Sample records for prolonged dose administration

  1. Prolonged priapism following single dose administration of sildenafil: A rare case report

    Sharma Sachit


    Full Text Available A case of priapism following the consumption of a single dose of sildenafil is reported. A 25-year-old unmarried healthy man consumed non-prescribed 50 mg sildenafil purchased over the counter. He developed painful priapism 30 min after the drug intake that had lasted for 4 days (96 h when he sought medical advice as an emergency. The corpus spongiosum and glans was soft and the corpus cavernosa was rigid. Winter′s shunt was done. Fifteen milliliters of dark blood was aspirated with 16 G needle. Detumescence was achieved within 30 min. He was discharged after 12 h. On one month follow-up, he had normal morning erections. A genetic basis with cross-reactivity of PDE-3 in addition to PDE-5 resulting in a cumulative erection effect may be possible elucidation for this unwanted side effect in rare cases. However, the number of cases reported with this side effect is still too less to draw further conclusions.

  2. Rat liver pathomorphology during prolonged sodium valproate administration.

    Sobaniec-Lotowska, M; Sobaniec, W; Kułak, W


    Prolonged administration (1, 3, 6, 9 and 12 months) to rats of an antiepileptic drug--sodium valproate (Vupral--"Polfa") in the dose of 200 mg/kg/day produced the first hepatic morphological lesions after 3 months of the experiment. These structural abnormalities progressively increased to achieve their peak within 12 months. The most prominent microscopic changes consisted of extensive microvesicular fatty change and vacuolar degeneration of periportal hepatocytes. Intralobular focal necrosis, infiltrations of lymphocytes, plasma cells, and phagocytes in the portal tracts, and centrilobular congestion were also present. The connective tissue did not proliferate either in periportal lobular zone or around the central veins. The described lesions seem thus to be reversible.

  3. Prolonged morphine administration alters protein expression in the rat myocardium

    Drastichova Zdenka; Skrabalova Jitka; Neckar Jan; Kolar Frantisek; Novotny Jiri


    Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day) for 10 days. Protein...


    Bronfenbrenner, J; Favour, C B


    (1) Restriction of fluid intake to 1,500 cc and the salt intake to 3 gm a day doubles the penicillin blood level following interrupted intramuscular [See Figure in the PDF file] injections of penicillin. (2) The administration of benzoic acid to a patient on an unrestricted diet Ilay double the penicillin blood level during similar treatment. (3) The combination of these two procedures results in a four- to eight-fold increase in penicillin blood level with a prolonged effective blood concentration.

  5. Prolonged morphine administration alters protein expression in the rat myocardium

    Drastichova Zdenka


    Full Text Available Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day for 10 days. Proteins from the plasma membrane- and mitochondria-enriched fractions or cytosolic proteins isolated from left ventricles were run on 2D gel electrophoresis, scanned and quantified with specific software to reveal differentially expressed proteins. Results Nine proteins were found to show markedly altered expression levels in samples from morphine-treaded rats and these proteins were identified by mass spectrometric analysis. They belong to different cell pathways including signaling, cytoprotective, and structural elements. Conclusions The present identification of several important myocardial proteins altered by prolonged morphine treatment points to global effects of this drug on heart tissue. These findings represent an initial step toward a more complex view on the action of morphine on the heart.

  6. The effects of prolonged oral administration of the disinfectant calcium hypochlorite in Nigerian commercial cockerels

    Temitayo O. Iji


    Full Text Available This study was designed to investigate the effects of prolonged oral administration of calcium hypochlorite in the drinking water of commercial cockerels. It was carried out in order to ascertain probable toxicity associated with prolonged exposure to calcium hypochlorite. Thirty-two healthy birds were used; they were grouped into four groups of eight. Group 1, which served as the control, received 10 mL/kg body weight of physiological saline. Groups 2, 3 and 4 received 0.0375 g, 0.375 g and 0.75 g of calcium hypochlorite per 10 litres of drinking water for six weeks respectively. Six weeks after the administration of calcium hypochlorite, blood was collected from the jugular vein to assess liver function, lipid profiles and for markers of oxidative stress. The results revealed a significant (p < 0.05 increase in alanine aminotransferase activity in a dose-dependent manner when compared with the control. Also, there was a significant (p < 0.05 increase in aspartate aminotransferase and alkaline phosphatase activity. Similarly, there was a significant (p < 0.05 increase in total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein levels compared with the control. There was a significant increase in malondialdehyde and hydrogen peroxide generation with a concomitant significant (p < 0.05 decrease in serum glutathione level in a dose-dependent manner when compared with the control. In this study, calcium hypochloriteinduced hepatic damage via oxidative stress and decrease in antioxidant defense system was found. Therefore, prolonged exposure of chickens to calcium hypochlorite is potentially harmful.

  7. Evaluation of Sphingolipids in Wistar Rats Treated to Prolonged and Single Oral Doses of Fumonisin B1

    Direito, Glória M.; Almeida, Adriana P.; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corrêa, Benedito


    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B1 (FB1). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB1. Prolonged exposure to FB1 caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB1. Animals receiving a single dose of FB1 presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  8. Development and Optimization of a Novel Prolonged Release Formulation to Resist Alcohol-Induced Dose Dumping

    Gujjar, Chaitanya Yogananda; Rallabandi, Balaramesha Chary; Gannu, Ramesh; Deulkar, Vallabh Subashrao


    Alcohol-induced dose dumping is a serious concern for the orally administered prolonged release dosage forms. The study was designed to optimize the independent variables, propylene glycol alginate (PGA), Eudragit RS PO (ERS) and coating in mucoadhesive quetiapine prolonged release tablets 200 mg required for preventing the alcohol-induced dose dumping. Optimal design based on response surface methodology was employed for the optimization of the composition. The formulations are evaluated for...

  9. Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

    Eagle, Andrew L.; Singh, Robby; Kohler, Robert J.; Friedman, Amy L.; Liebowitz, Chelsea P.; Galloway, Matthew P.; Enman, Nicole M.; Jutkiewicz, Emily M.; Perrine, Shane A.


    Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID:25712697

  10. Prolonged Administration of Twice-Daily Bolus Intravenous Tacrolimus in the Early Phase After Lung Transplantation.

    Hirano, Yutaka; Sugimoto, Seiichiro; Mano, Toshifumi; Kurosaki, Takeshi; Miyoshi, Kentaroh; Otani, Shinji; Yamane, Masaomi; Kobayashi, Motomu; Miyoshi, Shinichiro; Oto, Takahiro


    BACKGROUND Although administration of tacrolimus, whether by the enteric, sublingual, or continuous intravenous routes, has some limitations, twice-daily bolus intravenous tacrolimus administration has been shown to be beneficial in optimizing efficacy and safety after lung transplantation. However, at present, the duration of bolus intravenous tacrolimus administration is limited, and the effects of prolonged bolus intravenous tacrolimus administration remain unknown. Our study was aimed at assessing the safety and efficacy of prolonged twice-daily bolus intravenous tacrolimus administration in the early phase after lung transplantation. MATERIAL AND METHODS We retrospectively investigated the data of 62 recipients of lung transplantation who had received twice-daily bolus intravenous administration of tacrolimus, followed by oral tacrolimus, after lung transplantation at our institution between January 2011 and October 2015. RESULTS The median duration of bolus intravenous tacrolimus administration was 19 days (4-72 days). The target trough level was achieved in 89% of the patients by day 3. Acute kidney injury occurred in 27% of the patients during bolus intravenous tacrolimus. Two patients (3%) had neurotoxicity, necessitating discontinuation of tacrolimus. Suspected acute rejection requiring steroid pulse therapy occurred in 21% of patients during the follow-up period. Eight patients (13%) developed chronic lung allograft dysfunction during the follow-up period. The 1-year and 5-year survival rates after lung transplantation were 95% and 76%, respectively. CONCLUSIONS These results suggest that prolonged bolus intravenous tacrolimus administration in the early phase after lung transplantation is a safe and effective alternative to enteric, sublingual, or continuous intravenous administration.

  11. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.

    García-Arieta, Alfredo; Morales-Alcelay, Susana; Herranz, Marta; de la Torre-Alvarado, José María; Blázquez-Pérez, Antonio; Suárez-Gea, Ma Luisa; Alvarez, Covadonga


    In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.

  12. Development and Optimization of a Novel Prolonged Release Formulation to Resist Alcohol-Induced Dose Dumping.

    Gujjar, Chaitanya Yogananda; Rallabandi, Balaramesha Chary; Gannu, Ramesh; Deulkar, Vallabh Subashrao


    Alcohol-induced dose dumping is a serious concern for the orally administered prolonged release dosage forms. The study was designed to optimize the independent variables, propylene glycol alginate (PGA), Eudragit RS PO (ERS) and coating in mucoadhesive quetiapine prolonged release tablets 200 mg required for preventing the alcohol-induced dose dumping. Optimal design based on response surface methodology was employed for the optimization of the composition. The formulations are evaluated for in vitro drug release in hydrochloric acid alone and with 40% v/v ethanol. The responses, dissolution at 120 min without alcohol (R1) and dissolution at 120 min with alcohol (R2), were statistically evaluated and regression equations are generated. PGA as a hydrophilic polymeric matrix was dumping the dose when dissolutions are carried in 0.1 N hydrochloric acid containing 40% v/v ethanol. ERS addition was giving structural support to the swelling and gelling property of PGA, and thus, was reducing the PGA erosion in dissolution media containing ethanol. Among the formulations, four formulations with diverse composition were meeting the target dissolution (30-40%) in both the conditions. The statistical validity of the mathematical equations was established, and the optimum concentration of the factors was established. Validation of the study with six confirmatory runs indicated high degree of prognostic ability of response surface methodology. Further coating with ReadiLycoat was providing an additional resistance to the alcohol-induced dose dumping. Optimized compositions showed resistance to dose dumping in the presence of alcohol.

  13. Effects of a prolonged administration of valepotriates in rats on the mothers and their offspring.

    Tufik, S; Fujita, K; Seabra, M de L; Lobo, L L


    Valeriana officinalis L. (Valerianaceae) is widely known to be associated with sedative properties. The effects of a valepotriates mixtures on mothers and progeny were evaluated in rats. A 30-day administration of valepotriates did not change the average length of estral cycle, nor the number of estrous phases during this period. Also, there were no changes on the fertility index. Fetotoxicity and external examination studies did not show differences, although internal examination revealed an increase in number of retarded ossification after the highest doses employed--12 and 24 mg/kg. No changes were detected in the development of the offspring after treatment during pregnancy. As for temperature, valepotriates caused a hypothermizant effect after administration by the intraperitoneal route but not after oral administration. Generally, the valepotriates employed induced some alterations after administration by the intraperitoneal route, but doses given orally were innocuous to pregnant rats and their offspring.

  14. Hepatic and intestine alterations in mice after prolonged exposure to low oral doses of Microcystin-LR.

    Sedan, Daniela; Laguens, Martín; Copparoni, Guido; Aranda, Jorge Oswaldo; Giannuzzi, Leda; Marra, Carlos Alberto; Andrinolo, Darío


    Oral intake of Microcystin-LR (MC-LR) is the principal route of exposure to this toxin, with prolonged exposure leading to liver damage of unspecific symptomatology. The aim of the present paper was therefore to investigate the liver and intestine damage generated by prolonged oral exposure to low MC-LR doses (50 and 100 μg MC-LR/kg body weight, administrated every 48 h during a month) in a murine model. We found alterations in TBARS, SOD activity and glutathione content in liver and intestine of mice exposed to both doses of MC-LR. Furthermore, the presence of MC-LR was detected in both organs. We also found hepatic steatosis (3.6 ± 0.6% and 15.3 ± 1.6%) and a decrease in intraepithelial lymphocytes (28.7 ± 5.0% and 44.2 ± 8.7%) in intestine of 50- and 100-μg MC-LR/kg treated animals, respectively. This result could have important implications for mucosal immunity, since intraepithelial lymphocytes are the principal effectors of this system. Our results indicate that prolonged oral exposure at 50 μg MC-LR/kg every 48 h generates significant damage not only in liver but also in intestine. This finding calls for a re-appraisal of the currently accepted NOAEL (No Observed Adverse Effect Level), 40 μg MC-LR/kg body weight, used to derive the guideline value for MC-LR in drinking water.

  15. Toxicity after prolonged (more than four weeks administration of intravenous colistin

    Bliziotis Ioannis A


    Full Text Available Abstract Background The intravenous use of polymyxins has been considered to be associated with considerable nephrotoxicity and neurotoxicity. For this reason, the systemic administration of polymyxins had been abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant (MDR Gram-negative bacteria such us Pseudomonas aeruginosa and Acinetobacter baumanniii has led to the re-use of polymyxins. Our objective was to study the toxicity of prolonged intravenous administration of colistin (polymyxin E. Methods An observational study of a retrospective cohort at "Henry Dunant" Hospital, a 450-bed tertiary care center in Athens, Greece, was undertaken. Patients who received intravenous colistin for more than 4 weeks for the treatment of multidrug resistant Gram-negative infections were included in the study. Serum creatinine, blood urea, liver function tests, symptoms and signs of neurotoxicity were the main outcomes studied. Results We analyzed data for 19 courses of prolonged intravenous colistin [mean duration of administration (± SD 43.4 (± 14.6 days, mean daily dosage (± SD 4.4 (± 2.1 million IU, mean cumulative dosage (± SD 190.4 (± 91.0 million IU] in 17 patients. The median creatinine value increased by 0.25 mg/dl during the treatment compared to the baseline (p Conclusions No serious toxicity was observed in this group of patients who received prolonged intravenous colistin. Colistin should be considered as a therapeutic option in patients with infections due to multidrug resistant Gram-negative bacteria.

  16. Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.

    Britton, Gabrielle B; Bethancourt, José A


    Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.

  17. Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans.

    Rasmussen, Peter; Kim, Yu-Sok; Krogh-Madsen, Rikke; Lundby, Carsten; Olsen, Niels V; Secher, Niels H; van Lieshout, Johannes J


    Administration of erythropoietin (EPO) has been linked to cerebrovascular events. EPO reduces vascular conductance, possibly because of the increase in hematocrit. Whether EPO in itself affects the vasculature remains unknown; here it was evaluated in healthy males by determining systemic and cerebrovascular variables following acute (30,000 IU/d for 3 d; n=8) and chronic (5000 IU/week for 13 wk; n=8) administration of EPO, while the responsiveness of the vasculature was challenged during cycling exercise, with and without hypoxia. Prolonged administration of EPO increased hematocrit from 42.5 ± 3.7 to 47.6 ± 4.1% (PEPO administration. Yet, the two EPO regimes increased arterial pressure similarly (by 8±4 and 7±3 mmHg, respectively; P=0.01) through reduced vascular conductance (by 7±3 and 5±2%; PEPO regimes widened the arterial-to-jugular O(2) differences at rest as well as during normoxic and hypoxic exercise (PEPO to healthy humans lowers systemic and cerebral conductance independent of its effect on hematocrit.

  18. Prolonged Drainage and Intrapericardial Bleomycin Administration for Cardiac Tamponade Secondary to Cancer-Related Pericardial Effusion.

    Numico, Gianmauro; Cristofano, Antonella; Occelli, Marcella; Sicuro, Marco; Mozzicafreddo, Alessandro; Fea, Elena; Colantonio, Ida; Merlano, Marco; Piovano, Pierluigi; Silvestris, Nicola


    Malignant pericardial effusion (MPE) is a serious complication of several cancers. The most commonly involved solid tumors are lung and breast cancer. MPE can give rise to the clinical picture of cardiac tamponade, a life threatening condition that needs immediate drainage. While simple pericardiocentesis allows resolution of the symptoms, MPE frequently relapses unless further procedures are performed. Prolonged drainage, talcage with antineoplastic agents, or surgical creation of a pleuro-pericardial window are the most commonly suggested ones. They all result in MPE resolution and high rates of long-term control. Patients suitable for further systemic treatments can have a good prognosis irrespective of the pericardial site of disease. We prospectively enrolled patients with cardiac tamponade treated with prolonged drainage associated with Bleomycin administration. Twenty-two consecutive patients with MPE and associated signs of hemodynamical compromise underwent prolonged drainage and subsequent Bleomycin administration. After injection of 100 mg lidocaine hydrochloride, 10 mg Bleomycin was injected into the pericardial space. The catheter was clumped for 48 h and then reopened. Removal was performed when the drainage volume was <25 mL daily. Twelve patients (54%) achieved complete response and 9 (41%) a partial response. Only 1 (5%) had a treatment failure and underwent a successful surgical procedure. Acute toxicity was of a low degree and occurred in 7 patients (32%). It consisted mainly in thoracic pain and supraventricular arrhythmia. The 1-year pericardial effusion progression-free survival rate was 74.0% (95% confidence interval [CI]: 51.0-97.3). At a median follow-up of 75 months, a pericardial progression was detected in 4 patients (18%). One- and two-year overall survival rates were 33.9% (95% CI: 13.6-54.2) and 14.5% (95% CI: 0.0-29.5), respectively, with lung cancer patients having a shorter survival than breast cancer patients. The worst

  19. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats.

    James Phie

    Full Text Available Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h only, oxytocin only (20 or 100 ng/Kg/h, or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01. Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05 or both oxytocin and angiotensin II, compared to controls (P < 0.01. Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.

  20. The assessment of tolerability of prolonged oral eugenol administration in rats

    Jezdimirović Milanka


    Full Text Available The potential toxicity and general tolerability of eugenol following two-week or four-week continuous p.o. administration to rats has been investigated. An experiment was performed on 72 male rats of the Wistar strain. Four groups of rats were treated with different doses of eugenol (10 mg/kg bm/day, 50 mg/kg, 200 mg/kg and 400 mg/kg bm/day, the fifth group was administered vehicle (0.5 % methylcellulose, propylene glycol and water, and the sixth group comprised absolutely untreated controls. The corresponding doses of eugenol and vehicle were applied using a gastric probe in a volume of 1 ml/100 g body mass. The general tolerability of eugenol was evaluated on the basis of the daily intake of water and food, body mass, general health condition, behaviour, and lethality in the course of the experiment. In the investigated doses, eugenol applied p.o. in the course of two or four weeks does not influence significantly the intake of food, water, or body mass of rats. The dose of 400 mg/kg/day produced undesired reactions (agitation and hyperesthesia that were first observed on day 21 and lasted until the end of the experiment. Low subacute toxicity of eugenol was established following p.o. administration to rats. Eugenol in doses of 200 and 400 mg/kg tm/day has a low toxic potential and is safe for administration to this animal species. [Projekat Ministarstva nauke Republike Srbije, br. 46009

  1. Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis.

    Qashu, Felicia; Figueiredo, Taiza H; Aroniadou-Anderjaska, Vassiliki; Apland, James P; Braga, Maria F M


    An episode of status epilepticus (SE), if left untreated, can lead to death, or brain damage with long-term neurological consequences, including the development of epilepsy. The most common first-line treatment of SE is administration of benzodiazepines (BZs). However, the efficacy of BZs in terminating seizures is reduced with time after the onset of SE; this is accompanied by a reduced efficacy in protecting the hippocampus against neuronal damage, and is associated with impaired function and internalization of hippocampal GABA(A) receptors. In the present study, using Fluoro-Jade C staining, we found that administration of diazepam to rats at 3 h after the onset of kainic acid-induced SE, at a dose sufficient to terminate SE, had no protective effect on the hippocampus, but produced a significant reduction in neuronal degeneration in the amygdala, piriform cortex, and endopiriform nucleus, examined on days 7-9 after SE. Thus, in contrast to the hippocampus, the amygdala and other limbic structures are responsive to neuroprotection by BZs after prolonged SE, suggesting that GABA(A) receptors are not significantly altered in these structures during SE.

  2. Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study

    Pedersen, Juri L; Lillesø, Jesper; Hammer, Niels A;


    In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf...... concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration....

  3. Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease.

    Hattori, N; Hasegawa, K; Sakamoto, T


    Ropinirole hydrochloride, a dopamine receptor agonist with a non-ergot alkaloid structure, is highly selective for the dopamine D(2) /D(3) receptors. This study was conducted to evaluate the steady-state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with Parkinson's disease (PD). This was a multicenter, open-label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N-depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG) (standard 12-lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. After repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged-release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy

  4. Prolonged rest period enables the detection of micronucleated hepatocytes in the liver of young adult rats after a single dose of diethylnitrosamine or mitomycin C.

    Shimada, Keisuke; Yamamoto, Mika; Takashima, Miyuki; Seki, Jiro; Miyamae, Yoichi; Wakata, Akihiro


    A repeated-dose micronucleus assay utilizing young adult rat hepatocytes was recently developed to evaluate the genotoxicity. In this assay, accumulation of micronucleated hepatocytes (MNHEPs) induced by repeated dosing of genotoxic chemicals is considered to be a key factor in the detection of micronuclei induction. Then, we hypothesized that the period following chemical exposure enable the detection of MNHEP induction in young adult rats, namely that MNHEPs can be generated from chromosomally damaged cells and accumulate following initiation of chemical exposure until sampling. We therefore measured MNHEP induction at 2 or 4 weeks after a single oral administration of 12.5, 50, or 100mg/kg of diethylnitrosamine (DEN) or an intraperitoneal administration of 0.5, 1.0, or 2.0mg/kg of mitomycin C (MMC) to young adult rats. Results showed a statistically significant, dose-dependent increase in the numbers of MNHEPs in DEN- or MMC-treated rats, indicating that prolonged rest period following a single dose of a genotoxic chemical enables the detection of MNHEP induction in the liver of young adult rats. From these results, a single oral administration of 50mg/kg of DEN with a 2- or 4- week rest period can be used as a positive control in repeated-dose liver micronucleus assays. This procedure is superior in terms of labor saving and animal welfare to repeated dosing of DEN.

  5. Experimental and theoretical study of the transport of silver nanoparticles at their prolonged administration into a mammal organism

    Antsiferova, A. A.; Buzulukov, Yu. P.; Kashkarov, P. K.; Kovalchuk, M. V.


    The transport of silver nanoparticles in the organism of laboratory animals has been investigated. A mathematical model of the biokinetics of prolonged administration of nonmetabolizable and nonaglomerating pharmaceutical preparations is proposed, and its analytical solution is found. Based on the experimental data on the prolonged introduction and excretion of colloidal silver nanoparticles and the numerical approximation of the solutions to the equations for the proposed model, time dependences of the silver mass content in brain and blood are obtained and some other important biokinetic parameters are determined. It is concluded that both chronic1 and subchronic2 peroral application of these nanoparticles as an biologically active additive or antiseptic is potentially dangerous.

  6. Dosed versus prolonged exposure in the treatment of fear: an experimental evaluation and review of behavioral mechanisms.

    Rubin, Sophie; Spates, C Richard; Johnson, Douglas A; Jouppi, Leigh


    Exposure-based treatments have proven effective in treating a range of fears and phobias and can be accounted for by mechanisms described in behavioral theory. Enhanced dosed and dosed-only exposure are promising new behavioral approaches for treating fears and phobias. Thirty-nine participants with speech anxiety were randomly assigned to a prolonged exposure (PE) condition, a positively enhanced dosed exposure (PDE) condition, a dosed-only exposure (DE) condition, or a negatively-supplemented dosed exposure (NDE) condition. Results indicated that both the PDE and DE conditions produced less measured aversive arousal and significantly more rapid arousal reduction than the tested alternatives. These techniques may represent an important advancement, in that the treatment gains of traditional exposure therapies might be achieved without the degree of aversive arousal (and possibly high drop out rates) typically seen in exposure therapies. Additionally, these data contradict prevailing opinion concerning the necessity for sustained aversive arousal during exposure-based treatment.

  7. Biochemical and histologic changes in rats after prolonged administration of the crude aqueous extract of the leaves of Vitex grandifolia

    Owolabi, Mbang A.; Moyosola M Abass; Emeka, Promise M.; Jaja, Smith I.; Martin Nnoli; Dosa, Benjamin O. S.


    Background: In recent times, many herbal remedies are used to treat variety of ailments. The leaves of Vitex grandifolia is claimed to be effective in the treatment of diabetes mellitus and as a diuretic in the treatment of high blood pressure. However, there are no scientific reports on the therapeutic benefits or toxicity of this plant. This study therefore investigated the effect of prolonged administration of the aqueous extract of the leaves of this plant in Sprague-Dawley rats. Methods:...

  8. Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord.

    Shi, L; Tang, G P; Gao, S J; Ma, Y X; Liu, B H; Li, Y; Zeng, J M; Ng, Y K; Leong, K W; Wang, S


    Gene delivery into the spinal cord provides a potential approach to the treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis, and spinal muscular atrophy. These disorders progress over long periods of time, necessitating a stable expression of functional genes at therapeutic levels for months or years. We investigated in this study the feasibility of achieving prolonged transgene expression in the rat spinal cord through repeated intrathecal administration of plasmid DNA complexed with 25 kDa polyethylenimine (PEI) into the lumbar subarachnoid space. With a single injection, DNA/PEI complexes could provide transgene expression in the spinal cord 40-fold higher than naked plasmid DNA. The transgene expression at the initial level persisted for about 5 days, with a low-level expression being detectable for at least 8 weeks. When repeated dosing was tested, a 70% attenuation of gene expression was observed following reinjection at a 2-week interval. This attenuation was associated with apoptotic cell death and detected even using complexes containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene expression was detected after repeated intrathecal injections, even in those rats receiving three doses, administered 2 weeks apart. Lumbar puncture is a routine and relatively nontraumatic clinical procedure. Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord disorders.

  9. Restless Legs Syndrome After Single Low Dose Quetiapine Administration.

    Soyata, Ahmet Z; Celebi, Fahri; Yargc, Lutfi I


    Restless legs syndrome is an underdiagnosed sensori-motor disorder and psychotropic drugs are one of the main secondary causes of the illness. The most common psychotropic agents that cause restless legs syndrome are antidepressants; however, antipsychotics have also been reported to induce restless legs syndrome. The prevalence, vulnerability factors and the underlying mechanism of antipsychotic-induced restless legs syndrome are unclear. A possible explanation is that dopaminergic blockade is the main precipitator of the syndrome. Quetiapine-induced restless legs syndrome is another point of interest because of its low binding to D2 receptors. We herein report the case of a restless legs syndrome that emerged after a single low dose quetiapine administration.

  10. Prolongation of bleeding time and inhibition of platelet aggregation by low-dose acetylsalicylic acid in patients with cerebrovascular disease

    Boysen, G; Boss, A H; Ødum, Niels


    Platelet aggregation and bleeding time was measured in 43 cerebrovascular patients participating in a controlled double-blind study of low-dose acetylsalicylic acid. In 19 patients with satisfactory inhibition of the platelet aggregation obtained by 50 to 70 mg acetylsalicylic acid per day...... the bleeding time averaged 11.2 minutes in contrast to 7.0 minutes in the placebo group, p less than 0.001. This study confirms our previous findings of platelet inhibition by low-dose acetylsalicylic acid in patients with cerebrovascular disease. The prolongation of the bleeding time demonstrates that we...... are dealing not merely with an in vitro phenomenon but with a significant in vivo effect. The study provides the rationale for clinical evaluations of low-dose acetylsalicylic acid in stroke prophylaxis....

  11. Impact of prolonged fraction dose-delivery time modeling intensity-modulated radiation therapy on hepatocellular carcinoma cell killing

    Xiao-Kang Zheng; Long-Hua Chen; Xiao Yan; Hong-Mei Wang


    AIM: To explore the impact of prolonged fraction dosedelivery time modeling intensity-modulated radiation therapy (IMRT) on cell killing of human hepatocellular carcinoma (HCC) HepG2 and Hep3B cell lines.METHODS: The radiobiological characteristics of human HCC HepG2 and Hep3b cell lines were studied with standard clonogenic assays, using standard linear-quadratic model and incomplete repair model to fit the dose-survival curves. The identical methods were also employed to investigate the biological effectiveness of irradiation protocols modeling clinical conventional fractionated external beam radiotherapy (EBRT, fraction delivery time 3 min) and IMRT with different prolonged fraction delivery time (15, 30, and 45 min). The differences of cell surviving fraction irradiated with different fraction delivery time were tested with paired t-test. Factors determining the impact of prolonged fraction delivery time on cell killing were analyzed.RESULTS: The α/β and repair half-time (T1/2) of HepG2and Hep3b were 3.1 and 7.4 Gy, and 22 and 19 min respectively. The surviving fraction of HepG2 irradiated modeling IMRT with different fraction delivery time was significantly higher than irradiated modeling EBRT and the cell survival increased more pronouncedly with the fraction delivery time prolonged from 15 to 45 min,while no significant differences of cell survival in Hep3b were found between different fraction delivery time protocols.CONCLUSION: The prolonged fraction delivery time modeling IMRT significantly decreased the cell killing in HepG2 but not in Hep3b. The capability of sub-lethal damage repair was the predominant factor determining the cell killing decrease. These effects, if confirmed by clinical studies, should be considered in designing IMRT treatments for HCC.

  12. Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans

    Rasmussen, Peter; Kim, Yu-Sok; Krogh-Madsen, Rikke


    Administration of erythropoietin (EPO) has been linked to cerebrovascular events. EPO reduces vascular conductance, possibly because of the increase in hematocrit. Whether EPO in itself affects the vasculature remains unknown; here it was evaluated in healthy males by determining systemic...

  13. Pharmacokinetics of Ferrous Sulphate (Tardyferon®) after Single Oral Dose Administration in Women with Iron Deficiency Anaemia.

    Leary, A; Barthe, L; Clavel, T; Sanchez, C; Oulmi-Castel, M; Paillard, B; Edmond, J M; Brunner, V


    Iron-containing preparations available on the market vary in dosage, salt, and chemical state of iron contained in the preparation, as well as in the iron delivery process (immediate or prolonged-release). The present study aimed at characterizing the serum pharmacokinetics of iron in non pregnant women with iron deficiency anaemia (IDA) following a single oral administration of a prolonged-release ferrous sulphate tablet. This multicenter, single dose, open-label study was conducted in 30 women aged between 18 and 45 years with IDA. A single 160 mg oral dose of ferrous sulphate was given as 2 tablets of 80 mg of Tardyferon(®) under fasting conditions. Blood samples were collected before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method. Pharmacokinetic parameters were determined from the serum concentration profiles using a non compartmental approach. Serum profiles showed elevated levels of iron up to 12 h after drug intake. The median time to maximum serum concentrations (Tmax) occurred 4 h post-dosing. Between 2 and 8 h post-dosing, mean serum iron concentrations fluctuated by only 20%. Additionally, C8h and C12h represented on average 78.6% and 47.5% of the Cmax, respectively. This study demonstrates that a single oral dose of 160 mg Tardyferon(®) administered under fasting condition to 30 women with IDA leads to an optimal long-lasting release of iron in the gastrointestinal tract in the targeted population. This allows the attainment and maintenance of elevated serum iron levels for up to 12 h after administration. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

    Gharibian, Katherine N; Mueller, Bruce A


    Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

  15. Prolonged hypoglycemic effect in diabetic dogs due to subcutaneous administration of insulin in liposomes

    Stevenson, R.W.; Patel, H.M.; Parsons, J.A.; Ryman, B.E.


    The biologic action of insulin entrapped in liposomes (phospholipid vesicles) has been investigated following subcutaneous injection to dogs made diabetic with a combination of alloxan and streptozotocin. The fate of the liposomally entrapped material was determined by injecting rats subcutaneously with either /sup 125/I-insulin or the labeled polysaccharide /sup 14/C-inulin, incorporated in liposomes labeled with /sup 3/H-cholesterol. Injection of liposome insulin (0.75 U/kg) to five diabetic dogs resulted in a mean (+/- SEM) blood glucose fall from 16.4 +/- 0.8 to 2.9 +/- 0.4 mmol/L. The glucose level had still not returned to baseline after 24 h and, correspondingly, immunoreactive insulin (IRI) could still be detected in frozen and thawed plasma 24 h after injection. In contrast, the hypoglycemic effect of the same dose of free insulin with or without empty liposomes virtually ended within 8 h and IRI levels returned to baseline by 3 h after injection. In experiments on rats with liposomally entrapped /sup 125/I-insulin or /sup 14/C-inulin the proportion of the injected dose of tracer recoverable by excision of the injection site remained constant after about 1 h and 70% of the dose was still fixed in subcutaneous tissue for at least 5 h thereafter. When the plasma collected 3 h after subcutaneous injection of labeled liposomes containing /sup 125/I-insulin was passed through a column of Sepharose 6B, 50-75% of the /sup 125/I-activity was found in the fractions associated with intact liposomes. One possibility for the persistence of the hypoglycemic effect and of measurable IRI following injection of liposome insulin could be the presence of intact liposomes in the circulation for many hours after adsorption had ceased.

  16. Toxic effects of prolonged administration of leaves of cassava (Manihot esculenta Crantz) to goats.

    Soto-Blanco, Benito; Górniak, Silvana Lima


    Cassava (Manihot esculenta Crantz) is a major source of dietary energy for humans and domestic animals in many tropical countries. However, consumption of cassava is limited by its characteristic content of cyanogenic glycosides. The present work aimed to evaluate the toxic effects of ingestion of cassava leaves by goats for 30 consecutive days, and to compare the results with the toxic effects of cyanide in goats, which have been described previously. Eight Alpine cross-bred female goats were divided into two equal groups, and were treated with ground frozen cassava leaves at a target dose of 6.0mg hydrogen cyanide (HCN)/kg/day (treated animals), or with ground hay and water only (control group) by gavage for 30 consecutive days. Blood samples were collected on days 0, 7, 15, 21, and 30 for biochemical panel and cyanide determination. At the end of the experiment, fragments of pancreas, thyroid gland, liver, kidney, lungs, heart, spleen, and the whole central nervous system were collected for histopathological examination. Clinical signs were observed in all goats treated with cassava on the first day of the experiment. From the second day the dose of cassava leaves was reduced to 4.5mgHCN/kg/day. No changes were found in the blood chemical panel. A mild increase in the number of resorption vacuoles in the thyroid follicular colloid, slight vacuolation of periportal hepatocytes, and spongiosis of the mesencephalon were found in goats treated with cassava. The pattern of lesions seen in the present goats was similar to what has been described previously in cyanide-dosed goats. Thus, the toxic effects of the ingestion of cassava leaves by goats can be attributed to the action of cyanide released from cyanogenic glycosides, and none of the effects was promoted by these glycosides directly.

  17. Effect of a moderate caffeine dose on endurance cycle performance and thermoregulation during prolonged exercise in the heat.

    Beaumont, Ross E; James, Lewis J


    This study investigated the influence of a moderate caffeine dose on endurance cycle performance and thermoregulation during prolonged exercise in high ambient temperature. Double-blind cross-over study. Eight healthy, recreationally active males (mean±SD; age: 22±1 years; body mass: 71.1±8.5kg; VO2peak: 55.9±5.8mLkg(-1)min(-1); Wmax: 318±37W) completed one VO2peak test, one familiarisation trial and two experimental trials. After an overnight fast, participants ingested a placebo or a 6mgkg(-1) caffeine dose 60min before exercise. The exercise protocol consisted of 60min of cycle exercise at 55% Wmax, followed by a 30min performance task (total kJ produced) in 30°C and 50% RH. Performance was enhanced (Cohen's d effect size=0.22) in the caffeine trial (363.8±47.6kJ) compared with placebo (353.0±49.0kJ; p=0.004). Caffeine did not influence core (p=0.188) or skin temperature (p=0.577) during exercise. Circulating prolactin (p=0.572), cortisol (p=0.842) and the estimated rates of fat (p=0.722) and carbohydrate oxidation (p=0.454) were also similar between trial conditions. Caffeine attenuated perceived exertion during the initial 60min of exercise (p=0.033), with no difference in thermal stress across trials (p=0.911). Supplementation with 6mgkg(-1) caffeine improved endurance cycle performance in a warm environment, without differentially influencing thermoregulation during prolonged exercise at a fixed work-rate versus placebo. Therefore, moderate caffeine doses which typically enhance performance in temperate environmental conditions also appear to benefit endurance performance in the heat. Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  18. Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report

    Chantelau Ernst A


    Full Text Available Abstract Introduction Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. Case presentation We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion with the insulin analogue lispro (Humalog® in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. Conclusion Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®, triggered by an unknown endogenous mechanism.

  19. Effect of pinealectomy and prolonged melatonin administration on circadian testicular function in food restricted rats

    Ostrowska, Z.; Zwirska-Korczala, K.; Kajdaniuk, D.; Gorski, J.; Buntner, B. [Slaska Akademia Medyczna, Katowice (Poland)


    The effect of pinealectomy and exogenous melatonin on the circadian testosterone variations was investigated (using the radioimmunoassay method) after 3 weeks of 50% food restriction in sexually mature male Wistar rats at 3-h intervals under 12:12 light-dark cycle. The circadian periodicity of testosterone secretion was maintained after caloric deprivation, however its mean 24-h concentration was lower and rhythm disturbances appeared in the form of acrophase shifts from 18.00 to 0.50 h. In pinealectomized animals the mean 24-h testosterone level and amplitude values were significantly increased without the rhythm disturbances. As compared to the control animals, underfed pinealectomized rats had a partial recovery of reduced testosterone levels during the 24-h cycle and showed a normalization of the rhythm acrophase. Melatonin administration was found to inhibit the testosterone mesor value in pinealectomized rats with acrophase shifts from 16.58 to 14.51 h. In comparison with the pinealectomized ones the underfed pinealectomized rats had a greater reduction of the mesor and amplitude values after the melatonin administration. These findings indicate that long-term food restriction sensitizes the circadian testicular axis to antigonadotropic action of the pineal gland. (author). 42 refs, 3 figs, 1 tab.

  20. Effects of prolonged recombinant human erythropoietin administration on muscle membrane transport systems and metabolic marker enzymes

    Juel, C; Thomsen, J J; Rentsch, R L;


    Adaptations to chronic hypoxia involve changes in membrane transport proteins. The underlying mechanism of this response may be related to concomitant occurring changes in erythropoietin (Epo) levels. We therefore tested the direct effects of recombinant human erythropoietin (rHuEpo) treatment...... on the expression of muscle membrane transport proteins. Likewise, improvements in performance may involve upregulation of metabolic enzymes. Since Epo is known to augment performance we tested the effect of rHuEpo on some marker enzymes that are related to aerobic capacity. For these purposes eight subjects...... received 5,000 IU rHuEpo every second day for 14 days, and subsequently a single dose of 5,000 IU weekly for 12 weeks. Muscle biopsies were obtained before and after 14 weeks of rHuEpo treatment. The treatment increased hematocrit (from 44.7 to 48.8%), maximal oxygen uptake by 8.1%, and submaximal...

  1. Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study

    Pedersen, Juri L; Lillesø, Jesper; Hammer, Niels A


    In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf...... stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk...

  2. Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study

    Pedersen, Juri L; Lillesø, Jesper; Hammer, Niels A


    In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf...... was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat...... stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk...

  3. Comparison of ruminant anthelmintics, using multiple dose administration.

    Hass, D K; Holloway, E L; Brown, L J


    Eleven ruminant anthelmintics were administered to lambs over a 30-day period, using medicated feeds or multiple oral doses. Fenbendazole and its sulfinyl analog, oxfendazole, were effective (greater than 90%) in the control of clinical parasitism at feeding levels of 5 mg/kg of feed. Parbendazole and albendazole were effective at daily oral dose levels of 1 mg/kg of body weight and at feeding dose levels of 10 mg/kg of feed, respectively. Levamisole, mebendazole, and oxibendazole were ineffective in controlling intense natural parasitic infections of sheep at daily oral dose levels equal to or less than 1 mg/kg of body weight and/or a feeding level equal to or less than 10 mg/kg of feed.

  4. Gamma Knife Surgery as Monotherapy with Clinically Relevant Doses Prolongs Survival in a Human GBM Xenograft Model

    Bente Sandvei Skeie


    Full Text Available Object. Gamma knife surgery (GKS may be used for recurring glioblastomas (GBMs. However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P<0.001. In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P<0.006. Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P=0.04. Conclusion. GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.

  5. [Beta lactam antibiotics and the question of dose regimen for severe infection. Prolonged infusion theoretically appealing--yet no evidence of clinical benefit].

    Leander, Gunilla; Eliasson, Erik; Hanberger, Håkan; Giske, Christian


    Patients with severe sepsis/septic shock have a high mortality. Beta-lactam antibiotics are normally first line treatment. This antimicrobial class has been associated with time-dependent efficacy. It is therefore plausible that administration as prolonged infusion will increase the therapeutic effect, as compared to short term bolus injections, which is the most common practice today. We have reviewed 14 randomized controlled studies to investigate whether prolonged infusion provides lower mortality and/or increased clinical cure. In summary, convincing advantages with prolonged infusion could not be found, however randomized studies are heterogeneous, and it cannot be excluded that some subgroups of critically ill patients could benefit from such treatment.

