the nociceptive trigeminal inhibition splint showed any significant influence on the examined muscles. Different scientific methods should be considered in clinical applications that require either direct influence on the muscles' bioelectrical activity or a quantitative measurement of the treatment quality. © 2015 Australian Dental Association.

Nociception contributes to the formation of myogenic contracture in the early phase of adjuvant-induced arthritis in a rat knee.

Science.gov (United States)

Kaneguchi, Akinori; Ozawa, Junya; Moriyama, Hideki; Yamaoka, Kaoru

2017-07-01

It is unknown how joint contracture is generated in inflamed joints. This study aimed to clarify the role of nociception on the formation of joint contracture secondary to arthritis. Monoarthritis was induced by intra-articular injections of complete Freund's adjuvant (CFA) into rat knees. On day 5 after CFA injection, the passive extension range of motion (ROM) of knee joints were measured, both before and after myotomy of knee flexors, to evaluate the extent of muscular contribution to CFA-induced joint contracture. The steroidal anti-inflammatory drug dexamethasone could prevent ROM restrictions completely, both before and after myotomy. On the other hand, the opioid analgesic drug morphine did not prevent the development of restricted ROM observed after myotomy, while it did before myotomy. This indicates that nociception contributes to joint contracture through alterations in muscular structure (myogenic factors). Next, we tested the hypothesis that nociception-induced reflexive flexor muscle contractions cause myogenic contracture in arthritic joints. To do this, chemical denervation was performed by Botulinum toxin type A (BTX-A) injections into knee flexor muscles, simultaneously with CFA injections into the knee. As expected, BTX-A could alleviate ROM restrictions observed before myotomy. These findings suggest that nociceptive-related muscle contractions play an essential role in the formation of joint contracture. Thus, our study indicates that analgesic management during an early stage of joint arthritis is an essential mean to prevent the formation of joint contracture. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1404-1413, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis.

Science.gov (United States)

Greaves, Erin; Grieve, Kelsey; Horne, Andrew W; Saunders, Philippa T K

2014-09-01

Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. The study was performed using human tissue analysis and cell culture. The study was conducted at a university research institute. Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P endometriosis lesions (P endometriosis (P endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP.

Anti-nociceptive, anti-hyperalgesic and anti-arthritic activity of amides and extract obtained from Piper amalago in rodents.

Science.gov (United States)

da Silva Arrigo, Jucicléia; Balen, Eloise; Júnior, Ubirajara Lanza; da Silva Mota, Jonas; Iwamoto, Renan Donomae; Barison, Andersson; Sugizaki, Mario Mateus; Leite Kassuya, Cândida Aparecida

2016-02-17

Piper amalago (Piperaceae) has been used in folk medicine as an analgesic. This study aimed to evaluate the pharmacological effects of extract and pure amides obtained from P. amalago on pain to provide a pharmacological basis for their use in traditional medicine. This study evaluated the anti-nociceptive, anti-hyperalgesic, anti-arthritic and anti-depressive activities of the ethanolic extract of P. amalago (EEPA) and the amides N-[7-(3',4'-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl] pyrrolidine (1) and N-[7-(3',4'-methylenedioxyphenyl)-2(E),4(E)-heptadienoyl] pyrrolidine (2) obtained from P. amalago in animal models. Mice treated daily with EEPA (100mg/kg, p.o.) were assayed for 20 days for knee edema (micrometer measurement), mechanical hyperalgesia (analgesiometer analysis), heat sensitivity and immobility (forced swim test) in the Complete Freund's Adjuvant (CFA) model. Cold (acetone test) and mechanical hyperalgesia (electronic von Frey analysis) responses were evaluated for 15 days in rats treated with oral EEPA (100mg/kg) in the spared nerve injury (SNI) model. Meanwhile, mice were evaluated for carrageenan-induced edema and mechanical hyperalgesia and for nociception using the formalin model after a single administration of EEPA (100mg/kg) or amides 1 and 2 (1mg/kg). Amides (1) and (2) were detected and isolated from the EEPA. The EEPA inhibited mechanical hyperalgesia, knee edema, and heat hyperalgesia, but not depressive-like behavior, induced by the intraplantar injection of CFA. When evaluated in the SNI model, the EEPA inhibited mechanical and cold hyperalgesia. The EEPA, 1 and 2 prevented the mechanical hyperalgesia induced by carrageenan and the anti-nociceptive effects in both phases of formalin nociception. The EEPA did not induce alterations in the open field test. The EEPA was effective for inhibition of pain and arthritic parameters but was not effective against depressive-like behavior; additionally, it did not alter locomotor activity. The

Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion.

Science.gov (United States)

Ogata, M; Noda, K; Akita, H; Ishibashi, H

2015-03-19

Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. The formalin test revealed that rats with neonatal dopamine depletion exhibited a significant increase in nociceptive response during interphase (6-15min post formalin injection) and phase 2 (16-75min post formalin injection). This increase in nociceptive response to the formalin injection was not reversed by pretreatment with methamphetamine, which ameliorates motor hyperactivity observed in adolescent rats with neonatal 6-OHDA treatment. The von-Frey filament and tail flick tests failed to reveal significant differences in withdrawal thresholds between neonatal 6-OHDA-treated and vehicle-treated rats. The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I-II and V-VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of

Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture

OpenAIRE

Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou; Sun, Yuan; Wei, Tzuping; Clark, David J; Kingery, Wade S

2015-01-01

Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glia activation and central sensitization. At 4 weeks after tibia fracture and casting ...

3,6-Dimethoxy-6″,6″-Dimethyl-(7,8,2″,3″)-Chromeneflavone, a Flavonoid Isolated from Lonchocarpus Araripensis Benth. (Fabaceae), Reduces Nociceptive Behaviour in Mice.

Science.gov (United States)

Almeida, Jackson R G S; Silva, Juliane C; Guimarães, Amanda L; Oliveira, Ana P; Souza, Grasielly R; Oliveira-Júnior, Raimundo G; Lima-Saraiva, Sarah R G; Barbosa-Filho, José M; Braz-Filho, Raimundo; Queiroz, Dinalva Brito; Botelho, Marco Antônio

2015-10-01

Lonchocarpus araripensis Benth. is largely distributed in the northeast region of Brazil. It is popularly known as 'sucupira'. Recent studies have shown that some species of Lonchocarpus have interesting pharmacological activities. In this study, we evaluated the antinociceptive effect of a flavone isolated from L. araripensis. The chemical examination resulted in the isolation of 3,6-dimethoxy-6″,6″-dimethyl-(7,8,2″,3″)-chromeneflavone (DDF). The structure of the compound was established by spectral analysis. Antinociceptive activity of DDF was evaluated by measuring nociception by acetic acid, formalin and hot plate tests. The rota rod test was used to evaluate motor coordination. The results demonstrated that DDF was able to prevent acetic-acid-writhing-induced nociception (p < 0.001) in mice. Furthermore, DDF produced a significant reduction of the nociceptive behaviour at the early and late phases of paw licking in the formalin test. Also, DDF produced an inhibition of the nociceptive behaviour during a hot-plate test. No alteration in motor coordination was observed. These results confirm the hypothesis that DDF reduces the nociceptive behaviour in mice, probably through central mechanisms, but without compromising the motor coordination of animals. Copyright © 2015 John Wiley & Sons, Ltd.

Three different spectrophotometric methods manipulating ratio spectra for determination of binary mixture of Amlodipine and Atorvastatin

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Darwish, Hany W.; Hassan, Said A.; Salem, Maissa Y.; El-Zeiny, Badr A.

2011-12-01

Three simple, specific, accurate and precise spectrophotometric methods manipulating ratio spectra are developed for the simultaneous determination of Amlodipine besylate (AM) and Atorvastatin calcium (AT) in tablet dosage forms. The first method is first derivative of the ratio spectra ( 1DD), the second is ratio subtraction and the third is the method of mean centering of ratio spectra. The calibration curve is linear over the concentration range of 3-40 and 8-32 μg/ml for AM and AT, respectively. These methods are tested by analyzing synthetic mixtures of the above drugs and they are applied to commercial pharmaceutical preparation of the subjected drugs. Standard deviation is <1.5 in the assay of raw materials and tablets. Methods are validated as per ICH guidelines and accuracy, precision, repeatability and robustness are found to be within the acceptable limit.

A review of the benefits of early treatment initiation with single-pill combinations of telmisartan with amlodipine or hydrochlorothiazide

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Segura J

2013-09-01

Full Text Available Julian Segura, Luis Miguel Ruilope Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain Abstract: This review discusses the rationale for earlier use of single-pill combinations (SPCs of antihypertensive drugs, with a focus on telmisartan/amlodipine (T/A and telmisartan/hydrochlorothiazide (T/H SPCs. Compared with the respective monotherapies, the once-daily T/A and T/H SPCs have been shown to result in significantly higher blood pressure (BP reductions, BP goal rates, and response rates in patients at all stages of hypertension. As expected, BP reductions are highest with the highest dose (T80/A10 and T80/H25 SPCs. Subgroup analyses of the telmisartan trials have reported the efficacy of both SPCs to be consistent, regardless of the patients' age, race, and coexisting diabetes, obesity, or renal impairment. In patients with mild-to-moderate hypertension, the T/A combination provides superior 24-hour BP-lowering efficacy compared with either treatment administered as monotherapy. Similarly, the T/H SPC treatment provides superior 24-hour BP-lowering efficacy, especially in the last 6 hours relative to other renin–angiotensin system inhibitor-based SPCs. The T/A SPC is associated with a lower incidence of edema than amlodipine monotherapy, and the T/H SPC with a lower incidence of hypokalemia than hydrochlorothiazide monotherapy. Existing evidence supports the use of the T/A SPC for the treatment of hypertensive patients with prediabetes, diabetes, or metabolic syndrome, due to the metabolic neutrality of both component drugs, and the use of the T/H SPC for those patients with edema or in need of volume reduction. Keywords: calcium-channel blocker, essential hypertension, diuretic, primary care physician, renin-angiotensin system inhibitor

Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

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Henry James L

2009-09-01

Full Text Available Abstract Background Clinical data on osteoarthritis (OA suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons. Results At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. Conclusion These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.

Host-Guest Inclusion Complexes between Amlodipine Enantiomers in Biphasic Recognition Chiral Extraction System using Tartaric Acid and β-Cyclodextrin Derivatives as Positive Confirmation Using of their Enantioselective Extraction

OpenAIRE

AZZAM, Khaldun; ABDALLAH, Hassan; HALIM, Hairul; AHMAD, Maizatul; SHAIBAH, Hassan

2015-01-01

The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-?-cyclodextrin (HP-?-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simula...

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats.

Science.gov (United States)

Birol Muhammet, Er; Kocamanoğlu, İsmail Serhat; Bozkurt, Ayhan; Bilge, Sırrı; Çetinoğlu, Erhan Çetin

2016-05-01

Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Animal experimentation. Forty rats were randomized into 4 groups 7 days after intrathecal catheterization; the following drugs were given through catheter lumens: Group Lidocaine (Group L): Lidocaine 20 μg; Group Lidocaine-Morphine (Group LM): Lidocaine 20 μg and morphine 0.5 μgr; Group Lidocaine-Dexketoprofen (Group LD): Lidocaine 20 μg and dexketoprofen trometamol 100 μg; and Group Dexketoprofen (Group D): Dexketoprofen trometamol 100 μg. Paw incision was achieved under ether inhalation. To measure analgesic potential, hot plate and tail immersion tests were used as nociceptive tests during the postoperative period. The mean reaction times detected in groups during hot plate and tail immersion tests were shortest in Group L at 15, 30, 45, 60, 75, 90, 105, and 120 minutes after start of surgery (pdexketoprofen, as in the morphine group, longer reaction times were detected than in the lidocaine group at all measurement times except 120 minutes (pdexketoprofen in the optimal perioperative pain management is effective, and can be administered as an adjuvant in clinics after neurotoxicity studies in animals, and effective dose studies in volunteers.

Anti-nociceptive and anti-hyperprolactinemia activities of Fructus Viticis and its effective fractions and chemical constituents.

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Hu, Y; Xin, H-L; Zhang, Q-Y; Zheng, H-C; Rahman, K; Qin, L-P

2007-10-01

Vitex rotundifolia L. is widely distributed along the sea coast of China. The aim of this study was to investigate the anti-nociceptive and anti-hyperprolactinemia activities of substances isolated from Fructus Viticis (the fruit of Vitex rotundifolia), which may be effective in the treatment of pre-menstrual symptoms, using acetic-acid-induced writhing and metoclopramide-dihydrochloride-induced hyperprolactinemia in mice. The fractions effective in terms of anti-nociceptive and anti-hyperprolactinemia activities were obtained from Fructus Viticis by elution through macro-porous resin, and polyamide and silica gel column chromatography. The standardization of the fractions obtained from the separation procedures was carried out by means of high-performance liquid chromatography (HPLC)-fingerprint. In this study, the flavone-enriched fraction (Fraction 6) showed a higher inhibitory rate than indomethacin (69.4% vs. 56.4%) at a dose of 50 mg/kg body wt., and significantly reduced the prolactin level as compared to HPRL-treated mice (8.2 ng/ml vs. 25.5 ng/ml). Furthermore, this fraction showed anti-nociceptive activity in a dose-dependent manner (10-50 mg/kg body wt., i.g.). On further purification with silica gel, Casticin was isolated from this fraction and it decreased abnormal serum levels of prolactin by approximately 50% (p screening methods, our results indicate that the presence of flavonoids such as Casticin in this plant may be responsible for the activity effects. Casticin has potent analgesic and anti-hyperprolactinaemia properties, is likely to be one of the active components of Fructus Viticis, and may have a role in treating PMS (premenstrual syndrom).