  6. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

    Martín-Moreno Ana María


    Full Text Available Abstract Background Alzheimer's disease (AD brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG uptake by positron emission tomography (PET. Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

  7. Prolongation of islet allograft survival in mice by combined treatment with pravastatin and low-dose cyclosporine.

    Arita, S; Kasraie, A; Une, S; Ohtsuka, S; Smith, C V; Mullen, Y


    Pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is known to have suppressive effects on immune and inflammatory cells. We have previously shown in mice and dogs that this agent prevents primary nonfunction of islet iso- and autografts by reducing inflammation at the graft site. The present study was designed to further investigate whether pravastatin has a synergistic effect with cyclosporine (Cs) to prolong islet allograft survival in mice. Unpurified 3000 BALB/c newborn islets were transplanted under the renal capsule of a streptozotocin-diabetic C57BL/6 mouse. Pravastatin and Cs were administered for 10 days starting on the day of grafting (day 0). Five groups were set up based on the treatment protocol: group 1, treatment with 40 mg/kg pravastatin; group 2, 30 mg/kg Cs; group 3, 50 mg/kg Cs; group 4, 40 mg/kg pravastatin and 30 mg/kg Cs; group 5, vehicle alone. Graft survival was indicated by blood glucose levels sustained at 250 mg/dl for 2 consecutive days. Hyperglycemia persisted in six of the eight (75%) mice and grafts were rejected in 3.6 +/- 0.5 days (mean +/- SD) in group 5. In group 1, grafts were also rejected in 3.8 +/- 0.8 days, but blood glucose was transiently 60 days, the other rejected the graft on day 15, and the remaining four died with functioning grafts between 9 and 13 days due to Cs toxicity. A combination of a low dose of Cs and pravastatin (group 4) prolonged graft survival for >19 days in five of the eight mice, and for 7-13 days in the remaining three mice. Histological examination of the grafts in this group showed significantly reduced local inflammation. Results indicate a synergistic effect of pravastatin and Cs on prevention of islet allograft rejection.

  8. Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

    Y-J Choi; J Y Kim; S B Yoo; J-H Lee; J W Jahng


    This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.

  9. The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

    Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M


    Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

  10. Health effects of prolonged low-dose rate gamma-irradiation of a human population in Taiwan, 1983-2003

    Chang, W. P.; Hsieh, W. A.; Lin, Y. P.; Huang, S.; Hwang, B. F.; Lee, S. D.; Chen, J. C.; Tsai, M.; Yen, N. P.


    Health effects of low dose-rate , low LET irradiation on large numbers of human population have been rare and less well known and studied. However, the standards for safety and health regulation for radiation exposure depend on solid observations of related studies. during 1983 to mid 1990s, an unusual contamination occurred that was derived from several lost Co-60 orphan sources and un-intentionally recycled into thousands tons construction steels, eventually employed for construction in several cities in Taiwan. Continuous studies on the immediate and prolonged health effects of these 7,000 subjects, with more than 60% have been exposed during prenatal, childhood, and adolescents periods, have been able to form a stron scientific avenue to provide evidences for unusual observation on a human population in natural environments. Moreover, an exposure reconstruction program, co-joined with scientists in National Institute of Occupational Safety and Health and Oregan State University in the U. S.; were initiated and continued throughout the study program that critically provided dose response analysis feasible. These studies include bone marrow/hematological changes, lens opacities, thyroid function and thyroid glands abnormalities, growth and development in physical parameters, helper and suppressor T cell populations, serum p53 protein levels, and cancer incidences and risks. Moreover, several cytogenetic markers have been employed to analyze the subtle changes in the somatic tissues. These include frequencies of micronuclei formation, chromosomal aberrations and chromosomal translocations on circulating T-lymphocytes. Functional studies including IQ testing on prenatally exposed children and the reproductive potential as time-to-pregnancy, TTP, were also observed in married couples with offspring. The observations, published in more than 20 manuscripts, will be summarized and presented for future collaborative studies, based on the established database, case

  11. Effects of substitution and high-dose thyroid hormone therapy on deiodination, sulfoconjugation, and tissue thyroid hormone levels in prolonged critically ill rabbits

    Y. Debaveye (Yves); B. Ellger (Björn); L. Mebis (Liese); T.J. Visser (Theo); V.M. Darras (Veerle); G. van den Berghe (Greet)


    textabstractTo delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3′-diiodothyronine (T2) and T4S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidn

  12. High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

    Hansen, A; Kemp, K; Kemp, E;


    of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population...

  13. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Jodi L. Pawluski


    Full Text Available Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1 cookie and (2 osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.

  14. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    Hyldstrup, Lars; Flesch, G; Hauffe, S A


    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...

  15. Fetal radiation dose estimates for I-131 sodium iodide in cases where conception occurs after administration

    Sparks, R.B.; Stabin, M.G. [Oak Ridge Inst. for Science and Education, TN (United States)


    After administration of I-131 to the female patient, the possibility of radiation exposure of the embryo/fetus exists if the patient becomes pregnant while radioiodine remains in the body. Fetal radiation dose estimates for such cases were calculated. Doses were calculated for various maternal thyroid uptakes and time intervals between administration and conception, including euthyroid and hyperthyroid cases. The maximum fetal dose calculating was about 9.8E-03 mGy/MBq, which occurred with 100% maternal thyroid uptake and a 1 week interval between administration and conception. Placental crossover of the small amount of radioiodine remaining 90 days after conception was also considered. Such crossover could result in an additional fetal dose of 9.8E-05 mGy/MBq and a maximum fetal thyroid self dose of 3.5E-04 mGy/MBq.

  16. Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration.

    Nils Rudqvist

    Full Text Available 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation has been the preferential accumulation of released 211At in the thyroid gland, which is a critical organ for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional expression in mouse thyroid gland.BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively; mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially expressed transcripts and enriched GO terms were determined with adjusted p-value 1.5, and p-value <0.05, respectively.In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered 1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected in the present study. Regulation of immunological processes were prevalent at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy.

  17. Pharmacokinetic interaction between amprenavir and delavirdine after multiple-dose administration in healthy volunteers

    Justesen, Ulrik S; Klitgaard, Niels A; Brosen, Kim


    AIMS: To evaluate the safety and the pharmacokinetic interaction between amprenavir and delavirdine after multiple dose administration in healthy volunteers. METHODS: This was a prospective, open-label, randomized, controlled, two-sequence, two-period multiple dose study with 18 healthy subjects....

  18. Chest wall rigidity in two infants after low-dose fentanyl administration.

    Dewhirst, Elisabeth; Naguib, Aymen; Tobias, Joseph D


    Since its introduction into clinical practice, it has been known that fentanyl and other synthetic opioids may cause skeletal muscle rigidity. Involvement of the respiratory musculature, laryngeal structures, or the chest wall may impair ventilation, resulting in hypercarbia and hypoxemia. Although most common with the rapid administration of large doses, this rare adverse effect may occur with small doses especially in neonates and infants. We present 2 infants who developed chest wall rigidity, requiring the administration of neuromuscular blocking agents and controlled ventilation after analgesic doses of fentanyl. Previous reports regarding chest wall rigidity after the administration of low-dose fentanyl in infants and children are reviewed, the pathogenesis of the disorder is discussed, and treatment options offered.

  19. Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

    Shigeaki Otomo


    Full Text Available The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height or train-of-four ratio (TOFR as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245.

  20. Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

    Iwasaki, Hiroshi


    The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height) or train-of-four ratio (TOFR) as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245. PMID:24672542

  1. Prolonged Subdural Infusion of Kynurenic Acid Is Associated with Dose-Dependent Myelin Damage in the Rat Spinal Cord.

    Wojciech Dabrowski

    Full Text Available Kynurenic acid (KYNA is the end stage metabolite of tryptophan produced mainly by astrocytes in the central nervous system (CNS. It has neuroprotective activities but can be elevated in the neuropsychiatric disorders. Toxic effects of KYNA in the CNS are unknown. The aim of this study was to assess the effect of the subdural KYNA infusion on the spinal cord in adult rats.A total of 42 healthy adult rats were randomly assigned into six groups and were infused for 7 days with PBS (control or 0.0002 pmol/min, 0.01 nmol/min, 0.1 nmol/min, 1 nmol/min, and 10 nmol/min of KYNA per 7 days. The effect of KYNA on spinal cord was determined using histological and electron microscopy examination. Myelin oligodendrocyte glycoprotein (MOG was measured in the blood serum to assess a degree of myelin damage.In all rats continuous long-lasting subdural KYNA infusion was associated with myelin damage and myelin loss that was increasingly widespread in a dose-depended fashion in peripheral, sub-pial areas. Damage to myelin sheaths was uniquely related to the separation of lamellae at the intraperiod line. The damaged myelin sheaths and areas with complete loss of myelin were associated with limited loss of scattered axons while vast majority of axons in affected areas were morphologically intact. The myelin loss-causing effect of KYNA occurred with no necrosis of oligodendrocytes, with locally severe astrogliosis and no cellular inflammatory response. Additionally, subdural KYNA infusion increased blood MOG concentration. Moreover, the rats infused with the highest doses of KYNA (1 and 10 nmol/min demonstrated adverse neurological signs including weakness and quadriplegia.We suggest, that subdural infusion of high dose of KYNA can be used as an experimental tool for the study of mechanisms of myelin damage and regeneration. On the other hand, the administration of low, physiologically relevant doses of KYNA may help to discover the role of KYNA in control of

  2. Radiobiological evaluation of the radiation dose as used in high-precision radiotherapy: effect of prolonged delivery time and applicability of the linear-quadratic model.

    Shibamoto, Yuta; Otsuka, Shinya; Iwata, Hiromitsu; Sugie, Chikao; Ogino, Hiroyuki; Tomita, Natsuo


    Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensity-modulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.

  3. Effects of substitution and high-dose thyroid hormone therapy on deiodination, sulfoconjugation, and tissue thyroid hormone levels in prolonged critically ill rabbits.

    Debaveye, Yves; Ellger, Björn; Mebis, Liese; Visser, Theo J; Darras, Veerle M; Van den Berghe, Greet


    To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3'-diiodothyronine (T(2)) and T(4)S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5- fold higher dose of T(4) and T(3), either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T(3) (P=0.006), hepatic T(3) (P=0.02), and hepatic D1 activity (P=0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P=0.0006) and tissue T(4) (P=0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T(3) and tissue T(3)/reverse T(3) ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T(2). Plasma T(4)S was increased only by T(4) in high dose. We conclude that in prolonged critically ill rabbits, low plasma T(3) levels were associated with low liver and kidney T(3) levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.

  4. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro

    Fanoe, Søren; Jensen, Gorm Boje; Sjøgren, Per


    with the use of these drugs. WHAT THIS PAPER ADDS: This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length. AIMS: During recent years some...... patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing h...... dose was associated with a 10 ms(1/2) (95% CI 2-19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low-affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC(50) = 171 microM oxycodone...

  5. Early administration of the second surfactant dose in preterm infants with severe respiratory distress syndrome.

    Köksal, Nilgün; Akpinar, Reyhan; Cetinkaya, Merih


    The aim of this study was to determine whether early administration (2 hours after the first surfactant dose) of the second surfactant dose would be superior to late surfactant treatment (6 hours after the first surfactant dose) in preterm infants with severe respiratory distress syndrome. Between June 2003 and March 2005, 40 newborns born with respiratory distress syndrome in Uludağ University Hospital were investigated in this prospective study. The inclusion criteria for the recruitment of the infants were: age respiratory distress syndrome, and need for mechanical ventilation with inspiratory oxygen fraction > or = 0.4 and mean airway pressure > or = 7 cm H2O to obtain arterial pressure of oxygen between 70-80 mmHg. Infants with lethal congenital anomalies or being treated with high-frequency oscillatory ventilation were excluded from the study. Birth weight, gestational age, gender, and Apgar scores were recorded and complications of the surfactant therapy were examined. Twenty boys and 20 girls were enrolled in the study. The first surfactant dose was administered in the first hour of life in all infants. The second surfactant dose was given 2 hours after the first dose in 20 of them and 6 hours after the first dose in the other 20. Infants in both groups (early versus late) were similar with respect to gestational age, birth weight, gender, and the rate of prenatal corticosteroids. There were also no significant differences between the two groups in terms of the response to surfactant therapy and complications. The results of this study show that administration of the second surfactant dose earlier is as effective as late administration, and it may be suggested that the second surfactant dose can be applied earlier in severe respiratory distress syndrome.

  6. Blood volume measurement with indocyanine green pulse spectrophotometry: dose and site of dye administration

    M.R. Germans; P.C. de Witt Hamer; L.J. van Boven; K.A.H. Zwinderman; G.J. Bouma


    (1) To determine the optimal administration site and dose of indocyanine green (ICG) for blood volume measurement using pulse spectrophotometry, (2) to assess the variation in repeated blood volume measurements for patients after subarachnoid hemorrhage and (3) to evaluate the safety and efficacy of

  7. Single dose testosterone administration alleviates gaze avoidance in women with Social Anxiety Disorder.

    Enter, Dorien; Terburg, David; Harrewijn, Anita; Spinhoven, Philip; Roelofs, Karin


    Gaze avoidance is one of the most characteristic and persistent social features in people with Social Anxiety Disorder (SAD). It signals social submissiveness and hampers adequate social interactions. Patients with SAD typically show reduced testosterone levels, a hormone that facilitates socially dominant gaze behavior. Therefore we tested as a proof of principle whether single dose testosterone administration can reduce gaze avoidance in SAD. In a double-blind, within-subject design, 18 medication-free female participants with SAD and 19 female healthy control participants received a single dose of 0.5mg testosterone and a matched placebo, at two separate days. On each day, their spontaneous gaze behavior was recorded using eye-tracking, while they looked at angry, happy, and neutral facial expressions. Testosterone enhanced the percentage of first fixations to the eye-region in participants with SAD compared to healthy controls. In addition, SAD patients' initial gaze avoidance in the placebo condition was associated with more severe social anxiety symptoms and this relation was no longer present after testosterone administration. These findings indicate that single dose testosterone administration can alleviate gaze avoidance in SAD. They support theories on the dominance enhancing effects of testosterone and extend those by showing that effects are particularly strong in individuals featured by socially submissive behavior. The finding that this core characteristic of SAD can be directly influenced by single dose testosterone administration calls for future inquiry into the clinical utility of testosterone in the treatment of SAD.

  8. Kinetics of nebivolol and its active metabolite after single dose oral administration of nebivolol

    Gheldiu, Ana Maria; Muntean, Dana Maria; Cristea, Ileana


    A pharmacokinetic study of nebivolol and its active metabolite (4-hydroxy-nebivolol) after single dose oral administration of nebivolol to 20 healthy volunteers was realized. The representative pharmacokinetic model involves first order absorption kinetics for nebivolol with pre-systemic metaboli...

  9. Postmarketing review of intravenous acetaminophen dosing based on Food and Drug Administration prescribing guidelines.

    dela Cruz Ubaldo, Catherine; Hall, Natalie Semaan; Le, Brenden


    To evaluate the appropriateness of intravenous acetaminophen dosing-prescribed dose, frequency, duration, and indication-based on United States Food and Drug Administration (FDA)-approved prescribing guidelines and to evaluate the adverse effect profile of intravenous acetaminophen. Retrospective chart review. United States Navy medical center. Three hundred patients who received intravenous acetaminophen from August 1, 2011, to August 1, 2012. The indications, dose, frequency, and duration of intravenous acetaminophen were recorded for each patient. Adverse effects of intravenous acetaminophen were analyzed by thoroughly reviewing any adverse effects documented, including nausea, vomiting, headache, or any symptom specifically attributed to the drug. Baseline liver function tests, including aspartate aminotransferase and alanine aminotransferase levels, and elevations 3 times the upper limit of normal during intravenous acetaminophen therapy were recorded. The average patient weight was 78±21 kg, with 12 patients (4%) weighing less than 50 kg and 288 (96%) patients weighing 50 kg or greater. Two hundred forty-one patients (80%) were appropriately dosed, whereas 59 (20%) patients were not appropriately dosed based on the FDA-approved dosing. No patients exceeded the FDA-approved maximum daily dosing recommendations for intravenous acetaminophen (4 g). Sixty-five patients (22%) received intravenous acetaminophen for longer than 24 hours. Intravenous acetaminophen was well tolerated, without any reported adverse effects, including the commonly reported adverse effects of nausea, vomiting, headache, and insomnia. Ten patients (3%) had a documented history of liver disease and did not experience any adverse effects or increases in liver function tests after the administration of intravenous acetaminophen. Intravenous acetaminophen appeared to be a safe and effective analgesic and antipyretic agent. Dosing for patients weighing less than 50 kg needs to be appropriately

  10. Pharmacokinetics of guaifenesin following administration of multiple doses to exercised Thoroughbred horses.

    Knych, H K; Stanley, S D; Benson, D; Arthur, R M


    Guaifenesin is an expectorant commonly used in performance horses to aid in the clearance of mucus from the airways. Guaifenesin is also a centrally acting skeletal muscle relaxant and as such is a prohibited drug with withdrawal necessary prior to competition. To the authors' knowledge, there are no reports in the literature describing single or multiple oral administrations of guaifenesin in the horse to determine a regulatory threshold and related withdrawal time. Therefore, the objective of the current study was to describe the pharmacokinetics of guaifenesin following oral administration in order to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 2 g of guaifenesin orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum guaifenesin concentrations were determined and pharmacokinetic parameters calculated. Guaifenesin was rapidly absorbed (Tmax of 15 min) following oral administration. The Cmax was 681.3 ± 323.8 ng/mL and 1080 ± 732.8 following the first and last dose, respectively. The serum elimination half-life was 2.62 ± 1.24 h. Average serum guaifenesin concentrations remained above the LOQ of the assay (0.5 ng/mL) by 48 h postadministration of the final dose in 3 of 9 horses. © 2016 John Wiley & Sons Ltd.

  11. Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers.

    Allen, A; Bygate, E; Oliver, S; Johnson, M; Ward, C; Cheon, A J; Choo, Y S; Kim, I C


    Gemifloxacin (known as SB-265805 or LB-20304) is a potent, novel fluoroquinolone compound with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in healthy male volunteers after a single dose of 20, 40, 80, 160, 320, 600, or 800 mg. Multiple serum and urine samples were collected and analyzed for gemifloxacin using high-performance liquid chromatography with fluorescence detection. Safety assessments included vital signs, 12-lead electrocardiogram readings, hematology, clinical chemistry, urinalysis, and adverse-experience monitoring. Gemifloxacin was rapidly absorbed after all doses. Maximum concentrations of gemifloxacin in serum (C(max)) were achieved approximately 1 h after dosing, after which concentrations in serum declined in a biexponential manner. Values of C(max) and the area under the concentration-time curve in serum from 0 h to infinity (serum AUC(0-infinity)) increased linearly with dose. Serum AUC(0-infinity) values (mean +/- standard deviation) were 0.65+/-0.01, 1.28+/-0.22, 2.54+/-0.31, 5.48+/-1.24, 9.82+/-2.70, 24.4+/-7.1, and 31.4+/-7.6 microg. h/ml following 20-, 40-, 80-, 160-, 320-, 600-, and 800-mg doses, respectively. The terminal phase elimination half-life was independent of dose, with an overall mean of 7.4+/-2.0 h. The profiles indicated that the pharmacokinetic profile is suitable for a once-daily dosing regimen. Approximately 25 to 40% of the administered dose was excreted unchanged in the urine, and renal clearance (ca. 150 ml/min) was independent of dose. There were no significant changes in clinical chemistry, hematology, or urinalysis parameters, vital signs, or 12-lead electrocardiogram readings in subjects, irrespective of dose. The results of these studies support the further investigation of once-daily administration of gemifloxacin.

  12. Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells.

    Osipov, Andreyan N; Pustovalova, Margarita; Grekhova, Anna; Eremin, Petr; Vorobyova, Natalia; Pulin, Andrey; Zhavoronkov, Alex; Roumiantsev, Sergey; Klokov, Dmitry Y; Eremin, Ilya


    Diagnostic imaging delivering low doses of radiation often accompany human mesenchymal stem cells (MSCs)-based therapies. However, effects of low dose radiation on MSCs are poorly characterized. Here we examine patterns of phosphorylated histone H2AX (γH2AX) and phospho-S1981 ATM (pATM) foci formation in human gingiva-derived MSCs exposed to X-rays in time-course and dose-response experiments. Both γH2AX and pATM foci accumulated linearly with dose early after irradiation (5-60 min), with a maximum induction observed at 30-60 min (37 ± 3 and 32 ± 3 foci/cell/Gy for γH2AX and pATM, respectively). The number of γH2AX foci produced by intermediate doses (160 and 250 mGy) significantly decreased (40-60%) between 60 and 240 min post-irradiation, indicating rejoining of DNA double-strand breaks. In contrast, γH2AX foci produced by low doses (20-80 mGy) did not change after 60 min. The number of pATM foci between 60 and 240 min decreased down to control values in a dose-independent manner. Similar kinetics was observed for pATM foci co-localized with γH2AX foci. Collectively, our results suggest differential DNA double-strand break signaling and processing in response to low vs. intermediate doses of X-rays in human MSCs. Furthermore, mechanisms governing the prolonged persistence of γH2AX foci in these cells appear to be ATM-independent.

  13. A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once-Weekly DPP-4 Inhibitor, Does Not Prolong the QTc Interval.

    Tatosian, Daniel A; Cardillo Marricco, Nadia; Glasgow, Xiaoli Shirley; DeGroot, Bruce; Dunnington, Katherine; George, Laura; Gendrano, Isaias Noel; Johnson-Levonas, Amy O; Swearingen, Dennis; Kauh, Eunkyung


    Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis.

  14. Molecular biological study-effects of prolonged irradiation by low dose-rate ionizing radiation on the production of growth factors in murine bone marrow cells

    Saito, Mikio; Yamada, Yutaka; Nakamura, Shingo [Inst. for Environmental Sciences, Dept. of Radiobiology, Rokkasho, Aomori (JP)] [and others


    To evaluate effects of prolonged irradiation by low dose-rate ionizing radiation on the production of growth factors of cells, the gene expression of five cytokines, interleukin-1{alpha} (IL-1{alpha}), IL-6, IL-11 stem cell factor (SCF) and granulocyte-macrophage colony stimulating factor (GM-CSF), of mice was measured at accumulated doses between 1 and 8 Gy, with the dose interval of 1 Gy. Ten specific-pathogen-free (SPF) C3H/HeN female mice (8 w.o.) per experimental group were irradiated with {sup 137}Cs {gamma}-rays with the doses of 5 - 8 Gy at the dose rate of 20 mGy/(22 h-day), and the gene expression of five cytokines (IL-1{alpha}, IL-6, IL-11, SCF and GM-CSF) in bone marrow and two cytokines (IL-6 and GM-CSF) in spleen cells from the mice was measured semiquantitatively by both the reverse transcriptase-polymerase chain reaction (RT-PCR) and TaqMan Real-Time PCR method. (author)

  15. Exploration of α1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

    Baranovski, Boris M.; Ozeri, Eyal; Shahaf, Galit; Ochayon, David E.; Schuster, Ronen; Bahar, Nofar; Kalay, Noa; Cal, Pablo; Mizrahi, Mark I.; Nisim, Omer; Strauss, Pnina; Schenker, Eran; Eli C Lewis


    Lifelong weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Because the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related inj...

  16. Exploration of α1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration.

    Baranovski, Boris M; Ozeri, Eyal; Shahaf, Galit; Ochayon, David E; Schuster, Ronen; Bahar, Nofar; Kalay, Noa; Cal, Pablo; Mizrahi, Mark I; Nisim, Omer; Strauss, Pnina; Schenker, Eran; Lewis, Eli C


    Life-long weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Since the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injury. Islet-grafted mice were treated with hAAT (Glassia™; i.p. or s.c.) under an array of clinically relevant dosing plans. Serum hAAT and immunocyte cell membrane association were examined, as well as parameters of islet survival. Results indicate that dividing the commonly prescribed 60 mg/kg i.p. dose to three 20 mg/kg injections is superior in affording islet graft survival; in addition, a short dynamic descending dose protocol (240→120→60→60 mg/kg i.p.) is comparable in outcomes to indefinite 60 mg/kg injections. While hAAT pharmacokinetics after i.p. administration in mice resembles exogenous hAAT treatment in humans, s.c. administration better imitated the physiological progressive rise of hAAT during acute phase responses; nonetheless, only the 60 mg/kg dose depicted an advantage using the s.c. route. Taken together, this study provides a platform for extrapolating an islet-relevant clinical protocol from animal models that use hAAT to protect islets. In addition, the study places emphasis on outcome-oriented analyses of drug efficacy, particularly important when considering that hAAT is presently at an era of drug-repurposing towards an extended list of clinical indications outside genetic AATD.

  17. Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis.

    Thati, Sharadvi; Kuehl, Christopher; Hartwell, Brittany; Sestak, Joshua; Siahaan, Teruna; Forrest, M Laird; Berkland, Cory


    Soluble antigen arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared with distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation (p.i.) was included as reports suggest T cells are licensed in the lungs before moving to the CNS. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, and 10 also reduced efficacy compared with injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via p.i., however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice.

  18. Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats.

    Pelser, Andries; Müller, Douw G; du Plessis, Jeanetta; du Preez, Jan L; Goosen, Colleen


    The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.

  19. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration.

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao


    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

  20. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

    Geisler, Christian H; van T' Veer, Mars B; Jurlander, Jesper


    heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133......). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035...

  1. Pharmacokinetics of terbinafine after single oral dose administration in red-tailed hawks (Buteo jamaicensis).

    Bechert, Ursula; Christensen, J Mark; Poppenga, Robert; Fahmy, Sahar A; Redig, Patrick


    To determine pharmacokinetic parameters of orally administered terbinafine hydrochloride for potential treatment of aspergillosis in raptors, 10 adult red-tailed hawks (Buteo jamaicensis) were used in single dose trials by using 15, 30, and 60 mg/kg doses with a 2-week washout period between trials. After administration of 15 mg/kg terbinafine, mean (+/- SD) plasma concentration peaked in approximately 5 hours at 0.3 +/- 0.24 microg/mL, whereas a 30 mg/kg dose resulted in peak mean (+/- SD) plasma concentration of 1.2 +/- 0.40 microg/mL in 3 hours and a 60 mg/kg dose resulted in mean (+/- SD) concentration of 2.0 +/- 0.75 microg/mL in 5 hours. The volume of distribution decreased with increasing doses, averaging 76.8 +/- 38.06 mL/kg for the 15 mg/kg dose and falling to 55.2 +/- 17.4 mL/kg for the 30 mg/kg dose. This suggests that terbinafine accumulated in deep tissues, limiting further distribution at higher doses. The harmonic mean (+/- SD) half-life was biphasic, with initial values of 14.7 +/- 6.67 hours, 17.5 +/- 8.7 hours, and 13.3 +/- 5.03 hours for 15, 30, and 60 mg/kg doses, respectively. A rapid first-elimination phase was followed by a slower second phase, and final elimination was estimated to be 161 +/- 78.2 and 147 +/- 65.6 hours for 15 and 30 mg/kg doses, respectively. Linearity was demonstrated for the area under the curve but not for peak plasma concentrations for the 3 doses used. Calculations based on pharmacokinetic parameter values indicated that a dosage of 22 mg/kg terbinafine q24h would result in steady-state trough plasma concentrations above the minimum inhibitory concentration of terbinafine (0.8-1.6 microg/mL). This dosage is recommended as a potential treatment option for aspergillosis in raptors. However, additional research is required to determine both treatment efficacy and safety.

  2. Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration.

    Panossian, A; Wagner, H


    Plant adaptogens are compounds that increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors. The beneficial effects of multi-dose administration of adaptogens are mainly associated with the hypothalamic-pituitary-adrenal (HPA) axis, a part of the stress-system that is believed to play a primary role in the reactions of the body to repeated stress and adaptation. In contrast, the single dose application of adaptogens is important in situations that require a rapid response to tension or to a stressful situation. In this case, the effects of the adaptogens are associated with another part of the stress-system, namely, the sympatho-adrenal-system (SAS), that provides a rapid response mechanism mainly to control the acute reaction of the organism to a stressor. This review focuses primarily on the SAS-mediated stimulating effects of single doses of adaptogens derived from Rhodiola rosea, Schizandra chinensis and Eleutherococcus senticosus. The use of these drugs typically generates no side effects, unlike traditional stimulants that possess addiction, tolerance and abuse potential, produce a negative effect on sleep structure, and cause rebound hypersomnolence or 'come down' effects. Furthermore, single administration of these adaptogens effectively increases mental performance and physical working capacity in humans. R. rosea is the most active of the three plant adaptogens producing, within 30 min of administration, a stimulating effect that continues for at least 4-6 h. The active principles of the three plants that exhibit single dose stimulating effects are glycosides of phenylpropane- and phenylethane-based phenolic compounds such as salidroside, rosavin, syringin and triandrin, the latter being the most active. Copyright (c) 2005 John Wiley & Sons, Ltd.

  3. Changes in choroidal thickness after systemic administration of high-dose corticosteroids: a pilot study.

    Han, Jeong Mo; Hwang, Jeong-Min; Kim, Ji Soo; Park, Kyu Hyung; Woo, Se Joon


    To characterize the effects of corticosteroids on choroidal thickness, we measured the choroid thickness in patients treated systemically with a high-dose corticosteroid. A prospective, pilot study was conducted on 20 patients who required high-dose corticosteroid pulse therapy (>500 mg/d). Choroidal thickness was measured at baseline, 1 day, 1 week, and 1 month after corticosteroid administration. Blood pressure was measured four times a day for the first 5 days of steroid treatment. This study ultimately included 35 eyes from 18 patients. Each patient was treated with high-dose corticosteroid therapy at a concentration of 19.5 ± 4.1 mg per kg body weight for 5.2 ± 1.1 days. Mean subfoveal choroidal thickness at baseline was 259.8 μm (range, 86.4-394.7 μm). Choroidal thickness showed no significant change at 1 day, 1 week, or 1 month after corticosteroid administration (P = 0.197). Mean systolic blood pressure increased by 13 mmHg (P = 0.008), but diastolic pressure did not change (P = 0.117). One patient (5.6%) who had presented with pigment epithelial detatchment (PED) and thick choroid (381.1 μm) developed bilateral focal subretinal fluid during the study and showed central serous chorioretinopathy (CSC) with a 13.1% increase in subfoveal choroidal thickness. No consistent changes in choroidal thickness were observed after systemic high-dose corticosteroid treatment, but one patient with PED and thick choroid showed an increase in choroidal thickening as well as features of CSC. Thus, steroid-induced CSC may be an idiosyncratic response in selected vulnerable individuals rather than a dose-dependent effect.

  4. Nature of the suppressor cells mediating prolonged graft survival after administration of extracted histocompatibility antigen and cyclosporine

    Yoshimura, N.; Kahan, B.D.


    Antigen-specific suppressor T cells are induced by donor histocompatibility antigen extracted from spleen cells with 3M KCl combined with cyclosporine (Ag-CsA). A single i.v. injection of 5 mg 3M-KCl-extracted donor Buffalo (Buf, RT1b) antigen (Ag) combined with a three day course of CsA prolonged renal allograft survival in Wistar-Furth (WFu, RT1u) hosts to a greater extent (MST 26.5 days) than CsA alone (MST 11.8 days). Peripheral blood lymphocytes (PBL) or spleen cells harvested from Ag-CsA-treated recipients ten days after transplantation inhibited the mixed lymphocyte reaction (MLR) between normal responder WFu cells and irradiated Buf cells (55.6% and 64.4% suppression, respectively, P less than 0.025), but not third-party Brown-Norway (BN, RT1n) stimulator cells (13.6% and -18.3% suppression, respectively, NS). The suppressor effect was not mediated by cytolytic cells; there was neither primary nor secondary cytolytic activity against /sup 51/Cr-labeled Con-A blastoid Buf cells. The suppressor cells were neither adherent to plastic dishes nor to nylon-wool columns. PBL irradiated with 800 rads, but not 1500 rads, suppressed the MLR. A single injection of cyclophosphamide (CY, 25 mg/kg) seven days after transplantation abrogated the suppression induced by Ag-CsA treatment. Moreover, PBL from Ag-CsA recipients failed to suppress the MLR, if depleted either of all T cells by treatment with monoclonal antibody (Mab) W3/13 HLK (pan T cells; % suppression -15.8), or of cytotoxic/suppressor cells with Mab OX-8 (-19.3% suppression) together with rabbit antimouse immunoglobulin and complement.

  5. [Searching Radiation Countermeasures using the Model of Prolonged Irradiation of Mice with Low Dose Rate and Evaluation of Their Influence on Heat Shock Protein Genes Expression].

    Rozhdestvensky, L M; Mikhailov, V F; Schlyakova, T G; Shagirova, J M; Shchegoleva, R A; Raeva, N F; Lisina, N I; Shulenina, L V; Zorin, V V; Pchelka, A V; Trubitsina, K Y


    Different radiomodificators (cytokine betaleukine, antioxidant phenoxan, antigipoksant limontar and nucleoside riboxin) were investigated on mice for evaluating their radiation protective capacity against prolonged (21 h) exposure at a dose of 12.6 Gy at a low dose rate of 10 mGy/min. Bone marrow cellularity and endogenic CFUs were used as evaluation criteria 9 days after exposure. Simultaneously, expression of the heat shock proteins of 25, 70 and 90 kDa in unexposed mice bone marrow was studied 2, 24 and 48 h after injections. Betaleukine only had a positive significant effect in both tests in the variants of 50 mcg/kg and 3 mcg/kg when administered 2 h and 22 h before exposure, correspondingly. Effects of betaleukine HSPs on expression were both stimulating and inhibiting, that was in contradiction with a constant positive effect in 5 experiments on exposed mice for each betaleukine variant. It argues against the vital role of HSPs in the betaleukine antiradiation effect. In 2 experiments with high temperatures betaleukine administered at a dose of 50 mcg/kg evoked a very high HSP-70 gene expression after 24 h, and mice exposed to irradiation at that time in a parallel experiment showed an increased radiation effect. It corresponds to the idea that HSPs serve a stress indicator.

  6. Pregnancy outcomes following the administration of high doses of dexamethasone in early pregnancy.

    Namdar Ahmadabad, Hasan; Kayvan Jafari, Sabah; Nezafat Firizi, Maryam; Abbaspour, Ali Reza; Ghafoori Gharib, Fahime; Ghobadi, Yusef; Gholizadeh, Samira


    In the present study, we aimed to evaluate the effects of high doses of dexamethasone (DEX) in early pregnancy on pregnancy outcomes. Pregnant BALB/c mice were treated with high-dose DEX in the experimental group or saline in the control group on gestational days (GDs) 0.5 to 4.5. Pregnant mice were sacrificed on GDs 7.5, 13.5, or 18.5 and their peripheral blood, placentas, fetuses, and uterine tissue were collected. Decidual and placenta cell supernatants were examined to evaluate the effect of DEX on the proliferation of mononuclear cells, the quantity of uterine macrophages and uterine natural killer (uNK) cells, and levels of progesterone and 17β-estradiol, as determined by an 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. We also were measured fetal and placental growth parameters on GD 18.5. We found that high doses of DEX were associated with an increased abortion rate, enhancement of the immunosuppressive effect of the decidua, alterations in placental growth parameters, decreased progesterone and 17β-estradiol levels, and a reduced frequency of macrophages and uNK cells. Our data suggest that the high-dose administration of DEX during early pregnancy negatively affected pregnancy outcomes.

  7. Pharmacokinetic interaction between amprenavir and delavirdine after multiple-dose administration in healthy volunteers

    Justesen, Ulrik S; Klitgaard, Niels A; Brosen, Kim


    AIMS: To evaluate the safety and the pharmacokinetic interaction between amprenavir and delavirdine after multiple dose administration in healthy volunteers. METHODS: This was a prospective, open-label, randomized, controlled, two-sequence, two-period multiple dose study with 18 healthy subjects....... Volunteers were randomly assigned to amprenavir, 600 mg twice a day, or delavirdine, 600 mg twice a day, for 10 days, followed by both drugs for another 10 days with pharmacokinetic evaluation on day 10 and day 20. Adverse events were recorded throughout the study. RESULTS: Amprenavir decreased all...... the delavirdine pharmacokinetic parameters apart from tmax. Delavirdine C12h dropped from 7,916 to 933 ng ml-1 (median decrease 5,930 ng ml-1, 95% CI 3,013, 8,955 ng ml-1). A decrease in amprenavir t(1/2) was also seen leading to almost identical median amprenavir C24h values. No serious clinical adverse events...

  8. Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose.

    Garcia-Montijano, Marino; Waxman, Samanta; de Lucas, J Julio; Luaces, I; de San Andrés, María Dolores; Rodríguez, Casilda


    The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51±0.22L and total plasma clearance (Cl) of 0.109±0.023L/hkg. The permanence of this drug was long in vultures (T(1/2)(λ)=12.51±2.52h; MRT(∞)=13.54±2.29h). The optimal dose of marbofloxacin estimated is 2.73mg/kg per day for the treatment of infections in vultures with MIC(90)=0.2μg/mL.

  9. Short term cadmium administration dose dependently elicits immediate biochemical, neurochemical and neurobehavioral dysfunction in male rats.

    Haider, Saida; Anis, Lubna; Batool, Zehra; Sajid, Irfan; Naqvi, Fizza; Khaliq, Saima; Ahmed, Shoaib


    Cadmium is a toxic environmental and industrial pollutant. Cadmium toxicity has been reported to produce biochemical and behavioral dysfunction that may cause adverse effects on several organs including the central nervous system. The present study was designed to investigate the neurotoxic effects of Cadmium Chloride (CdCl2) at three different doses by using different behavioral models. Lipid peroxidation (LPO), superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities were also monitored following acute intraperitoneal injection of cadmium. Twenty four adult locally bred Albino Wistar rats were divided into control and 3 test groups (n = 6). Control rats were injected intraperitoneally with saline (0.9% NaCl) and test groups were injected with CdCl2 (1 mg/kg, 2 mg/kg and 3 mg/kg) dissolved in physiological solution. Behavioral activities of rats were monitored after 1 h of cadmium injection. Locomotor activity and depression-like symptoms were measured by Open Field Test (OFT) and Forced Swimming Test (FST) respectively. Anxiety like behavior was monitored using Light-dark Transition (LDT) test and memory functions of rats were assessed by Morris Water Maze test (MWM). In the present study acute cadmium administration dose dependently increased anxiety in rats as compared to control rats. A significant increase in depression-like symptoms was also exhibited by cadmium treated rats. These behavioral dysfunctions may be attributed to the decreased superoxide dismutase (SOD) activity and simultaneously increased brain lipid peroxidation (LPO). Moreover learning and memory assessed by MWM showed dose dependent impairment in memory function in cadmium treated rats as compared to control rats. Acetylcholinesterase (AChE) activity was also decreased in brains of cadmium administered rats. It is suggested in this study that behavioral, biochemical and neurochemical dysfunctions caused by acute cadmium administration occur in a dose dependent manner.

  10. Micro-dose hCG as luteal phase support without exogenous progesterone administration

    Andersen, C Yding; Fischer, R; Giorgione, V;


    For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the Gn......RHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple...... corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential...

  11. Estimation of ambient dose equivalent distribution in the (18)F-FDG administration room using Monte Carlo simulation.

    Nagamine, Shuji; Fujibuchi, Toshioh; Umezu, Yoshiyuki; Himuro, Kazuhiko; Awamoto, Shinichi; Tsutsui, Yuji; Nakamura, Yasuhiko


    In this study, we estimated the ambient dose equivalent rate (hereafter "dose rate") in the fluoro-2-deoxy-D-glucose (FDG) administration room in our hospital using Monte Carlo simulations, and examined the appropriate medical-personnel locations and a shielding method to reduce the dose rate during FDG injection using a lead glass shield. The line source was assumed to be the FDG feed tube and the patient a cube source. The dose rate distribution was calculated with a composite source that combines the line and cube sources. The dose rate distribution was also calculated when a lead glass shield was placed in the rear section of the lead-acrylic shield. The dose rate behind the automatic administration device decreased by 87 % with respect to that behind the lead-acrylic shield. Upon positioning a 2.8-cm-thick lead glass shield, the dose rate behind the lead-acrylic shield decreased by 67 %.

  12. Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.

    Gáll, Zsolt; Vancea, Szende; Szilágyi, Tibor; Gáll, Orsolya; Kolcsár, Melinda


    Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 μg/ml and 3.188 ± 0.71 μg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio.

  13. Prolonged perturbation of the oscillations of hepatoma Fao cell proliferation by a single small dose of methotrexate.

    Guerroui, S; Deschatrette, J; Wolfrom, C


    The proliferation rate of various cell types in vitro, including hepatoma Fao cells, displays aperiodic oscillations. The frequency of these oscillations is about one every 3-5 weeks, and there are variations in cell functions and polarity. Topological analysis has showed that these oscillations in growth rate are determined, and presumably chaotic. One characteristic of complex chaotic systems is that their dynamics can be persistently modified by a small external perturbation. We show that treatment with a single small dose of the anticancer drug methotrexate causes long-term stable alteration of the oscillatory dynamics of Fao cell proliferation. The oscillations of growth rate are shifted, and their mean level decreased according to a fractal pattern.

  14. Dose-dependent effects of intravenous alcohol administration on cerebral blood flow in young adults.

    Strang, Nicole M; Claus, Eric D; Ramchandani, Vijay A; Graff-Guerrero, Ariel; Boileau, Isabelle; Hendershot, Christian S


    Functional magnetic resonance imaging (fMRI) studies involving alcohol challenge are important for identifying neural correlates of alcohol's psychopharmacological effects. However, evaluating acute alcohol effects on blood oxygen level-dependent (BOLD) signal change is complicated by alcohol-related increases in cerebral blood flow (CBF). The present study aimed to further characterize acute alcohol effects on CBF using intravenous alcohol administration to maximize control over brain alcohol exposure. Twenty heavy-drinking young adults (M = 19.95 years old, SD = 0.76) completed alcohol and placebo imaging sessions in a within-subject, counter-balanced, placebo-controlled design. Arterial spin labeling (ASL) provided estimates of perfusion change at two target blood alcohol concentrations (40 and 80 mg%) relative to baseline and relative to a saline control infusion. Voxel-wise analyses showed widespread and dose-dependent effects of alcohol on CBF increase. Region-of-interest analyses confirmed these findings, also indicating regional variation in the magnitude of perfusion change. Additional findings indicated that lower self-reported sensitivity to alcohol corresponded with reduced perfusion change during alcohol administration. This study provides further evidence for widespread effects of acute alcohol on cerebral perfusion, also demonstrating regional, dose-dependent, and inter-individual variation. Further research is needed to evaluate implications of these effects for the design and interpretation of pharmacological fMRI studies involving alcohol challenge.

  15. Single dose of inducible nitric oxide synthase inhibitor induces prolonged inflammatory cell accumulation and fibrosis around injured tendon and synovium

    Homa Darmani


    Full Text Available THE aim of the current study was to investigate the effect of inhibition of nitric oxide (NO production after injury on inflammatory cell accumulation and fibrosis around digital flexor tendon and synovium. A standard crush injury was applied to the flexor tendons of the middle digit of the hindpaw and the overlying muscle and synovium of female Wistar rats. Thirty animals received an intraperitoneal injection of either isotonic saline or N(G-nitro-l-arginine methyl ester (L-NAME; 5 mg/kg immediately following the crush injury, and five animals were then sacrificed at various intervals and the paws processed for histology. Another group of five animals was sacrificed after 3 days for nitrite determinations. The results showed that nitrite production and hence NO synthase activity is doubled at the acute phase of tendon wound healing, and we can prevent this by administering a single dose of L-NAME immediately after injury. The incidence and severity of fibrocellular adhesions between tendon and synovium was much more marked in animals treated with L-NAME. Treatment with L-NAME elicited a chronic inflammatory response characterised by a persistent and extraordinarily severe accumulation of large numbers of inflammatory cells in the subcutaneous tissues, in muscle and in tendon. These findings indicate that in the case of injured tendon and synovium, NO could act to protect the healing tissue from an uncontrolled inflammatory response.

  16. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration.

    Bianco, A W; Constable, P D; Cooper, B R; Taylor, S D


    Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses.

  17. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan


    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  18. Prolonged high-dose intravenous magnesium therapy for severe tetanus in the intensive care unit: a case series

    Fligou Fotini


    Full Text Available Abstract Introduction Tetanus rarely occurs in developed countries, but it can result in fatal complications including respiratory failure due to generalized muscle spasms. Magnesium infusion has been used to treat spasticity in tetanus, and its effectiveness is supported by several case reports and a recent randomized controlled trial. Case presentations Three Caucasian Greek men aged 30, 50 and 77 years old were diagnosed with tetanus and admitted to a general 12-bed intensive care unit in 2006 and 2007 for respiratory failure due to generalized spasticity. Intensive care unit treatment included antibiotics, hydration, enteral nutrition, early tracheostomy and mechanical ventilation. Intravenous magnesium therapy controlled spasticity without the need for additional muscle relaxants. Their medications were continued for up to 26 days, and adjusted as needed to control spasticity. Plasma magnesium levels, which were measured twice a day, remained in the 3 to 4.5 mmol/L range. We did not observe hemodynamic instability, arrhythmias or other complications related to magnesium therapy in these patients. All patients improved, came off mechanical ventilation, and were discharged from the intensive care unit in a stable condition. Conclusion In comparison with previous reports, our case series contributes the following meaningful additional information: intravenous magnesium therapy was used on patients already requiring mechanical ventilation and remained effective for up to 26 days (significantly longer than in previous reports without significant toxicity in two patients. The overall outcome was good in all our patients. However, the optimal dose, optimal duration and maximum safe duration of intravenous magnesium therapy are unknown. Therefore, until more data on the safety and efficacy of magnesium therapy are available, its use should be limited to carefully selected tetanus cases.

  19. Evaluation of risk of nephrotoxicity with high dose, extended-interval colistin administration

    Arun Dewan


    Full Text Available Aim: The aim was to evaluate the risk of nephrotoxicity with high-dose, extended-interval regimen of colistin administration in critical ill patients. Materials and Methods: This prospective study was conducted on patients suffering from sepsis due to Gram-negative infection susceptible only to colistin. The dosing schedule for colistin was 9 million units stat followed by 4.5 million units at 12 hourly interval (adjusted as per body weight and renal functions. The serum creatinine and creatinine clearance were estimated at the start of therapy and daily during therapy. Results: Thirty-one patients suffering ventilator associated pneumonia (61.29%, blood stream infections (29.03% and urinary tract infections (9.67% due to Gram-negative multiple drug resistance organisms were assessed. Most commonly isolated organism were Acinetobacter baumannii (54.83%, Klebsiella pneumonia (16.12% and Pseudomonas (29.03%. Five patients (16.12% developed acute kidney injury within 4-5 days of start of therapy and returned to baseline after 6 days with no patient requiring renal replacement therapy or discontinuation of colistin. Conclusion: Our study showed that high-dose, extended-interval colistin can be given to critically ill patients without any significant risk of nephrotoxicity.

  20. Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF

    Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of,factors. Many parameters, such as dose, mode of administration,

  1. Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF


    Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of,factors. Many parameters, such as dose, mode of administration, do

  2. Chemoradiotherapy with twice-weekly administration of low-dose gemcitabine for locally advanced pancreatic cancer

    Hisato Igarashi; Tetsuhide Ito; Ken Kawabe; Terumasa Hisano; Yoshiyuki Arita; Toyoma Kaku; Ryoichi Takayanagi


    AIM:To evaluate the chemoradiotherapy for locally advanced pancreatic cancer utilizing low dose gemcitabine as a radiation sensitizer administered twice weekly.METHODS:We performed a retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2.After that,maintenance systemic chemotherapy with gemcitabine,at a dose of 1000 mg/m2,was administered weekly for 3 wk with 1-wk rest until disease progression or unacceptable toxicity developed.RESULTS:Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled.Three of those patients could not continue with the therapy;one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis during an early stage of the therapy.The median survival was 15.0 mo and the overall 1-year survival rate was 60%,while the median progression-free survival was 8.0 too.The subgroup which showed the reduction of tumor development,more than 50% showed a tendency for a better prognosis;however,other parameters including age,gender and performance status did not correlate with survival.The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 mo and 27.7 mo,respectively.CONCLUSION:Chemoradiotherapy with low-dose gemcitabine administered twice weekly could be effective to patients with locally advanced pancreatic cancer;however,patients developing liver metastases had a worse prognosis.Another chemoradiotherapy strategy might be needed for those patients,such as administrating one or two cycles of chemotherapy initially,followed by chemoradiotherapy for the cases with no distant metastases.

  3. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area.

    Alvaro eGarcía-Aviles


    Full Text Available Methylphenidate (MPD is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD. Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if methylphenidate administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered methylphenidate doses (1.3; 2.7 and 5mg/Kg to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3mg/Kg methylphenidate; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum, an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the medial septum the sparse tyrosine hydroxylase fibres did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons.


    Sander, Samantha J; Siegal-Willott, Jessica L; Ziegler, Jessie; Lee, Elizabeth; Tell, Lisa; Murray, Suzan


    Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ± 2.59 μg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr × μg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ± 0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ± 0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 μg/ml for 8 hr and above 2 μg/ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen.

  5. Determining optimal dosing regimen of oral administration of dicloxacillin using Monte Carlo simulation

    Yu W


    Full Text Available Wei Yu,1,2,* Jinru Ji,1,* Tingting Xiao,1 Chaoqun Ying,1 Jiaheng Fang,3 Ping Shen,1 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, 3Department of Gastroenterology, Hang Zhou Normal University Affiliated Hospital, Hangzhou, People’s Republic of China *These authors contributed equally to this work Background: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. Materials and methods: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People’s Republic of China. The minimum inhibitory concentration (MIC values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd, 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h, and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR was calculated to evaluate the efficacy of these regimens. Results: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Resistance to dicloxacillin was observed in 7.5% of coagulase

  6. Estimated radiation dose to breast feeding infant following maternal administration of 57Co labelled to vitamin B12.

    Pomeroy, Kay M; Sawyer, Laura J; Evans, Martyn J


    Administration of a radiopharmaceutical may result in a radiation dose to an infant due to ingestion of the radiopharmaceutical secreted in the breast milk. Following a maternal administration of Co labelled to vitamin B12 (cyanocobalamin) as part of a Schilling test an estimate of the absorbed dose to a breast feeding infant was calculated. Milk samples were collected from every feed in the first 24 h, and at approximately 48 and 72 h post-administration. The absorbed dose to the infant's liver (the organ receiving the highest dose) was calculated to be 0.23 mGy. The effective dose to the infant was calculated to be 0.025 mSv, which is considerably lower than the current regulatory limit of 1 mSv. The Administration of Radioactive Substances Advisory Committee advise that the first feed, at approximately 4 h after administration, be discarded. The data show that this was unwarranted, and that the peak concentration of Co in the breast milk occurred at around 24 h.

  7. An In Vivo Study of Low-Dose Intra-Articular Tranexamic Acid Application with Prolonged Clamping Drain Method in Total Knee Replacement: Clinical Efficacy and Safety

    Paphon Sa-ngasoongsong


    Full Text Available Background. Recently, combined intra-articular tranexamic acid (IA-TXA injection with clamping drain method showed efficacy for blood loss and transfusion reduction in total knee replacement (TKR. However, until now, none of previous studies revealed the effect of this technique on pharmacokinetics, coagulation, and fibrinolysis. Materials and Methods. An experimental study was conducted, during 2011-2012, in 30 patients undergoing unilateral TKR. Patients received IA-TXA application and then were allocated into six groups regarding clamping drain duration (2-, 4-, 6-, 8-, 10-, and 12-hours. Blood and drainage fluid were collected to measure tranexamic acid (TXA level and related coagulation and fibrinolytic markers. Postoperative complication was followed for one year. Results. There was no significant difference of serum TXA level at 2 hour and 24 hour among groups (p<0.05. Serum TXA level at time of clamp release was significantly different among groups with the highest level at 2 hour (p<0.0001. There was no significant difference of TXA level in drainage fluid, postoperative blood loss, blood transfusion, and postoperative complications (p<0.05.  Conclusions. Low-dose IA-TXA application in TKR with prolonged clamping drain method is a safe and effective blood conservative technique with only minimal systemic absorption and without significant increase in systemic absorption over time.

  8. Prolonged in vivo administration of testosterone-enanthate, the widely used and abused anabolic androgenic steroid, disturbs prolactin and cAMP signaling in Leydig cells of adult rats.

    Bjelic, Maja M; Stojkov, Natasa J; Radovic, Sava M; Baburski, Aleksandar Z; Janjic, Marija M; Kostic, Tatjana S; Andric, Silvana A


    This study was designed to systematically analyze and define the effects of 1-day, 2-weeks, 10-weeks intramuscular administration of testosterone-enanthate, widely used and abused anabolic androgenic steroid (AAS), on main regulators of steroidogenesis and steroidogenic genes expression in testosterone-producing Leydig cells of adult rats. The results showed that prolonged (10-weeks) intramuscular administration of testosterone-enanthate, in clinically relevant dose, significantly increased prolactin, but decreased Prlr2 and Gnrhr in pituitary of adult rat. The levels of testosterone, Insl3, cAMP and mitochondrial membrane potential of Leydig cells were significantly reduced. This was followed by decreased expression of some steroidogenic enzymes and regulatory proteins such as Lhcgr, Prlr1/2, Tspo, Star, Cyp11a1, Cyp17a1, Dax1. Oppositely, Hsd3b1/2, Hsd3b5, Hsd17b4, Ar, Arr19 increased. In the same cells, transcriptional milieu of cAMP signaling elements was disturbed with remarkable up-regulation of PRKA (the main regulator of steroidogenesis). Increased prolactin together with stimulated transcription of Jak2/Jak3 could account for increased Hsd3b1/2 and Hsd3b5 in Leydig cells following 10-weeks in vivo treatment with testosterone-enanthate. In vitro studies revealed that testosterone is capable to increase level of Prlr1, Prlr2, Hsd3b1/2, Hsd3b5 in Leydig cells. Accordingly, testosterone-induced changes in prolactin receptor signaling together with up-regulation of PRKA, Hsd3b1/2, Hsd3b5, Ar in Leydig cells, could be the possible mechanism that contribute to the establishment of a new adaptive response to maintain homeostasis and prevent loss of steroidogenic function. Presented data provide new molecular insights into the relationship between disturbed testosterone homeostasis and mammalian reproduction and are important in terms of wide use and abuse of AASs and human reproductive health.

  9. Potential detection of low-dose transdermal testosterone administration in blood, urine, and saliva.

    Schönfelder, M; Hofmann, H; Schulz, T; Engl, T; Kemper, D; Mayr, B; Rautenberg, C; Oberhoffer, R; Thieme, D


    Administration of low amounts of endogenous hormones - so-called micro-dosages - are supposed to represent a major challenge in doping analysis. To model such a situation, we have studied transdermal administrations of 2.4 mg/24 h testosterone patches and examined various steroid concentrations in blood, urine, and saliva of 11 volunteers. Multiple samples were collected at t = 0, 3, 6, 9, 24, 48, and 72 h in four different phases, i.e., all combinations with/without physical exercise and with/without testosterone. Testosterone was analyzed by enzyme-linked-immuno-assay as well as by mass spectrometry and validated in an accredited anti-doping laboratory. Circadian controls with and without exercise did not provoke prominent alterations of whole, free, and salivary testosterone. Testosterone application for 24 h led to a significant (all p  0.538, all p saliva after 9 h. After removal of the testosterone patch, all testosterone levels in blood, saliva, and urine returned to baseline within 24 h. Different techniques of hormone detection (enzyme-linked immunosorbent assay (ELISA), gas chromatography-tandem mass spectrometry (GC-MS/MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS)) indicated significant correlations. Results indicate that saliva, blood, and urine exhibit comparable hormone augmentation during micro-dose testosterone application, indicating a possible consideration in future doping analysis. The inter-individual variability was high in all biofluids, requiring the use of an individual biological passport rather than statistical values. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Marbofloxacin disposition after intravenous administration of a single dose in wild mallard ducks (Anas platyrhynchos).

    Garcia-Montijano, Marino; de Lucas, J Julio; Rodríguez, Casilda; González, Fernando; San Andrés, Manuel Ignacio; Waxman, Samanta


    Marbofloxacin, a fluoroquinolone developed specifically for veterinary use, has demonstrated considerable pharmokinetic variation among avian species. The goal of this study was to determine the disposition kinetics of marbofloxacin in mallard ducks (Anas platyrhynchos) after a single intravenous injection. Six wild mallard ducks were used in the study. Marbofloxacin was injected at a dose of 2 mg/kg into the basilic vein, and blood was subsequently collected at regular intervals from each bird. Plasma marbofloxacin concentrations were determined by using high-performance liquid chromatography. The volume of distribution at steady state was 1.78 +/- 0.37 L/kg, and the total plasma clearance was 0.59 +/- 0.08 L/kg per hour. Marbofloxacin had a relatively short permanence, with a elimination half-life of 2.81 +/- 1.20 hours, a terminal half-life of 2.43 +/- 0.61 hours, and a mean residence time of 2.99 +/- 0.52 hour. The maximum observed concentration (Cmax) and area under the curve (AUC) were 1.34 +/- 0.27 microg/mL and 3.75 +/- 0.56 microg x h/mL, respectively. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax: MIC value of 10 and an AUC: MIC ratio of 125-250 associated with optimal bactericidal effects. By using the study data and MIC breakpoints of 0.125 microg/mL or 0.2 microg/mL, values derived for Cmax: MIC were 9.37 +/- 0.99 and 5.85 +/- 0.62, respectively, and for AUC: MIC were 29.99 +/- 4.51 and 18.74 +/- 2.82, respectively. By using MIC values of 0.125 and 0.2 microg/mL and a target AUC: MIC = 125, the calculated optimal daily marbofloxacin dosages for mallard ducks were 9.24 and 14.78 mg/kg, respectively. These results suggest that, primarily because of the high total plasma clearance observed, the marbofloxacin dose for treatment of bacterial diseases in mallard ducks should be increased after intravenous administration. Intravenous doses

  11. Characteristics of changes in the number of yH2AX and Rad51 protein foci in human skin fibroblasts after prolonged exposure to low-dose rate X-ray radiation

    Ozerov I.V.


    Full Text Available Aim: to compare the repair process of DNA double-strand breaks in mammalian cells after acute versus prolonged exposure to X-ray irradiation with different dose rates. Material and methods. Studies were performed on primary human fibroblasts isolated from skin biopsies of healthy volunteers (women, 29 and 30 years. Cells were irradiated using an X-ray machine RUB RUST-M1 (JSC "Ruselectronics", Moscow, Russia at 37°C temperature with a dose rate of 400 mGy/min (200 kV, 2*2.4 mA, a filter of 1.5mm AI or 4 mGy/min (50 kV, 2*0.4 mA, a filter of 1.5 mm AI. Immuno-cytochemical protein staining was utilized for yH2AX and Rad51 foci analysis. Results. Phosphorylated histone H2AX (yH2AX and the key protein of homologous recombination Rad51 foci formation and disappearance kinetics were investigated simultaneously in primary human dermal fibroblasts after acute and prolonged exposure to X-ray radiation at a same dose. It was shown that the relative yield of yH2AX foci per dose reduces with decrease in dose rate, while the relative yield of Rad51 foci conversely increases. Conclusion. Our findings suggest the fundamental differences in the ratio of non-homologous end joining and homologous recombination DNA repair in acute versus prolonged irradiated cells.

  12. Inhibition of human lung adenocarcinoma growth using survivint34a by low-dose systematic administration

    Yan Shan; Chunting Wang; Li Yang; Li Juan Chen; Hong Xin Deng; Han Shuo Yang; Zhimian Li; Zhiyong Li; Li Pan; Fei Leng; Yuquan Wei


    Anti-apoptosis plays an important role in tumour formation and development. Survivin is a member of the inhibitor of apoptosis (IAP) family, which is a target for anti-cancer drug exploitation was replaced as development. We investigated the role of the homo dominant-negative mutant Survivin-T34A in suppressing human lung adenocarcinomas (A549). The anti-tumour activity of HSurvivinT34A plasmid was evaluated in the A549 cell line and nude mice bearing A549 subcutaneous tumours. Low-dose systemic administration was continuously used. The HSurvivinT34A plasmid (5 g/one) complexed with a cationic liposome (DOTAP/Chol) significantly inhibited tumour growth in our model. We observed microvessel density degradation by CD31 immunohistochemistry and apoptotic cell increase by TUNEL assay, PI staining and flow cytometric analysis in the treated group. The present findings suggest that the HSurvivinT34A plasmid complexed with a cationic liposome may provide an effective approach to inhibit the growth of human lung adenocarcinomas in vitro and in vivo.

  13. Population pharmacokinetics of a single dose of meloxicam after oral and intramuscular administration to captive lesser flamingos (Phoeniconaias minor).

    Zordan, Martín A; Papich, Mark G; Pich, Ashley A; Unger, Katy M; Sánchez, Carlos R


    OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach. ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age. PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography. RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours. CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

  14. Acute administration of high dose trimetazidine inhibits pentylenetetrazol-induced seizures in rats

    Serkan GURGUL


    Full Text Available Objective: Resistant epilepsy is widely seen in clinical settings manipulate the researchers to pursuit novel anti-epileptic treatments. Although trimetazidine (TMZ is commonly used in the treatment of angina and ischemic diseases, it is considered that the drug may be beneficial in the treatment of epileptic seizures and convulsions. We aimed to evaluate electrophysiologically the protective effects of high dose acute TMZ on epileptic seizures and convulsions in a rat model of epilepsy induced by pentilentetrazol (PTZ. Method: Forty-eight male Sprague-Dawley rats were used for the EEG evaluation (Group-A; n=24 and behavioral assessment (Group-B; n=24. Grup-A1 and Grup-B1 were determined as control group and given no medication. 35 mg/kg (Group-A2, -A3 and -A4 and 70 mg/kg (Group-B2, -B3 and -B4 of PTZ were administered intraperitoneally (ip. so as to generate seizures and convulsions. Group-A2 and Group-B2 were treated with saline. 40 mg/kg (Grup-A3 and Grup-B3 and 80 mg/kg of TMZ (Group-A4 and Group-B4 were administered to the treatment groups by ip. Brain malondialdehyde (MDA levels, spike-percentage values, Racine’s Convulsion Scale (RCS scores and "first myoclonic jerk (FMJ" latencies of each rat were determined. Results: Brain MDA levels, spike-percentage values, RCS scores, and FMJ latencies of Group-A2 and Group-B2 were significantly increased compared to those of the control’s (Grup-A1 and Grup-B1 (P<0.05 for all comparisons. However, in TMZ treated groups (Group-A3 and -A4; Group-B3 and -B4 the elevated values of these parameters were found to be significantly decreased (P<0.05 for all comparisons. Conclusions: This study has demonstrated that the high dose acute TMZ administration may prevent PTZ-induced seizures and convulsions in rats. Furthermore, it can be also said that TMZ has a neuroprotective effects on oxidative stress associated with PTZ. Therefore, it may be considered for use with therapeutic purposes of TMZ in

  15. A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration

    Koshi Hashimoto


    Full Text Available Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT and destructive thyroiditis (type 2 AIT. We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone, the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.

  16. Administration of a luteolytic dose of PGF2α at the time of AI

    G. Neglia


    Full Text Available The aim of this study was to verify if the administration of a luteolytic dose of PGF2α at the time of AI is able to anticipate ovulation and, hence, to increase fertility rate. Furthermore, the presence of a “farm effect” was also evaluated. The trial was performed in two commercial farms (A and B located in Caserta on 584 buffaloes (Farm A: n=389; Farm B: n=195, synchronized by the Ovsynch-TAI Program. In each farm buffaloes were divided in two groups: treated group (n=181 and n=95, respectively in farms A and B received an intramuscular injection of 0.524 mg cloprostenol (Estrumate®, Schering-Plough Animal health, S.p.A., Milan, Italy at the time of AI while control group (n=208 and n=100 received an intramuscular injection of physiologic saline (0.9% NaCl. No differences were present with regard to the number of AI/subject, in terms of pregnancy rate and ovulation rate between treated and control groups. It is worth pointing out that the control group in farm A showed a higher (P<0.01 conception rate compared to the control group in farm B (46.15 vs. 30.00. Furthermore, within farm B buffaloes treated by cloprostenol on the day of AI showed higher (P<0.01 pregnancy rate vs. animals that received saline (51.58% vs. 30.00%. These results suggest that if fertility in control group is high, treatment by cloprostenol does not affect pregnancy rate and ovulation rate.

  17. The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

    Rumpler, M J; Colahan, P; Sams, R A


    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. © 2013 John Wiley & Sons Ltd.

  18. Administration

    Bogen handler om den praksis, vi kalder administration. Vi er i den offentlige sektor i Danmark hos kontorfolkene med deres sagsmapper, computere, telefoner,, lovsamlinger,, retningslinier og regneark. I bogen udfoldes en mangfoldighed af konkrete historier om det administrative arbejde fra...... forskellige områder i den offentlige sektor. Hensigten er at forstå den praksis og faglighed der knytter sig til det administrative arbejde...

  19. Low-dose oral prolonged-release oxycodone/naloxone for chronic pain in elderly patients with cognitive impairment: an efficacy–tolerability pilot study

    Petrò, Emiliano; Ruffini, Elena; Cappuccio, Melania; Guerini, Valeria; Belotti, Gloria; Fascendini, Sara; Licini, Cristina; Marcassa, Claudio


    Objective This pilot study evaluated the efficacy and safety of prolonged-release oxycodone/naloxone (OXN-PR) in older subjects with chronic pain and mild-to-moderate cognitive impairment. Methods This was a prospective, observational, open-label study of 45-day duration. Patients with moderate-to-severe chronic pain and naïve to strong opioids were recruited from nursing homes and Alzheimer’s disease centers. OXN-PR was initiated at low doses (5 mg od or bid) and increased to a maximum of 20 mg bid. The primary efficacy endpoint was a pain intensity reduction of ≥30% from baseline (T0) to 15 days after OXN-PR initiation, as assessed by a numerical rating scale or the Pain Assessment in Advanced Dementia scale. Other assessments included the Barthel activities of daily living index, Neuropsychiatric Inventory, Bowel Function Index, and adverse events. Results The analysis included 53 patients (mean age, 83.0 years; mean Mini-Mental State Examination score, 18.6) with severe pain (median Numerical Rating Scale/Pain Assessment in Advanced Dementia 6) and substantial impairment in daily functioning (mean Barthel index, 32.2). The primary endpoint was achieved by 92.4% of patients. OXN-PR significantly reduced mean pain intensity from baseline to study end (numerical rating scale, 6.6±1.0 vs 2.3±1.1, P<0.0001; Pain Assessment in Advanced Dementia, 6.9±1.6 vs 0.9±0.8, P<0.0001). Substantial improvements from T0 to T45 in daily functioning (mean Barthel index, 32.2±16.8 vs 53.7±23.9, P<0.0001) and neuropsychiatric symptoms (mean Neuropsychiatric Inventory, 25.5±27.3 vs 8.8±9.0, P<0.0001) were also reported. OXN-PR was well tolerated and did not worsen bowel function. Conclusion In this pilot study, OXN-PR was effective in improving pain and other symptoms associated with dementia, with a favorable safety and tolerability profile. Large-scale trials in people with dementia are needed to improve clinical guidance for the assessment and treatment of pain in

  20. The effective dose and pattern of soybean extract administration to regulate body weight of laboratory rats

    Meilinah Hidayat


    the intake of protein and suppress appetite for short-term. Detam 1 variety is a high-quality soybean according to the Minister of Agriculture of Indonesia. Soybean protein extract Detam 1 by Deak method contains high levels of β conglycinin. The purpose of this study was to determine the effective dose of protein extract Detam 1 soybean Deak Method (PEDSDM in reducing food intake, regulate body weight, and plasma CCK level for 14 and 28 days at various dosage and pattern of treatment on male Wistar rats. Methods: There were eleven groups of treatment (n = 3, administrated with extracts at 5 mg/1x/day, 10 mg/1x/day, 20 mg/1x/day, 2.5 mg/2x/day, 5 mg/2x/day, 10 mg/2x/day and 1.7mg/3x/day, 3.4mg/3x/day, 6.7 mg/3x/day, negative control group (distilled water and positive control group (Sibutramine. Food intake (g, weight loss (g and measurement of plasma Cholecystokinin levels by ELISA (ng /ml Results: The results showed that the highest percentage decrease in food intake is: group 3.4mg /3x/ day (p <0.05, inhibition weight gain for 14 days: group 10 mg /1x/ day, for 28 days: group 1.7 mg/3x/day (p <0.05, increased plasma Cholecystokinin levels: group 20 mg /1x/day (p <0.05. Conclusions: The effective dose and pattern administrating the rats for 14 days is extract of 10 mg once a day in the morning, for 28 days is 1.7 mg three times a day. (Health Science Journal of Indonesia 2016;7:17-26 Keywords: Soybean var Detam 1 -effective dose - body weight - Cholecystokinin 

  1. Prolonged use of the etonogestrel implant and levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration-approved duration.

    McNicholas, Colleen; Swor, Erin; Wan, Leping; Peipert, Jeffrey F


    The subdermal contraceptive implant and the 52-mg levonorgestrel intrauterine device are currently Food and Drug Administration approved for 3 and 5 years of use, respectively. Limited available data suggested both of these methods are effective beyond that time. Demonstration of prolonged effectiveness will improve the cost-effectiveness of the device, and potentially patient continuation and satisfaction. We sought to evaluate the effectiveness of the contraceptive implant and the 52-mg hormonal intrauterine device in women using the method for 2 years beyond the current Food and Drug Administration-approved duration. We initiated this ongoing prospective cohort study in January 2012. We are enrolling women using the contraceptive implant or 52-mg levonorgestrel intrauterine device for a minimum of 3 and 5 years, respectively (started intrauterine device in ≥2007 or implant in ≥2009). Demographic and reproductive health histories, as well as objective body mass index, were collected. Implant users were offered periodic venipuncture for analysis of serum etonogestrel levels. The primary outcome, unintended pregnancy rate, was calculated per 100 woman-years. We analyzed baseline demographic characteristics using χ(2) test and Fisher exact test, and compared serum etonogestrel levels stratified by body mass index using the Kruskal-Wallis test. Implant users (n = 291) have contributed 444.0 woman-years of follow-up. There have been no documented pregnancies in implant users during the 2 years of postexpiration follow-up. Calculated failure rates in the fourth and fifth years for the implant are calculated as 0 (1-sided 97.5% confidence interval, 0-1.48) per 100 woman-years at 4 years and 0 (1-sided 97.5% confidence interval, 0-2.65) per 100 woman-years at 5 years. Among 496 levonorgestrel intrauterine device users, 696.9 woman-years of follow-up have been completed. Two pregnancies have been reported. The failure rate in the sixth year of use of the

  2. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie; Kreilgaard, Mads; Lund, Trine Meldgaard


    Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

  3. Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling of the dose and administration routes.

    Tornero Molina, Jesús; Ballina García, Francisco Javier; Calvo Alén, Jaime; Caracuel Ruiz, Miguel Ángel; Carbonell Abelló, Jordi; López Meseguer, Antonio; Moreno Muelas, José Vicente; Pérez Sandoval, Trinidad; Quijada Carrera, Jesús; Trenor Larraz, Pilar; Zea Mendoza, Antonio


    To describe the optimal therapeutic strategy for use of methotrexate in RA patients over the initial dose, route of administration, dose increase and decrease, patient monitoring, and use of folic/folinic acid. Eleven clinical experts proposed some questions to be solved. A systematic literature search was conducted. The contents were selected in a work session and subsequently validated via email to establish the level of agreement. The initial dose of methotrexate should not be 20mg/week), patient preference, very active disease or to avoid administration errors. Changing to a parenteral administration is proposed when the oral route is not effective enough, gastrointestinal toxicity appears, there is non-compliance or due to cost-effectiveness reasons before using more expensive drugs. On the contrary, due to patient preferences, intolerance to injections, dose reduction <7.5mg/week, non effectiveness of the route, poor compliance or gastrointestinal side effects. There should be a rapid dose escalation if inadequate responses occurr up to 15-20 or even 25mg/week in about 8 weeks, with increments of 2.5-5mg. The reduction will be carried out according to the dose the patient had, with decreases of 2.5-5mg every 3-6 months. Patient monitoring should be performed every 1-1.5 months until stability and then every 1-3 months. This document pretends to solve some common clinical questions and facilitate decision-making in RA patients treated with methotrexate. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  4. Oral dosing by voluntary  administration of jellybeans. Refinement and reduction of variability

    Pakula, Malgorzata Maria; Dagnæs-Hansen, Frederik


    induce stress and this may also influence parameters under study. Different methods for voluntary oral dosing has been described in the literature, among the methods proposed as an alternative to oral gavage is dosing in chocolate cream, sucker water etc. In this study we used jellybeans to give...

  5. Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

    Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas


    The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

  6. Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

    Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.


    Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

  7. Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

    Thompson, Gary A; Solomon, Gail; Albrecht, Helmut H; Reitberg, Donald P; Guenin, Eric


    This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  8. Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.

    Balan, Guhan; Thompson, Gary A; Gibb, Roger; Li, Lijuan; Hull, David; Seeck, Molly


    To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

  9. Subtleties in practical application of prolonged infusion of β-lactam antibiotics.

    De Waele, Jan J; Lipman, Jeffrey; Carlier, Mieke; Roberts, Jason A


    Prolonged infusion (PI) of β-lactam antibiotics is increasingly used in order to optimise antibiotic exposure in critically ill patients. Physicians are often not aware of a number of subtleties that may jeopardise the treatment. In this clinically based paper, we stress pragmatic issues, such as the importance of a loading dose before PI, and discuss a number of important practicalities that are mandatory to benefit from the pharmacokinetic advantages of prolonged β-lactam antibiotic administration.

  10. Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: A case report

    Hiroki Oikawa; Kazuyuki Suzuki; Tomoyuki Masuda; Chihaya Maesawa; Ryo Sato; Kanta Oikawa; Hiroyuki Yamada; Seizo Oriso; Sadahide Ono; Akiko Yashima-Abo; Koji Kotani


    The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless,asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease.Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure.Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore,periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.

  11. Low-dose oral prolonged-release oxycodone/naloxone for chronic pain in elderly patients with cognitive impairment: an efficacy–tolerability pilot study

    Petrò E


    Full Text Available Emiliano Petrò,1 Elena Ruffini,1 Melania Cappuccio,2 Valeria Guerini,2 Gloria Belotti,3 Sara Fascendini,4 Cristina Licini,4 Claudio Marcassa51Rehabiliation and Alzheimer Unit, San Pietro Polyclinic, Ponte San Pietro, 2Alzheimer Center, P. Gusmini Foundation, Vertova, 3Santa Maria Ausiliatrice Foundation, Bergamo, 4Alzheimer Center, Briolini Hospital FERB ONLUS, Gazzaniga, 5Cardiology, Maugeri Foundation IRCCS, Veruno, ItalyObjective: This pilot study evaluated the efficacy and safety of prolonged-release oxycodone/naloxone (OXN-PR in older subjects with chronic pain and mild-to-moderate cognitive impairment.Methods: This was a prospective, observational, open-label study of 45-day duration. Patients with moderate-to-severe chronic pain and naïve to strong opioids were recruited from nursing homes and Alzheimer’s disease centers. OXN-PR was initiated at low doses (5 mg od or bid and increased to a maximum of 20 mg bid. The primary efficacy endpoint was a pain intensity reduction of ≥30% from baseline (T0 to 15 days after OXN-PR initiation, as assessed by a numerical rating scale or the Pain Assessment in Advanced Dementia scale. Other assessments included the Barthel activities of daily living index, Neuropsychiatric Inventory, Bowel Function Index, and adverse events.Results: The analysis included 53 patients (mean age, 83.0 years; mean Mini-Mental State Examination score, 18.6 with severe pain (median Numerical Rating Scale/Pain Assessment in Advanced Dementia 6 and substantial impairment in daily functioning (mean Barthel index, 32.2. The primary endpoint was achieved by 92.4% of patients. OXN-PR significantly reduced mean pain intensity from baseline to study end (numerical rating scale, 6.6±1.0 vs 2.3±1.1, P<0.0001; Pain Assessment in Advanced Dementia, 6.9±1.6 vs 0.9±0.8, P<0.0001. Substantial improvements from T0 to T45 in daily functioning (mean Barthel index, 32.2±16.8 vs 53.7±23.9, P<0.0001 and neuropsychiatric symptoms

  12. A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion.

    Chai, J; Tang, O S; Hong, Q Q; Chen, Q F; Cheng, L N; Ng, E; Ho, P C


    The conventional timing of misoprostol administration after mifepristone for second trimester medical abortion is 36-48 h, but simultaneous administration, which may make the regimen more convenient, has not been studied. The objective of this randomized comparison study is to compare two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester medical abortion. Eligible women with gestational age between 12 and 20 weeks were randomized to receive mifepristone 200 mg orally followed by 600 microg misoprostol vaginally either immediately or 36-38 h later, followed by 400 microg vaginal misoprostol every 3 h for a maximum of four doses. The primary outcome measure was the success rate at 24 h after the start of misoprostol treatment and the secondary outcome measures were the induction-to-abortion interval and the frequency of side effects. There was a significant difference in the success rate at 24 h (36-38 h: 100%; immediate: 91.5%). The median induction-to-abortion interval was significantly shorter in the 36-38 h regimen (4.9 h) compared with the immediate regimen (10 h). Side effects in terms of febrile episodes and chills/rigors were significantly higher in the immediate administration group. Simultaneous use of mifepristone and misoprostol for second trimester medical abortion is not as effective as the regimen using a 36-38 h dosing interval.

  13. Reproducibility of neutron activated Sm-153 oral dose formulations intended for human administration

    Yeong, C.H. [Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Blackshaw, P.E. [Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH (United Kingdom); Ng, K.H.; Abdullah, B.J.J. [Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Blaauw, M. [Reactor Institute Delft, Faculty of Applied Sciences, Delft University of Technology, 2628 CJ Delft (Netherlands); Dansereau, R.J. [Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Rd, Mason (United States); Perkins, A.C., E-mail: [Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH (United Kingdom); Radiological and Imaging Sciences and Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham NG7 2UH (United Kingdom)


    Neutron activation of Sm-152 offers a method of radiolabeling for the in vivo study of oral dose formulations by gamma scintigraphy. Reproducibility measurements are needed to ensure the robustness of clinical studies. 204 enteric-coated guaifenesin core tablets (10 mg of Sm{sub 2}O{sub 3}) were irradiated by thermal neutrons to achieve 1 MBq at 48 h. Administered activities were 0.86{+-}0.03 MBq. Good reproducibility (CV=3.5%) was observed over 24 weeks ensuring that volunteer doses were within the dose reference level of 0.8 mSv. - Highlights: > 204 enteric-coated guaifenesin core tablets were irradiated by thermal neutrons. > Activity measured at 48 h after irradiation was 1.01{+-}0.03 MBq. > Activity administered per subject was 0.88{+-}0.03 MBq. > Good reproducibility (CV=3.5%) of Sm-153 radioactivity was obtained. > Effective doses to volunteers were within dose reference level of 0.8 mSv.

  14. Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: Mathematical modelling guides dose optimisation to minimise neutropenia.

    Craig, Morgan; Humphries, Antony R; Nekka, Fahima; Bélair, Jacques; Li, Jun; Mackey, Michael C


    The choice of chemotherapy regimens is often constrained by the patient's tolerance to the side effects of chemotherapeutic agents. This dose-limiting issue is a major concern in dose regimen design, which is typically focused on maximising drug benefits. Chemotherapy-induced neutropenia is one of the most prevalent toxic effects patients experience and frequently threatens the efficient use of chemotherapy. In response, granulocyte colony-stimulating factor (G-CSF) is co-administered during chemotherapy to stimulate neutrophil production, increase neutrophil counts, and hopefully avoid neutropenia. Its clinical use is, however, largely dictated by trial and error processes. Based on up-to-date knowledge and rational considerations, we develop a physiologically realistic model to mathematically characterise the neutrophil production in the bone marrow which we then integrate with pharmacokinetic and pharmacodynamic (PKPD) models of a chemotherapeutic agent and an exogenous form of G-CSF (recombinant human G-CSF, or rhG-CSF). In this work, model parameters represent the average values for a general patient and are extracted from the literature or estimated from available data. The dose effect predicted by the model is confirmed through previously published data. Using our model, we were able to determine clinically relevant dosing regimens that advantageously reduce the number of rhG-CSF administrations compared to original studies while significantly improving the neutropenia status. More particularly, we determine that it could be beneficial to delay the first administration of rhG-CSF to day seven post-chemotherapy and reduce the number of administrations from ten to three or four for a patient undergoing 14-day periodic chemotherapy.