Hypothalamic digoxin, hemispheric chemical dominance, and peptic ulcer disease.

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Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-10-01

The isoprenoid pathway produces three key metabolites--endogenous digoxin-like factor (EDLF) (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter transport), ubiquinone (free radical scavenger), and dolichol (regulator of glycoconjugate metabolism). The pathway was assessed in peptic ulcer and acid peptic disease and its relation to hemispheric dominance studied. The activity of HMG CoA reductase, serum levels of EDLF, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in acid peptic disease, right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals. All the patients with peptic ulcer disease were right-handed/left hemispheric dominant by the dichotic listening test. The pathway was upregulated with increased EDLF synthesis in peptic ulcer disease (PUD). There was increase in tryptophan catabolites and reduction in tyrosine catabolites in these patients. The ubiquinone levels were low and free radical production increased. Dolichol and glycoconjugate levels were increased and lysosomal stability reduced in patients with acid peptic disease (APD). There was increase in cholesterol:phospholipid ratio with decreased glyco conjugate levels in membranes of patients with PUD. Acid peptic disease represents an elevated EDLF state which can modulate gastric acid secretion and the structure of the gastric mucous barrier. It can also lead to persistence of Helicobacter pylori infection. The biochemical pattern obtained in peptic ulcer disease is similar to those obtained in left-handed/right hemispheric chemically dominant individuals. But all the patients with peptic ulcer disease were right-handed/left hemispheric dominant by the dichotic listen ing test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Peptic ulcer disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

The Discriminative validity of "nociceptive," "peripheral neuropathic," and "central sensitization" as mechanisms-based classifications of musculoskeletal pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-02-01

OBJECTIVES: Empirical evidence of discriminative validity is required to justify the use of mechanisms-based classifications of musculoskeletal pain in clinical practice. The purpose of this study was to evaluate the discriminative validity of mechanisms-based classifications of pain by identifying discriminatory clusters of clinical criteria predictive of "nociceptive," "peripheral neuropathic," and "central sensitization" pain in patients with low back (+\\/- leg) pain disorders. METHODS: This study was a cross-sectional, between-patients design using the extreme-groups method. Four hundred sixty-four patients with low back (+\\/- leg) pain were assessed using a standardized assessment protocol. After each assessment, patients\\' pain was assigned a mechanisms-based classification. Clinicians then completed a clinical criteria checklist indicating the presence\\/absence of various clinical criteria. RESULTS: Multivariate analyses using binary logistic regression with Bayesian model averaging identified a discriminative cluster of 7, 3, and 4 symptoms and signs predictive of a dominance of "nociceptive," "peripheral neuropathic," and "central sensitization" pain, respectively. Each cluster was found to have high levels of classification accuracy (sensitivity, specificity, positive\\/negative predictive values, positive\\/negative likelihood ratios). DISCUSSION: By identifying a discriminatory cluster of symptoms and signs predictive of "nociceptive," "peripheral neuropathic," and "central" pain, this study provides some preliminary discriminative validity evidence for mechanisms-based classifications of musculoskeletal pain. Classification system validation requires the accumulation of validity evidence before their use in clinical practice can be recommended. Further studies are required to evaluate the construct and criterion validity of mechanisms-based classifications of musculoskeletal pain.

Urethane anesthesia depresses activities of thalamocortical neurons and alters its response to nociception in terms of dual firing modes

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Yeowool eHuh

2013-10-01

Full Text Available Anesthetics are often used to characterize the activity of single neurons in-vivo for its advantages such as reduced noise level and convenience in noxious stimulations. Of the anesthetics, urethane had been widely used in some thalamic studies under the assumption that sensory signals are still relayed to the thalamus under urethane anesthesia and that thalamic response would therefore reflect the response of the awake state. We tested whether this assumption stands by comparing thalamic activity in terms of tonic and burst firing modes during ‘the awake state’ or under ‘urethane anesthesia’ utilizing the extracellular single unit recording technique. First we have tested how thalamic relay neurons respond to the introduction of urethane and then tested how urethane influences thalamic discharges under formalin-induced nociception. Urethane significantly depressed overall firing rates of thalamic relay neurons, which was sustained despite the delayed increase of burst activity over the 4 hour recording period. Thalamic response to nociception under anesthesia was also similar overall except for the slight and transient increase of burst activity. Overall, results demonstrated that urethane suppresses the activity of thalamic relay neurons and that, despite the slight fluctuation of burst firing, formalin-induced nociception cannot significantly change the firing pattern of thalamic relay neurons that was caused by urethane.

Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses

OpenAIRE

Franco,Leandro Guimarães; Moreno,Juan Carlos Duque; Teixeira Neto,Antônio Raphael; Souza,Moisés Caetano e; Silva,Luiz Antônio Franco da

2014-01-01

This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV) tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1), 2 (Tr2) or 3 (Tr3) mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR), arterial pressure, degree of sedation, gastrointestinal motility (GI), behavior changes and the mechanical nociceptive threshold (MNT) were evaluated. The MNT was determined with von Frey device method.Tr3 had ...

D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats.

Science.gov (United States)

Ohtani, Norimasa; Masaki, Eiji

2016-01-01

Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats. Male Sprague-Dawley rats (250-300 g) were anesthetized with sevoflurane and an intrathecal (IT) catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole), or a D2-like receptor antagonist (sulpiride) was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision. Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect. A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold.

Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

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Choong-Wan Woo

2015-01-01

Full Text Available Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS, an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.

Determination of the temperature causing a nociceptive response in the tail of albino BALB/c mice.

Science.gov (United States)

Aguirre Siancas, E E; Lam Figueroa, N M; Delgado Rios, J C; Ruiz Ramirez, E; Portilla Flores, O S; Crispín Huamaní, L J; Alarcón Velásquez, L

2018-06-08

Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful. Eight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13 cm. The animals' tails were immersed in the container with a starting temperature of 36°C. The water temperature was raised in 1°C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water. Six of the 8 mice began shaking their tails at the temperature of 51°C. All animals removed their tails from the water at the temperatures of 54°C, 55°C, and 56°C, taking a mean time of 8.54, 7.99, and 5.33seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). The response time was statistically similar for the temperatures of 54°C, 55°C, and 56°C; however, the data were less dispersed for the latter temperature. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats

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Birol Muhammet Er

2016-06-01

Full Text Available Background: Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. Aims: The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Study Design: Animal experimentation. Methods: Forty rats were randomized into 4 groups 7 days after intrathecal catheterization; the following drugs were given through catheter lumens: Group Lidocaine (Group L: Lidocaine 20 μg; Group Lidocaine-Morphine (Group LM: Lidocaine 20 μg and morphine 0.5 μgr; Group Lidocaine-Dexketoprofen (Group LD: Lidocaine 20 μg and dexketoprofen trometamol 100 μg; and Group Dexketoprofen (Group D: Dexketoprofen trometamol 100 μg. Paw incision was achieved under ether inhalation. To measure analgesic potential, hot plate and tail immersion tests were used as nociceptive tests during the postoperative period. Results: The mean reaction times detected in groups during hot plate and tail immersion tests were shortest in Group L at 15, 30, 45, 60, 75, 90, 105, and 120 minutes after start of surgery (p<0.01, all others. In the groups using dexketoprofen, as in the morphine group, longer reaction times were detected than in the lidocaine group at all measurement times except 120 minutes (p<0.01. Conclusion: Intrathecal dexketoprofen in the optimal perioperative pain management is effective, and can be administered as an adjuvant in clinics after neurotoxicity studies in animals, and effective dose studies in volunteers.

Anti-inflammatory and anti-nociceptive activities of methanolic leaf extract of Indigofera cassioides Rottl. Ex. DC.

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Raju Senthil Kumar

2013-01-01

Conclusions: All the results obtained revealed that the extract MEIC showed potent anti-inflammatory and anti-nociceptive activity against all the tested models and the results obtained were comparable with the standards used. The activity of the extract may be due to the presence of terpenoids, flavonoids and other phytochemicals.

Steady-state evoked potentials to study the processing of tactile and nociceptive somatosensory input in the human brain.

Science.gov (United States)

Colon, E; Legrain, V; Mouraux, A

2012-10-01

The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response of corresponding frequency, known as steady-state evoked potentials (SS-EP). In visual, auditory and vibrotactile modalities, studies have shown that SS-EP reflect mainly activity originating from early, modality-specific sensory cortices. Furthermore, it has been shown that SS-EP have several advantages over the recording of transient event-related brain potentials (ERP), such as a high signal-to-noise ratio, a shorter time to obtain reliable signals, and the capacity to frequency-tag the cortical activity elicited by concurrently presented sensory stimuli. Recently, we showed that SS-EP can be elicited by the selective activation of skin nociceptors and that nociceptive SS-EP reflect the activity of a population of neurons that is spatially distinct from the somatotopically-organized population of neurons underlying vibrotactile SS-EP. Hence, the recording of SS-EP offers a unique opportunity to study the cortical representation of nociception and touch in humans, and to explore their potential crossmodal interactions. Here, (1) we review available methods to achieve the rapid periodic stimulation of somatosensory afferents required to elicit SS-EP, (2) review previous studies that have characterized vibrotactile and nociceptive SS-EP, (3) discuss the nature of the recorded signals and their relationship with transient event-related potentials and (4) outline future perspectives and potential clinical applications of this technique. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats

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Ohtani N

2016-10-01

Full Text Available Norimasa Ohtani, Eiji Masaki Division of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan Background: Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats.Methods: Male Sprague-Dawley rats (250–300 g were anesthetized with sevoflurane and an intrathecal (IT catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole, or a D2-like receptor antagonist (sulpiride was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision.Results: Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect.Conclusion: A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold. Keywords: postoperative pain, descending pathway

Influence of dental correction on nociceptive test responses, fecal appearance, body condition score, and apparent digestibility coefficient for dry matter of Zamorano-leones donkeys (Equus asinus).

Science.gov (United States)

Rodrigues, J B; Ferreira, L M; Bastos, E; San Roman, F; Viegas, C; Santos, A S

2013-10-01

The influence of dental correction on nociceptive (pressure) test responses, fecal appearance, BCS, and apparent digestibility coefficient for DM was studied in 18 Zamorano-Leonés donkeys, an endangered local breed from the Zamora province in Spain. For this purpose, donkeys were divided into 2 homogeneous control and treatment groups, based on age, BCS, and dental findings. On d 1, 45, 90, and 135, BCS and nociceptive test responses were evaluated in all donkeys. Feed and fecal samples were collected from all donkeys for 3 consecutive days, starting at each of the aforementioned days. Apparent digestibility coefficient for DM was estimated, using ADL as an internal marker. A progressive decrease of positive nociceptive test responses was observed from d 1 up to 90 (P donkeys but also the equid population, in general, to improve their welfare.

Interaction of corneal nociceptive stimulation and lacrimal secretion.

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Situ, Ping; Simpson, Trefford L

2010-11-01

To investigate the interaction between corneal stimuli at different positions and tear secretion and to establish relationships between nociceptive stimuli detection thresholds and stimulated tearing. Using a computerized Belmonte-esthesiometer, mechanical and chemical stimuli, from 0% to 200% of the threshold in 50% steps, were delivered (in random order) to the central and peripheral (approximately 2-mm inside the limbus) cornea during four separate sessions to 15 subjects. Immediately after each stimulus, tear meniscus height (TMH) was measured using optical coherence tomography to quantify the amount of lacrimal secretion, and subjects reported whether they felt tears starting to accumulate in their eyes. Thresholds (50% detection) for detection of tearing were estimated. TMH increased with increasing stimulus intensity (P lacrimation reflex. Central mechanical corneal stimulation is the most effective stimulus-position pairing and appears to be the major sensory driving force for reflex tear secretion by the lacrimal functional unit.

Neuro chemical characteristic of structures of nociceptive system athyperthyroid function of the thyroid gland

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O. M. Demchenko

2015-06-01

Full Text Available The papercomprises the study of the conditionofpro-antioxidantprocesses in the formationso fnociceptivesystem (cerebral cortex, hippocampus, stem and thalamus in the presence of the experiment al induced hyperthyroidism. It was found that nociceptive irritation (laparotomy on the background of hyper thyroidism had not pronounced effect on the content of diene conjugates (DC and malondialdehyde. The level of enzymes of antioxidant system of superoxidedismutase (SOD and glutathioneperoxidase (GPO decreased.

Nociceptive afferents to the premotor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by means of axon collaterals.