    Wiwik Misaco Yuniarti; Ira Sari Yudaniayanti; Nusdianto Triakoso


    The aim of this study was to determine the effect of high dose calcium carbonate in rat (Rattus norvegicus) following ovaryohysterectomy. A total of twenty female rats at 13 week-old were used in this study. Following ovaryohitectomy, the animals were randomized in four treatment groups. Group P0 were :fed with standard food only P1, P2 and P2 groups treated with standard food but supplemented calcium carbonate respectively at the dose of 75 mg per animal per day, 225 mg per animal per day , ...

  16. Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

    Brokjær, Anne; Kreilgaard, Mads; Olesen, Anne Estrup


    data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 hours, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed...... that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side...

  17. Simultaneous administration of high-dose atorvastatin and clopidogrel does not interfere with platelet inhibition during percutaneous coronary intervention

    Kreutz RP


    Full Text Available Rolf P Kreutz,1,2 Jeffrey A Breall,1 Anjan Sinha,1 Elisabeth von der Lohe,1 Richard J Kovacs,1 David A Flockhart,2,† 1Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA †David A Flockhart passed away on November 26, 2015 Background: Reloading with high-dose atorvastatin shortly before percutaneous coronary interventions (PCIs has been proposed as a strategy to reduce periprocedural myonecrosis. There has been a concern that statins that are metabolized by cytochrome P450 3A4 may interfere with clopidogrel metabolism at high doses. The impact of simultaneous administration of high doses of atorvastatin and clopidogrel on the efficacy of platelet inhibition has not been established. Methods: Subjects (n=60 were randomized to receive atorvastatin 80 mg together with clopidogrel 600 mg loading dose (n=28 versus clopidogrel 600 mg alone (n=32 at the time of PCI. Platelet aggregation was measured at baseline, 4 hours after clopidogrel loading dose, and 16–24 hours after clopidogrel loading dose by light transmittance aggregometry using adenosine diphosphate as agonist. Results: Platelet aggregation was similar at baseline in both the atorvastatin and the control groups (adenosine diphosphate 10 µM: 57%±19% vs 61%±21%; P=0.52. There was no significant difference in platelet aggregation between the atorvastatin and the control groups at 4 hours (37%±18% vs 39%±21%; P=0.72 and 16–24 hours post-clopidogrel loading dose (35%±17% vs 37%±18%; P=0.75. No significant difference in incidence of periprocedural myonecrosis was observed between the atorvastatin and control groups (odds ratio: 1.02; 95% confidence interval 0.37–2.8. Conclusion: High-dose atorvastatin given simultaneously with clopidogrel loading dose at the time of PCI does not significantly alter platelet inhibition by clopidogrel. Statin reloading with high doses of atorvastatin at the time of PCI

  18. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis

    Oliveira João


    Full Text Available Abstract Background The effects of gonadotrophin-releasing hormone agonist (GnRH-a administered in the luteal phase remains controversial. This meta-analysis aimed to evaluate the effect of the administration of a single-dose of GnRH-a in the luteal phase on ICSI clinical outcomes. Methods The research strategy included the online search of databases. Only randomized studies were included. The outcomes analyzed were implantation rate, clinical pregnancy rate (CPR per transfer and ongoing pregnancy rate. The fixed effects model was used for odds ratio. In all trials, a single dose of GnRH-a was administered at day 5/6 after ICSI procedures. Results All cycles presented statistically significantly higher rates of implantation (P Conclusions These findings demonstrate that the luteal-phase single-dose GnRH-a administration can increase implantation rate in all cycles and CPR per transfer and ongoing pregnancy rate in cycles with GnRH antagonist ovarian stimulation protocol. Nevertheless, by considering the heterogeneity between the trials, it seems premature to recommend the use of GnRH-a in the luteal phase. Additional randomized controlled trials are necessary before evidence-based recommendations can be provided.

  19. Single- and multiple-dose pharmacokinetics of marbofloxacin after oral administration to rabbits.

    Carpenter, James W; Pollock, Christal G; Koch, David E; Hunter, Robert P


    OBJECTIVE-To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period. ANIMALS-8 healthy 9-month-old female New Zealand White rabbits. PROCEDURES-Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods. RESULTS-After oral administration, mean +/- SD area under the curve was 10.50 +/- 2.00 microg.h/mL and 10.90 +/- 2.45 microg.h/mL, maximum plasma concentration was 1.73 +/- 0.35 microg/mL and 2.56 +/- 0.71 microg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively. CONCLUSIONS AND CLINICAL RELEVANCE-Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.

  20. Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters.

    Chung, Sanny S W; Wang, Xiangyuan; Wolgemuth, Debra J


    We have previously shown that oral administration of a pan-retinoic acid receptor antagonist in mice daily at 2.5 mg/kg for 4 weeks reversibly inhibited spermatogenesis, with no detectable side effects. To elucidate the lowest dose and the longest dosing regimen that inhibits spermatogenesis but results in complete restoration of fertility upon cessation of administration of the drug, we examined the effects of daily doses as low as 1.0 mg/kg with dosing periods of 4, 8, and 16 weeks. We observed 100% sterility in all regimens, with restoration of fertility upon cessation of the drug treatment even for as long as 16 weeks. There was no change in testosterone levels in these males and the progeny examined from 2 of the recovered males were healthy and fertile, with normal testicular weight and testicular histology. Strikingly, a more rapid recovery, as assessed by mating studies, was observed at the lower dose and longer dosing periods. Insight into possible mechanisms underlying this rapid recovery was obtained at 2 levels. First, histological examination revealed that spermatogenesis was not as severely disrupted at the lower dose and with the longer treatment regimens. Second, gene expression analysis revealed that the more rapid recovery may involve the interplay of ATP-binding cassette efflux and solute carrier influx transporters in the testes.

  1. Hypertensive urgency after administration of a single low dose of mirtazapine-a case report.

    Jiana Shi


    Full Text Available Mirtazapine is a new antidepressant that can increase noradrenergic and serotonergic neurotransmission. It is also a postsynaptic antagonist of 5-HT2 and 5-HT3. In addition, it has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1 antagonist properties. We report a case of hypertensive urgency that ensued after a patient took a single low dose of mirtazapine.

  2. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto


    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  3. The Influence of Single-Dose and Short-Term Administration of Quercetin on the Pharmacokinetics of Midazolam in Humans.

    Nguyen, Mai Anh; Staubach, Petra; Wolffram, Siegfried; Langguth, Peter


    Quercetin is a plant flavonol that is available from both daily diet and nutraceuticals. To investigate the effect of acute and short-term intake of high-dose quercetin on CYP3A-mediated metabolism, 10 healthy volunteers received 7.5 mg oral midazolam without, with a single dose of 1500 mg quercetin and after 1-week supplementation with 1500 mg quercetin daily. A substudy was performed in three subjects to explore the impact of repeated quercetin intake on intravenously administered midazolam. Coadministration with a single dose of quercetin did not significantly alter the pharmacokinetics of midazolam and its 1'-hydroxymetabolite, but following short-term quercetin intake, there was a trend to reduced midazolam exposure (geometric mean ratio of test-control area under the plasma concentration-time curve (AUC0-∞ ): 0.82; 90% confidence interval: 0.61-1.10) and midazolam-metabolite AUC0-∞ ratios were decreased by 9.7%-47.6% from control in seven subjects. The tendency was opposite when midazolam was given intravenously. We conclude that a single dose of quercetin would not provoke any toxic adverse events when coadministered with midazolam, whereas repeated quercetin intake can reduce systemic exposure to the orally given drug by increasing its CYP3A-catalyzed metabolism. As the effect deviated after intravenous drug administration, different mechanisms of interaction may be involved at the intestinal site compared with the liver.

  4. Human cord blood cells and myocardial infarction: effect of dose and route of administration on infarct size.

    Henning, Robert J; Burgos, Jose D; Vasko, Mark; Alvarado, Felipe; Sanberg, Cyndy D; Sanberg, Paul R; Morgan, Michael B


    There is no consensus regarding the optimal dose of stem cells or the optimal route of administration for the treatment of acute myocardial infarction. Bone marrow cells, containing hematopoietic and mesenchymal stem cells, in doses of 0.5 x 10(6) to >30 x 10(6) have been directly injected into the myocardium or into coronary arteries or infused intravenously in subjects with myocardial infarctions to reduce infarct size and improve heart function. Therefore, we determined the specific effects of different doses of human umbilical cord blood mononuclear cells (HUCBC), which contain hematopoietic and mesenchymal stem cells, on infarct size. In order to determine the optimal technique for stem cell administration, HUCBC were injected directly into the myocardium (IM), or into the LV cavity with the ascending aorta transiently clamped to facilitate coronary artery perfusion (IA), or injected intravenously (IV) in rats 1-2 h after the left anterior coronary artery was permanently ligated. Immune suppressive therapy was not given to any rat. One month later, the infarct size in control rat hearts treated with only Isolyte averaged 23.7 +/- 1.7% of the LV muscle area. Intramyocardial injection of HUCBC reduced the infarct size by 71% with 0.5 x 10(6) HUCBC and by 93% with 4 x 10(6) HUCBC in comparison with the controls (p p p p < 0.05). Nevertheless, IM, IA, and IV HUCBC all produced significant reductions in infarct size in comparison with Isolyte-treated infarcted hearts without requirements for host immune suppression. The present experiments demonstrate that the optimal dose of HUCBC for reduction of infarct size in the rat is 4 x 10(6) IM, 4 x 10(6) IA, and 16 x 10(6) IV, and that the IM injection of HUCBC is the most effective technique for reduction in infarct size.

  5. Tumour Lysis Syndrome and Partial Remission Occurring After Administration of a Test Dose of Obinutuzumab

    Mohamad Jaffer Abdalkhalig Mustafa


    Full Text Available Chronic lymphocytic leukaemia (CLL is one of the most common haematological malignancies worldwide, with an increasing prevalence in the elderly population. Obinutuzumab is a type II anti-CD20 monoclonal antibody which showed superiority over rituximab in combination chemotherapy with chlorambucil for the treatment of CLL in the CLL11 trial (NCT01010061 and is becoming part of standard first line treatment for CLL in the elderly based on its potent efficacy and benign safety profile. We report the case of a chemotherapy naive patient who develop tumour lysis syndrome despite appropriate prophylaxis, and had partial remission of her disease after receiving only the initial test dose of obinutuzumab.


    Wiwik Misaco Yuniarti


    Full Text Available The aim of this study was to determine the effect of high dose calcium carbonate in rat (Rattus norvegicus following ovaryohysterectomy. A total of twenty female rats at 13 week-old were used in this study. Following ovaryohitectomy, the animals were randomized in four treatment groups. Group P0 were :fed with standard food only P1, P2 and P2 groups treated with standard food but supplemented calcium carbonate respectively at the dose of 75 mg per animal per day, 225 mg per animal per day , and 450 mg per animal per day. The calcium carbonate supplement were given daily in the morning for 42 days. The experimental animals were sacrificed at 21 week-old. Calcium and phosphor level in sinister kidneys were determined by spectrofotometric method. The data obtained from this study were analysed using one way analysis of variance. No significant difference was observed in calcium level among four treatment groups, with the lowest level were found in P3 group. However, the phosphor level of P1 was significantly lower than those of P2 and P3 groups. The highest phosphor level was observed in P3 group, indicating a phosphorous retension and the signs of renal failure.

  7. Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol.

    Markowitz, J S; DeVane, C L; Boulton, D W; Nahas, Z; Risch, S C; Diamond, F; Patrick, K S


    Ethylphenidate was recently reported as a novel drug metabolite in two overdose fatalities where there was evidence of methylphenidate and ethanol coingestion. This study explores the pharmacokinetics of ethylphenidate relative to methylphenidate and the major metabolite ritalinic acid, in six healthy subjects who received methylphenidate and ethanol under controlled conditions. Subjects (three males, three females) received a single oral dose of methylphenidate (20 mg; two 10-mg tablets) followed by consumption of ethanol (0.6 g/kg) 30 min later. Methylphenidate, ritalinic acid, and ethylphenidate were quantified using liquid chromatography-tandem mass spectrometry. Ethylphenidate was detectable in the plasma and urine of all subjects after ethanol ingestion. The mean (+/-S.D.) area under the concentration versus time curve for ethylphenidate was 1.2 +/- 0.7 ng/ml/h, representing 2.3 +/- 1.3% that of methylphenidate (48 +/- 12 ng/ml/h). A significant correlation was observed between the area under the concentration versus time curve of methylphenidate and that of ethylphenidate. In view of the known dopaminergic activity of racemic ethylphenidate, it remains possible that under certain circumstances of higher level dosing, e.g., in the abuse of methylphenidate and ethanol, the metabolite ethylphenidate may contribute to drug effects.

  8. Long-term administration of large doses of paracetamol impairs the reproductive competence of male rats

    W.D.Ratnasooriya; J.R.A.C.Jayakody


    Aim: To evaluate the anfireproductive effect of paracetamol in male rats. Methods: Male rats were orally administered daily with 500mg/kg or 1000mg/kg of paracetamol for 30 consecutive days. Their sexual behaviour and fertility were evaluated using receptive females. Results: At 2 h after treratment, sexual behaviour was not inhibited but on day 30 both doses of paracetamol caused marked impairment of libido (assessed by % mounting, % intromission and % ejaculation), sexual vigour (number of mounts and intromissions and copulatory efficiency) or sexual performance (intercopulatory interval). In mating experiments, the fertility (in terms of quantal pregnancy, fertility index, implantation index and number of implants) was significantly reduced. All these effects were reversible. The antireproductive effect was not due to a general toxicity but due to an increase in pre-implantation losses resulting from oligozoospermia,impairments of normal and hyper-activated sperm motility, and reduction in the fertilizing potential of spermatozoa.Conclusion: Long-term use of high doses of paracetamol may be detrimental to male reproductive competence.(Asian J Androl 2000 Dec;2:247-255)

  9. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    Baandrup, Lone; Fagerlund, Birgitte; Jennum, Poul


    Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged ben...... benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life....

  10. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    Baandrup, Lone; Fagerlund, Birgitte; Jennum, Poul


    Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged...... benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life....

  11. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

    Jung, J A; Kim, N; Yang, J-S; Kim, T-e; Kim, J-R; Song, G-S; Kim, H; Ko, J W; Huh, W


    Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

  12. Chronic Administration of High Doses of Nandrolone Decanoate on the Pituitary-Gonadal Axis in Male Rats



    Full Text Available Background Anabolic-androgenic steroids (AAS are abused by athletes. Objectives The present study was designed to evaluate chronic administration of high doses of nandrolone decanoate (ND on the pituitary-gonadal axis and hematological parameters in normal male rats. Materials and Methods Thirty Wistar-Albino male rats were divided assigned to control (C, placebo (P and test (T groups (n = 10. Group T received 15 mg/kg intramuscular (IM ND for eight weeks. Group P received the same volume of peanut oil, but group C did not receive any agent during the trial period. At the end, animals were anesthetized, killed and blood samples collected from cervical vessels. Serum follicle stimulating hormone (FSH and luteinizing hormone (LH levels were determined by sensitive rat gonadotropins kit, using ELISA methods. Serum testosterone and hematological parameters were measured by ordinary laboratory methods. Obtained data was analyzed using SPSS 17 by ANOVA and Tukey statistical tests. Results were expressed as Mean ± SD. Statistical difference considered significantly by P < 0.05. Results Serum testosterone, LH, FSH, weight gain, food and water intake in group T were significantly decreased compared to other groups (P < 0.05. In addition erythrocyte, leucocytes, hemoglobin and hematocrit in group T were significantly increased compared to those of other groups (P < 0.05. Conclusions Chronic administration of high doses of ND can alter serum FSH, LH and testosterone and hematological parameters in male rats.

  13. Intraperitoneal Administration of Low Dose Aluminium in The Rat: How Good is It to Produce a Model for Alzheimer Disease.

    Ulusoy, H B; Sonmez, M F; Kilic, E; Caliskan, K; Karaca, B; Kara, M; Ercal, O; Gunduz, Y; Karabulut, D; Bitiktas, S; Tan, B; Kavraal, S; İnal, A; Suer, C


    Since neurotoxicity of aluminium (Al) resembles the progressive neurodegeneration observed in Alzheimer Disease (AD), Al administration in several ways has been used to produce AD model. Intraperitoneal (ip) low dose (4.2 mg/ kg) Al injection in rats for long periods is the preferred method by some researchers. In this paper, the efficiency of this method for producing an AD model was evaluated. In this study, we looked at the neuropathology of Al and the characteristic lesions of AD by histological and immunohistochemical techniques and determined oxidative stress markers in the brains of Al-treated and control rats. We also made electrophysiological recordings at the hippocampus and evaluated possible behavioural changes by Morris water maze test. However, no pathologic changes occurred in the animals except for an impairment in long-term potentiation (LTP) in the hippocampus (e.g. the LTPs of population spike (PS) amplitude at 15 min post-tetanus were measured as 217±27% in Al-treated rats and as 240±42% in sham-treated rats, of baseline PS amplitude). According to the findings of the present study, low dose of ip Al in rats is not sufficient to produce a good AD model. Higher doses (≥10 mg/kg) should be used.

  14. A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

    Maison-Blanche, Pierre; Vermorken, Jan B; Goksel, Tuncay;


    : The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1...

  15. The Correlation of Age Factor, Administration, and Metformin Dose Against Risk of Side Effect on Type 2 Diabetes Mellitus

    Magdarita Riwu


    Full Text Available Metformin is an antidiabetic oral medicine commonly recommended as first line treatment on type 2 diabetes mellitus. Metformin can caused drug related problems (DRPs such as gastrointestinal disorders, e.g. diarrhea, nausea, and flatulence. This study aimed to analyze correlation profiles on age, administration, and metformin dosage factors against risk of gastrointestinal disorders among newly diagnosed diabetic outpatients of National Health Insurance in RSAU Dr. M. Salamun Bandung. This study was an analytic observational study with a cross sectional method. The study was carried out in the internal medicine outpatient clinic and data were extracted from patients medical records from April to June 2014. Metformin-treated patients were interviewed using a form check. The number of patients were 65 with the median rate was 48 years old. Side effect reported were flatulence (58.46% and nausea (41.54%. Administration and metformin dosage factors were correlated to the risk of side effects such as nausea and flatulence on type 2 diabetes mellitus (p0.05. The administration of metformin is recommended after meals and with a lower initial dose titrated slowly to reduce and avoid the side effects of nausea and flatulence in patients with type 2 diabetes mellitus.

  16. Pharmacokinetics of the individual enantiomer S-(+)-ketoprofen after intravenous and oral administration in dogs at two dose levels.

    Serrano-Rodríguez, J M; Serrano, J M; Rodríguez, J Morgaz; Machuca, M M Granados; Gómez-Villamandos, R J; Navarrete-Calvo, R


    The pharmacokinetic of the individual S-(+)-enantiomer of ketoprofen, S-(+)-ketoprofen, after intravenous (IV) and oral (PO) administration was determined in six dogs at 1 and 3 mg/kg. Plasma concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration-time curves were analyzed by non-compartmental methods. Steady-state volume of distribution (Vss) and clearance (Cl) of S-(+)-ketoprofen after IV administration were 0.22 ± 0.07 and 0.19 ± 0.03 L/kg, and 0.10 ± 0.02 and 0.09 ± 0.01 L/h/kg, at 1 and 3 mg/kg, respectively. Following PO administration, S-(+)-ketoprofen achieved maximum plasma concentrations of 4.91 ± 0.76 and 12.47 ± 0.62 μg/ml, at two dose levels, respectively. The absolute bioavailability after PO route was 88.66 ± 12.95% and 85.36 ± 13.90%, respectively.

  17. Reversal of prolonged isoniazid-induced coma by pyridoxine.

    Brent, J; Vo, N; Kulig, K; Rumack, B H


    Isoniazid overdose is known to result in the rapid onset of seizures, metabolic acidosis, and prolonged obtundation. Pyridoxine has been reported to be effective in treating isoniazid-induced seizures. We report three cases of obtundation secondary to isoniazid overdose that was immediately reversed by intravenous pyridoxine. In two of these cases, status seizures were stopped by intravenous pyridoxine administration, but the patients remained comatose for prolonged periods. The comas were immediately reversed by the administration of additional pyridoxine. In the third case, the patient's lethargy was treated by intravenous pyridoxine on presentation and was followed by immediate awakening. Pyridoxine is effective in treating not only isoniazid-induced seizures, but also the mental status changes associated with this overdose. The dose required to induce awakening may be higher than that required to control seizures.

  18. Sex-dependent behavioral changes in rat offspring after in utero administration of a single low dose PBDE 47

    Kuriyama, S.N.; Talsness, C.E.; Chahoud, I. [Charite Univ. Medical School Berlin (Germany). Inst. of Clinical Pharmacology and Toxicology, Dept. Toxicology, Campus Benjamin Franklin


    change which could manifest itself in an irreversible fashion at later time points in life. We administered a single dose to gravid dams on gestation day 6 of either 140 {mu}g/kg BW or 700 {mu}g/kg BW of the congener, 2,2'4,4'-tetrabromo diphenyl ether (PBDE 47). These doses are pertinent to human exposure levels because a study by She et al. found a mean level of 33.3 {mu}g PBDE 47 /kg fat in human breast adipose tissue with a range from 7.01 to 196 {mu}g PBDE 47 /kg fat (10). In this study, peri-pubertal behavior effects were evaluated in rat offspring after in utero administration of low dose PBDE 47.

  19. Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

    Khalilzadeh, Azita; Zarrindast, Mohammad-Reza; Djahanguiri, Bijan


    The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

  20. Antifertility Effects of Orally Administration of Low Dose Gossypol Acetic Acid Combined with Methyltestosterone Plus Ethinyl Estradiol on Male Rat


    Objective To investigate the feasibility and optimal regimen of orally administration of low close gossypol acetic acid (GA) combined with methyltestosterone (MT) plus ethinyl estradiol (EE) for contraception in males.Methods Wistar male rats were randomly assigned into four groups, 20 in each group. Animals in group A or B were administered daily with 1% methyl cellulose or GA (12 mg/kg) suspended in 1% methyl cellulose, respectively. Rats in group C or D took firstly GA 12 mg/kg+MT 20 mg/kg+EE 0.1 mg/kg or MT 20 mg/kg+EE 0.1 mg/kg, in a suspension with 1% methyl cellulose, via gastric intubation. After the infertilities were initiated(6 weeks for group C, 8 weeks for group D), GA was served alone while MT+EE were withdrawn in rats of groups C and D. The treatment was ceased after 18 weeks and some males from group C were permitted to recover. Fertility testing, 10 males per group, was served for determining infertility or restoration of fertility in treated rats. Examinations of histology and biochemistry in treated rats were used to examine the morphologic influences on sperm, testis, epididymides and viscera, and biochemical changes in blood. The growth and development of F1 generation of the rats would also be tested in a series of behavioral tests.Results Ten rats from group C were infertile at week 6 after treatment, and the fulfilled infertility was maintained with low-close GA (12 mg/kg) only daily. Six weeks after cessation of treatment, all of treated males recovered their fertility. However, 8 of 10 rats from group D were in sterility at 6th week of treatment and all at 8th week of treatment, but the infertility could not be kept with the similar dose GA alone later on. Moreover, no adverse effects were found in our present experiments.Conclusion Administration of oral low dose GA combined with MT and EE as loading dose could successfully induce infertility in short term, whereafter the efficacy could completely be maintained by similar low dose of GA

  1. Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: In vivo proton magnetic resonance spectroscopy findings.

    Han, Fang; Xiao, Bing; Wen, Lili; Shi, Yuxiu


    Posttraumatic stress disorder (PTSD) is an anxiety- and memory-based disorder. The hippocampus and amygdala are key areas in mood regulation. Fluoxetine was found to improve the anxiety-related symptoms of PTSD patients. However, little work has directly examined the effects of fluoxetine on the hippocampus and the amygdala. In the present study, male Wistar rats received fluoxetine or vehicle after exposure to a single prolonged stress (SPS), an animal model of PTSD. In vivo proton magnetic resonance spectroscopy ((1)H-MRS) was performed -1, 1, 4, 7 and 14 days after SPS to examine the effects of fluoxetine on neurometabolite changes in amygdala, hippocampus and thalamus. SPS increased the N-acetylaspartate (NAA)/creatine (Cr) and choline moieties (Cho)/Cr ratios in the bilateral amygdala on day 4, decreased the NAA/Cr ratio in the left hippocampus on day 1, and increased both ratios in the right hippocampus on day 14. But no significant change was found in the thalamus. Fluoxetine treatment corrected the SPS increases in the NAA/Cr and Cho/Cr levels in the amygdala on day 4 and in the hippocampus on day 14, but it failed to normalise SPS-associated decreases in NAA/Cr levels in the left hippocampus on day 1. These results suggested that metabolic abnormalities in the amygdala and the hippocampus were involved in SPS, and different effects of fluoxetine in correcting SPS-induced neurometabolite changes among the three areas. These findings have implications for fluoxetine treatment in PTSD.

  2. A comparative bioavailability study of two ibuprofen formulations after single-dose administration in healthy volunteers

    Metta S.S. Wiria


    Full Text Available This study was aimed to investigate the bioequivalence of ibuprofen 125 mg suppository formulation (Ibukal®, test formulation from PT. Kalbe Farma, Tbk., Jakarta and the ibuprofen suppository comparative formulation (Proris®, from PT. Pharos Indonesia, Jakarta in 12 healthy volunteers. The pharmacokinetic parameters used in this study were the area under the concentration-time curve from time zero to hour 10 (AUC0-t, the area under the concentration-time curve from time zero to infinite (AUC0-inf, the maximum concentration (Cmax, and the time needed to reach the maximum concentration (tmax. The study was designed as a random cross-over fashion, single-blinded which included 12 healthy adult volunteers. The volunteers were fasted overnight and in the morning they received a suppository of the test drug (Ibukal® or a suppository of the comparative drug (Proris®. Blood samples were withdrawn on hour 0 (control, 20 min; 40 min; 1; 1.5; 2; 2.5; 3; 4; 6; 8; and 10 time points after the administration of the drug. Following a wash-out period of 1 week, this procedure was repeated using the other drug. The serum concentration of the drug was determined by means of high-performance liquid chromatography with ultraviolet detection. The results of the study showed that, the mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the test drug were, respectively, 28.59(3.37 μg.h.mL-1, 30.47(3.56 μg.h.mL-1, 8.24(1.44 μg/mL, and 1.33(0.44 h. The mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the comparative drug were, respectively, 28.13(8.14 μg.h.mL-1, 30.56(8.05 μg.h.mL-1, 8.27(2.88 μg/mL, and 1.79(0.33 h. The geometric means ratio of the test to the comparative drug were 104.38% (CI 90%: 90.38-120.54% for AUC0-t, 101.97% (CI 90%: 89.51-116.16% for AUC0-inf, and 104.02% (CI 90%: 85.73-126.16% for Cmax. There was no side effect of the drug detected in this study. From the results we can conclude that the 125 mg of ibuprofen suppository of PT Kalbe Farma

  3. Central hemodynamics and androgen status in men with coronary heart disease, and androgen deficiency in its correction of prolonged administration of testosterone

    L. M. Gaivoronskaya


    Full Text Available This work was designed to study the dynamic of the central hemodynamic disorders symptoms at men with coronary heart disease, stable angina, obesity and androgen deficiency under replacement short-term therapy by Testosterone undecanoate (TU. The comparative assessment of central hemodynamic indicators and total and sub-scale AMS score at two groups of men who receiving (the main group and not receiving (control group replacement therapy of TU is carried out. Results showed that in the main group, unlike control group the positive tendency in a number of indicators (stroke volume, left ventricular end- diastolic volume, left ventricular end- systolic volume of the central hemodynamic and indicators of the androgenic status is observed. Positive dynamics of some parameters of the central hemodynamic even at short-term replacement therapy of TU indicates the therapeutic potential of testosterone at cardiovascular pathology which full realization may require longer period of testosterone administration.

  4. In vitro evaluation of the effect of metered-dose inhaler administration technique on aerosolized drug delivery.

    Shalansky, K F; Htan, E Y; Lyster, D M; Mouat, B; Tweeddale, M G


    The administration of aerosolized metered-dose inhalers (MDIs) to mechanically ventilated patients is labor intensive due to the large number of activations required and the currently recommended 30- to 60-second "wait and shake" between each puff. No studies have been published that assess the relationship between this delay between puffs and drug delivery. To address this issue, we conducted an in vitro, randomized, single-blind study using fenoterol MDI containing technetium-99m pertechnetate. Four modes of MDI administration were tested in triplicate by random sequence. Eight activations of the MDI were performed for each mode according to the following procedures: rapid succession (5 sec apart); 30-second intervals and shaking MDI between two rapid activations; 30-second intervals and shaking between each activation; and 60-second intervals and shaking between each activation. Two closed in vitro systems were designed to collect and measure the radiolabeled aerosol. In the first system, the MDI was activated into a plastic collection container; with the second system, the MDI was administered through an aerosol holding chamber with attached circuit filter positioned on the inspiratory line of the ventilator circuit. Sixty-second intervals between each activation were not tested with the second system. Radioactivity was measured before and after each mode of testing. No difference was found between the various modes of administration other than a 14% decrease in the amount of radioactivity released with the 60-second waiting period between puffs, compared with their rapid succession when using the plastic collection container system. Our results support the hypothesis that the delay after each activation of a MDI may not be necessary.

  5. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia.

    Mulligan, Stephen P; Karlsson, Karin; Strömberg, Mats; Jønsson, Viggo; Gill, Devinder; Hammerström, Jens; Hertzberg, Mark; McLennan, Roger; Uggla, Bertil; Norman, John; Wallvik, Jonas; Sundström, Gunnel; Johansson, Hemming; Brandberg, Yvonne; Liliemark, Jan; Juliusson, Gunnar


    We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

  6. Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

    Schwartz, J; O' Donoghue, J A; Humm, J L [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Jaggi, J S [Bristol-Myers Squibb, Plainsboro, NJ (United States); Ruan, S; Larson, S M [Nuclear Medicine Service Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); McDevitt, M; Scheinberg, D A, E-mail: [Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065 (United States)


    Clinical therapeutic studies using {sup 225}Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of {sup 225}Ac. The purpose of this study was to determine the amount of {sup 225}Ac and non-equilibrium progeny in the mouse kidney after the injection of {sup 225}Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with {sup 225}Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess {sup 213}Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess {sup 213}Bi reaching the kidney ({gamma}-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq{sup -1}, of which 0.46 (SD 0.16) Gy kBq{sup -1} (i.e. 60%) was due to non-equilibrium excess {sup 213}Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess {sup 213}Bi (0.31 (SD 0.11) Gy kBq{sup -1}) represented {approx}46% of the total. For the medulla the dose contribution from excess {sup 213}Bi (0.81 (SD 0.28) Gy kBq{sup -1}) was {approx}80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq{sup -1} following administration of {sup 225}Ac-huM195 with non-equilibrium excess {sup 213}Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the

  7. [Effects on the coagulation-fibrinolysis system of a single oral dose of mesoglycan at the beginning and at the end of a prolonged treatment in man].

    Blardi, P; Messa, G; Puccetti, L; La Placa, G; Ghezzi, A


    We evaluated the mesoglycan effects on the coagulative-fibrinolytic system in 10 patients with euglobulin lysis time (ELT) over 180 minutes. A mathematical model was used to analyze such phenomena. 100 mg of mesoglycan was administered to 10 patients for 14 days. The following parameters were evaluated: tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), euglobulin lysis time (ELT), plasminogen, alpha 2 antiplasmin, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TCT), and fibrinogen. Those parameters were evaluated on the first and on the last day of the mesoglycan treatment at the following times: 0 (basal), 2, 4, 6, 8, 10 and 12 hours. Our results suggest that the mesoglycan is able to reduce a profibrinolytic activity without any influence on the coagulative-fibrinolytic system, at the baseline conditions and after chronic administration. The pharmacodynamic study and the statistical analysis using our mathematic model resulted to be statistically significant.

  8. Optimal dose of an anesthetic in epidural anesthesia and its effect on labor duration and administration of vacuum extractor and forceps.

    Cutura, N; Soldo, V; Milovanović, S R; Orescanin-Dusić, Z; Curković, A; Tomović, B; Janković-Raznatović, S


    This study examined the factors that influence the optimal dose of epidural anesthesia (EA), its effect on labor duration, and the frequency of vacuum and forceps administration at the end of delivery. The study group included 100 women who underwent vaginal delivery with EA with administration of 0.125% bupivacaine. A control group included 100 vaginally delivered women, without EA administration. In both groups delivery was stimulated by syntocinon. The level of labor pain influenced the optimal bolus dose of EA more than the body mass. However, the maintenance dose was influenced by both of these factors equally. Labor in the study group was somewhat shorter. In the group with EA the percentage of forceps and vacuum extractor application was twice that in the control group. There was no difference in average value of 5-minute Apgar scor in newborns.

  9. Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs.

    Guan, Su; Hu, Chun-Yun; He, Meng-Ying; Yang, Ying-Ying; Tang, Yu-Xin; Chen, Jie-di; Huang, Li-Jie; Tan, Wen


    This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study.

  10. Prevention of neutropenia during chemotherapy by prolonged myelostimulatory preparations

    V. V. Ptushkin


    Full Text Available Neutropenia and associated infection, resulting in hospitalization and use of antibiotics, has a negative effect on chemotherapy. The need to reduce the dose of cytotoxic drugs during neutropenia leads to lower survival rates in patients with hematological malignancies and solid tumors. Since 1990s myelocytokines – proteins that accelerate neutrophil recovery after cytostatic chemotherapy and reduce the risk of infection – is widely used in the clinical practice. The use of these drugs can support the planned dose intensity of chemotherapy and improves the treatment efficacy. The disadvantages of these drugs include the need for their daily parenteral administration for 7–10 days. The development of long-acting forms (pegfilgrastim and lipegfilgrastim has solved this problem. Self-regulating clearance of prolonged forms allowed to use them only once on a chemotherapy course. Results of pegfilgrastim administration in 25 patients with hematological malignancies (8 patients and solid tumors (17 patients included in our analysis. Prolonged preparation showed high efficacy in secondary prophylaxis of neutropenia and infection decreasing the risk by 82 %. The single administration of pegfilgrastim allowed safe dose intensity chemotherapy with shorter intervals between courses (AC-14 in 8 patients with breast cancer. Tolerability was good; cases of hyperleukocytosis have notbeen reported. Recently in Europe and the Russian Federation a new drug from prolonged myelocytokine group – lipegfilgrastim – has been registered. The results of two controlled trials in patients with breast cancer (n = 410 receiving doxorubicin/docetaxel showed high efficacy of the drug as the pegfilgrastim with comparable tolerability.

  11. Short-term, high-dose administration of corticosterone by injection facilitates trace eyeblink conditioning in young male rats.

    Wentworth-Eidsaune, Christine L; Hennessy, Michael B; Claflin, Dragana I


    Glucocorticoids released as part of the physiological response to stress are known to affect cognitive function, presumably via effects on the hippocampus. Trace classical eyeblink conditioning is an associative learning task which depends on the hippocampus and has been used to examine the development of learning processes in young mammals. Previously, we demonstrated deficits in trace eyeblink conditioning associated with postnatal administration of the glucocorticoid corticosterone by creating a sustained elevation with methods such as subcutaneous timed-release pellets and osmotic mini-pumps which were active over several days. In the present study, we examined the effects of an oscillating pattern of corticosterone elevation on subsequent trace eyeblink conditioning. Twice daily corticosterone injections (high, low, or vehicle) were administered over a 3-day period, starting at postnatal day 15. Then, on postnatal day 28, animals underwent trace classical eyeblink conditioning to examine the possible influence of earlier corticosterone elevations on the development of learning and memory. Eyeblink conditioning was affected by corticosterone treatments, but only for males, and only very early in acquisition; Males receiving the high dose of corticosterone exhibited facilitation of learning relative to controls. These data demonstrate that oscillating corticosterone elevations produce opposite effects on this associative learning task than do sustained elevations.

  12. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica


    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  13. Uptake of indium-111 in the liver of mice following administration of indium-111-DTPA-labeled monoclonal antibodies: Influence of labeling parameters, physiologic parameters, and antibody dose

    Schuhmacher, J.; Klivenyi, G.; Matys, R.; Kirchgebner, H.; Hauser, H.; Maier-Borst, W.; Matzku, S. (Institute of Radiology and Pathophysiology, Heidelberg (Germany, F.R.))


    Liver uptake of indium-111 ({sup 111}In) in mice was investigated following administration of {sup 111}In-DTPA murine monoclonal antibodies ({sup 111}In-DTPA-MAbs) labeled by the cyclic anhydride method. Biodistribution of HPLC-purified {sup 111}In-DTPA-MAb preparations was checked with a low (0.2 micrograms) and a high (8.0 micrograms) MAb dose. Using Bio Gel P-30 for desalting the MAb-conjugates, {sup 111}In uptake in the liver amounted to 8%-9% of the injected dose (ID) and was independent from the MAb dose, the DTPA-to-MAb molar ratio, tumor growth and biologic variability (different MAbs and different strains of mice). Using Sephadex G-25 for desalting, 0.2 micrograms doses from 7 out of 26 preparations showed increased liver accumulation of {sup 111}In in non-tumor mice ranging from 15%-25% of ID. Corresponding high doses led to a normal value of 8%-9%. Increased liver uptake of the low dose could not be reduced by coadministration of the unconjugated MAb, but was normal after reinjection of in vivo filtered material. An inverse intracellular distribution of {sup 111}In activity between sediment and supernatant of liver homogenates, following the administration of the low and the high MAb dose, indicated an artifact of the labeling procedure rather than an inherent biological property of labeled MAbs.

  14. The effect of single and divided dose administration on the efficacy of fenbendazole against adult stages of benzimidazole resistant sheep trichostrongylids.

    Sangster, N C; Whitlock, H V; Kelly, J D; Gunawan, M; Hall, C A


    Sheep infected with benzimidazole resistant strains of Haemonchus contortus and Trichostrongylus colubriformis were used to compare the anthelmintic efficacy of fenbendazole given as a single dose or administered in a divided dose regime over five days. Statistical analysis showed no significant difference between the two methods of administration for H contortus. On the other hand, divided dose fenbendazole was significantly less effective than single doses against adult T colubriformis at dose rates of 5 and 7.5 mg/kg. In the case of H contortus a highly significant correlation coefficient between post treatment egg counts and worm counts (r = 0.789) was obtained. This suggests that reduction in faecal egg output following drug treatment would provide a useful field indication of anthelmintic performance of fenbendazole (and possibly related compounds) against benzimidazole resistant strains of this parasite.

  15. Evaluation of occupational radiation dose in nuclear medicine: radiopharmaceutical administration to scintiscanning exams of myocardial perfusion; Avaliacao da dose de radiacao ocupacional em medicina nuclear: administracao de radiofarmacos em exames de cintilografria de perfusao miocardica

    Komatsu, Cassio V., E-mail: [Medicina Nuclear do Triangulo (MNT), Uberlandia, MG (Brazil); Michelin, Charlie A.; Jakubiak, Rosangela R., E-mail:, E-mail: [Universidade Tecnologica Federal do Parana (UTFPR), Curitiba, PR (Brazil); Lemes, Alyne O.; Silva, Juliana L.M., E-mail:, E-mail: [Faculdade do Trabalho (FATRA), Uberlandia, MG (Brazil)


    In nuclear medicine, workers directly involved in exams are constantly exposed to ionizing radiation. The procedure for administration of the radiopharmaceutical to the patient is one of the most critical times of exposure. In tests of myocardial perfusion scintigraphy (MPS) administration of radiopharmaceutical repeats the steps of rest and cardiac stress. In this study, we used a Geiger -Mueller detector for measuring occupational radiation doses for during the administration of technetium- {sup 99m}- sestamibi in MPS tests. In the evaluation, discriminated the stages of examination and related professional experience time to doses measures at home. It were followed 110 procedures at home (55 conducted by professionals with over 5 years experience and 55 conducted by professionals with less than 1 year of experience) and 55 effort procedures. The results showed that the rest of the procedure time and dose are related to the experience of the worker. More experienced workers were faster (mean: 43 {+-} 16 vs 67 {+-} 25 seconds / procedure), and therefore received lower doses (mean 0.57 {+-} 0.16 versus 0.80 {+-} 0.24 {mu}Sv / procedure), both with statistical significance (p <0.001). In step effort, there were procedures lasting longer (mean: 19 {+-} 2 minutes / procedure), which resulted in higher doses (mean 3.0 {+-} 0.6 {mu}Sv / procedure)

  16. Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination.