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Yulin Dong

Full Text Available It is well known that the brainstem premotor neurons of the facial nucleus and hypoglossal nucleus coordinate orofacial nociceptive reflex (ONR responses. However, whether the brainstem PNs receive the nociceptive projection directly from the caudal spinal trigeminal nucleus is still kept unclear. Our present study focuses on the distribution of premotor neurons in the ONR pathways of rats and the collateral projection of the premotor neurons which are involved in the brainstem local pathways of the orofacial nociceptive reflexes of rat. Retrograde tracer Fluoro-gold (FG or FG/tetramethylrhodamine-dextran amine (TMR-DA were injected into the VII or/and XII, and anterograde tracer biotinylated dextran amine (BDA was injected into the caudal spinal trigeminal nucleus (Vc. The tracing studies indicated that FG-labeled neurons receiving BDA-labeled fibers from the Vc were mainly distributed bilaterally in the parvicellular reticular formation (PCRt, dorsal and ventral medullary reticular formation (MdD, MdV, supratrigeminal nucleus (Vsup and parabrachial nucleus (PBN with an ipsilateral dominance. Some FG/TMR-DA double-labeled premotor neurons, which were observed bilaterally in the PCRt, MdD, dorsal part of the MdV, peri-motor nucleus regions, contacted with BDA-labeled axonal terminals and expressed c-fos protein-like immunoreactivity which induced by subcutaneous injection of formalin into the lip. After retrograde tracer wheat germ agglutinated horseradish peroxidase (WGA-HRP was injected into VII or XII and BDA into Vc, electron microscopic study revealed that some BDA-labeled axonal terminals made mainly asymmetric synapses on the dendritic and somatic profiles of WGA-HRP-labeled premotor neurons. These data indicate that some premotor neurons could integrate the orofacial nociceptive input from the Vc and transfer these signals simultaneously to different brainstem motonuclei by axonal collaterals.

Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats.

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Xiao, Zhiying; Rogers, Marc J; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

2014-09-15

The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions. Copyright © 2014 the American Physiological Society.

Psychophysics of a nociceptive test in the mouse: ambient temperature as a key factor for variation.

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Ivanne Pincedé

Full Text Available The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and latency of the central decision-making process.Basically, the procedures involved heating of the tail with a CO(2 laser, recording of tail temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making.We have validated a psychophysical approach to nociceptive reactions for the mouse, which has already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using as "pain index" the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing of mice.

The role of protease-activated receptor type 2 in nociceptive signaling and pain

Czech Academy of Sciences Publication Activity Database

Mrózková, Petra; Paleček, Jiří; Špicarová, Diana

2016-01-01

Roč. 65, č. 3 (2016), s. 357-367 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH12058; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA15-11138S; GA MŠk(CZ) LH15279; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : protease-activated receptor (PAR2) * signaling pathways * nociception * pain * spinal cord Subject RIV: FH - Neurology Impact factor: 1.461, year: 2016

Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

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Wu José

2012-04-01

Full Text Available Abstract Background Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the α value. We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. Findings Neuronal activity was recorded with a 4 × 8 multichannel electrode array in the primary somatosensory cortex (S1 and anterior cingulate cortex (ACC. Under light anesthesia, peripheral pinch stimulation increased the slope of the α value in both the ACC and S1, whereas brush stimulation increased the α value only in the S1. The increase in α values was blocked in both regions under deep anesthesia. The increase in α values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in α values in the S1 induced by brush and pinch stimulation was not affected. Conclusions The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The α value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.

Evidence of altered pressure pain thresholds in persons with disorders of consciousness as measured by the Nociception Coma Scale-Italian version.

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Sattin, Davide; Schnakers, Caroline; Pagani, Marco; Arenare, Francesca; Devalle, Guya; Giunco, Fabrizio; Guizzetti, GianBattista; Lanfranchi, Maurizio; Giovannetti, Ambra M; Covelli, Venusia; Bersano, Anna; Nigri, Anna; Minati, Ludovico; Rossi Sebastiano, Davide; Parati, Eugenio; Bruzzone, MariaGrazia; Franceschetti, Silvana; Leonardi, Matilde

2017-02-28

Pain assessment in patients with disorders of consciousness (DoC) is a controversial issue for clinicians, who require tools and standardised procedures for testing nociception in non-communicative patients. The aims of the present study were, first, to analyse the psychometric properties of the Italian version of the Nociception Coma Scale and, second, to evaluate pressure pain thresholds in a group of patients with DoC. The authors conducted a multi-centre study on 40 healthy participants and 60 DoC patients enrolled from six hospitals in Italy. For each group an electronic algometer was used to apply all nociceptive pressure stimuli. Our results show that the Italian version of the NCS retains the good psychometric properties of the original version and is therefore suitable for standardised pain assessment in clinical practice. In our study, pressure pain thresholds measured in a group of patients in vegetative and minimally conscious state were relatively lower than pain threshold values found in a group of healthy participants. Such findings motivate additional investigation on possible pain sensitisation in patients with severe brain injury and multiple co-morbidities, and on application of tailored therapeutic approaches useful for pain management in patients unable verbally to communicate their feelings.

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

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Eiji Masaki

2016-03-01

Full Text Available Background: Brain-derived neurotrophic factor (BDNF from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. Results: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. Conclusion: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

The selective effect of N-feruloylserotonins isolated from Leuzea carthamoides on nociception and anxiety in rats

Czech Academy of Sciences Publication Activity Database

Yamamotová, A.; Pometlová, M.; Harmatha, Juraj; Rašková, H.; Rokyta, R.

2007-01-01

Roč. 112, č. 2 (2007), s. 368-374 ISSN 0378-8741 R&D Projects: GA MŠk(CZ) 1M0517; GA ČR(CZ) GA203/07/1227 Institutional research plan: CEZ:AV0Z40550506 Keywords : nociception * anxiety * N-feruloylserotonin * Leuzea carthamoides Subject RIV: CC - Organic Chemistry Impact factor: 2.049, year: 2007

Toll-like receptor 4 signaling in neurons of trigeminal ganglion contributes to nociception induced by acute pulpitis in rats.

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Lin, Jia-Ji; Du, Yi; Cai, Wen-Ke; Kuang, Rong; Chang, Ting; Zhang, Zhuo; Yang, Yong-Xiang; Sun, Chao; Li, Zhu-Yi; Kuang, Fang

2015-07-30

Pain caused by acute pulpitis (AP) is a common symptom in clinical settings. However, its underlying mechanisms have largely remained unknown. Using AP model, we demonstrated that dental injury caused severe pulp inflammation with up-regulated serum IL-1β. Assessment from head-withdrawal reflex thresholds (HWTs) and open-field test demonstrated nociceptive response at 1 day post injury. A consistent up-regulation of Toll-like receptor 4 (TLR4) in the trigeminal ganglion (TG) ipsilateral to the injured pulp was found; and downstream signaling components of TLR4, including MyD88, TRIF and NF-κB, and cytokines such as TNF-α and IL-1β, were also increased. Retrograde labeling indicated that most TLR4 positve neuron in the TG innnervated the pulp and TLR4 immunoreactivity was mainly in the medium and small neurons. Double labeling showed that the TLR4 expressing neurons in the ipsilateral TG were TRPV1 and CGRP positive, but IB4 negative. Furthermore, blocking TLR4 by eritoran (TLR4 antagonist) in TGs of the AP model significantly down-regulated MyD88, TRIF, NF-κB, TNF-α and IL-1β production and behavior of nociceptive response. Our findings suggest that TLR4 signaling in TG cells, particularly the peptidergic TRPV1 neurons, plays a key role in AP-induced nociception, and indicate that TLR4 signaling could be a potential therapeutic target for orofacial pain.

Development of dissolution test method for a telmisartan/amlodipine besylate combination using synchronous derivative spectrofluorimetry

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Panikumar Durga Anumolu

2014-04-01

Full Text Available The dissolution process is considered an important in vitro tool to evaluate product quality and drug release behavior. Single dissolution methods for the analysis of combined dosage forms are preferred to simplify quality control testing. The objective of the present work was to develop and validate a single dissolution test for a telmisartan (TEL and amlodipine besylate (AML combined tablet dosage form. The sink conditions, stability and specificity of both drugs in different dissolution media were tested to choose a discriminatory dissolution method, which uses an USP type-II apparatus with a paddle rotating at 75 rpm, with 900 mL of simulated gastric fluid (SGF without enzymes as the dissolution medium. This dissolution methodology provided good dissolution profiles for both TEL and AML and was able to discriminate changes in the composition and manufacturing process. To quantify both drugs simultaneously, a synchronous first derivative spectrofluorimetric method was developed and validated. Drug release was analyzed by a fluorimetric method at 458 nm and 675 nm for AML and TEL, respectively. The dissolution method was validated as per ICH guidance.

The effect of social isolation, gender and familiarity with the experimental procedure on tests of porcine nociceptive thresholds

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di Giminiani, Pierpaolo; Stausholm, Julie S.; Viitasaari, Eliina

2015-01-01

Objective To investigate the effects of habituation and isolation on mechanical nociceptive thresholds in pigs at the pelvic limbs and at the tail. Study design Prospective randomized multifactorial study. Animals Thirty-two healthy castrated male (experiment 1), and 12 castrated male and 12 female...

Divergent functions of the left and right central amygdala in visceral nociception.

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Sadler, Katelyn E; McQuaid, Neal A; Cox, Abigail C; Behun, Marissa N; Trouten, Allison M; Kolber, Benedict J

2017-04-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.

Modulation of melanocortin- induced changes in spinal nociception by µ-opioid receptor agonist and antagonist in neuropathic rats

NARCIS (Netherlands)

Gispen, W.H.; Starowitcz, K.; Przewlocki, R.; Przewlocka, B.

2002-01-01

Co-localization of opioid and melanocortin receptor expression, especially at the spinal cord level in the dorsal horn and in the gray matter surrounding the central canal led to the suggestion that melanocortins might play a role in nociceptive processes. In the present studies, we aimed to

Antinociceptive Effects of Transcytosed Botulinum Neurotoxin Type A on Trigeminal Nociception in Rats

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Kim, Hye-Jin; Lee, Geun-Woo; Kim, Min-Ji; Yang, Kui-Ye; Kim, Seong-Taek; Bae, Yong-Cheol

2015-01-01

We examined the effects of peripherally or centrally administered botulinum neurotoxin type A (BoNT-A) on orofacial inflammatory pain to evaluate the antinociceptive effect of BoNT-A and its underlying mechanisms. The experiments were carried out on male Sprague-Dawley rats. Subcutaneous (3 U/kg) or intracisternal (0.3 or 1 U/kg) administration of BoNT-A significantly inhibited the formalin-induced nociceptive response in the second phase. Both subcutaneous (1 or 3 U/kg) and intracisternal (0.3 or 1 U/kg) injection of BoNT-A increased the latency of head withdrawal response in the complete Freund's adjuvant (CFA)-treated rats. Intracisternal administration of N-methyl-D-aspartate (NMDA) evoked nociceptive behavior via the activation of trigeminal neurons, which was attenuated by the subcutaneous or intracisternal injection of BoNT-A. Intracisternal injection of NMDA up-regulated c-Fos expression in the trigeminal neurons of the medullary dorsal horn. Subcutaneous (3 U/kg) or intracisternal (1 U/kg) administration of BoNT-A significantly reduced the number of c-Fos immunoreactive neurons in the NMDA-treated rats. These results suggest that the central antinociceptive effects the peripherally or centrally administered BoNT-A are mediated by transcytosed BoNT-A or direct inhibition of trigeminal neurons. Our data suggest that central targets of BoNT-A might provide a new therapeutic tool for the treatment of orofacial chronic pain conditions. PMID:26170739

Polysaccharide rich fractions from barks of Ximenia americana inhibit peripheral inflammatory nociception in mice Antinociceptive effect of Ximenia americana polysaccharide rich fractions

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Kaira E.S. da Silva-Leite

Full Text Available Abstract Ximenia americana L., Olacaceae, barks are utilized in folk medicine as analgesic and anti-inflammatory. The objective was to evaluate the toxicity and antinociceptive effect of polysaccharides rich fractions from X. americana barks. The fractions were obtained by extraction with NaOH, followed by precipitation with ethanol and fractionation by ion exchange chromatography. They were administered i.v. or p.o. before nociception tests (writhing, formalin, carragenan-induced hypernociception, hot plate, or during 14 days for toxicity assay. The total polysaccharides fraction (TPL-Xa: 8.1% yield presented 43% carbohydrate (21% uronic acid and resulted in two main fractions after chromatography (FI: 12%, FII: 22% yield. FII showed better homogeneity/purity, content of 44% carbohydrate, including 39% uronic acid, arabinose and galactose as major monosaccharides, and infrared spectra with peaks in carbohydrate range for COO- groups of uronic acid. TPL-Xa (10 mg/kg and FII (0.1 and 1 mg/kg presented inhibitory effect in behavior tests that evaluate nociception induced by chemical and mechanical, but not thermal stimuli. TPL-Xa did not alter parameters of systemic toxicity. In conclusion, polysaccharides rich fractions of X. americana barks inhibit peripheral inflammatory nociception, being well tolerated by animals.

Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor.

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Yu, Xuan; Wang, Xin-Pei; Yan, Xiao-Jin; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; Guo, Yue-Ying; Du, Li-Jun

2017-08-09

To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confifirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (Peffect of PA. A decrease in the intracellular calcium level (Peffect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

Thermal nociception as a measure of non-steroidal anti-inflammatory drug effectiveness in broiler chickens with articular pain☆

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Caplen, Gina; Baker, Laurence; Hothersall, Becky; McKeegan, Dorothy E.F.; Sandilands, Victoria; Sparks, Nick H.C.; Waterman-Pearson, Avril E.; Murrell, Joanna C.