    Schneider, M; Paulin, A; Dron, F; Woehrlé, F


    The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl(®) ). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4-16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively.

  17. The effects of oral and intramuscular administration and dose escalation of enrofloxacin on the selection of quinolone resistance among Salmonella and coliforms in pigs

    Wiuff, C.; Lykkesfeldt, J.; Svendsen, O.;


    The effect of route of administration and dose of enrofloxacin (Baytril(R)) on the development of fluoroquinolone resistance in Salmonella and Escherichia coli in the intestinal tract of pigs was investigated. Healthy pigs at the age of 8-10 weeks were infected with a mixture of susceptible wild-...

  18. Severe Obesity Confounds the Interpretation of Low-Dose Dexamethasone Test Combined with the Administration of Ovine Corticotrophin-Releasing Hormone in Childhood Cushing Syndrome

    Batista, Dalia L.; Courcoutsakis, Nikos; Riar, Jehan; Keil, Margaret F.; Stratakis, Constantine A.


    Context: Suppression of cortisol secretion with a low-dose dexamethasone (Dex) followed by the administration of ovine CRH (Dex-oCRH) is used in the evaluation of adults with a pseudo-Cushing syndrome state (PCSS) vs. Cushing syndrome (CS).

  19. Chronic administration of l-sulpiride at non-neuroleptic doses reduces the duration of immobility in experimental models of "depression-like" behavior.

    Vergoni, A V; Forgione, A; Bertolini, A


    It has been shown that long-term administration of l-sulpiride induces a down-regulation of beta receptor-associated adenylate cyclase activity in the frontal cortex of rats, and adaptive response that is typically associated with the chronic administration of antidepressants. Here we show that in two animal models of "depression-like" behavior (forced swim in rats and tail suspension in mice), the long-term (21 days) administration of l-sulpiride at a non-neuroleptic dose (2 mg/kg IP twice a day) significantly decreases the duration of immobility, the effect being similar to that of desipramine (20 mg/kg IP). The same dose (2 mg/kg) of l-sulpiride, acutely administered, has no effect at all. On the other hand, either chronic (21 days) or acute administration of neuroleptic doses of l-sulpiride have an opposite effect, and indeed increase the duration of immobility. These results are an in vivo support to the in vitro findings suggesting that low doses of l-sulpiride may have antidepressant-like activity.

  20. Effects of label-dose permethrin administration in yearling beef cattle: I. Reproductive function and embryo quality of superovulated heifers.

    Dohlman, Tyler M; Jahnke, Marianna M; West, James K; Phillips, Patrick E; Gunn, Patrick J


    follicle and E2 per total ovarian structure was greater in flush 2 (P ≤ 0.03) but did not differ because of treatment (P ≥ 0.23). In summary, these data indicate that permethrin administration at label dose in superovulated beef heifers has a tendency to reduce P4, but embryo quality is not affected. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. The effect of different doses and different routes of acetylsalicylic acid administration on platelet aggregation in healthy volunteers and ischemic stroke patients.

    Chýlová, Miroslava; Moťovská, Zuzana; Osmančík, Pavel; Procházka, Bohumír; Kalvach, Pavel


    The purpose was to assess the effect of different doses and different routes of acetylsalicylic acid (ASA) administration on platelet aggregation and the comparison between platelet aggregation after the single and the repetitive administration of ASA in healthy individuals and in patients after ischemic stroke. The study group consists of 22 healthy individuals and 30 patients with documented ischemic stroke. Platelet aggregation was measured in healthy individuals: (a) twice before ASA and (b) 2 h after different single doses and different routes of ASA administration-(b1) 500 mg orally, (b2) 500 mg intravenously, and (b3) 100 mg orally. We measured aggregability in healthy individuals after five consecutive days of 100 mg of ASA q.d. and in patients on chronic ASA 100 mg q.d. The VerifyNow was used with results expressed in aspirin reaction units (ARU). In healthy individuals, the dose-(b1) 500 mg orally-reduced the aggregability to mean (SD) 392 (36) ARU (p administration, and the same is true for the suppression after single dose of 500 mg orally and 100 mg orally (p = 0.011). Oral dose 100 mg for 5 days in healthy individuals reduced aggregation to 405 (37) and in post-stroke patients to 433 (54). All doses of ASA, both orally and intravenously, have produced a significant reduction of platelet aggregation. Preference of the parenteral to oral application has not been established.

  2. The Effect of Nicotine Administration on Physical and Psychological Signs of Withdrawal Syndrome Induced by Single or Frequent Doses of Morphine in Rats

    Mohammad Allahtavakoli


    Full Text Available Introduction. Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Materials and methods. Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Findings. Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Conclusion. The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  3. Comparative pharmacokinetics of single-dose administration of mammalian and bacterially-derived recombinant human granulocyte-macrophage colony-stimulating factor.

    Hovgaard, D; Mortensen, B T; Schifter, S; Nissen, N I


    Pharmacokinetics of recombinant human non-glycosylated bacterially-synthesized (E. coli) granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied following single intravenous (i.v.) and subcutaneous (s.c.) bolus injection, and compared to equivalent doses of glycosylated mammalian-derived CHO-GM-CSF. Each route of administration gave a different GM-CSF concentration-time profile. The highest peak serum concentrations (Cmax) were observed following i.v. bolus injection. After i.v. administration, a two-phase decline in concentration was noted for both types of GM-CSF with a significantly shorter t1/2 alpha of 7.8 minutes for the E. coli GM-CSF versus 20.0 min for the CHO-GM-CSF, while no significant difference was observed for the terminal phase. Following s.c. administration of equivalent doses, a higher peak serum concentration was observed in the E. coli-treated patients and, again, a faster elimination where pretreatment serum levels were reached after 16-20 h, versus more than 48 h after administration of CHO-GM-CSF. Although the non-glycosylated E. coli GM-CSF thus seems to undergo a faster elimination that the glycosylated CHO-GM-CSF no significant difference could be demonstrated in the in vivo effect of corresponding doses of the two compounds with respect to stimulation of granulopoiesis--with reservation for small patient numbers and a large individual variations in response.

  4. Micro-dose hCG as luteal phase support without exogenous progesterone administration: mathematical modelling of the hCG concentration in circulation and initial clinical experience.

    Andersen, C Yding; Fischer, R; Giorgione, V; Kelsey, Thomas W


    For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the GnRHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential advances and disadvantages. Based on the pharmacokinetic characteristics of hCG, the mathematical modelling of the concentration profiles of hCG during the luteal phase has been evaluated in connection with several different approaches for hCG administration as LPS. It is suggested that the currently employed LPS provided in connection with the GnRHa trigger (i.e. 1.500 IU) is too strong, and that daily micro-dose hCG administration is likely to provide an optimised LPS with the current available drugs. Initial clinical results with the micro-dose hCG approach are presented.

  5. Effects of 4-week administration of simvastatin in different doses on heart rate and blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.

    Owczarek, Jacek; Jasińska, Magdalena; Wejman, Irena; Kurczewska, Urszula; Orszulak-Michalak, Daria


    Statins and β1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on β-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats. The experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally. Simvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min(-1) vs. 374.41±13.32 min(-1); pheart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone. Simvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.

  6. Estimation of the {beta}+ dose to the embryo resulting from {sup 18}F-FDG administration during early pregnancy

    Zanotti-Fregonara, P.; Trebossen, R.; Maroy, R. [CEA, DSV, I2BM, SHFJ, LIME, Orsay (France); Champion, C. [Univ Paul Verlaine Metz, Inst Phys, Lab Phys Mol et Collis, Metz (France); Hindie, E. [Univ Paris 07, IUH, Ecole Doctorale B2T, Paris (France); Hindie, E. [Hop St Louis, AP-HP, Nucl Med Serv, F-75475 Paris 10 (France)


    Although {sup 18}F-FDG examinations are widely used, data are lacking on the dose to human embryo tissues in cases of exposure in early pregnancy. Although the photon component can easily be estimated from available data on the pharmacokinetics of {sup 18}F-FDG in female organs and from phantom measurements (considering the uterus as the target organ), the intensity of embryo tissue uptake, which is essential for deriving the {beta}+ dose, is not known. We report the case of a patient who underwent {sup 18}F-FDG PET/CT for tumor surveillance and who was later found to have been pregnant at the time of the examination(embryo age, 8 wk). Methods: The patient received 320 MBq of {sup 18}F-FDG. Imaging started with an unenhanced CT scan 1 h after the injection, followed by PET acquisition. PET images were used to compute the total number of {beta}+ emissions in embryo tissues per unit of injected activity, from standardized uptake value (SUV) measurements corrected for partial-volume effects. A Monte Carlo track structure code was then used to derive the {beta}+ self-dose and the {beta}+ cross-dose from amniotic fluid. The photon and CT doses were added to obtain the final dose received by the embryo. Results: The mean SUV in embryo tissues was 2.7, after correction for the partial-volume effect. The mean corrected SUV of amniotic fluid was 1.1. Monte Carlo simulation showed that the {beta}+ dose to the embryo (self-dose plus cross-dose from amniotic fluid) was 1.8 E-2 mGy per MBq of injected {sup 18}F-FDG. Based on MIRD data for the photon dose to the uterus, the estimated photon dose to the embryo was 1.5 E-2 mGy/MBq. Thus, the specific {sup 18}F-FDG dose to the embryo was 3.3 E-2 mGy/MBq (10.6 mGy in this patient). The CT scan added a further 8.3 mGy. Conclusion: The dose to the embryo is 3.3 E-2 mGy/MBq of {sup 18}F-FDG. The {beta}+ dose contributes 55% of the total dose. This value is higher than previous estimates in late nonhuman-primate pregnancies. (authors)

  7. Pharmacokinetic and bioequivalence studies of trospium chloride after a single-dose administration in healthy Chinese volunteers.

    Zhang, R; Yuan, G; Li, R; Liu, X; Wei, C; Wang, B; Gao, H; Guo, R


    The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.

  8. The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat

    Kaji, Tatsuru; Tanaka, Hiroaki; Holst, Jens Juul


    intestinal trophic activity. A rodent model of total parenteral nutrition (TPN) mucosal atrophy was used, examining intestinal morphology in the adult male rat after 5 days. Groups were: controls, maintained with TPN alone and GLP-2 treated groups (high dose; 240 microg/kg/day, low dose; 24 microg...

  9. The effect of administration of a single dose of T-2 toxin on blood coagulation in the rabbit.

    Gentry, P A


    The single intravenous administration of T-2 toxin to rabbits at a dosage of 0.5 mg per kg body weight produced an alteration in several blood coagulation parameters. The activities of factors VII, VIII, IX, X and XI were decreased by approximately 40% six hours after T-2 toxin administration. Plasma fibrinogen concentration became elevated within 24 hours after T-2 toxin exposure. Circulating platelet numbers were unaffected by T-2 toxin administration. The similarity of coagulation paramete...

  10. Effect of a single dose of propofol and lack of dextrose administration in a child with mitochondrial disease: a case report.

    Mtaweh, Haifa; Bayır, Hülya; Kochanek, Patrick M; Bell, Michael J


    Propofol infusion syndrome is a recognized complication of prolonged propofol use in the pediatric population, but little is reported on other metabolic effects of propofol, especially in children with mitochondrial disorders. We report on a child with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome who received a single dose of propofol for procedural sedation. The patient's initial presentation was consistent with a mild exacerbation of her underlying disease. She received a single dose of propofol and non-dextrose-containing fluids during a magnetic resonance imaging (MRI) study to rule out stroke and progressed to develop severe acidosis, neurologic deterioration, and cardiorespiratory compromise. This is the first case report of severe metabolic disturbances after a single dose of propofol administered for procedural sedation in a patient with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome and it questions the safety of propofol and absence of dextrose infusions during an acute illness in patients with mitochondrial disorders. © The Author(s) 2013.

  11. Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke

    Andreas Reimann


    Full Text Available Background Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA remains the only approved medication for acute ischemic stroke, but incurs significant bleeding risks. Therefore, approaches to combine lower doses of thrombolytic therapy with other effective drugs aim at improving efficacy and reducing bleeding rates. We examined the safety and therapeutic effects of various dosings of rtPA, either alone or combined with glycoprotein VI-Fc fusion protein (GPVI-Fc, Revacept on experimental stroke in mice. Methods and results The effect of filament-induced intracerebral thrombus formation and embolization was investigated after a one-hour occlusion of the middle cerebral artery. In accordance with previous studies, treatment with 10 mg/kg rtPA significantly improved functional outcome, cerebral infarct size and edema, but also resulted in markedly increased intracranial bleeding volumes. In contrast, low doses of rtPA (0.1 or 0.35 mg/kg body weight did not change outcome parameters. However, addition of 1 mg/kg Revacept to 0.35 mg/kg rtPA led to improved reperfusion compared to rtPA alone. Moreover, these combined treatments resulted in improved grip strength, compared to the respective dose of rtPA alone. Infarct-surrounding edema improved after combined treatments, but not after respective single rtPA dosings. Intracranial bleeding volumes were below controls after all low-dose rtPA therapies, given either alone or combined with Revacept. Conclusions In contrast to using the equally effective full dose of rtPA, intracranial bleeding was not increased by low-dose rtPA combined with Revacept. Therefore, addition of Revacept to low-dose rtPA does not incur safety risks, but improves efficacy of treatment.

  12. [Dopplerometry at prolonged pregnancy].

    Salii-Prenichi, L; Milchev, N; Markova, D; Apiosjan, Zh


    Prolonged pregnancy, associated with low amniotic fluid is a reason for the increase of fetal mortality and morbidity. There is no a define test at prolonged pregnancy which can determine which pregnancy are at a risk for adverse outcome and complications. Dopplerometry as a noninvasive method for examination of blood circulation, and especially a. cerebri media and a. umbilicalis can be used for the prediction of the outcome of prolonged pregnancy.

  13. Efficacy comparison of combined intracoronary administration of high-dose adenosine and tirofiban versus intracoronary tirofiban during primary percutaneous coronary intervention in patients with acute myocardial infarction



    Objective To compare the efficacy of intracoronary administration of combined high-dose adenosine and tirofiban versus intracoronary tirofiban during primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction.Methods Consecutive 258 patients with acute ST-segment elevation myocardial infarction (STEMI) underwent primary PCI,treated with thrombus aspiration and then intracoronary tirofiban,and were randomly divided into adenosine group (n=130) and con-

  14. A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients.


    The clinical anticonvulsant efficacy of single dose rectal and oral administration of diazepam 20 mg was examined in two double-blind placebo-controlled trials in adult epileptic patients. All subjects suffered from drug resistant epilepsy and frequently experienced serial seizures. Diazepam was administered rectally as a new experimental suppository formulation immediately after a seizure and was highly effective in preventing recurrent fits within a 24 h observation period (p less than 0.00...

  15. Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

    Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Magil, Alex B; Owen, David; Clement, John G; Wasan, Kishor M


    The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

  16. [Effects of once-daily low-dose administration of sustained-release theophylline on airway inflammation and airway hyperresponsiveness in patients with asthma].

    Terao, Ichiro


    Bronchial asthma is eosinophilic airway inflammation with enhanced airway responsiveness induced by eosinophilic granule proteins such as eosinophilic cationic protein (ECP) that are released from eosinophils. In the present study using 30 outpatients with mild to moderate asthma who had no history of treatment with steroid inhalation, we examined the effects of 4-week low-dose (200 mg/day) treatment with Uniphyl Tablets, a sustained-release theophylline formulated for once-daily dosing, on airway inflammation and airway hyperresponsiveness, as well as on respiratory function. Uniphyl Tablets significantly (p statistically significant (p V50 also showed statistically significant (p < 0.05) improvement. Mean blood theophylline concentration at the time the improvements were seen was 3.95 mg/mL. These results suggest that low-dose administration of Uniphyl Tablets has anti-airway inflammatory and anti-airway hyperresponsiveness effects in mild to moderate asthmatic patients.

  17. Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination.

    Rohatagi, Shashank; Lee, James; Shenouda, Magdy; Haworth, Stephen; Bathala, Mohinder Singh; Allison, Mark; Rubets, Igor; Heyrman, Reinilde; Noveck, Robert; Salazar, Daniel E


    The pharmacokinetics of amlodipine and olmesartan in healthy volunteers after coadministration of amlodipine besylate and olmesartan medoxomil concomitantly as separate dosage forms and together in a fixed-dose combination tablet were characterized in 5 phase I, randomized, crossover studies. The mean steady-state pharmacokinetics of amlodipine and olmesartan were similar when olmesartan medoxomil 40 mg/day and amlodipine 10 mg/day were administered separately or concomitantly for 10 days. The total and maximum exposure to amlodipine and olmesartan after administration of fixed-dose combination amlodipine/olmesartan medoxomil 10 mg/40 mg was bioequivalent to amlodipine 10 mg plus olmesartan medoxomil 40 mg. The ratio of least squares mean and 90% confidence intervals for the area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of amlodipine and olmesartan fell within the prespecified range for bioequivalence (80.0% - 125.0%). The area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of both drugs also met the prespecified criterion for bioequivalence when the fixed-dose combination tablet was taken 30 minutes after a high-fat breakfast. Total exposure to amlodipine and olmesartan was dose-proportional after administration of olmesartan medoxomil 10 mg to 40 mg in the fixed-dose combination formulation with amlodipine 5 mg to 10 mg. From a pharmacokinetic perspective, the 2 drugs are well suited to coadministration in a fixed-dose combination.

  18. 外用他克莫司小鼠-大鼠异种触须毛囊移植%Topical administration of tacrolimus prolong the survival of xenotransplantion of the hair follicles from mouse to rats

    鲜华; 胡志奇; 苗勇; 孙宇


    Objective To study the establishment of xenotransplantation of vibrissa follicles in the mouse-to-rats mode and the effect of topical tacrolimus on the survival of the xenotransplantated hair follicles.Methods In our study, vihrissa follicles of C57BU6J mice were used as donor and Wister rats were used as recipients. We harvested the black vibrissa follicles of C57BL/6J inbred mice, then transplanted them into white Wister rats dorsal. Totally 20 couples of rats were divided in 2 groups: topical tacrolimus group ( Group A ),blank control group ( Group B ). Then we compared the survival time of vibrissa follicles and their histologic outcomes to verified the practicability of xenogeneic transplantion of vibrissa follicles, and the topical application of tacrolimus results postoperatively. Results The longest survival time was 15 days in Group A, and 10 days in Group B , respectively. It could be seen by comparing, topical therapy with tacrolimus could prolong the survival time of the xenograft temporarily. The blood cells in the vibrissa follicle sinus could induce immunological rejection. Conclusion It is a successful model to study xenotransplantation of vibrissa follicles and immune privilege. Topical administration of tacrolimus prolong the survival of the xenogeneic transplanted vibrissa follicles in rats.%目的 探讨建立小鼠-大鼠异种触须毛囊移植动物模型的可行性及局部辅助应用他克莫司的效果.方法 以C57BL/6J小鼠触须毛囊为供体、Wister大鼠为受体,进行异种毛囊移植.实验分两组:移植后局部外用他克莫司组(A组),移植后的空白对照组(B组).观察移植后毛囊的成活时间及形态学变化.结果 A组的毛囊最长成活15d,B组的毛囊最长成活10d.两组比较表明,他克莫司延长了异种移植毛囊的成活时间,但触须毛囊含血窦,易诱发免疫排斥反应.结论 本动物模型是一种研究异种毛囊移植和免疫赦免的良好动物模型.外用他克莫

  19. Long-term administration of high doses of transdermal buprenorphine in cancer patients with severe neuropathic pain

    Leppert W


    Full Text Available Wojciech Leppert, Grzegorz Kowalski Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland Background: Buprenorphine is often administered by the transdermal route (transdermal buprenorphine [TB] in cancer patients with severe neuropathic pain. However, high doses of TB of 140 µg/h are rarely used.Patients and methods: Three cancer patients with severe neuropathic Numeric Rating Scale (NRS pain scores of 8–10 who were successfully treated with high doses of TB up to 140 µg/h along with other opioids and adjuvant analgesics.Results: TB was administered for a long period of follow-up (9 months to 4 years, including 34–261 days of treatment with the dose of 140 µg/h, which allowed achievement of satisfactory analgesia (NRS 3–5 and good treatment tolerance. In all three patients, TB dose was gradually titrated from 35 to 140 µg/h, and all patients used morphine at least for some time for breakthrough and background pain management along with adjuvant analgesics. Two patients continued the treatment with TB until the end of life, and one patient is still receiving the treatment.Conclusion: TB at doses of up to 140 µg/h in cancer patients with severe neuropathic pain seems to be effective and safe in combination with other opioids and with adjuvant analgesics, and may significantly improve patients’ quality of life. Clinical studies may explore higher than maximal 140 µg/h TB doses recommended by a manufacturer, and also in combination with other opioids and adjuvant analgesics. Keywords: adverse effects, analgesia, cancer, neuropathic pain, transdermal buprenorphine, treatment

  20. Food and Drug Administration Approval for Use of Hiberix as a 3-Dose Primary Haemophilus influenzae Type b (Hib) Vaccination Series.

    Briere, Elizabeth C


    On January 14, 2016, GlaxoSmithKline Biologicals (Research Triangle Park, North Carolina) received approval from the Food and Drug Administration (FDA) to expand use of Hiberix (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]) for a 3-dose infant primary vaccination series at ages 2, 4, and 6 months. Hiberix was first licensed in the United States in August 2009 for use as a booster dose in children aged 15 months through 4 years under the Accelerated Approval Regulations, in response to a Haemophilus influenzae type b (Hib) vaccine shortage that lasted from December 2007 to July 2009 (1). Expanding the age indication to include infants provides another vaccine option in addition to other currently licensed monovalent or combination Hib vaccines recommended for the primary vaccination series.* Hiberix contains 10 μg purified capsular polyribosyl ribitolphosphate (PRP) conjugated to 25 μg tetanus toxoid (PRP-T) and is supplied as a single-dose vial of lyophilized vaccine to be reconstituted with saline diluent. For the 3-dose primary series, a single (0.5 mL) dose should be given by intramuscular injection at ages 2, 4, and 6 months; the first dose may be given as early as age 6 weeks. The recommended catch-up schedule for PRP-T vaccines ( should be followed. As previously recommended, a single booster dose should be administered to children aged 15 months through 18 months; to facilitate timely booster vaccination, Hiberix can be administered as early as age 12 months, in accordance with Hib vaccination schedules for routine and catch-up immunization (1-3).

  1. Drug synergistic antifertility effect of combined administration of low-dose gossypol with steroid hormones in rats

    CHANG Qing; LIU Zhe; MA Wen-zhi; HEI Chang-chun; SHEN Xin-sheng; QIAN Xiao-jing; XU Zeng-lu


    Background Our previous studies suggested that low-dose gossypol combined with steroid hormones has a reversible antifertility role in adult male rats, and the course of treatment was shorter than that of either gossypol or steroid hormones alone. This result suggested that low-dose gossypol and steroid hormones have a drug synergistic effect on antifertility. The aim of the study was to find the target organs of the antifertility synergistic effect of the combined regimen.Methods Thirty-two adult male rats were divided into four groups randomly: group GH, rats were fed orally with group H, the same dosage of DSG/EE/TU as in group GH were administered; group C, rats were treated with vehicle (1% methyl cellulose) as control. Testes and epididymis were removed at 8 weeks post-treatment for evaluating their weight,volumes, volume fraction, and total volume of testicular tissue structures and the seminiferous tubule diameter using stereological assay. Sperm cell numbers and the motility of epididymal sperm were quantitated by flow cytometry and morphological methods.Results Compared with group C, spermatogenesis was normal in group G and suppressed in groups H and GH.Similar changes of testicular tissue structures and sperm number were found in groups H and GH. The decreases of epididymal sperm number and motility in group GH were greater than that of the low-dose gossypol or steroid hormones alone group.Conclusions The suppression of spermatogenesis was induced by steroid hormones in the combined regimen, and the epididymis was the target organ of low-dose gossypol. Combined use of low-dose gossypol and steroid hormones played a comprehensive antifertility role in their synergistic effect on reducing the number and motility of epididymal sperm.

  2. Comparative anthelmintic activity of strategic sustained low-level administration of albendazole in feed pellets compared to single doses of closantel and tetramisole against natural ovine parasitic gastroenteritis.

    Khan, F A; Sanyal, P K; Swarnkar, C P; Singh, D; Bhagwan, P S


    The strategic use of single therapeutic doses of closantel, tetramisole or sustained low-level administration of albendazole in feed pellets in controlling naturally acquired parasitic gastroenteritis in sheep was investigated on a farm in semi-arid Rajasthan, India. A total of 303 5- to 6-month-old sheep were divided into three groups. Two groups were dosed with single therapeutic doses of closantel and tetramisole and the third group was given a low-level medication with albendazole through feed pellets for 30 days. Faecal egg counts revealed significantly lower counts (pclosantel compared to the other two groups. The faecal egg counts in the group receiving sustained low-level albendazole rose after withdrawal of the medication but remained significantly lower than those in the group treated with tetramisole up to 7 weeks after treatment (pclosantel-treated group gained more body weight but the first six-monthly greasy fleece yield was greater in the group treated with medicated pellets. During the first 3 months of the experiment, three animals in the group treated with tetramisole died of parasitic gastroenteritis. Following sustained low-level administration of albendazole in feed pellets, the plasma disposition curve of both the sulphoxide and sulphone metabolites reached its plateau level by day 5 and remained almost constant thereafter. The comparative cost-effectiveness of the three treatment regimes during the first 3 months of treatment was best for the group treated with closantel followed by the group treated with medicated feed pellets.

  3. Cardiac troponin I in isoproterenol-induced cardiac injury in the Hanover Wistar rat: studies on low dose levels and routes of administration.

    Brady, Sally; York, Malcolm; Scudamore, Cheryl; Williams, Thomas; Griffiths, William; Turton, John


    The current studies demonstrate the effect of low-dose intraperitoneal (IP) administration of isoprotenerol (ISO) and subcutaneous (SC) versus IP routes of administration of ISO on serum cardiac troponin I (cTnI) levels in female Hanover Wistar rats, providing additional evidence to support acceptance of cTnI as a cardiac biomarker. At 2 hr postdosing with 0-500 microg/kg ISO, mean serum cTnI levels were increased in a dose-related fashion at > or =10 microg/kg with no evidence of cardiac pathology. At 24 h, cTnI concentrations were generally at control levels, but histologic cardiomyocyte injury was evident in a proportion of the animals given > or =10 microg/kg. In a second experiment, rats given SC ISO at 5,000 microg/kg and necropsied at 0, 1, 2, and 4 hr postdosing had higher levels of serum cTnI than animals given the same dose IP.

  4. Metronomic paclitaxel-loaded mPEG-PLA nanoparticles show enhanced anti-tumor efficacy compared to maximum tolerated dose administration

    Fei, Tan; Yang, Lian-juan; Mo, Xiao-hui; Wang, Xiu-li; Jun, Gu


    Low-dose metronomic (LDM) chemotherapy with cytotoxic agents, aimed at disrupting tumor endothelial cells, is an alternative method to maximum tolerated dose chemotherapy targeting proliferating tumor cells in clinical practice. However, even in the LDM schedule, cytotoxic agents still exhibit serious side effects due to non-distribution and high accumulated doses in the body. Nanocarriers can maximize the efficacy of the encapsulated drug by adjusting the pharmacokinetics and bio-distribution pattern, and minimize excessive toxic side effects. In the present study, we prepared polyethylene glycol (PEG)-coated stealth nanoparticles containing paclitaxel (PTX-NP) in order to evaluate their accumulation in tumor and their anti-tumor activity following LDM administration. PTX-NPs were prepared by a modified emulsification/solvent diffusion method with methoxy PEG-poly(lactide). The in vitro viability, migration, and tube formation of primary human umbilical vein endothelial cells, in addition to thrombospondin-1 positive expression and microvessel density in vivo, confirmed the anti-angiogenic activity of PTX-NP. The cellular uptake and retention study, in addition to pharmacokinetics in Sprague-Dawley rats demonstrated sustained circulation of PTX-NP. The in vivo tumor accumulation of PTX-NP was monitored using the Xenogen IVIS 200 non-invasive optical imaging system. The anti-tumor activity of LDM PTX-NP was studied in B16 melanoma cancer-bearing mice in vivo. In conclusion, PTX-NP improved tumor accumulation and anti-tumor efficacy following LDM administration.

  5. Concomitant Administration of Different Doses of Simvastatin with Ivabradine Influence on PAI-1 and Heart Rate in Normo- and Hypercholesterolaemic Rats

    Jacek Owczarek


    Full Text Available Ivabradine is a novel heart rate lowering agent that inhibits If ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg×kg−1 bw with ivabradine (10 mg×kg−1 bw during a 4-week period. Ivabradine exacerbated the decrease of PAI-1 in normocholesterolemic animals receiving simvastatin at a dose of 1 mg/kg bw and was not observed to have any significant influence on the PAI-1 values in rats receiving 20 mg×kg−1 bw simvastatin. Ivabradine, coadministered with simvastatin given at a dose of 20 mg×kg−1 bw, significantly slowed the heart rate in normocholesterolaemic and hypercholesterolaemic groups as compared to the group receiving ivabradine alone. Conclusion. The administration of ivabradine to normocholesterolaemic and hypercholesterolaemic rats receiving simvastatin significantly exacerbated the slowing of heart rate with no effect on blood pressure. The administration of ivabradine has been shown to demonstrate different effects on PAI-1 values depending on lipid disorders.

  6. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial.

    Kristin Brekke

    Full Text Available Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.Vacc-4x proliferative T cell responses increased only among the vaccinated (p ≤ 0.031. The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037 and developed larger DTH (p = 0.005 than the adjuvant group. Rectal (distal Vacc-4x IgA and IgG antibodies also increased (p = 0.043 in this group. In contrast, the high dose generated higher nasal (local Vacc-4x IgA (p = 0.028 and serum IgG (p = 0.030 antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = -0.82, p < 0.001 and high regulation (r = 0.61, p = 0.010 at baseline.Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further NCT01473810.

  7. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.

    Akiyama, Hiroki; Takase, Hiroshi; Kubo, Fumito; Miki, Tohru; Yamamoto, Masahide; Tomita, Makoto; Mochizuki, Manabu; Miura, Osamu; Arai, Ayako


    In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m(2) ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).

  8. Peripheral blood morphologic changes after high-dose antineoplastic chemotherapy and recombinant human granulocyte colony-stimulating factor administration.

    Kerrigan, D P; Castillo, A; Foucar, K; Townsend, K; Neidhart, J


    The peripheral blood morphologic findings in 17 patients with cancer who had received high-dose cytotoxic chemotherapy followed by recombinant human-granulocyte colony-stimulating factor (rh-GCSF) were reviewed and compared with a control group of patients who received only high-dose chemotherapy. Both groups showed dysmyelopoiesis (abnormal granulation and nuclear lobulation) in the granulocytic series during the period of bone marrow recovery that followed the cytotoxic chemotherapy. Most of these morphologic abnormalities were more prominent in the rh-GCSF-treated group. Monocytic cells in both groups showed prominent vacuolation and immature nuclei. The percentages and absolute numbers of large granular lymphocytes were increased in the rh-GCSF group compared with the control group. No quantitative or qualitative abnormalities of eosinophilic or basophilic granulocytes were detected in either group. Both groups showed nonspecific red blood cell abnormalities, and large platelets were present in half of the control group smears. This report provides the first detailed peripheral blood morphologic description in patients treated with rh-GCSF and high-dose chemotherapy.

  9. Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration.

    Center, Sharon A; Randolph, John F; Warner, Karen L; Simpson, Kenneth W; Rishniw, Mark


    Influence of body condition (over-conditioned vs. normal-conditioned) on plasma glucocorticoid concentrations after single dose oral prednisolone or prednisone in 11 cats (5 normal-conditioned and 6-over-conditioned) was investigated using a two-drug crossover trial (3-week washout interval). Body condition was determined using criterion-referenced bioelectrical impedance together with plasma drug concentrations (prednisolone [active drug] and prednisone [pro-drug]) measured by HPLC. Although interconversion of each drug to the other was confirmed, a single 2mg/kg body weight oral dose of prednisolone produced significantly higher plasma prednisolone concentration (∼4-fold higher AUC) compared to prednisone. Significantly higher plasma drug concentrations in over-conditioned cats (∼2-fold) compared to normal-conditioned cats might explain their perceived increased risk for glucocorticoid associated side effects (hepatic lipidosis, diabetes mellitus). Findings suggest low comparative bioavailability of oral prednisone compared to prednisolone in cats and consideration of lean body mass or ideal body weight for dosing practices.

  10. Efficacy of low doses of fenbendazole and its administration via drinking water in the prophylaxis of nematodiasis in grazing calves.

    Downey, N E; O'Shea, J


    Under experimental conditions, fenbendazole given at doses of 0.4 and 1.0 mg/kg body weight suppressed calves' faecal output of Ostertagia and Cooperia species eggs and Dictyocaulus viviparus larvae. Both dose levels were given in the form of small daily drenches and the higher level showed greater efficacy. In a grazing experiment, medication with fenbendazole at 1.0 mg/kg/day administered intermittently to calves using an automatic dose dispenser almost completely suppressed the output of trichostrongylid eggs. As a result, infection on the pasture and in the calves remained at a low level throughout the grazing season. By contrast, control pasture and control calves showed rather heavy infection from mid-August onwards with significantly lower weight gains and widespread signs of parasitic gastroenteritis. At post mortem examination of representative calves from each group in November, the medicated animals had 99 per cent less Ostertagia species, whether adults or larvae arrested at the early fourth stage, and 95 per cent less Cooperia species compared with controls. Medication in the drinking water suppressed the faecal output of D viviparus larvae for most of the grazing season by comparison with the controls but the medicated calves became infected with this parasite towards the end of the season. Until this problem is overcome, precautions against parasitic bronchitis are advised when this system of medication is adopted.

  11. Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block.

    McAleer, Sarah D; Mills, Richard J; Polack, Torsten; Hussain, Tanweer; Rolan, Paul E; Gibbs, Alan D; Mullins, Frank G P; Hussein, Ziad


    Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naïve healthy male subjects received Subutex tablets (buprenorphine 2 and 8 mg [N=27] or 12 and 16 mg [N=27]) or Suboxone (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [N=36]) sublingually, under a naltrexone block for assessment of buprenorphine pharmacokinetics and tablet disintegration times. Plasma buprenorphine was quantified up to 72 h post-dose using a sensitive LC-MS/MS assay. Mean Cmax values ranged from 1.6 to 6.4 ng/ml and tmax from 0.5 to 3 h. Concentrations declined bi-exponentially and fluctuations after a meal suggested enterohepatic recirculation of buprenorphine. The terminal half-life was approximately 26 h (range 9-69). Cmax and AUC appeared to increase in proportion to Subutex dose over 8-16 mg. The Suboxone formulations were bioequivalent. The least squares mean (90% CI) treatment ratio for Cmax was 1.00 (0.92-1.10) and AUC was 1.00 (0.95-1.06). Median times of disintegration were similar for all doses and formulations (range 6-12 min). Sublingual buprenorphine, up to 40 times the 400 microg analgesic dose, was well tolerated in these opioid naïve subjects, as administration of naltrexone 50-150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects.

  12. Intrathecal administration of low-dose nociceptin/orphanin FQ induces allodynia via c-Jun N-terminal kinase and monocyte chemoattractant protein-1.

    Kawabata, Kenta; Nishimura, Isamu; Fujiwara, Takeshi; Terauchi, Shoko; Minami, Toshiaki; Ito, Seiji; Okuda-Ashitaka, Emiko


    Pathological chronic pain, which is frequently associated with prolonged tissue damage, inflammation, tumour invasion, and neurodegenerative diseases, gives rise to hyperalgesia and allodynia. We previously reported that intrathecal administration of nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for the orphan opioid receptor-like receptor, in the femtomole range induces touch-evoked allodynia. N/OFQ has been implicated in multiple signalling pathways, such as inhibition of cAMP production and Ca(2+) channels, or activation of K(+) channels and mitogen-activated protein kinase, although the signalling pathways of N/OFQ-induced allodynia remain unclear. To address these issues, we developed an ex vivo mitogen-activated protein kinase assay by using intact slices of mouse spinal cord. N/OFQ markedly increased the phosphorylation of c-Jun N-terminal kinase (JNK) in the superficial dorsal horn of the spinal cord. The N/OFQ-stimulated JNK phosphorylation was significantly inhibited by pertussis toxin, the phospholipase C inhibitor U73122, and the inositol trisphosphate receptor antagonist Xestospongin C. Intrathecal administration of the JNK inhibitor SP600125 inhibited N/OFQ-evoked allodynia. The N/OFQ-induced increase in JNK phosphorylation was observed in astrocytes that expressed glial fibrillary acidic protein. N/OFQ also induced monocyte chemoattractant protein-1 (MCP-1) release via the JNK pathway, and N/OFQ-induced JNK phosphorylation was observed in MCP-1-immunoreactive astrocytes. Intrathecal administration of the MCP-1 receptor antagonist RS504393 inhibited N/OFQ-evoked allodynia. These results suggest that, in the spinal dorsal horn, N/OFQ induces allodynia through activation of JNK via the phospholipase C-inositol trisphosphate pathway, which is coupled to pertussis toxin-sensitive G-protein, and following the release of MCP-1 from astrocytes.

  13. Comparison the Analgesic Effects of Single Dose Administration of Tramadol or Piroxicam on Postoperative Pain after Cesarean Delivery

    Amir Farshchi


    Full Text Available "nA multimodal approach to postcesarean pain management may enhance analgesia and reduce side effects after surgery. We investigated postoperative pain in a double-blinded, randomized, single-dose comparison of the monoaminergic and µ-opioid agonist tramadol, 100 mg (Group T and piroxicam 20 mg (Group P given IM alone- single dose in 150 patients who had elective cesarean delivery. All patients were assessed at 0, 6, 12 and 24 hours post operation for pain degree (by Visual Analogue Score: VAS 1-10, nausea and vomiting. Pain degree was classified as: Painless: 0, Mild: 1-4, Moderate: 5-8, Severe: 9-10. There was no significant difference between the efficacy of tramadol and piroxicam injections (P>0.05. Pain intensity decreased markedly over time in both groups. Mean±SEM pain degrees were as follows: P=7.7±0.5, T=8.2±0.8 after 0 hours; P=5.4±0.6, T=6.1±0.5 after 6 hours; P=3.3±0.4, T=3.4±0.7 after 12 hours; P=1.1±0.4, T=1.3±0.5 after 24 hours of surgery. Side effects were similarly minimal with all treatments. It might be concluded that i.m. injections of 20 mg piroxicam (single dose therapy could relieve postoperative pain after cesarean section as well as tramadol and it could reduce opioid analgesic requirements with less adverse side effects during the first postoperative 24 h.


    Darwin Karyadi


    Full Text Available Suatu penyelidikan mengenai pencegahan dan pengobatan penyakit defisiensi vit. A. di Cibatok, Bogor, telah dilakukan dengan menggunakan oral massive dose vit. A. (retinol palmitat e 300,000 I.U. dikombinasikan dengan vit E (a tocopherol acetate 50 I.U. dl. Dua group anak-anak umur 1-6 tahun dipilih masing-masing sebagai group Experiment dan Control yang hanya diberikan placebo. Sedangkan masing-masing group dibagi lagi menjadi golongan-golongan penderita dan golongan Non vit. A. defisiensi (normal. Ternyata setelah 6 (enam bulan kemudian 90 percent penderita yang mendapat pengobatan menjadi sembuh dan sebaliknya 88.9 percent dari penderita yang mendapat placebo masih tetap menderita defisiensi vit. A. (table 2 Table 3. Menunjukkan adanya pengaruh penyakit infeksi G.I tract terhadap berhasilnya pengobatan dan juga pada umumnya dapat disimpulkan bahwa gizi penderita tidak mempengaruhi pengobatan. Table 4 Kadar Vit. A. didalam darah penderita setelah pengobatan ternyata jauh lebih tinggi dari semula. Sedangkan dalam group yang mendapat placebo tidak terjadi kenaikan. Dari data penyelidikan tersebut dapat disimpulkan bahwa pemberian oral massive dose kombinasi dari vit. A dan E pada anak-anak sebelum sekolah dapat mencegah, mengobati gejala-gejala defisiensi vit. A. di mata.