2013-01-01

Pain associated with poultry lameness is poorly understood. The anti-nociceptive properties of two non-steroidal anti-inflammatory drugs (NSAIDs) were evaluated using threshold testing in combination with an acute inflammatory arthropathy model. Broilers were tested in six groups (n = 8 per group). Each group underwent a treatment (saline, meloxicam (3 or 5 mg/kg) or carprofen (15 or 25 mg/kg)) and a procedure (Induced (arthropathy-induction) or sham (sham-handling)) prior to testing. Induced groups had Freund’s complete adjuvant injected intra-articularly into the left intertarsal joint (hock). A ramped thermal stimulus (1 °C/s) was applied to the skin of the left metatarsal. Data were analysed using random-intercept multi-level models. Saline-induced birds had a significantly higher skin temperature (± SD) than saline-sham birds (37.6 ± 0.8 °C vs. 36.5 ± 0.5 °C; Z = −3.47, P carprofen: Z = 2.58, P = 0.010) in induced birds. Saline-induced birds also had significantly lower TT than saline-sham birds (Z = −2.17, P = 0.030). This study found direct evidence of an association between inflammatory arthropathies and thermal hyperalgesia, and showed that NSAID treatment maintained baseline thermal sensitivity (via anti-nociception). Quantification of nociceptive responsiveness in a predictable broiler pain model identified thermal anti-hyperalgesic properties of two NSAIDs, which suggested that therapeutically effective treatment was provided at the doses administered. Such validation of analgesic strategies will increase the understanding of pain associated with specific natural broiler lameness types. PMID:24129110

Ethanolic extract of Aconiti Brachypodi Radix attenuates nociceptive pain probably via inhibition of voltage-dependent Na⁺ channel.

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Ren, Wei; Yuan, Lin; Li, Jun; Huang, Xian-Ju; Chen, Su; Zou, Da-Jiang; Liu, Xiangming; Yang, Xin-Zhou

2012-01-01

Aconiti Brachypodi Radix, belonging to the genus of Aconitum (Family Ranunculaceae), are used clinically as anti-rheumatic, anti-inflammatory and anti-nociceptive in traditional medicine of China. However, its mechanism and influence on nociceptive threshold are unknown and need further investigation. The analgesic effects of ethanolic extract of Aconiti Brachypodi Radix (EABR) were thus studied in vivo and in vitro. Three pain models in mice were used to assess the effect of EABR on nociceptive threshold. In vitro study was conducted to clarify the modulation of the extract on the tetrodotoxin-sensitive (TTX-S) sodium currents in rat's dorsal root ganglion (DRG) neurons using whole-cell patch clamp technique. The results showed that EABR (5-20 mg/kg, i.g.) could produce dose-dependent analgesic effect on hot-plate tests as well as writhing response induced by acetic acid. In addition, administration of 2.5-10 mg/kg EABR (i.g.) caused significant decrease in pain responses in the first and second phases of formalin test without altering the PGE₂ production in the hind paw of the mice. Moreover, EABR (10 µg/ml -1 mg/ml) could suppress TTX-S voltage-gated sodium currents in a dose-dependent way, indicating the underlying electrophysiological mechanism of the analgesic effect of the folk plant medicine. Collectively, our results indicated that EABR has analgesic property in three pain models and useful influence on TTX-S sodium currents in DRG neurons, suggesting that the interference with pain messages caused by the modulation of EABR on TTX-S sodium currents in DRG neurones may explain some of its analgesic effect.

Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide

Science.gov (United States)

Darwish, Hany W.; Hassan, Said A.; Salem, Maissa Y.; El-Zeany, Badr A.

2013-09-01

Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20 μg/mL for AML, VAL and HCT, respectively.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

Science.gov (United States)

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

[THE CHANGES OF NOCICEPTIVE THRESHOLD AND ACTIVITY OF THE ADENYLYL CYCLASE SYSTEM IN THE SKELETAL MUSCLES OF RATS WITH ACUTE AND MILD TYPE 1 DIABETES MELLITUS ].

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Shipilov, V N; Trost, A M; Chistyakova, O V; Derkach, K V; Shpakov, A O

2016-02-01

Diabetic peripheral neuropathy (DPN) is one of the most common complications of the type 1 diabetes mellitus (DM1). The aim of the work was to study the dynamics of a painful DPN and functional state of the hormone-sensitive ACSS in the skeletal muscles of rats with the models of acute and mild DM1, as well as the study of impact on them of insulin therapy with different ways of hormone delivery - intranasal and peripheral. In both models of DM1, the level of nociceptive threshold in rats decreased and the stimulatory effects of guanine nucleotides (GppNHp) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) activity were attenuated. The AC stimulating effect of relaxin decreased in animals with acute DM1, but in mild DM1, the decrease was insignificant. Peripheral administration of insulin in rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of ß 3-agonist BRL-37344. Intranasal administration of insulin in rats with DM1 also increased the nociceptive threshold and partially restored the basal and BRL-37344-stimulated AC activity in the skeletal muscles of diabetic animals. Thus, in the skeletal muscles of rats with acute and mild DM1 the nociceptive sensitivity and the functions of ACSS were disturbed, and they were partially restored by the treatment with peripheral (acute DM1) or intranasal (mild DM1) insulin.

Effect of combination tablets containing amlodipine 10 mg and irbesartan 100 mg on blood pressure and cardiovascular risk factors in patients with hypertension

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Yagi S

2015-01-01

Full Text Available Shusuke Yagi,1 Akira Takashima,1 Minoru Mitsugi,2 Toshihiro Wada,2 Junko Hotchi,1 Ken-ichi Aihara,3 Tomoya Hara,1 Masayoshi Ishida,1 Daiju Fukuda,4 Takayuki Ise,1 Koji Yamaguchi,1 Takeshi Tobiume,1 Takashi Iwase,1 Hirotsugu Yamada,1 Takeshi Soeki,1 Tetsuzo Wakatsuki,1 Michio Shimabukuro,4 Masashi Akaike,5 Masataka Sata11Department of Cardiovascular Medicine, Graduate School of Health Biosciences, University of Tokushima, Tokushima, 2Department of Internal Medicine, Shikoku Central Hospital, Shikokuchuo, 3Department of Medicine and Bioregulatory Sciences, 4Department of Cardio-Diabetes Medicine, 5Department of Medical Education, Graduate School of Health Biosciences, University of Tokushima, Tokushima, JapanBackground: Hypertension is one of the major risk factors for cardiovascular and cerebrovascular disease and mortality. Patients who receive insufficient doses of antihypertensive agents or who are poorly adherent to multidrug treatment regimens often fail to achieve adequate blood pressure (BP control. The aim of this study was to determine the efficacy of an angiotensin II receptor blocker (ARB and calcium channel blocker (CCB combination tablet containing a regular dose of irbesartan (100 mg and a high dose of amlodipine (10 mg with regard to lowering BP and other risk factors for cardiovascular disease.Methods: We retrospectively evaluated data from 68 patients with essential hypertension whose treatment regimen was changed either from combination treatment with an independent ARB and a low-dose or regular-dose CCB or from a combination tablet of ARB and a low-dose or regular-dose CCB to a combination tablet containing amlodipine 10 mg and irbesartan 100 mg, because of incomplete BP control. Previous treatments did not include irbesartan as the ARB.Results: The combination tablet decreased systolic and diastolic BP. In addition, it significantly decreased serum uric acid, low-density lipoprotein cholesterol, and increased high

Nociceptive responses to thermal and mechanical stimulations in awake pigs

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di Giminiani, Pierpaolo; Petersen, Lars Jelstrup; Herskin, Mette S.

2013-01-01

body sizes (30 and 60 kg) were exposed to thermal (CO(2) laser) and mechanical (pressure application measurement device) stimulations to the flank and the hind legs in a balanced order. The median response latency and the type of behavioural response were recorded. RESULTS: Small pigs exhibited...... animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different...... significantly lower pain thresholds (shorter latency to response) than large pigs to thermal and mechanical stimulations. Stimulations at the two anatomical locations elicited very distinct sets of behavioural responses, with different levels of sensitivity between the flank and the hind legs. Furthermore...

Evaluation by N-terminal prohormone of brain natriuretic peptide concentrations and ross scoring of the efficacy of digoxin in the treatment of heart failure secondary to congenital heart disease with left-to-right shunts.

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Elkiran, Ozlem; Sandikkaya, Ayse; Kocak, Gulendam; Karakurt, Cemsit; Taskapan, Cagatay; Yologlu, Saim

2013-10-01

This study aimed to evaluate the effectiveness of digoxin in children with heart failure secondary to left-to-right shunt lesions and normal left ventricular systolic function. The study registered 37 such patients (ages 10 days to 24 months, groups 1 and 2) and used 20 healthy children as a control group (group 3). Left ventricular systolic function, as assessed by conventional echocardiography, was normal in all the subjects. Congestive heart failure was diagnosed by clinical evaluation and modified Ross scoring. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations and complete blood counts were assessed in all the children. Group 1 was treated with digoxin, enalapril, and furosemide and group 2 with enalapril and furosemide. Approximately 1 month after starting treatment, the patients were reevaluated by physical and echocardiographic examinations, modified Ross scoring, plasma NT-proBNP concentrations, and complete blood counts. The pre- and posttreatment Ross scores of group 1 (p = 0.377) and group 2 (p = 0.616) did not differ significantly. The NT-proBNP values in both groups decreased after treatment (p = 0.0001). The pre- and posttreatment NT-proBNP values did not differ significantly in group 1 (p = 0.094)) and group 2 (p = 0.372). The pretreatment NT-proBNP values in groups 1 and 2 (p = 0.0001) were significantly higher than in the control group (p = 0.003). A smaller difference was observed between posttreatment NT-proBNP values in group 1 and the control group (p = 0.045). We found no significant difference between the posttreatment NT-proBNP values of group 2 and those of the control group (p = 0.271). The study showed that both treatments currently used to treat heart failure secondary to congenital heart disease with left-to-right shunts and preserved left ventricular systolic function are effective and do not differ significantly. Thus, digoxin does not provide any extra benefit in the treatment of such patients.

Factors affecting mechanical nociceptive thresholds in healthy sows.

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Nalon, Elena; Maes, Dominiek; Piepers, Sofie; Taylor, Polly; van Riet, Miriam M J; Janssens, Geert P J; Millet, Sam; Tuyttens, Frank A M

2016-05-01

To describe anatomical and methodological factors influencing mechanical nociceptive thresholds (MNTs) and intra-site variability in healthy sows. Prospective, randomized validation. Eight pregnant, healthy, mixed-parity sows (176-269 kg). Repeated MNT measurements were taken: 1) with a hand-held probe and a limb-mounted actuator connected to a digital algometer; 2) at nine landmarks on the limbs and tail; and 3) at 1 and 3 minute intervals. Data were analysed using linear mixed regression models. The MNTs (±SEM) of the limbs were lower with the probe (14.7 ± 1.2 N) than with the actuator (21.3 ± 1.2 N; p testing compared with day 1 (p < 0.001). The mean CV (±SE) was 38.9% (±1.1%). MNTs and intra-site variability in healthy sows were affected by several factors, indicating that this methodology requires considerable attention to detail. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword.

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Chen, Jun; Lariviere, William R

2010-10-01

Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study. Copyright 2010 Elsevier Ltd. All rights reserved.

Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

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Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

2016-08-25

Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor. Copyright © 2016. Published by Elsevier Ireland Ltd.

Intrathecal administration of clonidine or yohimbine decreases the nociceptive behavior caused by formalin injection in the marsh terrapin (Pelomedusa subrufa)

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Makau, Christopher M; Towett, Philemon K; Abelson, Klas S P

2014-01-01

BACKGROUND: The role of noradrenergic system in the control of nociception is documented in some vertebrate animals. However, there are no data showing the role of this system on nociception in the marsh terrapins. METHODOLOGY: In this study, the antinociceptive action of intrathecal administration...... of the α 2-adrenoreceptor agonist clonidine and α 2-adrenoreceptor antagonist yohimbine was evaluated in the African marsh terrapin using the formalin test. The interaction of clonidine and yohimbine was also evaluated. RESULTS: Intrathecal administration of clonidine (37.5 or 65 μg/kg) caused...... a significant reduction in the mean time spent in pain-related behavior. Yohimbine, at a dose of 25 μg/kg, significantly blocked the effect of clonidine (65 μg/kg). However, administration of yohimbine (40 or 53 μg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Intrathecal...

Ventrolateral periaqueductal gray lesion attenuates nociception but does not change anxiety-like indices or fear-induced antinociception in mice.

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Mendes-Gomes, Joyce; Amaral, Vanessa Cristiane Santana; Nunes-de-Souza, Ricardo Luiz

2011-06-01

The exposure of rodents to an open elevated plus-maze (oEPM: four open arms raised from the floor) elicits naloxone-insensitive antinociception. Midazolam infusion into the dorsal portion of the periaqueductal gray (dPAG), a structure of the descending inhibitory system of pain, failed to alter oEPM-induced antinociception. Chemical lesion of dorsomedial and dorsolateral PAG attenuated defensive behavior in the standard EPM (sEPM), an animal model of anxiety, but failed to change oEPM-induced antinociception. The present study investigated the effects of bilateral lesion, with the injection of NMDA (N-methyl-D-aspartic acid), of the ventrolateral column of PAG (vlPAG) (i) on nociceptive response induced by 2.5% formalin injected into the right hind paw (nociception test) in mice exposed to the enclosed EPM (eEPM: four enclosed arms - a non-aversive situation) or to the oEPM and (ii) on anxiety indices in mice exposed to the sEPM without prior formalin injection. Results showed that oEPM-induced antinociception was not altered by lesion of vlPAG. Nevertheless, the lesion reduced the nociceptive response in mice exposed to the eEPM and increased general locomotor activity during the eEPM and oEPM exposure. Furthermore, vlPAG lesion did not alter anxiety-like indices in mice exposed to the sEPM. The results suggest that vlPAG does not play a role in oEPM-induced antinociception or in defensive reactions assessed in the sEPM. Moreover, vlPAG inactivation induces pain inhibition in mice not exposed to an aversive situation and seems to increase general activity. Copyright © 2011 Elsevier B.V. All rights reserved.

Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide.

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Darwish, Hany W; Hassan, Said A; Salem, Maissa Y; El-Zeany, Badr A

2013-09-01

Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20 μg/mL for AML, VAL and HCT, respectively. Copyright © 2013 Elsevier B.V. All rights reserved.

Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation.

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Zhao, Yonglie; Martins-Oliveira, Margarida; Akerman, Simon; Goadsby, Peter J

2017-01-01

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Host-Guest Inclusion Complexes between Amlodipine Enantiomers in the Biphasic Recognition Chiral Extraction System using Tartaric Acid and β-Cyclodextrin Derivatives as Positive Confirmation by using their Enantioselective Extraction.

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Al Azzam, Khaldun M; Abdallah, Hassan H; Halim, Hairul N Abdul; Ahmad, Maizatul Akmam; Shaibah, Hassan

2015-01-01

The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simulated using a semi-empirical PM3 method as a part of the Gaussian09 software package and were used to optimize the structures of the hosts, guests, and host-guest complexes in the gas phase without any restrictions. It was found that HP-β-CD has the strongest recognition ability among the three β-CD derivatives studied, namely HP-β-CD, hydroxyethyl-β-cyclodextrin (HE-β-CD), and methylated-β-cyclodextrin (Me-β-CD), due to the large interaction energies (Ecomp = -14.3025 kcal/ mol), while D-diisopropyl tartrate has the strongest ability among the four tartaric acid derivatives studied namely; L-diisopropyl tartrate, D-diisopropyl tartrate, L-diethyl tartrate, and D-diethyl tartrate (Ecomp = -5.9964 kcal/ mol). The computational calculations for the enantioselective partitioning of amlodipine enantiomers rationalized the reasons for the different behaviors for this extraction. The present theoretical results may be informative to scientists who are devoting themselves to developing models for their experimental parts or for enhancing the hydrophobic drug solubility in drug delivery systems.

Host-Guest Inclusion Complexes between Amlodipine Enantiomers in the Biphasic Recognition Chiral Extraction System using Tartaric Acid and β-Cyclodextrin Derivatives as Positive Confirmation by using their Enantioselective Extraction

Science.gov (United States)

Al Azzam, Khaldun M.; Abdallah, Hassan H.; Halim, Hairul N. Abdul; Ahmad, Maizatul Akmam; Shaibah, Hassan

2015-01-01

The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simulated using a semi-empirical PM3 method as a part of the Gaussian09 software package and were used to optimize the structures of the hosts, guests, and host-guest complexes in the gas phase without any restrictions. It was found that HP-β-CD has the strongest recognition ability among the three β-CD derivatives studied, namely HP-β-CD, hydroxyethyl-β-cyclodextrin (HE-β-CD), and methylated-β-cyclodextrin (Me-β-CD), due to the large interaction energies (Ecomp = −14.3025 kcal/ mol), while D-diisopropyl tartrate has the strongest ability among the four tartaric acid derivatives studied namely; L-diisopropyl tartrate, D-diisopropyl tartrate, L-diethyl tartrate, and D-diethyl tartrate (Ecomp = −5.9964 kcal/ mol). The computational calculations for the enantioselective partitioning of amlodipine enantiomers rationalized the reasons for the different behaviors for this extraction. The present theoretical results may be informative to scientists who are devoting themselves to developing models for their experimental parts or for enhancing the hydrophobic drug solubility in drug delivery systems. PMID:26839848

Simultaneous Detemination of Atorvastatin Calcium and Amlodipine Besylate by Spectrophotometry and Multivariate Calibration Methods in Pharmaceutical Formulations

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Amir H. M. Sarrafi

2011-01-01

Full Text Available Resolution of binary mixture of atorvastatin (ATV and amlodipine (AML with minimum sample pretreatment and without analyte separation has been successfully achieved using a rapid method based on partial least square analysis of UV–spectral data. Multivariate calibration modeling procedures, traditional partial least squares (PLS-2, interval partial least squares (iPLS and synergy partial least squares (siPLS, were applied to select a spectral range that provided the lowest prediction error in comparison to the full-spectrum model. The simultaneous determination of both analytes was possible by PLS processing of sample absorbance between 220-425 nm. The correlation coefficients (R and root mean squared error of cross validation (RMSECV for ATV and AML in synthetic mixture were 0.9991, 0.9958 and 0.4538, 0.2411 in best siPLS models respectively. The optimized method has been used for determination of ATV and AML in amostatin commercial tablets. The proposed method are simple, fast, inexpensive and do not need any separation or preparation methods.

Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA-induced arthritis.

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Morado-Urbina, Carlos Eduardo; Alvarado-Vázquez, Perla Abigail; Montiel-Ruiz, Rosa Mariana; Acosta-González, Rosa Issel; Castañeda-Corral, Gabriela; Jiménez-Andrade, Juan Miguel

2014-11-01

This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 μg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 μg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naïve mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities. © 2014 Wiley Periodicals, Inc.

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

International Nuclear Information System (INIS)

Silva, L.C.R.; Romero, T.R.L.; Guzzo, L.S.; Duarte, I.D.G.

2012-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E 2 (PGE 2 , 2 µg/paw) in the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE 2 , which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 µg/paw) and AM-630 (100 µg/paw) were used as CB 1 and CB 2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 µg dipyrone (mean = 5.825 ± 2.842 g), 20 µg diclofenac (mean = 4.825 ± 3.850 g) and 40 µg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB 1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB 2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac

Objective evaluation for venous leg ulcer-related nociceptive pain using thermography

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Goto T

2014-08-01

Full Text Available Taichi Goto,1 Ayumi Naito,1,2 Nao Tamai,1 Gojiro Nakagami,1 Makoto Mo,3 Hiromi Sanada1 1Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; 2Fujisawa City Hospital, Fujisawa, Kanagawa, Japan; 3Department of Cardiovascular Surgery, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan Purpose: We aimed to identify distinguishing characteristics in thermographic images of venous leg ulcer (VLU, for objective evaluation of VLU-related nociceptive pain. Patients and methods: Secondary analysis was performed, using existing data obtained from April to November 2010, for patients with VLU. Thermographic images of wounds and their surrounding area were classified according to the periwound temperature pattern as "normal temperature" or "high temperature". These results were compared with the self-reported pain intensity assessed by the short-form McGill Pain Questionnaire. Cohen's kappa coefficients were used to evaluate the interrater reliability for temperature assessment, and Wilcoxon rank sum test was used to compare pain intensities between the two groups. Results: Among 39 thermographic examinations in eight patients, 22 were classified into the high-temperature group and 17 into the normal-temperature group. Kappa coefficients for the temperature classification were 0.90 between the wound, ostomy, and continence nurse and a wound care specialist, and 0.90 between the wound, ostomy, and continence nurse and a graduate student. The pain rating index (Z=−2.981, P=0.003, sensory pain (Z=−3.083, P=0.002, affective pain (Z=−2.764, P=0.006, and present pain intensity (Z=−2.639, P=0.006 ratings were significantly higher in the high-temperature group than in the normal-temperature group, but the visual analog scale (Z=−0.632, P=0.527 was not significantly different between the two groups. Conclusion: Thermographic pattern may reflect VLU

Regulation of body temperature and nociception induced by non-noxious stress in rat.

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Vidal, C; Suaudeau, C; Jacob, J

1984-04-09

The effects of 3 different non-noxious stressors on body temperature (Tb) were investigated in the rat: (1) loose restraint in cylinders, (2) removal of the rats from cylinders, exposure to a novel environment and replacement in cylinders, a stressor called here 'novelty', and (3) gentle holding of the rats by the nape of the neck. Loose restraint and 'novelty' produced hyperthermia. On the contrary, holding induced hypothermia. Hypophysectomy (HX) reduced basal Tb, abolished restraint hyperthermia and reduced both 'novelty' hyperthermia and holding hypothermia. Dexamethasone ( DEXA ) had no effect upon either restraint or novelty hyperthermia but reduced the hypothermia. Naloxone (Nx) produced a slight fall in basal Tb accounting for its reduction of restraint and 'novelty' hyperthermias ; it did not affect holding hypothermia. The inhibitory effects of HX suggest a participation of the pituitary in the hyperthermias ; the neurointermediate lobe would be involved as the hyperthermias were not affected by DEXA , which is known to block the stress-induced release of pituitary secretions from the anterior lobe but not from the neurointermediate lobe. In contrast, substances from the anterior lobe might participate in hypothermia due to holding since it is reduced by HX and DEXA . As to the effects of Nx, endogenous opioids would not be significantly involved in the thermic effects of the stressors used in this study; they might play, if any, only a minor role in the regulation of basal Tb. These results are compared with those previously obtained on nociception using the same non-noxious stressors. It emerges that, depending on the stressor, different types of association between thermoregulation and nociception may occur, i.e. hyperthermia with analgesia, hyperthermia with hyperalgesia and hypothermia with hyperalgesia.

Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy?

DEFF Research Database (Denmark)

Aasvang, Eske Kvanner; Hansen, J.B.; Kehlet, H.

2008-01-01

Preoperative identification of patients at risk for high-intensity postoperative pain may be used to predict patients at risk for development of a persistent pain state and allocate patients to more intensive specific pain therapy. Preoperative pain threshold to electrocutaneus stimulation has...... repair. The correlation between the pain data for electrical stimulation was compared with the postoperative pain during the first week in 165 patients, whereof 3 were excluded. Preoperative electrical pain detection threshold and electrical pain tolerance threshold did not correlate to postoperative...... pain (rho = -0.13, P = .09, and rho = -1.2, P = .4, respectively. PERSPECTIVE: Although preoperative electrical nociceptive stimulation may predict patients at risk of high-intensity acute pain after other surgical procedures, this was not the case in groin hernia repair patients receiving concomitant...

Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain.

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Sun, Shukai; Yin, Yue; Yin, Xin; Cao, Fale; Luo, Daoshu; Zhang, Ting; Li, Yunqing; Ni, Longxing

2012-09-01

Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-β, IL-6 and TNF-α were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-κB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. Copyright © 2012 Elsevier Inc. All rights reserved.

Phosphorylation of the Transient Receptor Potential Ankyrin 1 by Cyclin-dependent Kinase 5 affects Chemo-nociception

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Hall, Bradford E.; Prochazkova, Michaela; Sapio, Matthew R.; Minetos, Paul; Kurochkina, Natalya; Binukumar, B. K.; Amin, Niranjana D.; Terse, Anita; Joseph, John; Raithel, Stephen J.; Mannes, Andrew J.; Pant, Harish C.; Chung, Man-Kyo; Iadarola, Michael J.; Kulkarni, Ashok B.

2018-01-01

Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and th...

Adherence to Treatment, Safety, Tolerance, and Effectiveness of Perindopril/Amlodipine Fixed-Dose Combination in Greek Patients with Hypertension and Stable Coronary Artery Disease: A Pan-Hellenic Prospective Observational Study of Daily Clinical Practice.

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Liakos, Charalampos I; Papadopoulos, Dimitrios P; Kotsis, Vasilios T

2017-10-01

Initiation of antihypertensive therapy with a two-drug fixed-dose combination (FDC) in a single tablet may be recommended in patients at high risk of cardiovascular events to improve adherence and effectiveness. Preferred combinations include an angiotensin-converting enzyme inhibitor with a dihydropyridine calcium antagonist. This study assessed adherence to and the safety, tolerance, and effectiveness of the perindopril/amlodipine FDC in Greek patients with hypertension and stable coronary artery disease (CAD) over a 4-month period. A total of 1907 patients with hypertension and CAD (59.1% males) who had recently (≤2 weeks) commenced treatment with the perindopril/amlodipine FDC (5/5, 5/10, 10/5, or 10/10 mg) were studied at baseline and at 1 and 4 months. Adherence to treatment was assessed with the Morisky Medication-taking Adherence Scale (MMAS). Seven patients (0.4%) did not attend the scheduled visits. In total, 1607 (84.6%) patients received a constant treatment dose throughout the study. High adherence (MMAS score = 0) was reported by 1592 (83.6%), 1628 (85.7%), and 1477 (77.7%) patients at the second and the third visit and at both visits, respectively. Adverse reactions were reported by only 13 (0.7%) patients, were all minor, and did not result in treatment discontinuation. Office blood pressure (BP) was significantly decreased at the third visit (130.8 ± 8.4/78.2 ± 6.4 mmHg) compared with baseline (156.5 ± 15.0/89.9 ± 9.6 mmHg; p < 0.001), regardless of previous antihypertensive treatment. Patients with grade 1, 2, and 3 hypertension at baseline showed a reduction in BP of 19.3/9.4, 31.5/13.5, and 47.8/22.2 mmHg, respectively (p < 0.001). Uncontrolled hypertension (≥140/90 mmHg) was notably reduced from 90.3% at baseline to 18.5% at the third visit. The perindopril/amlodipine FDC is characterized by high adherence and effectiveness, regardless of previous treatment. Degree of BP reduction was related to baseline BP levels

The Anti-Nociceptive Effect of Aloe. Vera Aqueous Extract in Fructose-Fed Male Rats

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Mohammad Reza Shahraki

2010-05-01

Full Text Available A B S T R A C T Introduction: Aloe Vera extract is used as an anti-inflammatory and anti-bradikinin agent in laboratory animals. The aim of this survey was to evaluate the ant-nociceptive effect of A. Vera aqueous extract in fructose-fed male rats. Methods: Forty-five Wistar-Albino male rats were equally and randomly divided into five groups including sham operated and four test groups. Sham operated group consumed tap water and the test groups consumed fructoseenriched water. Test groups 2, 3 and 4 additionally received, 0, 100, 150 and 200 mg/kg of A. Vera extract, respectively, whereas the other test group received distilled water daily. Tail flick reaction time, serum glucose and oral glucose tolerance test (OGTT were measured. The results were analyzed by SPSS software using ANOVA and Tukey tests. Results were expressed as mean ± SD. Statistical differences were considered significant at p<0.05. Results: The results showed that tail flick reaction time significantly increased in test group 3 which received 200 mg/kg A. Vera extract comparing with that of sham operated group. However, OGTT and serum glucose value were significantly increased in all fructose-fed male rats comparing with those of sham operated group. Discussion: These results indicated that A. Vera aqueous extract can affect tail flick reaction time in fructose-fed male rats. Further studies are required to show the exact mechanism of anti-nociceptive effect of A. Vera extract.

Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy

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K. M. Maheswari

2014-01-01

Full Text Available The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs of Amlodipine Besylate (AMLO to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC and methyl cellulose (MC along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30, and sodium lauryl sulphate (SLS as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism.

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

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Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

DNA Methylation Modulates Nociceptive Sensitization after Incision.

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Yuan Sun

Full Text Available DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT inhibitor 5-Aza-2'-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2'-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding β-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision.

Combinação de anlodipino e enalaprila em pacientes hipertensos com doença coronariana Combinación de amlodipino y enalapril en pacientes hipertensos con enfermedad coronaria Combination of amlodipine and enalapril in hypertensive patients with coronary disease

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Marcos Rienzo

2009-03-01

Full Text Available FUNDAMENTO: Pacientes (pts com doença coronariana (DAC estável podem se beneficiar de menor pressão arterial (PA, conforme estudos recentes. OBJETIVO: Avaliar a eficácia e a tolerabilidade da combinação fixa anlodipino + enalaprila, comparada a anlodipino na normalização da PA diastólica (PAD ( 90 e 110 mmHg durante o wash-out de quatro semanas, em uso só de atenolol. Após wash-out randomizamos para combinação (A ou anlodipino (B e seguimos de quatro em quatro semanas até 98 dias. As doses (mg iniciais foram, respectivamente: A- 2,5/10 e B- 2,5, sendo incrementadas se PAD> 85mmHg, nas visitas. Estatística com χ2, Fischer e análise de variância, para pFUNDAMENTO: Pacientes (pts con enfermedad coronaria (EAC estable pueden beneficiarse con una menor presión arterial (PA, de acuerdo con estudios recientes. OBJETIVO: Evaluar la eficacia y la tolerancia de la combinación fija amlodipino + enalapril, comparada a el amlodipino en la normalización de la PA diastólica (PAD (90 y 110 mmHg durante el wash-out de cuatro semanas, en uso sólo de atenolol. Después del wash-out randomizamos para combinación (A o amlopidino (B y seguimos de cuatro en cuatro semanas hasta 98 días. Las dosis (mg iniciales fueron, respectivamente: A- 2,5/10 y B- 2,5, siendo incrementadas si PAD> 85mmHg, en las visitas. Estadística con χ2, Fischer y análisis de varianza, para pBACKGROUND: Patients (pts with stable coronary artery disease (CAD can benefit from a decrease in the blood pressure (BP, according to recent studies. OBJECTIVE: To evaluate the efficacy and tolerability of the fixed combination: amlodipine + enalapril, when compared to amlodipine in the normalization of the diastolic arterial pressure (DAP (90 and 110 mmHg during the four-week wash-out with atenolol treatment alone, were excluded. After the wash-out, pts were randomly distributed for the use of the combination (A or amlodipine (B and were followed every four weeks up to 98 days

Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain.

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Kim, Shi Hyoung; Park, Jae Gwang; Sung, Gi-Ho; Yang, Sungjae; Yang, Woo Seok; Kim, Eunji; Kim, Jun Ho; Ha, Van Thai; Kim, Han Gyung; Yi, Young-Su; Kim, Ji Hye; Baek, Kwang-Soo; Sung, Nak Yoon; Lee, Mi-nam; Kim, Jong-Hoon; Cho, Jae Youl

2015-07-01

Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regulation of the Na,K-ATPase gamma-subunit FXYD2 by Runx1 and Ret signaling in normal and injured non-peptidergic nociceptive sensory neurons.

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Stéphanie Ventéo

Full Text Available Dorsal root ganglia (DRGs contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury.

Experimental and clinical study on the digitalis in renal function disturbance

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Okubo, Mitsuru

1977-01-01

By using radioimmunoassay, movement of digoxin in the bodies of normal rabbits and dogs was discussed experimentally, and pathophysiology digoxin excretion in renal function disturbance was also discussed experimentally and clinically. The concentration of digoxin in each organ 30 minutes after intravenous administration of digoxin of 0.5 mg/kg to normal rabbits was the highest in the kidney, and it was high in order of skeletal muscles, ventricular muscles, and auricular muscles. A significant positive correlation was recognized between concentration of digoxin in blood and that in ventricular muscles. Digoxin clearance showed high values in normal dogs and dogs whose single kidney were extracted, when the concentration of digoxin in blood was low. A significant correlation between the concentration of digoxin in blood and BUN or creatinine was not recognized in patients with renal diseases, but a significant negative correlation between the concentration of digoxin in blood and creatinine clearance and between urinary excretion of digoxin and creatinine clearance was recognized. Therefore, creatinine clearance was thought to be useful for index to determine the administration dose of digoxin in renal dysfunction. In the patients who received external dialysis, decrease of the concentration of digoxin in blood after intravenous administration of digoxin delayed significantly in contrast to that of normal control group. (Tsunoda, M.)

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

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Silva, L.C.R.; Romero, T.R.L.; Guzzo, L.S.; Duarte, I.D.G. [Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

2012-09-21

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E{sub 2} (PGE{sub 2}, 2 µg/paw) in the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE{sub 2}, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 µg/paw) and AM-630 (100 µg/paw) were used as CB{sub 1} and CB{sub 2} cannabinoid receptor antagonists, respectively. Ipl injection of 40 µg dipyrone (mean = 5.825 ± 2.842 g), 20 µg diclofenac (mean = 4.825 ± 3.850 g) and 40 µg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB{sub 1} cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB{sub 2} cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

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L.C.R. Silva

2012-12-01

Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group. Hyperalgesia was induced by a subcutaneous intraplantar (ipl injection of prostaglandin E2 (PGE2, 2 μg/paw in the rat’s hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g. AM-251 (80 μg/paw and AM-630 (100 μg/paw were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 μg dipyrone (mean = 5.825 ± 2.842 g, 20 μg diclofenac (mean = 4.825 ± 3.850 g and 40 μg indomethacin (mean = 6.650 ± 3.611 g elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g, diclofenac (mean = 2.50 ± 0.8337 g and indomethacin (mean = 6.650 ± 4.069 g or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g, diclofenac (mean = 6.675 ± 1.368 g and indomethacin (mean = 2.85 ± 5.01 g. Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

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Li, Ai-Ling; Sibi, Jiny E; Yang, Xiaofei; Chiao, Jung-Chih; Peng, Yuan Bo

2016-06-01

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain.

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Deng, Bo; Jia, Liqun; Pan, Lin; Song, Aiping; Wang, Yuanyuan; Tan, Huangying; Xiang, Qing; Yu, Lili; Ke, Dandan

2016-01-01

One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

Automated single-trial assessment of laser-evoked potentials as an objective functional diagnostic tool for the nociceptive system.

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Hatem, S M; Hu, L; Ragé, M; Gierasimowicz, A; Plaghki, L; Bouhassira, D; Attal, N; Iannetti, G D; Mouraux, A

2012-12-01

To assess the clinical usefulness of an automated analysis of event-related potentials (ERPs). Nociceptive laser-evoked potentials (LEPs) and non-nociceptive somatosensory electrically-evoked potentials (SEPs) were recorded in 37 patients with syringomyelia and 21 controls. LEP and SEP peak amplitudes and latencies were estimated using a single-trial automated approach based on time-frequency wavelet filtering and multiple linear regression, as well as a conventional approach based on visual inspection. The amplitudes and latencies of normal and abnormal LEP and SEP peaks were identified reliably using both approaches, with similar sensitivity and specificity. Because the automated approach provided an unbiased solution to account for average waveforms where no ERP could be identified visually, it revealed significant differences between patients and controls that were not revealed using the visual approach. The automated analysis of ERPs characterized reliably and objectively LEP and SEP waveforms in patients. The automated single-trial analysis can be used to characterize normal and abnormal ERPs with a similar sensitivity and specificity as visual inspection. While this does not justify its use in a routine clinical setting, the technique could be useful to avoid observer-dependent biases in clinical research. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

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Serena Boccella

2015-01-01

Full Text Available D-Aspartate (D-Asp is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO. D-Asp acts as an agonist on NMDA receptors (NMDARs. Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/− or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS neurons of the dorsal horn of the spinal cord (L4–L6 and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.

In vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Moringa oleifera leaves on complete Freund's adjuvant (CFA)-induced arthritis in rats.

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Mahdi, Harith Jameel; Khan, Nurzalina Abdul Karim; Asmawi, Mohd Zaini Bin; Mahmud, Roziahanim; A/L Murugaiyah, Vikneswaran

2018-03-01

The medicinal uses of plants are in many cases based exclusively on traditional knowledge without enough scientific evidences. Different parts of Moringa oleifera were traditionally used for the treatment of wide variety of ailments including arthritis and joints pain. The present study had been designed to evaluate the anti-arthritic and anti-nociceptive activities of ethanol extract of Moringa leaves, this being the most abundant plant part suitable for commercial mass production of botanical medicinal products. Complete Freund's adjuvant (CFA)-induced arthritis in rats was used as disease model. CFA-induced inflammatory paw edema, body weight, arthritic index, X-ray radiography, hematological parameters, and walk track and locomotion analysis were all evaluated for the assessment of disease progression. In addition to that, anti-nociceptive activity was examined at different dose levels in both normal and arthritic-induced rats using Eddy's hot plate and tail flick thermal analgesia. The analysis of various arthritic assessment parameters used in this study revealed that Moringa extract has a considerable effect in preventing development or ameliorate arthritis disease severity. Moreover, the ethanol extract of Moringa leaves revealed significant anti-nociceptive activity at in both normal and CFA-induced arthritis rats in a dose-dependent manner. Ethanol extract of Moringa leaves appears to be a really promising as analgesic and arthritis medication, but a larger and more detailed preclinical and clinical studies especially in human is highly recommended.

Chemical composition and anti-inflamatory, anti-nociceptive and antipyretic activity of rhizome essential oil of Globba sessiliflora Sims. collected from Garhwal region of Uttarakhand

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Ravendra Kumar

2017-07-01

Full Text Available Background & Aim: Family Zingiberaceae is worldwide in distribution. Plants of the zingiberaceae family are used in traditional herbal folk medicine besides their uses in spices, cosmetic, ornamental, food preservatives etc. In Uttarakhand the herbs grow from sub-tropical to temperate region. Globba sessiliflora Simsrhizomes were collected at maturity stage in November from Garhwal region of Uttarakhand, India. In present communication the medicinal use of various zingiberaceous herb provoked us to study the chemical diversity and pharmacological activity determination of this important traditional herb. Experimental: The essential oil was extracted using hydrodistillation method and analyzed by GC-MS. Anti-inflamatory, anti-nociceptive and antipyretic activities of essential oil were experimently determined using mice model. Results: The major compounds identified were β-eudesmol (27.6%, (E-β-caryophyllene (24.3%, α-humulene (3.0%, (6E-nerolidol (4.1%, caryophyllene oxide (9.7%, γ-eudesmol (6.4% and τ-muurolol (8.3% besides other minor constituents. Essential oil of G. sessiliflora rhizome showed good anti-inflamatory, anti-nociceptive and antipyretic activities at the dose level of 100 mg/kg body weight. The oral administration of the essential oil exhibited no toxicity at 400, 600 and 800 mg/kg b.wt. concentration. Ibuprofen, indomthacin and paracetamol were used as standard drugs for comparison. Recommended applications/industries: G. sessiliflora essential oil can be used as herbal remedy for its nontoxicityanti-inflamatory, anti-nociceptive and antipyretic activities.

Learned control over spinal nociception: Transfer and stability of training success in a long-term study.

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Bäumler, Maximilian; Feller, Moritz; Krafft, Stefanie; Schiffer, Manuela; Sommer, Jens; Straube, Andreas; Weinges, Fabian; Ruscheweyh, Ruth

2017-12-01

Healthy subjects can learn to use cognitive-emotional strategies to suppress their spinal nociception, quantified by the nociceptive flexor reflex (RIII reflex), when given visual RIII feedback. This likely reflects learned activation of descending pain inhibition. Here, we investigated if training success persists 4 and 8 months after the end of RIII feedback training, and if transfer (RIII suppression without feedback) is possible. 18 and 8 subjects who had successfully completed feedback training were investigated 4 and 8 months later. At 4 months, RIII suppression during feedback and transfer was similar to that achieved at the final RIII feedback training session (to 50 ± 22%, 53 ± 21% and 52 ± 21% of baseline, all differences n.s.). At 8 months, RIII suppression was somewhat (not significantly) smaller in the feedback run (to 64 ± 17%) compared to the final training session (56 ± 19%). Feedback and transfer runs were similar (to 64 ± 17% vs. 68 ± 24%, n.s.). Concomitant reductions in pain intensity ratings were stable at 4 and 8 months. RIII feedback training success was completely maintained after 4 months, and somewhat attenuated 8 months after training. Transfer was successful. These results are an important pre-requisite for application of RIII feedback training in the context of clinical pain. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Adaptation of a T3-uptake test and of radioimmunoassays for serum digoxin, thyroxine, and triiodothyronine to an automated radioimmunoassay system: ''Centria''

International Nuclear Information System (INIS)

Ertingshausen, G.; Shapiro, S.I.; Green, G.; Zborowski, G.

1975-01-01

We report the adaptation of four radioassays to the prototype of an automated radioimmunoassay system (''Centria,'' Union Carbide). The system consists of three integrated modules: an automated pipettor, which dispenses samples and reagents; the key module, an incubator/separator, in which centrifugal force is used to initiate and terminate multiple radioassay incubations and separations simultaneously; and a gamma-counter/computer, which counts three tubes simultaneously and converts counts into concentration units. Radioimmunoassays for thyroxine, triiodothyronine, and digoxin were developed with use of well-characterized antibodies and of prepackaged Sephadex-containing columns to separate bound and free radioactive ligand. A triiodothyronine-uptake test in which the same kind of columns were used was also adapted to the instrument. Results for clinical samples compared favorably with those obtained by manual procedures. We report data on correlation between different methods and preliminary data on precision of the prototype system

Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

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Conte, Antonella; Bettolo, Chiara Marini; Onesti, Emanuela; Frasca, Vittorio; Iacovelli, Elisa; Gilio, Francesca; Giacomelli, Elena; Gabriele, Maria; Aragona, Massimiliano; Tomassini, Valentina; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio

2009-05-01

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

Anti-nociceptive and anti-inflammatory activities of ethanolic flower extract of Newbouldia laevis in mice and rats

OpenAIRE

Y Tanko; B Kamba; MI Saleh; K Y Musa; A Mohammed

2008-01-01

Summary: The ethanolic flower extract of Newbouldia laevis was investigated for possible anti-nociceptive and anti-inflammatory effects in rodents. Acetic acid induced writhing (in mice) and formalin tests (in rats) were used to study. The extract caused a significant decrease (P< 0.05), which was not dose a dependent inhibition on acetic acid-induced writhing and the neurogenic pain induced by formalin. The extract at the doses (25, 50 and 100mg/kg) tested showed 59, 71 and 47% inhibition...

Upregulation of Ih expressed in IB4-negative Aδ nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain

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Liu, Da-Lu; Lu, Na; Han, Wen-Juan; Chen, Rong-Gui; Cong, Rui; Xie, Rou-Gang; Zhang, Yu-Fei; Kong, Wei-Wei; Hu, San-Jue; Luo, Ceng

2015-01-01

Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4− Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4- Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy. PMID:26577374

The nociceptive withdrawal reflex does not adapt to joint position change and short-term motor practice [v2; ref status: indexed, http://f1000r.es/2lr

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Nathan Eckert

2013-12-01

Full Text Available The nociceptive withdrawal reflex is a protective mechanism to mediate interactions within a potentially dangerous environment. The reflex is formed by action-based sensory encoding during the early post-natal developmental period, and it is unknown if the protective motor function of the nociceptive withdrawal reflex in the human upper-limb is adaptable based on the configuration of the arm or if it can be modified by short-term practice of a similar or opposing motor action. In the present study, nociceptive withdrawal reflexes were evoked by a brief train of electrical stimuli applied to digit II, 1 in five different static arm positions and, 2 before and after motor practice that was opposite (EXT or similar (FLEX to the stereotyped withdrawal response, in 10 individuals. Withdrawal responses were quantified by the electromyography (EMG reflex response in several upper limb muscles, and by the forces and moments recorded at the wrist. EMG onset latencies and response amplitudes were not significantly different across the arm positions or between the EXT and FLEX practice conditions, and the general direction of the withdrawal response was similar across arm positions. In addition, the force vectors were not different after practice in either the practice condition or between EXT and FLEX conditions. We conclude the withdrawal response is insensitive to changes in elbow or shoulder joint angles as well as remaining resistant to short-term adaptations from the practice of motor actions, resulting in a generalized limb withdrawal in each case. It is further hypothesized that the multisensory feedback is weighted differently in each arm position, but integrated to achieve a similar withdrawal response to safeguard against erroneous motor responses that could cause further harm. The results remain consistent with the concept that nociceptive withdrawal reflexes are shaped through long-term and not short-term action based sensory encoding.

Tachycardia in response to remote capsaicin injection as a model for nociception in the ball python (Python regius).

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Williams, Catherine J A; James, Lauren E; Bertelsen, Mads F; Wang, Tobias

2016-07-01

To quantify the effect of subcutaneous (SC) capsaicin injection on heart rate (HR) in ball pythons (Python regius) and to assess the efficacy of two opioids (morphine and butorphanol) in modifying this response. Prospective, randomized, unmatched study. Eleven mixed-sex, captive-bred ball pythons. Snakes were randomly assigned to three groups (n = 6) by intramuscular premedication: 1) control: saline (0.9 mL); 2) morphine (10 mg kg(-1) ); and 3) butorphanol (10 mg kg(-1) ). Three snakes were tested twice and another two were tested three times in different treatments administered 1 month apart. Under isoflurane anaesthesia, snakes were instrumented with SC electrocardiogram (ECG) electrodes and an SC catheter for remote stimulus delivery. After recovery from anaesthesia, all snakes, in visual and audial isolation from the experimenter, received a sham stimulus of saline (0.4 mL) via the SC catheter. A nociceptive stimulus of SC capsaicin (3 mg in 0.2 mL saline with 7% Tween 80) was then applied by catheter at 7 hours after premedication. In a subset (n = 3), two sham injections (saline 0.2 mL) preceded the capsaicin treatment. HR was recorded via ECG, and changes in HR (ΔHR) from baseline were calculated for all stimulations. Capsaicin injection was associated with a significant increase in HR [peak ΔHR: saline group: 8.8 ± 7.1 beats minute(-1) ; capsaicin group: 21.1 ± 5.8 beats minute(-1) (p = 0.0055)] and integrated ΔHR as a function of time. The administration of morphine or butorphanol 7 hours prior to nociception failed to significantly reduce the peak and integrated ΔHR. Butorphanol caused marked, long-lasting sedation as assessed by muscle tone. The HR response to an SC capsaicin injection can serve as a nociceptive model in P. regius. Morphine and butorphanol administration did not reduce HR response to capsaicin stimulation but produced significantly different effects on pre-stimulation HR and sedation. © 2015 Association

BOLD fMRI of C-Fiber Mediated Nociceptive Processing in Mouse Brain in Response to Thermal Stimulation of the Forepaws.

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Simone C Bosshard

Full Text Available Functional magnetic resonance imaging (fMRI in rodents enables non-invasive studies of brain function in response to peripheral input or at rest. In this study we describe a thermal stimulation paradigm using infrared laser diodes to apply noxious heat to the forepaw of mice in order to study nociceptive processing. Stimulation at 45 and 46°C led to robust BOLD signal changes in various brain structures including the somatosensory cortices and the thalamus. The BOLD signal amplitude scaled with the temperature applied but not with the area irradiated by the laser beam. To demonstrate the specificity of the paradigm for assessing nociceptive signaling we administered the quaternary lidocaine derivative QX-314 to the forepaws, which due to its positive charge cannot readily cross biological membranes. However, upon activation of TRPV1 channels following the administration of capsaicin the BOLD signal was largely abolished, indicative of a selective block of the C-fiber nociceptors due to QX-314 having entered the cells via the now open TRPV1 channels. This demonstrates that the cerebral BOLD response to thermal noxious paw stimulation is specifically mediated by C-fibers.

Differences in neurotransmitter systems of ventrolateral periaqueductal gray between the micturition reflex and nociceptive regulation: An in vivo microdialysis study.

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Kitta, Takeya; Mitsui, Takahiko; Kanno, Yukiko; Chiba, Hiroki; Moriya, Kimihiko; Yoshioka, Mitsuhiro; Shinohara, Nobuo

2016-07-01

To elucidate the possible involvement of glutamate and serotonin (5-hydroxytryptamine) neurons in the ventrolateral midbrain periaqueductal gray during noxious stimulation. The study was carried out by evoking a noxious stimulation by acetic acid in an animal model of cystitis. Changes in glutamate and 5-hydroxytryptamine in the periaqueductal gray during the micturition reflex and acetic acid-induced cystitis were determined using in vivo microdialysis combined with cystometry in rats. Extracellular glutamate levels slightly, but significantly, increased during the micturition reflex induced by saline infusion into the bladder. Intravesical infusion of acetic acid facilitated the micturition reflex characterized by increases in voiding pressure and decreases in the intercontraction interval. Glutamate levels were markedly increased by acetic acid, and this enhancement was sustained for at least 3 h. 5-Hydroxytryptamine levels, which were not altered during the micturition reflex, were increased after intravesical infusion of acetic acid. The results suggest that periaqueductal gray glutamate and 5-hydroxytryptamine neurons differentially participate in the modulation of both nociception and the micturition reflex. Furthermore, periaqueductal gray 5-hydroxytryptamine levels appear to reflect the nociceptive stimuli. © 2016 The Japanese Urological Association.

Estudo "LOTHAR": avaliação de eficácia e tolerabilidade da combinação fixa de anlodipino e losartana no tratamento da hipertensão arterial primária The "LOTHAR" study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and losartan in the treatment of essential hypertension

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Osvaldo Kohlmann Jr

2006-01-01

Full Text Available OBJETIVO: O estudo LOTHAR avaliou a eficácia, tolerabilidade e os efeitos metabólicos em médio e longo prazo (um ano da combinação fixa de anlodipino e losartana versus anlodipino e losartana isoladamente. MÉTODOS: Estudo multicêntrico brasileiro, randomizado, duplo-cego e comparativo realizado com 198 pacientes com hipertensão arterial primária em estágios 1 e 2. RESULTADOS: A combinação fixa apresenta alta eficácia anti-hipertensiva que se mantém em longo prazo com percentual reduzido de escape do controle pressórico, inferior a dos dois regimes monoterápicos de comparação. Em longo prazo, mais de 60% dos pacientes tratados com a combinação fixa permaneceram com níveis da PAD OBJECTIVE: The LOTHAR study evaluated medium and long term (one year efficacy, tolerability and metabolic effects of the fixed combination of amlodipine and losartan compared to amlodipine or losartan alone. METHODS: Brazilian multicenter, randomized, double-blind and comparative trial performed with 198 patients in stage 1 and 2 essential hypertension. RESULTS: The fixed combination has a high antihypertensive efficacy that is sustained in the long term with very low percentage of loss of blood pressure control. This percentage is incidentally lower than that of the two monotherapy comparative regimens. In the long term, more than 60% of the patients treated with the fixed combination remained with DBP < 85 mmHg, and the antihypertensive effect, when assessed by ABPM persisted for 24 hours with a trough-to-peak ratio of 76.7%. The frequency of adverse events was quite low in this group, and the long-term incidence of leg edema was approximately four-fold lower than that observed with amlodipine alone. The fixed combination did not change glucose and lipid metabolism in the medium or in the long term. CONCLUSION: Based on these results, we can say that the combination of amlodipine and losartan - the first fixed combination of a calcium channel

Characterization of nociceptive behavioural responses in the awake pig following UV–B-induced inflammation

DEFF Research Database (Denmark)

di Giminiani, Pierpaolo; Petersen, Lars J.; Herskin, Mette S

2014-01-01

due to its great homology with humans. Methods The skin in the flank of awake pigs was irradiated by a UV-B light source (1 J/cm2) and changes in thermal and mechanical sensitivity 24 and 48 h following irradiation were measured via assessment of nociceptive behaviours. Results Thermal sensitivity...... skin site than at the control site 24 and 48 h following irradiation (P UV-B irradiation (P = 0.092). Following the inflammatory challenge, the mechanical sensitivity was higher at the site...... of irradiation compared with the control skin at both 24 and 48 h (P UV-B inflammation in porcine skin, but they were not capable of providing a clear indication...

Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

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Aunis Dominique

2010-12-01

Full Text Available Abstract Background- Mice deficient for the stable tubule only peptide (STOP display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p. produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

Recent studies of cutaneous nociception in atopic and non-atopic subjects.

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Heyer, G R; Hornstein, O P

1999-02-01

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and

Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.