  15. Early induction of secretoneurin expression following kainic acid administration at convulsant doses in the rat and gerbil hippocampus.

    Marti, E; Blasi, J; Ferrer, I


    The expression of secretogranin-II and its major proteolytic product secretoneurin (SN) is under the control of neuronal excitation, as demonstrated by treating rats with the excitotoxic kainic acid (KA). Differences in the structure and function of the hippocampus in rats and gerbils have been described; these suggest possible differential reactive responses to KA. In the present study, the SN immunostaining pattern in relation with cell damage is analyzed from 6 h to 4 days following KA administration in rats and gerbils. Dramatic differences in the expression of SN were found in the hippocampal complex following KA administration in gerbils and rats. A robust increase in SN immunoreactivity was detected in the pyramidal cell layer of the rat hippocampus, especially in the CA1 area. In the gerbil, however, a strong increase in SN immunostaining was detected in interneurons of the hippocampal formation, as shown by double-labeling immunohistochemistry to SN and the calcium-binding proteins parvalbumin, calbindin, and calretinin. In addition, no damage (in the hippocampal formation) or moderate damage (in the entorhinal cortex) was observed in the gerbil, in contrast to the rat. The administration of KA and the GABA-B receptor inhibitors (CGP56999A or CGP36742) to the gerbil resulted in a strong rise in SN immunoreactitivty in the CA1 pyramidal cell layer of the hippocampus, as in the rat. However, no increased cell damage was observed under these conditions. The present data provide evidence of a species-differential reactive response to KA that might be based, in part, on distinct inhibitory intrahippocampal circuitry.

  16. N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

    Levi Bolin, B; Alcorn, Joseph L; Lile, Joshua A; Rush, Craig R; Rayapati, Abner O; Hays, Lon R; Stoops, William W


    Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. In vitro and in vivo assessment of platelet function in healthy dogs during administration of a low-dose aspirin regimen.

    Haines, Jillian M; Thomason, John M; Seage, Eileen C; Wills, Robert W; Bulla, Camilo; Lunsford, Kari V; Mackin, Andrew J


    To assess the in vitro and in vivo platelet function of healthy dogs during administration of a low-dose aspirin regimen. 16 dogs. Dogs received aspirin (1 mg/kg, PO, q 24 h) for 7 days. Blood and urine samples were collected before (day 1; baseline) and on days 3 and 7 of the low-dose aspirin regimen. Platelet function was evaluated by use of turbidimetric and conventional impedance aggregometry, multiple-electrode impedance aggregometry, a platelet function analyzer (PFA), and determination of urine 11-dehydro-thromboxane B2 concentration. Turbidimetric aggregometry results were compared with the results obtained by the other 4 methods. Fourteen days after cessation of aspirin, platelet-rich plasma was incubated with acetylsalicylic acid and platelet function was assessed by turbidimetric aggregometry to determine whether this technique could accurately identify dogs that responded to the low-dose aspirin regimen. Of the 16 dogs, 13 had turbidimetric and conventional impedance aggregometry results that were decreased by > 25% from baseline on days 3 and 7, and 4 and 7 dogs had PFA closure times > 300 seconds on days 3 and 7, respectively. The median urine 11-dehydro-thromboxane B2 concentration-to-creatinine concentration ratio decreased by 49% between days 1 and 7. Turbidimetric aggregometry results were correlated with conventional impedance aggregometry results. There was poor agreement between the turbidimetric aggregometry and PFA results. The multiple-electrode impedance aggregometry protocol failed to reliably detect aspirin-induced platelet dysfunction. In vitro incubation of platelet-rich plasma with acetylsalicylic acid followed by turbidimetric aggregometry did not predict whether dogs responded to the low-dose aspirin regimen. Results indicated that the response to a low-dose aspirin regimen varied among healthy dogs.

  18. Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination.

    Schaller, Stefan J; Alam, Saad M; Mao, Jianren; Zhao, Yanli; Blobner, Manfred; Greenblatt, David J; Martyn, J A Jeevendra


    Chronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone. To elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples. Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline-saline, saline-midazolam, saline-morphine and midazolam-morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R(2) = 0.48, P midazolam, when administered alone or combination, for extended periods. © 2016 Royal Pharmaceutical Society.

  19. Reversed phase HPLC determination of tamoxifen in dog plasma and its pharmaco-kinetics after a single oral dose administration

    Davi Pereira de Santana


    Full Text Available The analytical method developed to evaluate tamoxifen in dog plasma samples was precise, accurate, robust and linear in the range of 5-200 ng/mL. The limits of detection and quantification were 0.981 ng/mL and 2.97 ng/mL, respectively. Besides, the intra-day precision and accuracy variations were 8.78 and 10.16%, respectively. Tamoxifen concentrations were analyzed by combined reversed phase liquid chromatography and UV detection (lambda=280 nm. The study was conducted using an open randomized 2-period crossover balanced design with a 1-week washout period between the doses. This simple, rapid and selective method is suitable for pharmacokinetic, bioavailability and bioequivalence studies.

  20. Heart block and prolonged Q-Tc interval following muscle relaxant reversal: a case report.

    Shields, John A


    Heart block and Q-Tc interval prolongation have been reported with several agents used in anesthesia, and the US Food and Drug Administration mandates evaluation of the Q-T interval with new drugs. Drug-induced Q-T interval prolongation may precipitate life-threatening arrhythmias, is considered a precursor for torsades de pointes, and may predict cardiovascular complications. In the patient described in this article, heart block occurred and the Q-Tc interval became prolonged after muscle relaxant reversal with neostigmine; both were considered to be related to the combination of agents used in the case, as well as to other predisposing factors such as morbid obesity. The agents used that affected cardiac conduction were neostigmine, desflurane, droperidol, dolasetron, and dexmedetomidine. Although the heart block was resolved after 2 doses of atropine, prolonged P-R and Q-Tc intervals persisted into the immediate postoperative period but returned to baseline within 4 hours. Clinical implications of this report include increasing awareness of the multitude of factors affecting Q-T interval prolongation during anesthesia.

  1. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice.

    Mayer, Lawrence D; Harasym, Troy O; Tardi, Paul G; Harasym, Natashia L; Shew, Clifford R; Johnstone, Sharon A; Ramsay, Euan C; Bally, Marcel B; Janoff, Andrew S


    Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

  2. Comparative pharmacokinetics of tylosin or florfenicol after a single intramuscular administration at two different doses of tylosin-florfenicol combination in pigs.

    Kim, Mi-Hee; Gebru, Elias; Chang, Zhi-Qiang; Choi, Jae-Young; Hwang, Mi-Hyun; Kang, Eun-Hee; Lim, Jong-Hwan; Yun, Hyo-In; Park, Seung-Chun


    Clinical pharmacokinetic profiles were investigated following intramuscular (i.m.) administration to pigs with a commercial tylosin-florfenicol combination product at a dose of 2.5 mg/kg tylosin and 5 mg/kg florfenicol or 10 mg/kg tylosin and 20 mg/kg florfenicol. The quantitation limit (QL) of florfenicol was 0.1 microg/ml, the inter-day and intra-day precision (CV%) were both beow 10%. The quantitation limit (QL) of tylosin was 0.05 microg/mL. The pharmacokinetic characteristics after i.m. doses were fitted by a one compartment open model. A fourfold decrease in the normal dose of each drug (20 mg/kg to 5 mg/kg for florfenicol, and 10 mg/kg to 2.5 mg/kg for tylosin) resulted in a corresponding two fold decrease in each drug of the maximum plasma concentration (C(max)) and the area under curve (AUC) values.

  3. Effect of zinc or S-adenosyl-l-methionine on long term administration of low doses of lead to rats.

    Muñoz, J J; Roca, C; Santos, J L; Arroyo, M; de Salamanca, R E


    Two alternatives for the treatment of lead intoxication, administration of zinc or a thiol donor, S-adenosyl-L-methionine (SAM), were analysed. Rats were exposed to lead (Pb)-acetate (60 mg/l) in drinking water during 90 days; one group also received SO4Zn in water (40 mg/l), while another received both Pb and SAM (5 mg/24 hr intraperitoneally. Erythrocytic delta-aminolaevulinic dehydratase (ALA-D) activity was significantly reduced (P treatments. The high erythrocytic uroporphyrinogen synthetase (URO-S) activity noticed in Pb administered rats, was significantly (P treatment causes a surplus of thiols that allows the full expression of ALA-D catalytic activity.

  4. Exhaustion from prolonged gambling

    Fatimah Lateef


    Full Text Available Complaints of fatigue and physical exhaustion are frequently seen in the acute medical setting, especially amongst athletes, army recruits and persons involved in strenuous and exertional physical activities. Stress-induced exhaustion, on the other hand, is less often seen, but can present with very similar symptoms to physical exhaustion. Recently, three patients were seen at the Department of Emergency Medicine, presenting with exhaustion from prolonged involvement in gambling activities. The cases serve to highlight some of the physical consequences of prolonged gambling.

  5. Exhaustion from prolonged gambling

    Fatimah Lateef


    Complaints of fatigue and physical exhaustion are frequently seen in the acute medical setting, especially amongst athletes, army recruits and persons involved in strenuous and exertional physical activities.Stress-induced exhaustion, on the other hand, is less often seen, but can present with very similar symptoms to physical exhaustion.Recently, three patients were seen at theDepartment ofEmergencyMedicine, presenting with exhaustion from prolonged involvement in gambling activities.The cases serve to highlight some of the physical consequences of prolonged gambling.

  6. Deciding about treatments that prolong life

    Palliative care - treatments that prolong life; Palliative care - life support; End-of-life-treatments that prolong life; Ventilator - treatments that prolong life; Respirator - treatments that prolong life; ...

  7. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H


    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  8. Single-dose pharmacokinetics of ampicillin/sulbactam (2:1) combination after intravenous administration to sheep and goats.

    Carceles, C M; Espuny, A; Vicente, M S; Diaz, M S; Escudero, E


    The pharmacokinetic behaviour of a combination of ampicillin and sulbactam (2:1) in six sheep and six goats after single intravenous doses of 20 mg kg body weight-1 (13.33 mg kg-1 of ampicillin and 6.67 mg kg-1 of sulbactam) was investigated by using a high-performance liquid chromatographic method for determining plasma concentrations. The objective was to determine whether there are differences between sheep and goats in the disposition kinetics of ampicillin and sulbactam. The plasma concentration-time curves were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in both sheep and goats. The mean (SD) elimination half-lives of ampicillin were 0.32 (0.05) h in sheep and 0.32 (0.04) h in goats, and the half-lives of sulbactam were 0.74 (0.10) h and 0.79 (0.18) h in sheep and goats, respectively. The apparent volumes of distribution of ampicillin and sulbactam were similar in the two species. Mean (SD) body clearances of ampicillin were 0.69 (0.07) litre h-1 kg-1 in sheep and 0.72 (0.11) litre h-1 kg-1 in goats, and the body clearances of sulbactam were 0.38 (0.03) and 0.38 (0.07) litre h-1 kg-1 in sheep and goats, respectively. There were no significant differences between any of the pharmacokinetic parameters of ampicillin and sulbactam in the sheep and goats.

  9. Pharmacokinetics of dl-praeruptorin A after single-dose intravenous administration to rats with liver cirrhosis

    X Zhu


    Full Text Available "n  Background and the purpose of the study: As a novel drug in the treatment of cardiac diseases, dl-praeruptorin A (Pd-Ia is the major active component of traditional herbal medicine Peucedanum praeruptorum Dunn and is metabolized primarily via cytochrome P450 isozymes (CYP 3A1 and 3A2 in rats. In the present study, the influence of liver cirrhosis on pharmacokinetics of Pd-Ia and hepatic mRNA expression of CYP3A1 and 3A2 in rats with experimental liver cirrhosis (LC rats were evaluated. "n  Methods: Pd-Ia was given intravenously (5 mg·kg-1 to LC rats induced by dimethylnitrosamine and pharmacokinetic variables were measured. Enzyme kinetic metabolism of Pd-Ia in rat hepatic microsomes was also investigated and hepatic mRNA expression of CYP3A1 and 3A2 were measured by real-time PCR. "n  Results and major conclusion: After intravenous administration in LC rats, the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞ was significantly greater than that in control rats, which might be due to slower rate of the hepatic blood flow and significant slower hepatic intrinsic clearance (CLint in rats. The decreased metabolic clearance of Pd-Ia in LC rats might be at least partly caused by the decreased levels of CYP3A1 and 3A2 responsible for Pd-Ia metabolism. These findings may provide new insights into the inter- and intra-individual pharmacokinetic variability of Pd-Ia.

  10. Implementation of a Prolonged Infusion Guideline for Time-Dependent Antimicrobial Agents at a Tertiary Academic Medical Center.

    Hohlfelder, Benjamin; Kubiak, David W; Degrado, Jeremy R; Reardon, David P; Szumita, Paul M

    Administration of time-dependent beta-lactam antibiotic as a prolonged infusion may maximize the pharmacodynamic target of time above the minimum inhibitory concentration. We describe the implementation of a prolonged infusion at a tertiary academic medical center, and a 1-year compliance analysis with the guideline. After performing a thorough literature search, a guideline was developed by members of the Department of Infectious Diseases and Department of Pharmacy. Approval and endorsement of the guideline was obtained by the Antimicrobial Subcommittee and Pharmacy and Therapeutics Committee. Physical champions were instrumental in the implementation of the guideline institution-wide. We then performed a 1-year retrospective analysis of guideline compliance from January 1, 2011 to December 31, 2011. Noncompliant administrations were obtained from smart infusion pumps. The total number of doses administered was taken from pharmacy information resources. In total, nearly 85,000 time-dependent doses were administered. Compliance with the prolonged infusion guideline was 89%. Rates of compliance did not significantly differ between medications (P = 0.555). Obtaining support from key stakeholders in collateral services and institutional leadership was vital for the success of this guideline. Compliance with the guideline 1 year after implementation was high. Implementation of a prolonged infusion guideline is feasible with institutional support and motivation.

  11. The influence of dose, time of administration, body temperature and salicylate kinetics on the antithrombotic action of acetylsalicylic acid in male rats.

    Philp, R B; Paul, M L; Killackey, J J; Killackey, B A


    Acetylsalicylic acid (ASA), given i.v. to male rats 10 min before electrical injury to the carotid artery, was found to reduce rate and extent of thrombosis at 3.3 and 10.0 mg/kg but not at 1.7, 20 or 100 mg/kg, indicating a narrow, low-dose window for antithrombotic effect. ASA was more effective in rats in which body temperature was allowed to fall greater than 0.5 degrees C but protection was lost if injury was delayed 15 min or more after ASA administration. Serum salicylate studies did not support the view that loss of protection was due to competition between salicylate and ASA for cyclooxygenase-binding sites. ASA was also protective at 200 mg/kg i.v., possibly through non-specific toxic effects.


    Kalemenev, S V; Sizov, V V; Ischenko, A M; Zubareva, O E


    The aim of this study was to discover the effects of chronic intraperitoneal administration of proinflammatory cytokine interleukin-1β (IL-1β) on rat investigative behavior and spatial memory. Rats were injected with a moderate pyrogenic dose of IL-1β (0.5 mkg/kg) daily during 14 days (7 days before tests and 7 testing days). The behavior was examined in 23.5 hours after the previous injection of cytokine. The test battery included: "The open field" (within 3 consecutive days), "The exploration of novel objects", and "The Morris water maze". The animals treated with IL-1β differed from the control animals in an essential decrease of locomotor activity, slight increase of anxiety and suppression of exploratory behavior. The impairment of spatial memory was not revealed.

  13. Population Pharmacokinetics of High-dose Methotrexate After Intravenous Administration in Chinese Osteosarcoma Patients from a Single Institution

    Wei Zhang; Qing Zhang; Xiaohuang Tian; Haitao Zhao; Wei Lu; Jiancun Zhen; Xiaohui Niu


    Background:High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma.The plasma concentration of MTX is closely related to efficacy and toxicity.There are large individual differences.Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances.However,no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported.The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients,and to explore the influence of patient covariates and between-occasion variability on drug disposition.Methods:An intravenous HD-MTX solution (10 g/m2) was given 274 times to 148 osteosarcoma patients.MTX plasma concentrations were measured at 0,6,12,24,48 and 72 h after commencement of the infusion,and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations.The PPK model and parameters were estimated using NONMEM software.The effects of fixed-effect factors were evaluated,and the final regression model was obtained.Results:The following population parameters were obtained using a two-compartment model:CL1 (clearance of central compartment):(CL1)i =CL1 Tv × [1-θCt-MTXNUM × MTXNUM] × [1-θCL1-CrCl1 × (CrCl1-1.89)] × eηCLi (L/h).V1 (central volume):(V11)i =V1TV × eηV1i (L).CL2 (clearance of peripheral compartment):(CL2)i =CL2TV × [1-θCL2-BODYAREA × (bodyarea-1.62)] × eηCL2i (L/h).V2 (peripheral compartment):(V2)i =V2Tv × [1-θV2-bodyarea × (bodyarea-1.62)] × eηV2i (L).The PPK parameters (RSD%) were CL1,V1,CL2 and V2 with values of 6.20 L/h (8.48%),19.6 L (extremely small),0.0172 L/h (50.9%) and 0.515 L (39.1%),respectively.Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL 1,and body

  14. A Naturalistic, Single-blind Comparison of Rapid Dose Administration of Divalproex ER Versus Quetiapine in Patients with Acute Bipolar Mania

    Galangue, Barbara; MacDonald, Kai; Cobb, Patrice; Dinca, Ana; Becker, Olga; Cooper, J.; Hadley, Allison


    Objective: When treating acute bipolar mania, the speed of onset of anti-manic effects is crucial. Quetiapine and divalproex ER are widely used agents to treat acute mania. Rapid dose administration regimens for divalproex ER and for quetiapine have been described. We conducted a naturalistic, head-to-head, pilot study comparing the efficacy and safety of rapidly titrated divalproex ER and quetiapine in acutely manic inpatients, with the primary outcome being improvement within the first seven days. Method: Thirty consenting bipolar patients with acute mania (Young Mania Rating Scale >17 ) needing hospitalization due to acute mania were randomized to receive rapidly loaded divalproex ER (30mg/kg/day) or rapidly titrated quetiapine (200mg Day 1, raised by 200mg/day up to 800mg as tolerated). Assessments were made on Day 1 (baseline), Day 3, Day 7, Day 14, and Day 21 and included Young Mania Rating Scale, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and Montgomery-Asberg Depression Rating Scale. Raters but not patients or treating physicians were blinded (single-blinded study). Results: Subjects in both treatment groups exhibited significant and rapid improvement in their mania starting at Day 3 with few significant adverse effects; however, there were no significant differences in the degree or rate of improvement between the two treatment groups in any of the efficacy or adverse effects scales. Conclusion: Results of this small study indicate that rapid-dose administration of both quetiapine and divalproex ER produce rapid improvement in acute mania within the first seven days and both seem to be well tolerated. PMID:21311705

  15. [Nootropic and analgesic effects of Semax following different routes of administration].

    Manchenko, D M; Glazova, N Iu; Levitskaia, N G; Andreeva, L A; Kamenskiĭ, A A; Miasoedov, N F


    Heptapeptide Semax (MEHFPGP) is the fragment of ACTH(4-10) analogue with prolonged neurotropic activity. The aim of the present work was to study the Semax effects on learning capability and pain sensitivity in white rats following intraperitoneal and intranasal administration in different doses. Semax nootropic effects were studied in the test of acquisition of passive avoidance task. Pain sensitivity was estimated in Randall-Selitto paw-withdrawal test. It was shown that Semax exerts nootropic and analgesic activities following intraperitoneal administration. Analysis of dependence of these effects on dose resulted in different dose-response curves. Following intranasal administration, Semax was more potent in learning improvement compared to intraperitoneal administration. The peptide failed to affect the animal pain sensitivity following intranasal administration as opposed to intraperitoneal administration. The data obtained suggest different mechanisms and brain structures involved in realization of the nootropic and analgesic effects of Semax.

  16. Novel mouse model of combined hyperlipidemia associated with steatosis and liver injury by a single-dose intragastric administration of schisandrin B/cholesterol/bile salts mixture.

    Pan, Si-Yuan; Jia, Zhan-Hong; Zhang, Yi; Yu, Qing; Wang, Xiao-Yan; Sun, Nan; Zhu, Pei-Li; Yu, Zhi-Ling; Ko, Kam-Ming


    Hyperlipidemia is referred to as hypercholesterolemia, hypertriglyceridemia, or both in combined hyperlipidemia. Here, a novel mouse model of combined hyperlipidemia is described. Mice were orally given a single dose of a modeling agent (MA) made of a mixture of schisandrin B/cholesterol/bile salts (1/2/0.5 g/kg) suspended in olive oil. MA treatment increased serum triglycerides (TG) and total cholesterol (TC) (up to 422% and 100% at 12 - 96 h post-treatment, respectively) and hepatic TG and TC (up to 220% and 26%, respectively) in a time- and dose-dependent manner, associated with elevation of high-density lipoprotein and low-density lipoprotein levels. Serum alanine/aspartate aminotransferase activities, indicators of liver cell damage, were also elevated (up to 198%) at 48 and 72 h post-MA treatment. Fenofibrate blocks MA-induced hyperlipidemia, lipid accumulation in the liver, as well as liver injury. Oral administration of a mixture of schisandrin B, cholesterol, and bile salt could generate an interesting mouse model of combined hyperlipidemia associated with hepatic steatosis and steatohepatitis.

  17. TRPV1, NK1 receptor and substance P immunoreactivity and gene expression in the rat lumbosacral spinal cord and urinary bladder after systemic, low dose vanilloid administration.

    Heng, Yujing J; Saunders, Cassandra I M; Kunde, Dale A; Geraghty, Dominic P


    Transient receptor potential vanilloid 1 (TRPV1), neurokinin 1 (NK1) receptor and substance P (SP) immunoreactivity (-ir) and mRNA in the rat lumbosacral spinal cord and urinary bladder were measured 24h after s.c. injection of the vanilloids, capsaicin (50mg/kg) and resiniferatoxin (RTX, 100μg/kg), or vehicle (10% ethanol/10% Tween 80/saline). In the spinal cord, capsaicin significantly reduced TRPV1 and SP-ir (40-45%) in laminae I/II compared to controls, while RTX produced decreases of ~35%. NK1-ir in the spinal cord was unaffected by both vanilloid treatments. In the bladder, SP-ir was reduced in urothelial cells of some capsaicin- and RTX-treated rats, while SP-ir in the suburothelium and muscularis was significantly reduced by RTX. A significant increase in NK1-ir was observed in the urothelium and muscularis after capsaicin administration. Capsaicin significantly increased SP mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder, whereas RTX increased TRPV1, SP and NK1 mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder. These data suggest that stimulation of TRPV1 by low dose vanilloid administration can rapidly (within 24h) alter both transcription and translation of TRPV1 channels, SP and NK1 receptors in the rat urinary bladder and spinal cord. 2011 Elsevier B.V. All rights reserved.

  18. Time- and dose-dependent responses of brain histamine to intracerebroventricular and intraperitoneal administrations of growth hormone-releasing factor (GRF1-44).

    Cacabelos, R; Yamatodani, A; Fukui, H; Niigawa, H; Miyake, A; Watanabe, T; Nishimura, T; Wada, H


    Changes in the level of histamine (HA) in rat brain induced by intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administrations of growth hormone-releasing factor (GRF1-44) were studied. HA was determined by high-performance liquid chromatography (HPLC) in the anterior hypothalamic region, posterior hypothalamic region, median eminence, adenohypophysis, neurohypophysis, hippocampus and prefrontal cortex. GRF1-44 (1-10 micrograms, i.c.v.) induced significant time- and dose-dependent increases in the concentration of HA in the hypothalamo-hypophyseal system and time-dependent decrease of HA in the hippocampus. In contrast, after i.p. administration of GRF1-44 (10 micrograms) the level of HA in the hypothalamus tended to decrease but the total amount of H-1 receptors in the hypothalamo-hypophyseal system did not change. Circadian variations in the GRF-induced HA and growth hormone responses were also observed, responses being lower in the evening than in the morning. It is concluded that GRF interacts with HA at the central level to optimize the function of the somatotropinergic system.

  19. Prolonged labour : women's experiences

    Nystedt, Astrid


    Aim: The overall aim of this thesis was to illuminate, describe, and promote understanding of women’s experiences of prolonged labour. The thesis compromises four studies. Methods: Paper I describes a case-referent study that recruited women (n = 255) giving singleton live birth to their first child by spontaneous labour after more than 37 completed weeks’ pregnancy. Participants completed a questionnaire that investigated childbirth experiences, previous family relationships, and childhood e...

  20. Epidemiology of two large measles virus outbreaks in Catalonia: what a difference the month of administration of the first dose of vaccine makes.

    Torner, Núria; Anton, Andres; Barrabeig, Irene; Lafuente, Sara; Parron, Ignasi; Arias, César; Camps, Neus; Costa, Josep; Martínez, Ana; Torra, Roser; Godoy, Pere; Minguell, Sofia; Ferrús, Glòria; Cabezas, Carmen; Domínguez, Ángela; Spain


    Measles cases in the European Region have been increasing in the last decade; this illustrates the challenge of what we are now encountering in the form of pediatric preventable diseases. In Catalonia, autochthonous measles was declared eliminated in the year 2000 as the result of high measles-mumps-rubella vaccine (MMR) coverage for first and second dose (15 mo and 4 y) since the mid-1990s. From then on, sporadic imported cases and small outbreaks appeared, until in 2006-2007 a large measles outbreak affecting mostly unvaccinated toddlers hit the Barcelona Health Region. Consequently, in January 2008, first dose administration of MMR was lowered from 15 to 12 mo of age. A new honeymoon period went by until the end of 2010, when several importations of cases triggered new sustained transmission of different wild measles virus genotypes, but this time striking young adults. The aim of this study is to show the effect of a change in MMR vaccination schedule policy, and the difference in age incidence and hospitalization rates of affected individuals between both outbreaks.   Epidemiologic data were obtained by case interviews and review of medical records. Samples for virological confirmation and genotyping of cases were collected as established in the Measles Elimination plan guidelines. Incidence rate (IR), rate ratio (RR) and their 95% CI and hospitalization rate (HR) by age group were determined. Statistic z was used for comparing proportions. Total number of confirmed cases was 305 in the 2010 outbreak and 381 in the 2006-2007 outbreak; mean age 20 y (SD 14.8 y; 3 mo to 51 y) vs. 15 mo (SD 13.1 y; 1 mo to 50 y). Highest proportion of cases was set in ≥ 25 y (47%) vs. 24.2% in 2006 (p < 0.001). Differences in IR for ≤ 15 mo (49/100,000 vs. 278.2/100,000; RR: 3,9; 95%CI 2,9-5.4) and in overall HR 29.8% vs. 15.7% were all statistically significant (p < 0.001). The change of the month of age for the administration of the first MMR dose proved successful to

  1. A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration.

    Kongsui, R; Johnson, S J; Graham, B A; Nilsson, M; Walker, F R


    Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 μg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

  2. Blood CoQ10 levels and safety profile after single-dose or chronic administration of PureSorb-Q40: animal and human studies.

    Nukui, Kazuki; Yamagishi, Toshihiko; Miyawaki, Hiromi; Kettawan, Aikkarach; Okamoto, Tadashi; Belardinelli, Romualdo; Tiano, Luca; Littarru, Gian Paulo; Sato, Kiyoshi


    Coenzyme Q10 (CoQ10) is known to be highly hydrophobic and, as such, insoluble in water: this leads to serious inconvenience when trying to incorporate it in food products. Its absorption is also known to be very limited. PureSorb-Q40 (P40) (Water-soluble type CoQ10 powder, CoQ10 content 40 w/w % was developed in order to improve its use with food products and to enhance its absorption. In the present study the absorption of this novel formulation was compared to a conventional lipid soluble CoQ10 by administering both products to rats and humans. Acute, single-administration studies in rats showed that P40 has a higher absorption, compared to lipid soluble CoQ10, both in prandial and fasting states. Similarly, single administration in humans revealed a higher absorption level for P40, taken in the fasting state or together with meals. In the rat study, no adverse effects were observed with P40 at doses up to 2,000 mg/kg in both sexes. In a double-blind, placebo controlled, comparative study conducted on 46 healthy volunteers and randomly divided into two groups, in the group receiving 900~mg of CoQ10 per day, for 4 consecutive weeks, the average level at two weeks was 8.79 +/- 3.34 microg/mL, similar to the corresponding level after 4 weeks (8.33 +/- 4.04 microg/mL). After 2 weeks of washout, serum CoQ10 level decreased to 1.30 +/- 0.49 microg/mL. P40 intake did not cause any significant changes in symptoms and clinical laboratory tests as assessed by physical, hematological, blood biochemical or urinalysis. Clinical examinations also did not reveal any abnormalities. The above blood (serum) CoQ10 level at 2 weeks after start of intake was compared with other reported values. The same dose of CoQ10 (900mg/day), when administered by softgel capsules yielded a plasma CoQ10 concentration of 3.6 microg/mL, while P40 levels were 8.79 +/- 3.34 microg/mL. These levels are remarkably high for instance when compared to the corresponding levels obtained, in patients

  3. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

    S. Christensen; Kusano, E; Yusufi, A N; Murayama, N; Dousa, T P


    A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study...

  4. Use of octreotide to treat prolonged sulfonylurea-induced hypoglycemia in a patient with chronic renal failure.

    Nzerue, C M; Thomas, J; Volcy, J; Edeki, T


    A diabetic patient with chronic renal failure who developed recurrent and prolonged episodes of hypoglycemia associated with use of sulfonylurea agent is presented here. This patient was hospitalized with neuroglycopenic symptoms of hypoglycemia that persisted in spite of large doses of parenteral glucose replacement. On administration of somatostatin analogue octreotide, hypoglycemia resolved and, blood glucose levels were maintained even after cessation of parenteral glucose. The patient received 2 subcutaneous doses of octreotide 12 hours apart, and made a complete recovery. Our experience suggests that use of octerotide to treat refractory or prolonged sulfonylurea-included hypoglycemia in renal failure patients is safe and effective; large prospective studies would be needed to validate these findings.

  5. 替莫唑胺联合小剂量缓激肽对延长胶质瘤大鼠生存期的观察%Observe effects of Temozolomide combined with low dose Bradykinin in prolonging survival time of rat with glioma

    于倩; 宋飞; 刘贺; 白莉娜


    Objective To investigate the effect of Temozolomide combined with low dose Bradykinin for glioma therapy. Methods To use the stereotactic method to establish the C6 glioma model rats,and lest the glioma growth by MRI. Observerd the survival condition of the models treated with Temozolomide and Temozolomide with low dose Bradykinin,studied the survival times in different groups by statistical analysis. Resnlts Temozolomide could prolong the survival times of the models,and prolonged more signally after treated with low dose Bradykinin. Conclusion Temozolomide has curative effect for glioma,low dose Bradykinin can open blood brain barrier,temozolomide combined with low dose Bradykinin can treat glioma effectively,prolong the survival times of the rat models.%目的 探讨替莫唑胺联合小剂量缓激肽对胶质瘤的治疗作用.方法 立体定向法建立大鼠C6胶质瘤模型,MRI检测胶质瘤生长情况.观察常规使用替莫唑胺及替莫唑胺联合小剂量缓激肽后C6胶质瘤大鼠的生存情况,不同组别大鼠的生存期进行统计学分析.结果 替莫唑胺可以有效延长C6胶质瘤大鼠的生存期,联合小剂量缓激肽后C6胶质瘤大鼠的生存期延长更显著.结论 替莫唑胺对胶质瘤有治疗作用,小剂量缓激肽可以选择性开放血脑屏障,替莫唑胺联合小剂量缓激肽可以有效治疗胶质瘤,延长大鼠生存期.

  6. Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

    Kraemer, Thomas; Roditis, Susanne K; Peters, Frank T; Maurer, Hans H


    Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

  7. Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval

    Naessens Ineke


    Full Text Available Abstract Background Several clinical studies have established the efficacy, safety, and tolerability of long-acting risperidone administered once every 2 weeks in patients with schizophrenia or schizoaffective disorder. This report evaluates preliminary efficacy, safety, tolerability, and pharmacokinetic data for a novel (once-monthly administration of long-acting injectable risperidone 50 mg in patients with schizophrenia or schizoaffective disorder. Methods Clinically stable patients participated in a 1-year, open-label, single-arm, multicenter pilot study. During the 4-week lead-in phase, patients received long-acting risperidone 50 mg injections every 2 weeks, with 2 weeks of oral risperidone supplementation. Injections of long-acting risperidone 50 mg every 4 weeks followed for up to 48 weeks, without oral supplementation. The primary endpoint was relapse; other assessments included PANSS, CGI-S, adverse event reports, and determination of risperidone and 9-hydroxyrisperidone plasma concentrations. Results Twelve patients in the intent-to-treat population (n = 67 met relapse criteria (17.9%. Relapse risk at 1 year was estimated as 22.4%. Non-statistically significant improvements in symptoms (PANSS and clinical status (CGI-S at endpoint were observed. The most common adverse events included schizophrenia aggravated not otherwise specified (19.5%, anxiety (16.1%, insomnia (16.1%, and headache (11.5%. There were no unexpected safety and tolerability findings. Mean plasma concentrations for risperidone and 9-hydroxyrisperidone were generally stable during the study. Conclusion Once-monthly dosing of long-acting risperidone was well tolerated, associated with a relatively low relapse rate (similar to that reported with other antipsychotics, and maintained the clinically stable baseline status of most patients. Although the results suggest that some symptomatically stable patients with schizophrenia or schizoaffective disorder might be safely

  8. Effect of large contrast agent dose and prolong scanning time on the image quality of CT portal venous phase images in patients with liver cirrhosis%延长扫描时间和大剂量对比剂对肝硬化患者门静脉期CT图像质量的影响

    鲁慧; 杨剑


    目的:探讨大剂量对比剂及延长扫描时间对肝硬化患者门静脉期CT图像质量的影响。方法选取75例肝硬化患者,其中采用常规时间常规剂量扫描(60 s,1.5 ml/kg)患者为对照组(25例),延长扫描时间(70 s)患者为延长组(25例),在延长扫描时间的基础上增加对比剂剂量(2.5 ml/kg)患者为大剂量组(25例),不同延长扫描时间和不同扫描剂量肝静脉、肝实质、门静脉强化峰值、平均强化峰值时间与图像质量双盲目测评分值的差异。结果延长扫描时间后,延长组肝静脉、肝实质、门静脉强化峰值、静脉与肝实质差值、图像质量评分为(206.4±3.6)Hu、(110±13)Hu、(188±13)Hu、(74±11)Hu、(3.0±1.2)分,均明显高于对照组,肝实质、门静脉平均强化峰值时间明显低于对照组,2组比较差异具有统计学意义(P<0.05);在延长扫描时间的基础上增大对比剂剂量后,大剂量组上述指标分别为(218±11)Hu、(115±14)Hu、(214±16)Hu、(86±13)Hu、(3.6±0.7)分、(63.8±2.9)s、(44±5)s,均明显优于延长组,2组比较差异具有统计学意义(P<0.05)。结论延长扫描时间(70 s)和增加对比剂剂量(2.5 ml/kg)在一定程度上改善肝硬化患者门静脉期CT图像质量,有利于获取更清晰的CT图像。%Objective To discuss effect of large contrast agent dose and prolonged scanning time on the image quality of CT portal venous phase images in patients with liver cirrhosis. Methods Seventy-five cases of liver cirrho-sis were divided into three groups, which used the conventional time and dose scan (60 s, 1.5 ml/kg) were chosen as control group (25 cases), prolonged scanning time (70 s) and conventional dose scan were as prolonged group (25 cases), high dose (2.5 ml/kg) and prolonged scanning time were as high dose group (25 cases). The

  9. Analysis on the allocation of administrative dose control of personal dosimetry in the HU Ramon y Cajal in Madrid; Analisis sobre la asignacion de dosis adminsitrativas en el control de dosimetria personal en el Hu Ramon y Cajal de Madrid

    Sanchez, K.; Prieto, D.; Alonso, L.; Sastre, J. M.; Ferrer, N.; Arranz, L.


    Continuing education programs and information and personal follow through written and verbal notifications implemented in the hospital have allowed to know the causes of non-delivery of the dosimeter, reduce the percentage of administrative dose assignment and achieve a more effective dosimetric control.

  10. Comparison of the Concentrations of Lidocaine in Different Body Fluids/Tissues after Subarachnoid Space and Intravenous Administration of a Lethal Dose of Lidocaine

    Nan Zhang


    Full Text Available The objective of the study was to compare the concentration of lidocaine in different body fluids/tissues after subarachnoid space and intravenous administrations of a lethal dose of lidocaine. Totally 18 dogs were used in the experiment. Six dogs were given subarachnoid anesthesia, another were given an intravenous injection of a dose of 75 mg/kg weight of lidocaine hydrochloride in 5 min and the last 6 dogs were used as the blank control dogs and given a subarachnoid space injection or a femoral artery injection of the same volume of sodium chloride. As soon as its vital signs disappeared, each dog was dissected and the specimen, such as brain, cerebrospinal fluid (CSF in lateral ventricle, CSF in subarachnoid space, spinal cord (cervical spinal cord, thoracic spinal cord, lumbar spinal cord, and waist spinal cord, heart, lung, liver, spleen, kidney, bile, urine, heart blood, peripheral blood, muscle in injection location, and muscle in no injection location, were collected for analysis of lidocaine immediately. Analysis was performed with gas chromatography-mass spectrometry (GC-MS. From the maximum to the minimum, the order of lidocaine concentration detected in the subarachnoid space-administered dogs was as follows: CSF in subarachnoid space, waist spinal cord, thoracic spinal cord, CSF in lateral ventricle, lumbar spinal cord, cervical spinal cord, lung, kidney, muscle in injection location, heart, brain, spleen, heart blood, liver, peripheral blood, bile, muscle in no injection location, and urine. The order of lidocaine concentration detected in the intravenously administered dogs was as followed: Kidney, heart, lung, spleen, brain, liver, peripheral blood, bile, heart blood, cervical spinal cord, thoracic spinal cord, muscle in injection location, lumbar spinal cord, muscle in no injection location, CSF in subarachnoid space, urine, and CSF in lateral ventricle. The maximum concentration of lidocaine was detected in the subarachnoid

  11. Low doses of paraquat and polyphenols prolong life span and locomotor activity in knock-down parkin Drosophila melanogaster exposed to oxidative stress stimuli: implication in autosomal recessive juvenile parkinsonism.