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Sonja M Mueller-Tribbensee

Full Text Available Various transient receptor potential (TRP channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin8 was suggested to be involved in murine colonic mechano-nociception.To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT were used. Visceromotor responses (VMR to colorectal distension (CRD in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA.Distension-induced colonic CGRP release was markedly reduced in TRPA1-/- and TRPV4-/- mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 μM; RN1734, 10 μM; AMTB, 10 μM showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM and stretch-activated channels (gadolinium, 50 μM. VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg in TRPA1-/- and TRPV4-/- but not TRPM8-/- mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene.TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

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D.O. Gonçalves

2011-02-01

Full Text Available Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g, which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan, at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively. Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively and second phase (73, 57, and 66% inhibition of licking time, respectively. The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc. Lovastatin (0.01, 0.1, and 1 µg/mL inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α and the inducible form of nitric oxide synthase (iNOS activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.

Potential Nociceptive Regulatory Effect of Probiotic Lactobacillus rhamnosus PB01 (DSM 14870 on Mechanical Sensitivity in Diet-Induced Obesity Model

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Fereshteh Dardmeh

2016-01-01

Full Text Available Treatments for obesity have been shown to reduce pain secondary to weight loss. Intestinal microbiota, as an endogenous factor, influences obesity and pain sensitivity but the effect of oral probiotic supplementation on musculoskeletal pain perception has not been studied systematically. The present study examined the effect of a single daily oral dose (1 × 109 CFU of probiotics (Lactobacillus rhamnosus PB01, DSM14870 supplement on mechanical pain thresholds in behaving diet-induced obese (DIO mice and their normal weight (NW controls. The mice (N=24, 6-week-old male were randomly divided into four groups on either standard or high fat diet with and without probiotic supplementation. Both DIO and NW groups with probiotic supplementation maintained an insignificant weight gain while the control groups gained significant weight (P<0.05. Similarly, both DIO and NW probiotics supplemented groups demonstrated a significantly (P<0.05 lower sensitivity to mechanical stimulation compared to their corresponding control. The results of this study suggest a protective effect of probiotics on nociception circuits, which propose a direct result of the weight reduction or an indirect result of anti-inflammatory properties of the probiotics. Deciphering the exact underlying mechanism of the weight loss and lowering nociception effect of the probiotic applied in this study require further investigation.

Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat

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Marchand Fabien

2011-11-01

Full Text Available Abstract Background Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP, a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs following formalin administration. In addition, Complete Freund's Adjuvant (CFA-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

Efficacy of an amlodipine/olmesartan treatment algorithm in patients with or without type 2 diabetes and hypertension (a secondary analysis of the BP-CRUSH study).

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Nesbitt, S D; Shojaee, A; Maa, J-F; Weir, M R

2013-07-01

A prespecified subgroup analysis of an open-label, multicenter, single-arm, dose-titration study is presented. The efficacy and safety of 20-week treatment with an amlodipine (AML)/olmesartan medoxomil (OM)±hydrochlorothiazide (HCTZ) algorithm were assessed in patients with hypertension and type 2 diabetes mellitus (T2DM) who were uncontrolled by antihypertensive monotherapy. Eligible patients received AML/OM 5/20 mg for 4 weeks, followed by stepwise uptitration to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg+HCTZ 12.5 mg and AML/OM 10/40 mg+HCTZ 25 mg at 4-week intervals if blood pressure (BP) remained uncontrolled. The primary end point was the achievement of the seated cuff systolic BP (SeSBP) goal (hypertension and T2DM.

Coregulation of endoplasmic reticulum stress and oxidative stress in neuropathic pain and disinhibition of the spinal nociceptive circuitry.

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Ge, Yanhu; Jiao, Yingfu; Li, Peiying; Xiang, Zhenghua; Li, Zhi; Wang, Long; Li, Wenqian; Gao, Hao; Shao, Jiayun; Wen, Daxiang; Yu, Weifeng

2018-05-01

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.

Jumping in aquatic environment after sciatic nerve compression: nociceptive evaluation and morphological characteristics of the soleus muscle of Wistar rats.

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Malanotte, Jéssica Aline; Kakihata, Camila Mayumi Martin; Karvat, Jhenifer; Brancalhão, Rose Meire Costa; Ribeiro, Lucinéia de Fátima Chasko; Bertolini, Gladson Ricardo Flor

2017-01-01

To evaluate the effect of jumping in aquatic environment on nociception and in the soleus muscle of trained and not trained Wistar rats, in the treatment of compressive neuropathy of the sciatic nerve. Twenty-five Wistar rats were distributed into five groups: Control, Lesion, Trained + Lesion, Lesion + Exercise, and Trained + Lesion + Exercise. The training was jumping exercise in water environment for 20 days prior to injury, and treatment after the injury. Nociception was evaluated in two occasions, before injury and seven after injury. On the last day of the experiment, the right soleus muscles were collected, processed and analyzed as to morphology and morphometry. In the assessment of nociception in the injury site, the Control Group had higher average than the rest, and the Lesion Group was larger than the Trained + Lesion and Lesion + Exercise Groups. The Control Group showed higher nociceptive threshold in paw, compared to the others. In the morphometric analysis, in relation to Control Group, all the injured groups showed decreased muscle fiber area, and in the Lesion Group was lower than in the Lesion + Exercise Group and Trained + Lesion Group. Considering the diameter of the muscle fiber, the Control Group had a higher average than the Trained + Lesion Group and the Trained + Lesion + Exercise Group; and the Lesion Group showed an average lower than the Trained + Lesion and Lesion + Exercise Groups. Resistance exercise produced increased nociception. When performed prior or after nerve damage, it proved effective in avoiding hypotrophy. The combination of the two protocols led to decrease in diameter and area of the muscle fiber. Avaliar os efeitos do salto em meio aquático, na nocicepção e no músculo sóleo, em ratos Wistar treinados e não treinados, no tratamento de neuropatia compressiva do nervo isquiático. Foram distribuídos em cinco grupos 25 ratos Wistar: Controle, Lesão, Treinado + Lesão, Lesão + Exercício e Treinado + Lesão + Exerc

Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses

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Leandro Guimarães Franco

2014-03-01

Full Text Available This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1, 2 (Tr2 or 3 (Tr3 mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR, arterial pressure, degree of sedation, gastrointestinal motility (GI, behavior changes and the mechanical nociceptive threshold (MNT were evaluated. The MNT was determined with von Frey device method.Tr3 had a significant increase in their fR and more pronounced behavioral changes than other treatments.The Tr1 showed a significant increase in arterial pressure. The GI reduced significantly, mainly in Tr2. The tramadol did not change the MNT of the horses.The clinical alterations observed with the different treatments were considered mild and transitory, being most evident in Tr2. However the tramadol did not have any analgesic effect with any of the doses evaluated.

Bilateral blindness secondary to optic nerve ischemia from severe amlodipine overdose: a case report.

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Kao, Raymond; Landry, Yves; Chick, Genevieve; Leung, Andrew

2017-08-03

Calcium channel blockers are commonly prescribed medications; calcium channel blocker overdose is becoming increasingly prevalent. The typical presentation of a calcium channel blocker overdose is hypotension and decreased level of consciousness. We describe a case of a calcium channel blocker overdose that led to bilateral cortical blindness, a presentation that has not previously been reported. A 49-year-old white woman with known bilateral early optic atrophy presented to our hospital with hypotension and obtundation following a known ingestion of 150 mg of amlodipine. She was transferred to our intensive care unit where she was intubated, mechanically ventilated, and required maximal vasopressor support (norepinephrine 40 mcg/minute, epinephrine 40 mcg/minute, and vasopressin 2.4 units/hour) along with intravenously administered crystalloid boluses. Despite these measures, she continued to deteriorate with persistent hypotension and tachycardia, as well as anuria. Intralipid emulsion therapy was subsequently administered to which no initial response was observed. A chest X-ray revealed diffuse pulmonary edema; intravenous diuresis as well as continuous renal replacement therapy was initiated. Following the initiation of continuous renal replacement therapy, her oxygen requirements as well as urine output began to improve, and 3 days later she was liberated from mechanical ventilation. Following extubation, she complained of new onset visual impairment, specifically seeing only red-green colors, but no objects. An ophthalmologic examination revealed that this was due to bilateral optic atrophy from prolonged hypotension during the first 24 hours after the overdose. Persistent hypotension in the setting of a calcium channel blocker overdose can lead to worsening optic atrophy resulting in bilateral cortical blindness.

Interactions between superficial and deep dorsal horn spinal cord neurons in the processing of nociceptive information.

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Petitjean, Hugues; Rodeau, Jean-Luc; Schlichter, Rémy

2012-12-01

In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites

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2013-01-01

Background Aim of the study was to compare the effect of neuroleptic sedation with acepromazine and neuroleptanalgesia with acepromazine and buprenorphine on thermal thresholds (TT) obtained at the nostrils and at the withers. The study was carried out as a randomized, blinded, controlled trial with cross-over design. Thermal thresholds were determined by incremental contact heat applied to the skin above the nostril (N) or the withers (W). Eleven horses were treated with saline (S), acepromazine (0.05 mg/kg) (ACE) or acepromazine and buprenorphine (0.0075 mg/kg) (AB) intravenously (IV). Single stimulations were performed 15 minutes prior and 15, 45, 75, 105, 165, 225, 285, 405 and 525 minutes after treatment. Sedation score, gastrointestinal auscultation score and occurrence of skin lesions were recorded. Data were analysed with analysis of variance for repeated measurements. Results There were no significant differences in TT between N and W with all treatments. The TT remained constant after S and there was no difference in TT between S and ACE. After AB there was a significant increase above baseline in TT until 405 minutes after treatment. Restlessness occurred 30–90 minutes after AB in 7 horses. All horses had reduced to absent borborygmi after AB administration for 165 to 495 minutes. Conclusion Thermal stimulation at both described body areas gives comparable results in the assessment of cutaneous anti-nociception in horses. There is no differential influence of neuroleptic sedation or neuroleptanalgesia on TTs obtained at N or W. Buprenorphine combined with acepromazine has a long lasting anti-nociceptive effect associated with the typical opioid induced side effects in horses. PMID:23837730

Preferential distribution of nociceptive input to motoneurons with muscle units in the cranial portion of the upper trapezius muscle.

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Dideriksen, Jakob L; Holobar, Ales; Falla, Deborah

2016-08-01

Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface electromyography (EMG) recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is, however, not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a nonuniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers during baseline, control (intramuscular injection of isotonic saline), and painful (hypertonic saline) conditions. The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 ± 3.6 pulses/s (pps) in the cranial region but not in the caudal region (1.4 ± 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motoneurons of the two regions. These adjustments were observed, irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a nonuniform way across regions of the upper trapezius muscle. Copyright © 2016 the American Physiological Society.

Different approaches in Partial Least Squares and Artificial Neural Network models applied for the analysis of a ternary mixture of Amlodipine, Valsartan and Hydrochlorothiazide

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Darwish, Hany W.; Hassan, Said A.; Salem, Maissa Y.; El-Zeany, Badr A.

2014-03-01

Different chemometric models were applied for the quantitative analysis of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in ternary mixture, namely, Partial Least Squares (PLS) as traditional chemometric model and Artificial Neural Networks (ANN) as advanced model. PLS and ANN were applied with and without variable selection procedure (Genetic Algorithm GA) and data compression procedure (Principal Component Analysis PCA). The chemometric methods applied are PLS-1, GA-PLS, ANN, GA-ANN and PCA-ANN. The methods were used for the quantitative analysis of the drugs in raw materials and pharmaceutical dosage form via handling the UV spectral data. A 3-factor 5-level experimental design was established resulting in 25 mixtures containing different ratios of the drugs. Fifteen mixtures were used as a calibration set and the other ten mixtures were used as validation set to validate the prediction ability of the suggested methods. The validity of the proposed methods was assessed using the standard addition technique.

Dgroup: DG01925 [KEGG MEDICUS

Lifescience Database Archive (English)

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Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity

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Petruska, Jeffrey C.; Barker, Darrell F.; Garraway, Sandra M.; Trainer, Robert; Fransen, James W.; Seidman, Peggy A.; Soto, Roy G.; Mendell, Lorne M.; Johnson, Richard D.

2013-01-01

Detailed characterization of neural circuitries furthers our understanding of how nervous systems perform specific functions and enables the use of those systems to test hypotheses. We have characterized the sensory input to the cutaneous trunk muscle (CTM; also cutaneus trunci (rat) or cutaneus maximus (mouse)) reflex (CTMR), which manifests as a puckering of the dorsal thoracolumbar skin and is selectively driven by noxious stimuli. CTM electromyography (EMG) and neurogram recordings in naïve rats revealed that CTMR responses were elicited by natural stimuli and electrical stimulation of all segments from C4 to L6, a much greater extent of segmental drive to the CTMR than previously described. Stimulation of some subcutaneous paraspinal tissue can also elicit this reflex. Using a selective neurotoxin, we also demonstrate differential drive of the CTMR by trkA-expressing and non-expressing small diameter afferents. These observations highlight aspects of the organization of the CTMR system which make it attractive for studies of nociception and anesthesiology and plasticity of primary afferents, motoneurons, and the propriospinal system. We use the CTMR system to qualitatively and quantitatively demonstrate that experimental pharmacological treatments can be compared to controls applied either to the contralateral side or to another segment, with the remaining segments providing controls for systemic or other treatment effects. These data indicate the potential for using the CTMR system as both an invasive and non-invasive quantitative assessment tool providing improved statistical power and reduced animal use. PMID:23983104

Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

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Haley, Jane E; Dickenson, Anthony H

2016-08-15

We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.