    Bonilla-Ramirez, Leonardo; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos


    Previous studies have shown that polyphenols might be potent neuroprotective agents in Drosophila melanogaster wild type Canton-S acutely or chronically treated with paraquat (PQ), a selective toxin for elimination of dopaminergic (DAergic) neurons by oxidative stress (OS), as model of Parkinson's disease (PD). This study reports for the first time that knock-down (K-D) parkin Drosophila melanogaster (TH-GAL4; UAS-RNAi-parkin) chronically exposed to PQ (0.1-0.25 mM), FeSO(4) (Fe, 0.1mM), deferoxamine (DFO, 0.01 mM) alone or (0.1mM) PQ in combination with polyphenols propyl gallate (PG, 0.1mM) and epigallocathecin gallate (EGCG, 0.1, 0.5mM) showed significantly higher life span and locomotor activity than untreated K-D flies or treated with (1, 5, 20mM) PQ alone. Whilst gallic acid (GA, 0.1, 0.5mM) alone or in the presence of PQ provoked no effect on K-D flies, epicathecin (EC, 0.5mM) only showed a positive effect on prolonging K-D flies' life span. It is shown that PG (and EGCG) protected protocerebral posterolateral 1 (PPL1) DAergic neurons against PQ. Interestingly, the protective effect of low PQ concentrations, DFO and iron might be explained by a phenomenon known as "hormesis." However, pre-fed K-D flies with (0.1mM) PQ for 7 days and then exposed to (0.25 mM) for additional 8 days affect neither survival nor climbing of K-D Drosophila compared to flies treated with (0.25 mM) PQ alone. Remarkably, K-D flies treated with 0.1mM PQ (7 days) and then with (0.25 mM) PQ plus PG (8 days) behaved almost as flies treated with (0.25 mM) PQ. Taken these data suggest that antioxidant supplements that synergistically act with low pro-oxidant stimuli to prolong and increase locomotor activity become inefficient once a threshold of OS has been reached in K-D flies. Our present findings support the notion that genetically altered Drosophila melanogaster as suitable model to study genetic and environmental factors as causal and/or modulators in the development of autosomal

  12. Comparison of the deviation distribution in the doses administrated with and without mask in radiotherapeutic procedures; Comparacion de la distribucion de los desvios en las dosis administradas con y sin mascara en procedimientos radioterapicos

    Santos Junior, S. dos; Ghilardi N, T. [Departamento de Fisica e Matematica FFCLRP-USP, Av. Bandeirantes, 3900 CEP 14040-901, Cidade Universitari, Ribeirao Preto, SP (Brazil)


    In order to guarantee that the error limit in the dose administration is inside of the recommended limit by the ICRU (the ICRU recommends that the doses administrated in radiotherapy must be inside of a total deviation {+-} 5 %), the radiotherapy services are maintaining quality control programs and dosimetry which guarantee that the equipment yield or source should be known with precision. The Quality Control Programs foresee moreover the radiation beam calibration dosimetry, the In vivo dosimetry for obtaining a greater control of the administered doses. At present it counts on greater devices for maintaining the deviations inside this margin, and one of them is the u se of masks. The present work was carried out on a Siemens equipment model Gammatron S-80 (Co-60) in the Radiotherapy Service of the Sao Paulo University Hospital where teletherapy procedures are realized. (Author)

  13. 大剂量rhG-CSF早期单次给药对60Coγ射线照射小鼠的治疗作用%Therapeutic effects of early administration of a single high dose of rhG-CSF on mice irradiated by 60Coγ rays

    韩阿如娜; 余祖胤; 柳晓兰; 从玉文


    Objective To observe the therapeutic effects of early administration with a single high dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on mice irradiated with 60Co γ rays, and provide a reference for the treatment of acute radiation syndrome (ARS) by using cytokines. Methods Male C57 mice underwent a total body irradiation of 8. Ogy 60Co y ray, and they were treated with rhG-CSF, at 0.5h and 24h, subcutaneously in a dose of 2, 1 and 0. 5mg/kg, respectively. The 30-day survival rate and mean survival time were observed in the lethal irradiated mice. The peripheral blood cell counts and bone marrow nucleated cell counts were evaluated in the sublethally irradiated mice. Results Early administration of a high dose of rhG-CSF significantly increased 30-day survival rate and prolonged mean survival time of mice with lethal irradiation dose. A single injection of rhG-CSF (lmg/kg) at 0. 5h after irradiation was an optimal administration schedule. In addition, early administration with a single high dose of rhG-CSF improved the recovery of bone marrow nucleated cell counts and peripheral blood counts, including white blood cell (WBC), red blood cell (RBC) and platelet in mice exposed to 6. Ogy irradiation. Conclusion Early administration of a single high dose rhG-CSF may have a favorable therapeutic effect on mice irradiated with 60Co y ray.%目的 观察大剂量rhG-CSF早期单次给药对60Coγ射线照射小鼠的治疗作用,为细胞因子治疗急性放射病提供实验依据.方法 雄性C57小鼠,经8.0Gy 60Co γ射线全身照射后于0.5、24h各皮下注射一次不同剂量rhG-CSF(2、1mg/kg和0.5mg/kg),观察致死剂量照射小鼠的30d存活率及平均生存时间.小鼠经6.0Gy 60Co γ射线全身照射后,通过不同给药方案及不同剂量rhG-CSF早期干预,观察亚致死剂量照射小鼠的外周血象和骨髓有核细胞数的变化.结果 大剂量rhG-CSF早期干预明显提高致死剂量照射小鼠的30d存

  14. Severe bradycardia and prolonged hypotension in ciguatera.

    Chan, Thomas Yan Keung


    Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed.

  15. [(111)In-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: an overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy.

    Pool, Stefan E; Kam, Boen L R; Koning, Gerben A; Konijnenberg, Mark; Ten Hagen, Timo L M; Breeman, Woulter A P; Krenning, Eric P; de Jong, Marion; van Eijck, Casper H J


    With the aim to improve peptide receptor radionuclide therapy effects in patients with gastroenteropancreatic neuroendocrine tumor (GEPNET) liver metastases we explored the effect of intra-arterial (IA) administration of [(111)In-DTPA]octreotide ((111)In-DTPAOC) on tumor uptake in an animal model and in a patient study. Preclinical study: After administering (111)In-DTPAOC intra-venously (IV) or IA, biodistribution studies were performed in rats with a hepatic somatostatin receptor subtype 2 (sst2)-positive tumor. Clinical study: 3 patients with neuroendocrine liver metastases were injected twice with (111)In-DTPAOC. The first injection was given IV, and 2 weeks later, the second was injected IA (hepatic artery). Planar images of the abdomen were made up to 72 hours after injection. Blood samples were taken and urine was collected. Pharmacokinetic modeling was performed on the IV and IA data of the same patient. Based on this model, additional (177)Lu dosimetry calculations for IV and IA administrations were performed. The preclinical study showed a two-fold higher (111)In-DTPAOC tumor uptake after IA administration than after IV injection. Patient data showed a large variability in radioactivity increment in liver metastases after IA administration compared with IV administration. Renal radioactivity was not significantly lower after IA administration; (177)Lu dosimetry simulations in 1 patient using a maximum kidney radiation dose of 23 Gy showed IA administration resulted in a mean increase in tumor radiation dose of 2.9-fold. Preclinical and clinical data both indicate that IA administration of radiolabeled somatostatin analogs via the hepatic artery can significantly increase radionuclide uptake in GEPNET, sst2-positive, liver metastases up to 72 hours postinjection, although the effect of IA administration can differ between patients.

  16. Decrease of D2 receptor binding but increase in D2-stimulated G-protein activation, dopamine transporter binding and behavioural sensitization in brains of mice treated with a chronic escalating dose 'binge' cocaine administration paradigm.

    Bailey, A; Metaxas, A; Yoo, J H; McGee, T; Kitchen, I


    Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

  17. Comparison of administration of single dose ceftriaxone for elective caesarean section before skin incision and after cord clamping in preventing post-operative infectious morbidity.

    Kalaranjini, S; Veena, P; Rani, Reddi


    To compare the efficacy of ceftriaxone before skin incision and after cord clamping in preventing post-operative infectious morbidity and neonatal outcome in elective caesarean section and to determine the effect of antibiotic prophylaxis before skin incision on neonatal outcome. Our study was a randomised controlled trial conducted among 874 women undergoing elective caesarean section from October 2010 to July 2012. These women were randomly categorised into two groups with 437 women in each group. Group 1 received single dose of ceftriaxone 1 g intravenously 15-45 min before skin incision. Group 2 received the antibiotic after cord clamping. Primary outcome measures were maternal post-operative infectious morbidities like surgical site wound infection, febrile morbidity, endometritis, urinary tract infections and neonatal sepsis. Results were analysed using Chi-square test and unpaired t test. Surgical site wound infection occurred in 3 women in group 1 (0.7%) and 6 women in group 2 (1.4%). Fever occurred in 9 women in group 1 (2.1%) and 5 in group 2 (1.1%) with the p value of 0.419, not statistically significant. Urinary tract infection occurred in 9 women in group 1 (2.1%) and 7 women in group 2 (1.6%) with the p value of 0.801. None of the women in either group developed endometritis. About 20 neonates [10 neonates (2.3%) in group 1 and 10 neonates (2.3%) in group 2] required NICU admission after caesarean delivery. The reasons for admission were respiratory distress, prematurity and congenital anomaly. About 0.9% of neonates in group 1 and 1.8% in group 2 developed neonatal sepsis with positive blood culture (p = 0.388). Timing of administration of prophylactic antibiotics for elective caesarean section either before skin incision or after cord clamping did not have significant difference in the occurrence of post-operative infectious morbidity. No adverse neonatal outcome was observed in women who received the antibiotic before skin incision.

  18. High-Dose Pyridoxine and Magnesium Administration in Children with Autistic Disorder: An Absence of Salutary Effects in a Double-Blind, Placebo-Controlled Study.

    Findling, Robert L.; Maxwell, Kathleen; Scotese-Wojtila, Lynette; Huang, Jie; Yamashita, Toyoko; Wiznitzer, Max


    Evaluation of high doses of pyridoxine and magnesium in a 10-week double-blind placebo-controlled trial with 10 patients (mean age 6 years) having autism concluded that the high doses used were ineffective in ameliorating autistic behaviors. (DB)

  19. Prevention of Postoperative Nausea and Vomiting by Administration of Sub Hypnotic Doses of Propofol and Midazolam during Spinal Anesthesia for Cesarean Section

    Saghar Samimi Sade


    Conclusion: Sub hypnotic dose of midazolam was as effective as the sub hypnotic dose of propofol for preventing of nausea and vomiting in parturients undergoing cesarean section under spinal anesthesia. We undertook this study in regard to examine a simple, safe and non-expensive antiemetic method.

  20. Anti-nociceptive effect induced by intrathecal injection of ATPA, an effect enhanced and prolonged by concanavalin A.

    Wu, Dong-Chuan; Zhou, Ning; Yu, Long-Chuan


    The present study investigated the effect of intrathecal injection of (RS)-2-alpha-amino-3-(3-hydroxy-5-tbutylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist to kainate receptor, on nociception in rats. Intrathecal administration of 1, 4 and 10 nmol of ATPA induced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats. Pretreatment with intrathecal injection of 300 microg of concanavalin A (ConA) to block the desensitization of kainate receptors enhanced and prolonged the anti-nociceptive effect induced by intrathecal injection of ATPA. The results suggest that the pre-synaptic kainate receptor in the primary afferent terminals is involved in the transmission of nociceptive information in dorsal horn of the spinal cord in rats. Furthermore, blocking the desensitization of kainate receptor enhanced and prolonged the ATPA-induced anti-nociceptive effects.

  1. Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects.

    Darwish, Mona; Kirby, Mary; Hellriegel, Edward T


    Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil. At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

  2. Concomitant Administration of High-dose Methotrexate and Low-dose Aspirin Without Any Delay in Methotrexate Clearance in a Patient With Osteosarcoma: A Case Report and Review of the Literature.

    Renzi, Samuele; Tsimerman, Ekaterina; Taylor, Tracey; Hopyan, Sevan; Koo, Alicia; Gupta, Abha


    Methotrexate (MTX) is a commonly used agent in the treatment of oncology patients whose clearance depends on renal health maintaining glomerular filtration and tubular secretion. Thus concomitant use of other drugs that utilize the same mechanism of clearance are generally avoided as this may contribute to increased MTX-associated toxicity. Herein, we describe the use of low-dose aspirin with high-dose MTX in a patient with osteosarcoma. Concomitant aspirin use did not affect the clearance of high-dose MTX and the patient did not experience any MTX-related toxicity including mucositis or renal impairment.

  3. 循环应用低剂量环磷酰胺联合过继免疫治疗的抗黑色素瘤作用%The anti-melanoma effect of cyclical administration of low-dose cyclophosphamide combined with cellular immunotherapy

    李卫泊; 尹昱; 张峻岭; 谢绍建; 蔡建辉


    Objective:To observe the influence of cyclical low-dose cyclophosphamide (CTX) administration on regulatory T cell of melanoma-bearing mice, and the anti-tumor effects of combination with CTLs adoptive transfusion, explore its possible mechanism. Methods: Models of tumor-bearing mice were established by subcutaneous inoculation with melanoma cells. The changes of the CD4 + CD25 + Foxp3 + Treg in spleens were detected by flow cytometry. The dendritic cells derived from the bone marrow of mice were cultured, and the tumor antigen-specific CTLs were prepared by cultivation in vitro. Tumor-bearing mice were injected intraperitoneally with CTX every 7 days, then received CTLs by veinous transfusion 4 days later, which were repeated 3 cycles. The growth curves of tumor were drawn. Results: With time prolonged after tumor inoculation, the proportion of CD4 + CD25 + Foxp3 + /CD4 + was increased gradually in mice. Single administration of CTX only inhibited Tregs in short time, while cyclical administration of CTX could prolong the period in which Tregs was kept at low level. Cyclical administration of CTX could not delay the growth of tumor. But the tumor growth was delayed more significantly in cyclical CTX + CTLs group (P < 0. 05) , autoimmune vitiligo and other adverse side effect were not observed in mice treated with CTX. Conclusion: Cyclical administration of low-dose CTX could enhence the anti-tumor effect of CTLs adoptive transfusion by regulating Tregs.%目的:观察循环应用低剂量环磷酰胺(CTX)对荷瘤鼠调节性T细胞(Tregs)的影响,及联合细胞毒性T细胞(CTLs)过继免疫治疗的实际抗瘤效果并探讨其中可能的机制.方法:通过皮下接种瘤细胞制备黑色素瘤荷瘤鼠模型;腹腔注射CTX,每隔7天给药一次,共3次;应用流式细胞术检测小鼠脾脏中CD4+CD25+Foxp3+调节性T细胞(Tregs)的变化.体外培养小鼠骨髓来源的树突状细胞(DCs),制备肿瘤抗原特异性的CTLs.在腹腔注射CTX后4

  4. Chronic oral administration of low-dose combination of fenofibrate and rosuvastatin protects the rat heart against experimentally induced acute myocardial infarction.

    Garg, Monika; Khanna, Deepa; Kalra, Sanjeev; Balakumar, Pitchai


    Fenofibrate and rosuvastatin at low doses might have experimental pleiotropic benefits. This study investigated the combined effect of low doses of fenofibrate and rosuvastatin in isoproterenol-induced experimental myocardial infarction. Rats administered isoproterenol (85 mg/kg/day, s.c.) for 2 days (day 29 and day 30) of 30 days experimental protocol developed significant myocardial infarction that was accompanied with high myocardial oxidative stress and lipid peroxidation, elevated serum markers of cardiac injury, lipid abnormalities, and elevated circulatory levels of C-reactive protein. Pretreatment with low doses of fenofibrate (30 mg/kg/day p.o., 30 days) and rosuvastatin (2 mg/kg/day p.o., 30 days) both alone or in combination markedly prevented isoproterenol-induced myocardial infarction and associated abnormalities while the low-dose combination of fenofibrate and rosuvastatin was more effective. Histopathological study in isoproterenol control rat heart showed necrosis with edema and acute inflammation at the margins of necrotic area. The rat heart from low-dose fenofibrate and rosuvastatin pretreated group showed scanty inflammation and no ischemia. In conclusion, fenofibrate and rosuvastatin pretreatment in low doses might have a therapeutic potential to prevent the pathogenesis of myocardial infarction. Moreover, their combined treatment option might offer superior therapeutic benefits via a marked reduction in myocardial infarct size and oxidative stress, suggesting a possibility of their pleiotropic cardioprotective action at low doses. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  5. Comparison of Gavage, Water Bottle, and a High-Moisture Diet Bolus as Dosing Methods for Quantitative D-xylose Administration to B6D2F1 (Mus musculus) Mice

    Zimmer, J. Paul; Lewis, Sherry M.; Moyer, Jerry L.


    Gavage, water bottle, and diet incorporation are 3 dosing methods used orally to administer test compounds to rodents. These 3 methods were compared in mice to determine which represented the most quantitative delivery system. For dietary incorporation, a high-moisture bolus form of NIH-31 rodent meal was developed using hydroxypropyl methylcellulose as an autoclave-stable binding agent. A high-moisture bolus were selected to increase the acceptability of the dosed diet and to promote quantitative consumption through reduced wastage. The test compound used was D-xylose, a pentose sugar that may be quantitatively detected, colorimetrically, in urine following oral dosing. Six male and 6 female B6D2FI mice were placed in metabolism cages and dosed with a known quantity of D-xylose by each of the 3 methods. Urine was collected before and after each method of administration and analysed for total D-xylose; the per cent recovery was based upon the amount of D-xylose consumed. Quantitative consumption was apparently greatest for water bottle dosing with an average recovery of 56.0% of the original D-xylose dose. High-moisture bolus incorporation ranked second with 50.0% D-xylose recovery, and gavage was third with 41.0% D-xylose recovery.

  6. Tolerability and efficacy of single dose albendazole, diethylcarbamazine citrate (DEC) or co-administration of albendazole with DEC in the clearance of Wuchereria bancrofti in asymptomatic microfilaraemic volunteers in Pondicherry, South India: a hospital-based study

    Pani, SP; Subramanyam Reddy, G; Das, LK; P. Vanamail; Hoti, SL; Ramesh, J.; Das, PK


    Background The tolerability and efficacy of single dose albendazole (400 mg), diethylcarbamazine citrate (DEC) (6 mg/kg bodyweight) or co-administration of albendazole (400 mg) + DEC (6 mg/kg bodyweight) was studied in 54 asymptomatic Wuchereria bancrofti microfilaraemic volunteers in a double blind hospital-based clinical study. Results There was no significant difference in the overall incidence of adverse reactions between the three drug groups [42.1% (albendazole), 52.9% (DEC) and 61.1% (...

  7. Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

    Childers, Martin K; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W; Doering, Jonathan A; Lawlor, Michael W; Rider, Branden E.; Jamet, Thibaud; Danièle, Nathalie; Martin, Samia; Rivière, Christel; Soker, Thomas; Hammer, Caroline; Van Wittenberghe, Laetitia; Lockard, Mandy; Guan, Xuan; Goddard, Melissa; Mitchell, Erin; Barber, Jane; Williams, J. Koudy; Mack, David L; Furth, Mark E; Vignaud, Alban; Masurier, Carole; Mavilio, Fulvio; Moullier, Philippe; Beggs, Alan H; Buj-Bello, Anna


    Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype-8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged lifespan to more than one year in the absence of toxicity, humoral and cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small and large animal models, and provide proof of concept for future clinical trials in XLMTM patients. PMID:24452262


    Hema Divakar


    Full Text Available BACKGROUND The aim of the study is to determine the non-inferiority of a single dose of 500 mg Ferric Carboxymaltose (FCM (Group 1 to a single dose of 1000 mg (Group 2 in treating women with postpartum anaemia. MATERIALS AND METHODS Women were recruited within 24 hours of delivery and randomised to one of the two study groups excluded were mothers with non-iron deficiency anaemia, iron intolerance and haematological disease. Haematological markers were measured at baseline and at 6 weeks after treatment. Main Outcome Measures- The primary outcome was an Hb increase ≥20 g/L. Secondary outcomes included the proportion of patients attaining Hb ≥120 g/L and the mean Hb change. Design- Open label, randomised, non-blinded, prospective study. Setting- Maternity units of four hospitals in Southern India. Population- Women ≥18 years old with haemoglobin of >60 - 20 g/L between Groups 1 and 2 (91.4% versus 96.7%. Similar proportions of women in both groups became non-anaemic achieving an Hb of >120 g/L (57% versus 45.7%. The mean Hb change was comparable between the groups and both doses were well tolerated. CONCLUSION A single dose of 500 mg FCM (cost INR 2000.00 is non-inferior to a 1000 mg dose (cost INR 5000.00 in the treatment of postpartum anaemia. This has major implications for the scaling up of the eradication of iron-deficiency anaemia in India, since double the number of women who would otherwise have been treated with the 1000 mg dose can be treated with half the dose at less than half the cost with similar outcomes. Tweetable Abstract- A single dose of 500 mg FCM is a safe, efficacious and cost-effective treatment for PPA in India.

  9. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N


    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  10. The timing of administration, dose dependence and efficacy of dopa decarboxylase inhibitors on the reversal of motor disability produced by L-DOPA in the MPTP-treated common marmoset.

    Tayarani-Binazir, Kayhan A; Jackson, Michael J; Fisher, Ria; Zoubiane, Ghada; Rose, Sarah; Jenner, Peter


    Dopa decarboxylase inhibitors are routinely used to potentiate the effects of L-DOPA in the treatment of Parkinson's disease. However, neither in clinical use nor in experimental models of Parkinson's disease have the timing and dose of dopa decarboxylase inhibitors been thoroughly explored. We now report on the choice of dopa decarboxylase inhibitors, dose and the time of dosing relationships of carbidopa, benserazide and L-alpha-methyl dopa (L-AMD) in potentiating the effects of L-DOPA in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated common marmoset. Pre-treatment with benserazide for up to 3h did not alter the motor response to L-DOPA compared to simultaneous administration with L-DOPA. There was some evidence of a relationship between carbidopa and benserazide dose and increased locomotor activity and the reversal of motor disability. But in general, commonly used dose levels of dopa decarboxylase inhibitors appeared to produce a maximal motor response to L-DOPA. In contrast, dyskinesia intensity and duration continued to increase with both carbidopa and benserazide dose. The novel dopa decarboxylase inhibitor, L-AMD, increased locomotor activity and improved motor disability to the same extent as carbidopa or benserazide but importantly this was accompanied by significantly less dyskinesia. This study shows that currently, dopa decarboxylase inhibitors may be routinely employed in the MPTP-treated primate at doses which are higher than those necessary to produce a maximal potentiation of the anti-parkinsonian effect of L-DOPA. This may lead to excessive expression of dyskinesia in this model of Parkinson's disease and attention should be given to the dose regimens currently employed.

  11. RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study

    Proescholdt Martin


    Full Text Available Abstract Background Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. Methods In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx™, PEG-Dox and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. Results The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12 was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. Conclusion Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data Trial registration NCT00944801.

  12. Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.

    Cheung, P Y; Tyebkhan, J M; Peliowski, A; Ainsworth, W; Robertson, C M


    Sensorineural hearing loss (SNHL) is a significant neurologic morbidity in survivors of neonatal congenital diaphragmatic hernia (CDH), with a reported incidence of up to 60%. In a historical cohort study of 37 neonates with CDH, we investigated the use of pancuronium bromide (PB) and common ototoxic drugs during the neonatal period and their relationship to SNHL in childhood survivors. Survivors with SNHL (n = 23) had significantly higher cumulative dose of PB administered during the neonatal illness than survivors without SNHL (n = 14). The cumulative dose and duration of PB use significantly correlated (r = 0.66-0.81) and independently predicted (adjusted r (2) = 0.42-0.64) the greatest intensity (in decibels) and the widest band (lowest frequency in hertz) loss of SNHL. No differences were identified between survivors with and without SNHL regarding demographic and neonatal characteristics (including oxygenation and ventilation variables and the cumulative dose and duration of therapy with aminoglycosides, vancomycin, and furosemide), although survivors with SNHL had received a modestly higher cumulative dose of ethacrynic acid than survivors without SNHL. Although we show that prolonged administration of PB during the neonatal period is associated with SNHL in childhood survivors of CDH, further multicenter studies are required to investigate the possible etiologies of SNHL in this high-risk population.

  13. Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats.

    Barbosa, Joana; Faria, Juliana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge


    Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused

  14. Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database.

    Chikuda, Hirotaka; Yasunaga, Hideo; Takeshita, Katsushi; Horiguchi, Hiromasa; Kawaguchi, Hiroshi; Ohe, Kazuhiko; Fushimi, Kiyohide; Tanaka, Sakae


    To examine the magnitude of the adverse impact of high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury (SCI). We examined the abstracted data from the Japanese Diagnosis Procedure Combination database, and included patients with ICD-10 code S141 who were admitted on an emergency basis between 1 July and 31 December in 2007-2009. The investigation evaluated the patients' sex, age, comorbidities, Japan Coma Scale, hospital volume and the amount of methylprednisolone administered. One-to-one propensity-score matching between high-dose methylprednisolone group (>5000 mg) and control group was performed to compare the rates of in-hospital death and major complications (sepsis; pneumonia; urinary tract infection; gastrointestinal ulcer/bleeding; and pulmonary embolism). We identified 3508 cervical SCI patients (2652 men and 856 women; mean age, 60.8 ± 18.7 years) including 824 (23.5%) patients who received high-dose methylprednisolone. A propensity-matched analysis with 824 pairs of patients showed a significant increase in the occurrence of gastrointestinal ulcer/bleeding (68/812 vs 31/812; prisk of complications (144/812 vs 96/812;OR, 1.66; 95% CI 1.23 to 2.24; p=0.001) than the control group. There was no significant difference in in-hospital mortality between the high-dose methylprednisolone group and the control group (p=0.884). Patients receiving high-dose methylprednisolone had a significantly increased risk of major complications, in particular, gastrointestinal ulcer/bleeding. However, high-dose methylprednisolone treatment was not associated with any increase in mortality.

  15. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests

    A. Ribeiro


    Full Text Available The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor® (18:1:1 and administered ip (0.1 mL/10 g body weight; control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg increased (P < 0.05 the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05 after exposing the animals to the open field test.

  16. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J


    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P open field test.

  17. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.

    Zhang, Donglu; Frost, Charles E; He, Kan; Rodrigues, A David; Wang, Xiaoli; Wang, Lifei; Goosen, Theunis C; Humphreys, W Griffith


    The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

  18. The Effect of Ethanol on the Release of Opioids from Oral Prolonged-Release Preparations

    Walden, Malcolm; Nicholls, Fiona A.; Smith, Kevin J.; Tucker, Geoffrey T


    Recent experience has prompted the US FDA to consider whether ethanol ingestion may modify the release characteristics of prolonged-release formulations, where dose dumping may be an issue for patient safety. The influence of ethanol on the in vitro release of opioid drugs from some prolonged-release formulations utilizing different release technologies was examined. Results indicated that the prolonged-release mechanisms remained intact under the testing conditions, although one product show...

  19. The effect of intraoperative and 6-h postoperative intravenous administration of low-dose prostacyclin on the endothelium, hemostasis, and hemodynamics in patients undergoing a pancreaticoduodenoctemy

    Johansson, Pär I; Mortensen, Christian R; Nielsen, Tatiana


    vasodilatory and antiplatelet effects. The present pilot study investigated the safety and endothelial protective effects of low-dose prostacyclin infusion. PATIENTS AND METHODS: A randomized placebo-controlled pilot study evaluating the effect of prostacyclin (iloprost) infusion (1.0 ng/kg/min) versus placebo...

  20. Dose Reduction in Contrast-Enhanced Cervical MR Angiography: Field Strength Dependency of Vascular Signal Intensity, Contrast Administration, and Arteriographic Quality.

    Dehkharghani, Seena; Qiu, Deqiang; Albin, Lauren S; Saindane, Amit M


    Cervical contrast-enhanced MR angiography (MRA) has proven accurate and superior to noncontrast alternatives. We proposed the systematic investigation of dose reduction in contrast-enhanced MRA, hypothesizing heightened tolerance at 3 T vs 1.5 T. Quantitative and qualitative features were compared between full-dose and 50%-reduced dose examinations at 1.5 T and 3 T. One hundred eight cervical contrast-enhanced MRA examinations were reviewed for qualitative and quantitative (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) features across four dose-field strength combinations: 1.5 T, 0.05 mmol/kg; 3 T, 0.05 mmol/kg; 1.5 T, 0.1 mmol/kg; and 3 T, 0.1 mmol/kg. Quantitative features were evaluated among the following segments: aortic arch, common carotid arteries, common carotid bifurcations, and cervical internal carotid arteries. A qualitative visual rating scale was applied for the same segments as well as to the vertebral arteries along their proximal (V1), intraforaminal (V2), and distal extraforaminal (V3) courses. Significant between-group differences were reported at p contrast-enhanced MRA is feasible at 3 T without significant compromise in arteriographic quality in most segments. Particularly at 3 T, arteriography is quantitatively and qualitatively robust and may be advisable in high-risk patients.

  1. Comparison of two doses and two routes of administration of misoprostol after pre-treatment with mifepristone for early pregnancy termination

    Marions Lena


    Full Text Available Abstract Background It is not known whether a 400 μg dose of misoprostol has a similar efficacy as an 800 μg dose when administered sublingually or vaginally 24 hours after 200 mg mifepristone. Methods It is proposed to undertake a placebo-controlled, randomized, non-inferiority trial (3% margin of equivalence of the two misoprostol doses when administered sublingually or vaginally using factorial design. A total of 3008 pregnant women ( The four treatment regimens will be compared in terms of: (i their efficacy to induce complete abortion; (ii induction-to-abortion interval when possible; (iii the frequency of side effects; and (iv women's perceptions. The initial judgment of the outcome of treatment is made at the follow-up visit on day 15 of the study and the final assessment four weeks later. It is estimated that the clinical phase will require 12–14 months for data collection. To compare the two routes and two doses, relative risks (RR of failure to achieve a complete abortion and failure to terminate pregnancy and the two-sided 95% CIs will be calculated by standard methods, as well as risk differences and two-sided 95% CIs. The latter will be used to test the non-inferiority hypotheses (at 2.5% level of significance for achieving complete abortion. The factorial structure will be taken into account in the analysis after testing the interaction. Trial registration ISRCTN87811512

  2. Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

    Ravi S.Talluri


    Full Text Available Objective: To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods: Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine- D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results: Following i.v. administration, the area under the curve (AUC in µM*min of generated ACV was in the order of LACV › LDACV › DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 µM*min, respectively. DLACV exhibited poor oral absorption. Cmax (µM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions: LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

  3. Body fluids, circadian blood pressure and plasma renin during growth hormone administration: a placebo-controlled study with two growth hormone doses in healthy adults

    Møller, Jens; Jørgensen, Jens Otto Lunde; Frandsen, Erik


    Abstract Side effects that can be related to fluid retention are common during the initial phases of growth hormone (GH) administration. The aim of this study was to examine the changes in body fluid compartments, diurnal blood pressure and plasma renin concentration during GH administration...... of treatment a significant increase in renin (p = 0.03) was observed. Mean diurnal blood pressure levels remained unchanged, whereas mean diurnal heart rate (min-1) increased significantly (placebo, 75 +/- 3.6; 3 IU m-2, 79 +/- 3.2; 6 IU m-2, 79 +/- 3.7; p

  4. Comparison of sedation scores and propofol induction doses in dogs after intramuscular administration of dexmedetomidine alone or in combination with methadone, midazolam, or methadone plus midazolam.

    Canfrán, S; Bustamante, R; González, P; Cediel, R; Re, M; de Segura, I A Gómez


    The objectives of this study were to determine: (1) the sedative effects of dexmedetomidine in combination with methadone, midazolam, or both, and (2) the propofol dose required to achieve endotracheal intubation in healthy dogs. Seven healthy Beagle dogs were included in a prospective experimental, crossover, randomised and masked design. All dogs received four treatments IM, with at least 1 week between sessions, as follows: dexmedetomidine 5 µg/kg (D) alone, or combined with methadone 0.3 mg/kg (DMe), midazolam 0.3 mg/kg (DMi), or both (DMeMi). The degree of sedation was evaluated using a numerical scale (maximum 15 points). The dose of propofol required for intubation was also calculated for each group. Recovery time and quality were determined. Statistical analysis was performed using parametric (ANOVA) and nonparametric tests (Friedman, Cochran Q), as appropriate. The degree of sedation obtained with DMe and DMeMi (13, [7-14]; 13, [6-14], respectively) was significantly higher than in the control group (2, [1-4]; P = 0.023, P = 0.006, respectively). The required dose of propofol was lower in all groups (DMi, 1.5 ± 0.5 mg/kg, P = 0.002; DMe, 1.2 ± 0.5 mg/kg, P midazolam did not enhance the sedative effects of dexmedetomidine or a dexmedetomidine-methadone combination at the doses studied, and propofol requirements were reduced. The sedative effect of dexmedetomidine was enhanced with methadone, and the required dose of propofol was reduced. Copyright © 2016 Elsevier Ltd. All rights reserved.


    张春驰; 李小梅; 董艳娟; 何跃


    Objective:To observe and evaluate the analgesic efficacy and safety of gabapentin combined with low dose prolonged-release oxycodone hydrochloride for the treatment of diabetic peripheral neuropathic pain (DPNP).Method:A total of 70 elderly patients with DPNP were randomized into 2 groups (each contains 35 cases),one accepted gabapentin monotherapy (G1),and the other received both gabapentin and low dose prolonged-release oxycodone hydrochloride (G2).The initial dose of gabapentin was 100 mg/d and gradually titrated.The dose of prolonged-release oxycodone hydrochloride was fixed at 10 mg/q 12 h,and the therapy keeps 2 weeks.VAS was evaluated before and at the 8th and 15th day of the treatment.Side effects were observed and recorded.Results:Totally 62 (G1 =30,G2 =32) patients completed the 2 weeks treatment.Basic characteristics have no significant difference including mean VAS scores between the 2 groups.After the treatment,the total rate of pain relief at the 8th and 15th day were significantly higher in G 1 compared with G2 (P < 0.05) and the rate of excellent pain relief in G1 was higher than G2 at the 8th day (P < 0.05).The mean daily dose of gabapentin at the 8th day have no significant difference between G1 and G2,but at the 15th day,G2 was significant higher than G1 (P < 0.05).The occurrence rate of constipation in G2 was obviously higher compared with G1 (P < 0.05).Conclusion:Gabapentin monotherapy or combined with low dose Prolongedrelease oxycodone hydrochloride could effectively release elderly patients' DPNP,and the efficacy of the combination therapy was better,but should give preventive measures to constipation.%目的:观察加巴喷丁联合低剂量盐酸羟考酮缓释片治疗老年糖尿病周围神经痛(diabeticperipheral neuropathic pain,DPNP)的疗效及安全性.方法:70例老年DPNP患者随机均分为两组(n=35),分别接受2周加巴喷丁单药(单药组)或加巴喷丁联合低剂量盐酸羟考酮缓释

  6. Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children.

    Sahin, Mustafa; Menache, Caroline C; Holmes, Gregory L; Riviello, James J


    High-dose suppressive therapy (HDST) is used to treat refractory status epilepticus (RSE). Prolonged therapy is required in some cases, and prognosis is important in making therapeutic decisions. The authors therefore studied the long-term outcome in previously normal children who survived prolonged HDST for acute symptomatic RSE. All have intractable epilepsy, and none returned to baseline.

  7. Effects of sildenafil on the gastrocnemius and cardiac muscles of rats in a model of prolonged moderate exercise training.

    Barbara Rinaldi

    Full Text Available Moderate exercise training improves energetic metabolism, tissue perfusion and induces cardiac and skeletal muscle remodeling. Sildenafil, a potent phosphodiesterase-5 inhibitor used to treat erectile dysfunction, reduces infarct size and increases tissue oxygenation in experimental models of cardiovascular disease. We have evaluated the effects of prolonged moderate exercise training and a repeat administration of sildenafil on the rat gastrocnemius and cardiac muscles. Animals were divided into two groups: sedentary and trained. Each group was subdivided into animals treated with vehicle or with two doses of sildenafil (10 or 15 mg/kg/day during the last week of training. Physical exercise did not induce cardiac hypertrophy, whereas it increased mRNA levels of the PGC-1α, HIF-1α and VEGF genes, which are involved in mitochondrial biogenesis and angiogenesis, and reduced mRNA levels of FoxO3a, MuRF-1 and Atrogin-1. Sildenafil dose-dependently promoted both angiogenesis, as shown by increased capillary density, and muscle atrophy, as shown by muscle fibre size. These effects were more pronounced in trained animals. Our data confirm the beneficial effects of a moderate and prolonged training on cardiovascular and skeletal systems and document the positive and negative effects of sildenafil on these tissues at doses higher than those used in clinical practice. This report may impact on the use of sildenafil as a substance able to influence sports performance.

  8. Intracerebroventricular and intravenous administration of growth hormone secretagogue L-692,585, somatostatin, neuropeptide Y and galanin in pig: dose-dependent effects on growth hormone secretion.

    Cho, S-J; Lee, J-S; Mathias, E D; Chang, C; Hickey, G J; Lkhagvadorj, S; Anderson, L L


    Central regulation of growth hormone (GH) secretion by the GH secretagogue, L-692,585 (585), was determined in Yorkshire barrows (40-45kg BW) with intracerebroventricular (icv) stainless steel cannulas placed by stereotaxic coordinates and indwelling external jugular vein (iv) cannulas for injecting 585 or saline during 3h serial blood sampling. Dose-dependent effects of 585 were determined by icv injections of saline vehicle, 3, 10, and 30microg/kg BW by once daily increment. A switchback study of iv and icv 585 treatment determined central and peripheral regulation of GH secretion by the secretagogue at 30microg/kg BW. When administered icv, 585 increased GH concentration in a dose-dependent manner, with a return to baseline by 60min. GH secretion was attenuated by increased numbers of icv 585 injections (padministration of somatostatin (SRIF) decreased (padministration indicate that the GH secretagogue and neuropeptides act at the level of both porcine pituitary and hypothalamus.

  9. Assessment of radiation dose to infants from breast milk following the administration of /sup 99m/Tc pertechnetate to nursing mothers

    Ogunleye, O.T.


    Results of measurements of /sup 99m/Tc activity in the milk samples of nursing mothers who received /sup 99m/Tc pertechnetate for thyroid scans are presented. The maximum concentration is found around 2 hours after injection. The total body dose to a 3-month-old infant feeding on the assayed milk varied with time from about 685 mrad to 0.5 mrad.

  10. Prolonged unexplained fatigue in paediatrics

    Bakker, R.J.


    Prolonged Unexplained Fatigue in Paediatrics. Fatigue, as the result of mental or physical exertion, will disappear after rest, drinks and food. Fatigue as a symptom of illness will recover with the recovering of the illness. But when fatigue is ongoing for a long time, and not the result of exertio

  11. Prolongation structures for supersymmetric equations

    Roelofs, G.H.M.; Hijligenberg, van den N.W.


    The well known prolongation technique of Wahlquist and Estabrook (1975) for nonlinear evolution equations is generalized for supersymmetric equations and applied to the supersymmetric extension of the KdV equation of Manin-Radul. Using the theory of Kac-Moody Lie superalgebras, the explicit form of




    Full Text Available : BACKGROUND: The prolongation of spinal anaesthesia by using clonidine through the oral, intravenous and spinal route has been known. The new alpha-2 agonist, dexmedetomidine has been proved to prolong the spinal anaesthesia through the intrathecal route. We hypothesized that dexmedetomidine when administered intravenously following spinal block also prolongs spinal analgesia. A placebo controlled randomized controlled trial study was done. METHODOLOGY: 50 Patients were randomly allocated into two equal groups group D and group C. Both group received spinal hyperbaric bupivacaine 15mg intrathecally. Patients in group D received intravenously a loading dose of 1mcg/kg dexmedetomidine over 10 min followed by C maintenance dose of 0.5mcg/kg/hr till the end of surgery. Patients in group C (The control group received normal saline. The regression times to reach S1 sensory level and bromage 0 motor scale, hemodynamic changes and the level of sedation were recorded. RESULTS: The duration of sensory block was longer in intravenous dexmedetomidine group compared with control group (264.32+15.3 min vs 164.2+13.12 min, p 0.001. The duration of motor block was longer in dexmedetomidine group than control group (198.8+16.9 min vs 135.8+12.38 min, p 0.001 CONCLUSION: Intravenous dexmedetomidine administration prolonged the sensory and motor blocks of bupivacaine spinal analgesia with good sedation effect and hemodynamic stability. The incidence of bradycardia is significantly high when intravenous dexmedetomidine is used as an adjuvant to bupivacaine spinal anaesthesia. Dexmedetomidine induced bradycardia and hypotension can be easily managed with atropine and mephentermine respectively. Dexmedetomidine provides excellent sedation and postoperative analgesia.

  13. Estradiol valerate and alcohol intake: dose-response assessments

    Quirarte, Gina L; Reid, Larry D; de la Teja, I Sofía Ledesma; Reid, Meta L; Sánchez, Marco A; Díaz-Trujillo, Arnulfo; Aguilar-Vazquez, Azucena; Prado-Alcalá, Roberto A


    Background An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. Results With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. Conclusion The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries. PMID:17335585

  14. Body fluids, circadian blood pressure and plasma renin during growth hormone administration: a placebo-controlled study with two growth hormone doses in healthy adults

    Møller, Jens; Jørgensen, Jens Otto Lunde; Frandsen, Erik


    Abstract Side effects that can be related to fluid retention are common during the initial phases of growth hormone (GH) administration. The aim of this study was to examine the changes in body fluid compartments, diurnal blood pressure and plasma renin concentration during GH administration......, and extracellular volume (ECV) and plasma volume (PV) were isotopically determined at day 6. Blood samples were obtained regularly. Diurnal blood pressure was recorded and 24-h urinary samples were collected at days 0, 6 and 14. ECV (l) was increased by GH (placebo, 19.58 +/- 0.82; 3 IU m-2, 20.77 +/- 1.22; 6 IU m...... of treatment a significant increase in renin (p = 0.03) was observed. Mean diurnal blood pressure levels remained unchanged, whereas mean diurnal heart rate (min-1) increased significantly (placebo, 75 +/- 3.6; 3 IU m-2, 79 +/- 3.2; 6 IU m-2, 79 +/- 3.7; p

  15. The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis

    Haase, Christoffer Bjerre; Backer, Vibeke; Kalsen, Anders


    The present study investigated the influence of exercise and dehydration on the urine concentrations of salbutamol after inhalation of that maximal permitted (1600 µg) on the 2015 World Anti-Doping Agency (WADA) prohibited list. Thirteen healthy males participated in the study. Urine concentrations......-24 h after drug administration. Adjustment of urine concentrations of salbutamol to a specific gravity (USG) of 1.020 g/mL was compared with no adjustment. The 2015 WADA decision limit (1200 ng/mL) for salbutamol was exceeded in 23, 31, and 10% of the urine samples during EX, EXD, and R, respectively......, when unadjusted for USG. When adjusted for USG, the corresponding percentages fell to 21, 15, and 8%. During EXD, mean urine concentrations of salbutamol exceeded (1325±599 ng/mL) the decision limit 4 h after administration when unadjusted for USG. Serum salbutamol Cmax was lower (P

  16. Effect of Dose and Administration Period of Seed Cake of Genetically Modified and Non-Modified Flax on Selected Antioxidative Activities in Rats.

    Matusiewicz, Magdalena; Kosieradzka, Iwona; Zuk, Magdalena; Szopa, Jan


    Flaxseed cake containing antioxidants is a valuable dietary component. Its nutritional effect may be diminished by the presence of anti-nutrients. The work was aimed at determining the effect of different contents of flaxseed cake in diets and their administration period on the development of rats and selected parameters of their health status. Diets with 15% and 30% addition of genetically modified (GM) flax seed cake with enhanced synthesis of polyphenols, as well as Linola non-GM flax were administered in short-term (33 days) and long-term (90 days) experiments. The 30% addition of flaxseed cake reduced digestibility of dietary nutrients, GM flaxseed cake lowered body weight gains. The relative weight of selected organs, hematological blood markers and serum activities of aspartate and alanine aminotransferases (AST, ALT) were not affected. Flaxseed cake consumption reduced serum concentration of albumins and increased globulins. Administration of 30% flaxseed cake improved plasma total antioxidant status and 30% GM flaxseed cake lowered liver thiobarbituric acid reactive substances. The activities of superoxide dismutase in erythrocytes, glutathione peroxidase in plasma and the liver concentration of 8-oxo-2'-deoxyguanosine were not changed. Most morphometric parameters of the small intestine did not differ between feeding groups. The administration of diets with 30% addition of flaxseed cake for 90 days improved the antioxidant status in rats.

  17. A novel oromucosal prolonged release mucoadhesive suspension by one step spray coagulation method.

    Cilurzo, Francesco; Gennari, Chiara G M; Selmin, Francesca; Musazzi, Umberto M; Rumio, Cristiano; Minghetti, Paola


    An oromucosal mucoadhesive suspension (OMS) able to combine the peculiarities of prolonged release mucoadhesive microparticles with those of an immediate release oromucosal solution is described. Microparticles were obtained by ionotropic gelation of alginate blended with another mucoadhesive material in a one step process where the cross-linking bath constituted the suspension vehicle. The effects of formulation and processing conditions on OMS performances were measured in-vitro determining the enhancement of drug penetration in buccal porcine mucosa and inhibition of tooth plaque formation using flurbiprofen and delmopinol as model drugs, respectively. Well-formed and spherical microparticles were obtained combining alginate with carbomer; linear dependence of particle size from the feed composition, viscosity and atomization pressure was found. As demonstrated by using FITC-labelled microparticles, the system remained onto the buccal mucosa at least for a six hour period. As a consequence, 0.1% flurbiprofen OMS guaranteed a concentration of flurbiprofen into buccal porcine mucosa over 6 hours comparable to 0.25% flurbiprofen reference solution, allowing a potential reduction of the 60% administered dose. The use of in-house made artificial mouth revealed that the once-a-day administration of 0.1% delmopinol OMS was as effective in plaque inhibition as the 0.2% delmopinol reference solution product given twice-a-day. These results suggested that the development of bioadhesive oromucosal suspensions, localizing the drug into buccal cavity, can reduce regimen and administrated dose.

  18. Alterations in brain metabolism and function following administration of low-dose codeine phosphate: (1)H-magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging studies.

    Cao, Zhen; Lin, Pei-Yin; Shen, Zhi-Wei; Wu, Ren-Hua; Xiao, Ye-Yu


    The aim of the present study was to identify alterations in brain function following administration of a single, low-dose of codeine phosphate in healthy volunteers using resting-state functional magnetic resonance imaging (fMRI). In addition, the metabolic changes in the two sides of the frontal lobe were identified using (1)H-magnetic resonance spectroscopy ((1)H-MRS). A total of 20 right-handed healthy participants (10 males, 10 females) were evaluated, and a Signa HDx 1.5T MRI scanner was used for data acquisition. An echo planar imaging sequence was used for resting-state fMRI, whereas a point resolved spectroscopy sequence was used for (1)H-MRS. Regional Saturation Technique, Data Processing Assistant for Resting-State fMRI, and Statistical Parameter Mapping 8 were used to analyze the fMRI data. The (1)H-MRS data were analyzed using LCModel software. At 1 h after oral administration of codeine phosphate (1.0 mg/kg), the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity were altered in different brain areas. The choline content was significantly increased in the right and left frontal lobes following codeine phosphate administration (P=0.02 and P=0.03, respectively), whereas the inositol content was significantly decreased in the left frontal lobe (P=0.02). There was no change in the glutamic acid content in the frontal lobes. In conclusion, the functions of different brain regions can be affected by a single, low-dose administration of codeine phosphate. The alterations in metabolite content in the two frontal lobes may be associated with changes in brain function, whereas the ALFF in the globus pallidus may have an effect on codeine phosphate addiction. Finally, glutamic acid may be useful in the estimation of codeine dependence.

  19. Hepatic scar in a case of healed candidiasis showing prolonged enhancement on CT

    Itai, Yuji; Yashiro, Naobumi


    A patient with acute myelocytic leukemia recovering from hepatic candidiasis after long-term administration of amphotericin B had large scar in the liver which showed prominent prolonged enhancement on postcontrast CT. Prolonged enhancement can occur in regions other than hepatic masses.

  20. Dose-dependent effect of donepezil administration on long-term enhancement of visually evoked potentials and cholinergic receptor overexpression in rat visual cortex.

    Chamoun, Mira; Groleau, Marianne; Bhat, Menakshi; Vaucher, Elvire


    Stimulation of the cholinergic system tightly coupled with periods of visual stimulation boosts the processing of specific visual stimuli via muscarinic and nicotinic receptors in terms of intensity, priority and long-term effect. However, it is not known whether more diffuse pharmacological stimulation with donepezil, a cholinesterase inhibitor, is an efficient tool for enhancing visual processing and perception. The goal of the present study was to potentiate cholinergic transmission with donepezil treatment (0.5 and 1mg/kg) during a 2-week visual training to examine the effect on visually evoked potentials and to profile the expression of cholinergic receptor subtypes. The visual training was performed daily, 10min a day, for 2weeks. One week after the last training session, visual evoked potentials were recorded, or the mRNA expression level of muscarinic (M1-5) and nicotinic (α/β) receptors subunits was determined by quantitative RT-PCR. The visual stimulation coupled with any of the two doses of donepezil produced significant amplitude enhancement of cortical evoked potentials compared to pre-training values. The enhancement induced by the 1mg/kg dose of donepezil was spread to neighboring spatial frequencies, suggesting a better sensitivity near the visual detection threshold. The M3, M4, M5 and α7 receptors mRNA were upregulated in the visual cortex for the higher dose of donepezil but not the lower one, and the receptors expression was stable in the somatosensory (non-visual control) cortex. Therefore, higher levels of acetylcholine within the cortex sustain the increased intensity of the cortical response and trigger the upregulation of cholinergic receptors.

  1. Concomitant Administration of Different Doses of Simvastatin with Ivabradine Influence on PAI-1 and Heart Rate in Normo- and Hypercholesterolaemic Rats

    Jacek Owczarek; Magdalena Jasińska-Stroschein; Daria Orszulak-Michalak


    Ivabradine is a novel heart rate lowering agent that inhibits If ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg × kg−1 bw) with ivabradine (10 mg × kg−1 bw) d...

  2. FTY720 treatment prolongs skin graft survival in a completely incompatible strain combination.

    Lima, R S M; Nogueira-Martins, M F; Silva, H T; Pestana, J O M; Bueno, V


    FTY720 has shown potent immunomodulatory activity in a variety of animal organ transplant models. However, the in vivo immunosuppressive mechanism of FTY720 is still not fully understood. It has been suggested that the marked decrease in the number of peripheral blood lymphocytes during FTY720 administration could be responsible for its immunosuppressive effects. Our aims were: (1) to study the effects of FTY720 treatment on skin graft survival using a fully mismatched strain combination and (2) to evaluate lymphocyte numbers in different sites at 5 days after skin transplant. C57BL/6 mice and BALB/c mice were the donors and recipients respectively. BALB/c mice received FTY720 (1 mg/kg/d) orally for 4 consecutive days. Drug administration started 1 day before skin transplants. A small segment of tail skin was affixed on the right dorsal side of the mouse via sutures. The administration of FTY720 (4 mg/kg) prolonged skin graft survival from 12.6 +/- 2.2 days (no treatment) to 16.6 +/- 4.2 days. The histologic findings of rejection were similar for all groups. Five days after transplant, lymphocyte numbers were significantly increased in lymph nodes compared with nontransplanted or isogenic graft mice. FTY720 decreased lymphocyte numbers only in the spleen. In conclusion, FTY720 prolonged skin graft survival in a fully mismatched strain combination when administered for 4 days (day -1 to day +2) at a dose of 1 mg/kg/d. The decreased number of lymphocytes in the spleen suggests that the spleen may be a target of FTY720 activity, during the early posttransplant period.

  3. A phase I/II study of dose and administration of non-glycosylated bacterially synthesized G-M CSF in chemotherapy-induced neutropenia in patients with non-Hodgkin's lymphomas.

    Hovgaard, D; Nissen, N I


    Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) derived from E. coli was administered to 24 previously untreated patients with non-Hodgkin's lymphoma following the first cycle of CHOP chemotherapy. Four dose levels were examined, 1.5, 3.0, 5.5 and 11 micrograms/kg and patients were randomized to receive the drug either once or twice daily subcutaneously (s.c.). During rhGM-CSF treatment, the leucocyte counts increased up to 3-4 fold in 20/24 patients, reaching a peak 24-48 (mean 35) hours after initiation of rhGM-CSF. The leukopenic period in cycle one of the CHOP chemotherapy with rhGM-CSF, was shorter than after the course of chemotherapy without rhGM-CSF and also shorter when compared to cycle one of CHOP in the 127 historical controls (p effect was seen on platelet counts at nadir but a significant, although moderate increase occurred in the recovery period on days 15 and 22 when compared to control cycles and historical controls. When dose levels were compared, there was only a trend to higher WBC counts at the higher dose groups (5.5 and 11 micrograms/kg) when compared to the two lower dose groups (1.5 and 3.0 micrograms/kg). In the overall evaluation there was no statistical significant difference in results between patients treated s.c. once daily versus twice daily. However when only the two highest dose levels (5.5 + 11 micrograms/kg) were compared, s.c. administration of rhGM-CSF twice daily led to higher leucocyte counts than once daily in the recovery period on day 15 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  4. The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis.

    Haase, Christoffer Bjerre; Backer, Vibeke; Kalsen, Anders; Rzeppa, Sebastian; Hemmersbach, Peter; Hostrup, Morten


    The present study investigated the influence of exercise and dehydration on the urine concentrations of salbutamol after inhalation of that maximal permitted (1600 µg) on the 2015 World Anti-Doping Agency (WADA) prohibited list. Thirteen healthy males participated in the study. Urine concentrations of salbutamol were measured during three conditions: exercise (EX), exercise+dehydration (EXD), and rest (R). Exercise consisted of 75 min cycling at 60% of VO2max and a 20-km time-trial. Fluid intake was 2300, 270, and 1100 mL during EX, EXD, and R, respectively. Urine samples of salbutamol were collected 0-24 h after drug administration. Adjustment of urine concentrations of salbutamol to a specific gravity (USG) of 1.020 g/mL was compared with no adjustment. The 2015 WADA decision limit (1200 ng/mL) for salbutamol was exceeded in 23, 31, and 10% of the urine samples during EX, EXD, and R, respectively, when unadjusted for USG. When adjusted for USG, the corresponding percentages fell to 21, 15, and 8%. During EXD, mean urine concentrations of salbutamol exceeded (1325±599 ng/mL) the decision limit 4 h after administration when unadjusted for USG. Serum salbutamol Cmax was lower (Psalbutamol and increase the risk of Adverse Analytical Findings in samples collected after inhalation of that maximal permitted (1600 µg) for salbutamol. This should be taken into account when evaluating doping cases of salbutamol. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Prolonged fever after Infliximab infusion

    Jennifer; Katz; Michael; Frank


    Pharmacologic management for ulcerative colitis (UC) has recently been expanded to include antitumor necrosis factor (TNF) therapy for severe disease. Infliximab, a chimeric monoclonal antibody directed again TNF α was first tested in patients with Crohn’s disease. In addition to serious infections, malignancy, drug induced lupus and other autoimmune diseases, serum sickness-like reactions, neurological disease, and infusion reactions further complicate the use of Infliximab. We report a case of prolonged fever after Infliximab infusion to treat steroid refractory UC.

  6. Parsley extract inhibits in vitro and ex vivo platelet aggregation and prolongs bleeding time in rats.

    Gadi, Dounia; Bnouham, Mohamed; Aziz, Mohammed; Ziyyat, Abderrahim; Legssyer, Abdelkhaleq; Legrand, Chantal; Lafeve, Françoise Fauvel; Mekhfi, Hassane


    Many cardiovascular diseases are associated with an increase in blood platelet activity. In Morocco, parsley (Petroselinum crispum, Apiaceae) is one of the medicinal herbs used to treat cardiovascular diseases such as arterial hypertension. In this study, crude aqueous extract (CAE) of parsley was evaluated for its anti-platelet activity in experimental animals on platelet aggregation in vitro and ex vivo; and on bleeding time in vivo. The in vitro aggregation was monitored after pre-incubation of platelets with CAE. The bleeding time and ex vivo aggregation were performed after oral treatment. CAE inhibited dose dependently platelet aggregation in vitro induced by thrombin, ADP, collagen and epinephrine. The oral administration of CAE (3g/kg) inhibited significantly (p<0.001) platelet aggregation ex vivo and prolonged bleeding time (p<0.001) without changes in the platelet amount. The prolongation of bleeding time by CAE may be attributed to the observed inhibition of platelet aggregation. These effects could be related in part to the polyphenolic compounds present in the extract. These results support the hypothesis that the dietary intake of parsley may be benefit in the normalization of platelet hyperactivation, in the nutritional prevention of cardiovascular diseases and are potentially interesting in the development of new prevention strategies.

  7. Single dose adenovirus vectored vaccine induces a potent and long-lasting immune response against rabbit hemorrhagic disease virus after parenteral or mucosal administration.

    Fernández, Erlinda; Toledo, Jorge R; Chiong, Maylin; Parra, Francisco; Rodríguez, Elsa; Montero, Carlos; Méndez, Lídice; Capucci, Lorenzo; Farnós, Omar


    Rabbit hemorrhagic disease virus (RHDV) is the etiological agent of a lethal and contagious disease of rabbits that remains as a serious problem worldwide. As this virus does not replicate in cell culture systems, the capsid protein gene has been expressed in heterologous hosts or inserted in replication-competent viruses in order to obtain non-conventional RHDV vaccines. However, due to technological or safety issues, current RHDV vaccines are still prepared from organs of infected rabbits. In this work, two human type 5 derived replication-defective adenoviruses encoding the rabbit hemorrhagic disease virus VP60 capsid protein were constructed. The recombinant protein was expressed as a multimer in mouse and rabbit cell lines at levels that ranged from approximately 120 to 160 mg/L of culture. Mice intravenously or subcutaneously inoculated with a single 10(8) gene transfer units (GTU) dose of the AdVP60 vector (designed for VP60 intracellular expression) seroconverted at days 7 and 14 post-immunization, respectively. This vector generated a stronger response than that obtained with a second vector (AdVP60sec) designed for VP60 secretion. Rabbits were then immunized by parenteral or mucosal routes with a single 10(9)GTU dose of the AdVP60 and the antibody response was evaluated using a competition ELISA specific for RHDV or RHDVa. Protective hemagglutination inhibition (HI) titers were also promptly detected and IgG antibodies corresponding with inhibition percentages over 85% persisted up to one year in all rabbits, independently of the immunization route employed. These levels were similar to those elicited with inactivated RHDV or with VP60 obtained from yeast or insect cells. IgA specific antibodies were only found in saliva of rabbits immunized by intranasal instillation. The feasibility of VP60 production and vaccination of rabbits with replication-defective adenoviral vectors was demonstrated.

  8. Pharmacokinetics and selected pharmacodynamics of cobalt following a single intravenous administration to horses.

    Knych, H K; Arthur, R M; Mitchell, M M; Holser, I; Poppenga, R; Smith, L L; Helm, M N; Sams, R A; Gaskill, C L


    Cobalt has been used by human athletes due to its purported performance-enhancing effects. It has been suggested that cobalt administration results in enhanced erythropoiesis, secondary to increased circulating erythropoietin (EPO) concentrations leading to improvements in athletic performance. Anecdotal reports of illicit administration of cobalt to horses for its suspected performance enhancing effects have led us to investigate the pharmacokinetics and pharmacodynamic effects of this compound when administered in horses, so as to better regulate its use. In the current study, 18 horses were administered a single intravenous dose of cobalt chloride or cobalt gluconate and serum and urine samples collected for up to 10 days post administration. Cobalt concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and pharmacokinetic parameters determined. Additional blood samples were collected for measurement of equine EPO concentrations as well as to assess any effects on red blood cell parameters. Horses were observed for adverse effects and heart rate monitored for the first 4 h post administration. Cobalt was characterized by a large volume of distribution (0.939 L/kg) and a prolonged gamma half-life (156.4 h). Cobalt serum concentrations were still above baseline values at 10 days post administration. A single administration of cobalt had no effect on EPO concentrations, red blood cell parameters or heart rate in any of the horses studied and no adverse effects were noted. Based on the prolonged gamma half-life and prolonged residence time, regulators should be able to detect administration of a single dose of cobalt to horses.

  9. Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis

    Lorena Neris Barboza


    Full Text Available Although several studies indicate high effectiveness in the use of the hydroethanolic extract from Tropaeolum majus (HETM as a diuretic, the impact of its prolonged use in the presence of low estrogen levels remains unclear. Thus, the aim of this study was to investigate the diuretic effects of prolonged administration of HETM in ovariectomized rats and their interrelationship between calcium excretion and bone turnover. Forty-two female Wistar rats were ovariectomized (OVX and treated orally with different doses of HETM (3, 30, and 300 mg/kg for 4 weeks. On the first day of treatment and at weekly intervals for four weeks the diuretic activity was evaluated. Electrolyte concentrations and creatinine levels were estimated from urine sample of each rat. The serum lipids, urea, creatinine, and osteocalcin were also measured at the end of the experiment. The data revealed that the HETM was able to sustain its diuretic effect after prolonged treatment. Moreover, its use has not affected the urinary calcium or potassium excretion, reduces lipid levels, and maintains osteocalcin levels similarly to untreated rats. These findings support the potential of HETM as a candidate to be used in clinical conditions in which the renal loss of calcium is not desired.

  10. Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis

    Barboza, Lorena Neris; Prando, Thiago Bruno Lima; Dalsenter, Paulo Roberto; Gasparotto, Francielly Mourão; Gasparotto, Francielli; Jacomassi, Ezilda; Araújo, Valdinei de Oliveira; Lourenço, Emerson Luiz Botelho; Gasparotto Junior, Arquimedes


    Although several studies indicate high effectiveness in the use of the hydroethanolic extract from Tropaeolum majus (HETM) as a diuretic, the impact of its prolonged use in the presence of low estrogen levels remains unclear. Thus, the aim of this study was to investigate the diuretic effects of prolonged administration of HETM in ovariectomized rats and their interrelationship between calcium excretion and bone turnover. Forty-two female Wistar rats were ovariectomized (OVX) and treated orally with different doses of HETM (3, 30, and 300 mg/kg) for 4 weeks. On the first day of treatment and at weekly intervals for four weeks the diuretic activity was evaluated. Electrolyte concentrations and creatinine levels were estimated from urine sample of each rat. The serum lipids, urea, creatinine, and osteocalcin were also measured at the end of the experiment. The data revealed that the HETM was able to sustain its diuretic effect after prolonged treatment. Moreover, its use has not affected the urinary calcium or potassium excretion, reduces lipid levels, and maintains osteocalcin levels similarly to untreated rats. These findings support the potential of HETM as a candidate to be used in clinical conditions in which the renal loss of calcium is not desired. PMID:25028592

  11. [A comparative study of antiarrhythmic and antihypoxic effects of magnesium sulfate, its prolonged form and blockers of calcium channels].

    Samsonia, M D; Kandelaki, M A


    The aim of the study is the comparative study of treatment of heart and brain damages during the hypoxia with magnesium sulfate, verapamil, diltiazem. As a result of the experiment carried out on rats it was proved that magnesium sulfate and its prolonged form are not less active than the blockers of calcium channels, such as verapamil and diltiazem. It is possible to avoid lethal fibrillations caused by calcium chloride with the help of 25% magnesium sulfate solution (after intraperitoneal administration with the dose of 1000 mg/kg) in case we make arrythmogenic injection 5 minutes after inputting magnesium sulfate solution. During the arrhythmia induced by calcium chloride prolonged form of magnesium sulfate is also effective only if we inject the drug subcutaneous 30 minutes before the arrythmogenic injection. If the interval is 5 minutes lethal fibrillations cant be avoided as the release of magnesium ions from the drug form is slowed down. The drugs containing magnesium ions also displayed cytoprotective activity on the model of normobaric hypoxia. This was resulted in the increase of protective index. Neuroprotective action of magnesium ions (in the condition of hypoxia) is caused by maintaining homeostasis of calcium ions and by inhibition of exocytosis of neuromediators in the synaptic cleft. Thus, magnesium sulfate and its prolonged form can be used with the purpose of pharmacocorrection of heart and brain injuries during hypoxic conditions.

  12. Low-dose ouabain constricts small arteries from ouabain-hypertensive rats: implications for sustained elevation of vascular resistance

    Zhang, Jin; Hamlyn, John M.; Karashima, Eiji; Raina, Hema; Mauban, Joseph R. H.; Izuka, Michelle; Berra-Romani, Roberto; Zulian, Alessandra; Wier, W. Gil; Blaustein, Mordecai P.


    Prolonged ouabain administration to normal rats causes sustained blood pressure (BP) elevation. This ouabain-induced hypertension (OH) has been attributed, in part, to the narrowing of third-order resistance arteries (∼320 μm internal diameter) as a result of collagen deposition in the artery media (see Ref. 6). Here we describe the structural and functional properties of fourth-order mesenteric small arteries from control and OH rats, including the effect of low-dose ouabain on myogenic tone...

  13. Concentrations of tilmicosin in mammary gland secretions of dairy cows following subcutaneous administration of one or two doses of an experimental preparation of tilmicosin and its efficacy against intramammary infections caused by Staphylococcus aureus.

    Mendoza, Jesus; Martínez-Cortés, Ismael; López-Ordaz, Reyes; Gutiérrez, Lilia; Sumano, Hector


    OBJECTIVE To determine the concentration of tilmicosin in mammary gland secretions of dairy cows following administration of an experimental preparation once or twice during the dry period (45-day period immediately prior to calving during which cows are not milked) and to evaluate its efficacy for the treatment of cows with intramammary infections (IMIs) caused by Staphylococcus aureus at dry off (cessation of milking; first day of dry period), compared with that of an intramammary infusion of ceftiofur. ANIMALS 172 cows. PROCEDURES Milk samples were collected for microbiological culture 5 days before dry off and at calving and 15 and 30 days after calving. Cows with Staphylococcus IMIs were randomly assigned to receive an experimental preparation of tilmicosin (20 mg/kg, SC) once at dry off (n = 58) or at dry off and again 20 days later (56) or receive a long-acting intramammary preparation of ceftiofur (500 mg/mammary gland; 56) at dry off. Mammary gland secretions were collected from 5 cows in the tilmicosin-treated groups every 5 days after dry off until calving for determination of tilmicosin concentration. RESULTS Mean maximum concentration of tilmicosin in mammary gland secretions ranged from 14.4 to 20.9 μg/mL after the first dose and was 17.1 μg/mL after the second dose. The bacteriologic cure rate was 100% for all 3 treatments. Tilmicosin was detectable for 0 and 18 days after calving in the milk of cows treated with 1 and 2 doses of tilmicosin, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Administration of an experimental preparation of tilmicosin (20 mg/kg, SC) once to dairy cows at dry off might be useful for the treatment of S aureus IMIs.

  14. Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration.

    Towiwat, Pasarapa; Phattanarudee, Siripan; Maher, Timothy J


    Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs.

  15. Uptake and gene expression with antitumoral doses of iodine in thyroid and mammary gland: evidence that chronic administration has no harmful effects.

    Anguiano, Brenda; García-Solís, Pablo; Delgado, Guadalupe; Aceves Velasco, Carmen


    Several studies have demonstrated that moderately high concentrations of molecular iodine (I(2)) diminish the symptoms of mammary fibrosis in women, reduce the occurrence of mammary cancer induced chemically in rats (50-70%), and have a clear antiproliferative and apoptotic effect in the human tumoral mammary cell line MCF-7. Nevertheless, the importance of these effects has been underestimated, in part because of the notion that exposure to excess iodine represents a potential risk to thyroid physiology. In the present work we demonstrate that uptake and metabolism of iodine differ in an organ-specific manner and also depend on the chemical form of the iodine ingested (potassium iodide vs. I(2)). Further, we show that a moderately high I(2) supplement (0.05%) causes some of the characteristics of the "acute Wolff-Chaikoff effect"; namely, it lowers expression of the sodium/iodide symporter, pendrin, thyroperoxidase (TPO), and deiodinase type 1 in thyroid gland without diminishing circulating levels of thyroid hormone. Finally, we confirm that I(2) metabolism is independent of TPO, and we demonstrate that, at the doses used here, which are potentially useful to treat mammary tumors, chronic I(2) supplement is not accompanied by any harmful secondary effects on the thyroid or general physiology. Thus, we suggest that I(2) could be considered for use in clinical trials of breast cancer therapies.

  16. Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial.

    Koh, Jin-Sin; Park, Yongwhi; Tantry, Udaya S; Ahn, Jong-Hwa; Kang, Min Gyu; Kim, Kyehwan; Jang, Jeong Yoon; Park, Hyun Woong; Park, Jeong Rang; Hwang, Seok-Jae; Kwak, Choong Hwan; Hwang, Jin-Yong; Gurbel, Paul A; Jeong, Young-Hoon


    Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG(®)). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG(®) measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.

  17. Administration doses of antifebriles in pediatrics of our hospital%我院儿科住院患者常用退热药应用剂量分析

    万正兰; 吕台中


    Objective To investigate the administration doses of antifebriles in pediatrics of our hospital,and to provide references to clinical rational use.Methods The prescriptions of antifebriles in hospitalized children were selected from September 2010 to September 2012 through HIS,the single dose of antifebrile was statistically analyzed based and compared according to the package inserts,the rationality was discussed.Results There were 352 prescriptions with 8 kinds of antifebriles,and the top use frequency was Lingyangjiao Diwan(56.25%),and the top single dosage of off-label use was Paracetamol Suppositories(26.70%).Conclusion The off-label use of administration doses of antifebriles is common in pediatrics of our hospital.Clinicians should make correct and rational decision for administration dosage to ensure the medication safety.%目的 调查我院儿科住院患者退热药临床应用剂量,为临床合理用药提供参考.方法 调查我院HIS系统中2010年9月至2012年9月住院患儿退热药使用情况,统计退热药单次应用剂量,并根据说明书用量进行对比,探讨其合理性.结果 使用了退热药的病历352份,涉及8种退热药.使用频率最高的是羚羊角滴丸(56.25%),6种超说明书剂量使用的退热药中比例最高的是对乙酰氨基酚栓(26.70%).结论 我院儿科退热药超说明书剂量使用较常见.临床医师在用药时需要正确、合理选择药物剂量,确保患儿用药安全.

  18. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat.

    Antkiewicz-Michaluk, Lucyna; Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy


    Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both

  19. Nifekalant hydrochloride terminating sustained ventricular tachycardia accompanied with QT dispersion prolongation

    WANG Jing; HUA Wei; ZHU Jun; YANG Yan-min; WANG Fang-zheng; PU Jie-lin; CHEN Ke-ping; ZHANG Shu


    Background Ventricular tachycardia (VT) and ventricular fibrillation are the main reasons causing sudden cardiac death.This study aimed to investigate the effects of nifekalant hydrochloride (NIF) on QT dispersion (QTd) in treating VT.Methods A total of 16 consecutive patients suffered sustained VT was included and then randomly divided into two groups according to the administration duration of NIF.In long-time group (group L), patients were injected with NIF continuously for at least 12 hours after a bolus dose.The patients in short-time group (group S) were injected with NIF just for 1 hour.Results There were 7 of all 10 episodes of VT which were terminated by NIF, including 4 episodes in group L were stopped over 1 hour after continuous infusion of NIF.One patient suffered from torsade de pointes.Electrocardiography analysis indicated that QTd was significantly decreased 12 hours after stopping of infusing NIF compared with that when VT stopped ((45.4±22.1) ms vs.(73.4±33.2) ms, P <0.01), and the corrected QTd (QTcd) decreased too ((47.8±22.9) ms vs.(78.3±36.5) ms, P <0.01 ).There was a positive correlation between the increase in QTd and dose of administrating NIF (P <0.01), so was QTcd (P <0.01).Conclusions More administration of NIF indicates higher terminating rate of VT and more QTd prolongation.However,the safety is acceptable if several important issues were noticed in using NIF, such as serum potassium concentration,stopping side-effect related agents, and carefully observing clinical responses.

  20. Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy-Related Neutropenia in Patients with Non-Hodgkin's Lymphomas-A Phase I/II Study of Dose and Mode of Administration.

    Hovgaard, D J; Nissen, N I


    The effect of mammalian glycosylated recombinant granulocyte-macrophage colony-stimulating factor was investigated in 24 patients with newly diagnosed non-Hodgkin's lymphoma in a phase I/II study. All patients received standard chemotherapy with CHOP. RhGM-CSF was administered after the first cycle for 5 days, and at one of four dose levels (2, 4, 8 and 16 μg/kg). Patients were randomized to receive the drug either by continuous intravenous infusion or twice daily as subcutaneous injection. No significant difference in results was observed between subcutaneous administration of rhGM-CSF and continuous i.v. infusion and these patient groups could therefore be combined in the analysis. Administration of rhGM-CSF resulted in a significant dose-dependent increase of total WBC, mainly neutrophils, eosinophils and monocytes. The increase was observed in 18/24 patients, reaching a peak 24-72 (median 24) hours after the start of rhGM-CSF. The CHOP chemotherapy-induced leucocyte nadir occurred on day 12 (mean) compared to day 14 for the 127 historical controls. The WBC nadir values were higher (2.4 ± 1.4) than for historical controls (1.8 ± 1.1) and the leucopenic/neutropenic period was of shorter duration. Following the chemotherapy nadir a more rapid recovery of WBC was seen than in controls. GM-CSF was well tolerated, the side effects were mild and transient, and included myalgias, low grade fever, headache, chest/bone discomfort, nausea, erythema at injection site and superficial phlebitis. The encouraging results of this phase I/II study indicate the need for a prospective controlled study of GM-CSF in chemotherapy of malignant lymphoma.

  1. Effect of Administration of Single Dose GnRH Agonist in Luteal Phase on Outcome of ICSI-ET Cycles in Women with Previous History of IVF/ICSI Failure: A Randomized Controlled Trial

    Zafardoust, Simin; Jeddi-Tehrani, Mahmood; Akhondi, Mohammad Mehdi; Sadeghi, Mohammad Reza; Kamali, Koroush; Mokhtar, Sara; Badehnoosh, Bita; Arjmand-Teymouri, Fatemeh; Fatemi, Farnaz; Mohammadzadeh, Afsaneh


    Background GnRH agonist administration in the luteal phase has been suggested to beneficially affect the outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This blind randomized controlled study evaluates the effect of GnRH (Gonadotropine Releasing Hormone) agonist administration on ICSI outcome in GnRH antagonist ovarian stimulation protocol in women with 2 or more previous IVF/ICSI-ET failures. Methods One hundred IVF failure women who underwent ICSI cycles and stimulated with GnRH antagonist ovarian stimulation protocol, were included in the study. Women were randomly assigned to intervention (received a single dose injection of GnRH agonist (0.1 mg of Decapeptil) subcutaneously 6 days after oocyte retrieval) and control (did not receive GnRH agonist) groups. Implantation and clinical pregnancy rates were the primary outcome measures. Results Although the age of women, the number of embryos transferred in the current cycle and the quality of the transferred embryos were similar in the two groups, there was a significantly higher rate of implantation (Mann Whitney test, p = 0.041) and pregnancy (32.6% vs. 12.5%, p = 0.030, OR = 3.3, 95%CI, 1.08 to 10.4) in the intervention group. Conclusion Our results suggested that, in addition to routine luteal phase support using progesterone, administration of 0.1 mg of Decapeptil 6 days after oocyte retrieval in women with previous history of 2 or more IVF/ICSI failures led to a significant improvement in implantation and pregnancy rates after ICSI following ovarian stimulation with GnRH antagonist protocol. PMID:25927026

  2. Prolonged cholestasis and ductopenia associated with tenoxicam.

    Trak-Smayra, Viviane; Cazals-Hatem, Dominique; Asselah, Tarik; Duchatelle, Veronique; Degott, Claude


    Cholestatic liver diseases leading to progressive destruction of intra-hepatic bile ducts and ductopenia encompass multiple etiologies. Pathophysiology and natural history of drug-induced cholangiopathies remain unclear. We report a case of prolonged ductopenia attributed to Tenoxicam (Tilcotil o--a non-steroidal anti-inflammatory drug of the oxicam family) ingested at therapeutic dose. A 36 year-old male patient was admitted for jaundice and Lyell syndrome starting 1 week after the ingestion of Tenoxicam. Liver biopsy showed cholestasis, non-suppurative cholangitis and polymorphous inflammatory infiltrate of the portal tracts (round cells, macrophages an eosinophils). Treatment with ursodesoxycholic acid and cholestyramine was instituted and the patient was asymptomatic 1 year after. Three years later mild biological cholestasis persisted and ductopenia was evidenced on liver biopsy. In this report we found that: (1) The toxicity of tenoxicam was probably mediated by an immunoallergic mechanism (Lyell syndrome and eosinophils on histology); (2) ductopenia was secondary to inflammatory cholangitis. Factors responsible for this chronic evolution are still unknown (genetic predisposition, vascular factors, etc.); and (3) the presence of ductopenia contrasted with the "clinical recovery" of the disease suggesting accessory bile drainage by cholangioles or partial reconstruction of the biliary tree.

  3. A centrally mediated prolonged hypotension produced by oxotremorine or pilocarpine

    Dage, R.C.


    1 Oxotremorine, methyloxotremorine, pilocarpine or arecoline were given intravenously to anaesthetized cats, dogs or rats, and intraperitoneally to conscious normotensive and spontaneously hypertensive rats, pretreated with doses of methylatropine that completely blocked peripheral muscarinic receptors, to ascertain their effects on blood pressure and heart rate. 2 Oxotremorine but not methyloxotremorine produced a prolonged hypotension in cats and dogs but not in rats. Heart rate was not changed. Pilocarpine, although less potent, produced an identical effect, whereas the effect of arecoline was short by comparison. The hypotensive effect of these drugs was reversed by atropine. 3 In dogs, oxotremorine produced a prolonged hypotension with no change in heart rate or cardiac output. 4 A decrease in spontaneous sympathetic nerve activity accompanied the hypotension in cats. Both effects were reversed by atropine but could be reinvoked by large doses of oxotremorine. 5 The oxotremorine-induced hypotension in cats was not altered by decerebration but was abolished by high cervical spinal section. 6 The results indicate that the prolonged hypotension elicited by oxotremorine is mediated by an action at muscarinic receptors in the brain stem resulting in a decrease in sympathetic nerve activity and peripheral resistance but not heart rate or cardiac output. PMID:760887

  4. The effect of ethanol on the release of opioids from oral prolonged-release preparations.

    Walden, Malcolm; Nicholls, Fiona A; Smith, Kevin J; Tucker, Geoffrey T


    Recent experience has prompted the US FDA to consider whether ethanol ingestion may modify the release characteristics of prolonged-release formulations, where dose dumping may be an issue for patient safety. The influence of ethanol on the in vitro release of opioid drugs from some prolonged-release formulations utilizing different release technologies was examined. Results indicated that the prolonged-release mechanisms remained intact under the testing conditions, although one product showed initial sensitivity to ethanol in its release characteristics. Nevertheless, in this case, extrapolation of the findings to likely outcome in vivo indicated no risk of dose-dumping. It is proposed that prolonged-release medicinal products should be tested during development to ensure robustness to the effects of ethanol on drug release.

  5. Prolonged QT interval in Rett syndrome


    Rett syndrome is a severe neurodevelopmental disorder of unknown aetiology. A prolonged QT interval has been described previously in patients with Rett syndrome. To investigate QT prolongation and the presence of cardiac tachyarrhythmias in Rett syndrome electrocardiography and 24 hour Holter monitoring were performed prospectively in a cohort of 34 girls with Rett syndrome. The corrected QT value was prolonged in nine patients. Compared with a group of healthy controls of a...

  6. The prolonged effect of repeated maternal glucocorticoid exposure on the maternal and fetal leptin/insulin-like growth factor axis in Papio spp

    Schlabritz-Loutsevitch, Natalia E.; Lopez-Alvarenga, Juan C.; Comuzzie, Anthony G.; Miller, Myrna M.; Ford, Stephen P.; Li, Cun; Hubbard, Gene B.; Ferry, Robert J.; Nathanielsz, Peter W.


    Background Maternal obesity represents a risk factor for pregnancy-related complications. Glucocorticoids are known to promote obesity in adults. Methods We evaluated maternal and fetal metabolic changes during and after three weekly courses of betamethasone (BM) administered to pregnant baboons (Papio spp.) at doses equivalent to those given to pregnant women. Results BM administration during the second half of pregnancy increased maternal weight, but neither maternal food intake nor fetal weight, as assessed at the end of gestation. BM increased maternal serum glucose concentration, IGF-I:IGFBP-3 ratio, and serum leptin during treatment (normalized by 17, 35, and 45 days post-treatment respectively for each parameter). Maternal and fetal serum leptin concentrations did not differ between groups at the end of gestation. Conclusion Prolonged maternal hyperleptinemia caused by BM administration in the second half of gestation did not change fetal metabolic parameters measured and placental leptin distribution at the end of gestation. PMID:19087979

  7. Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration.

    Pepinsky, R Blake; Shao, Zhaohui; Ji, Benxiu; Wang, Qin; Meng, Gym; Walus, Lee; Lee, Xinhua; Hu, Yinghui; Graff, Christilyn; Garber, Ellen; Meier, Werner; Mi, Sha


    LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.

  8. Sleep-prolonging effect of Coriandrum sativum hydro-alcoholic extract in mice.

    Rakhshandeh, Hassan; Sadeghnia, Hamid Reza; Ghorbani, Ahmad


    The present study was planned to investigate sleep-prolonging effect of C. sativum. The hydro-alcoholic extract (HAE) and its three fractions namely water (WF), ethyl acetate (EAF) and N-butanol (NBF) were prepared from C. sativum aerial parts and administrated to mice. Also, the possible cytotoxicity of the extracts was tested using cultured PC12 cells. The HAE, EAF and NBF significantly prolonged sleep duration. Only the NBF could significantly decrease sleep latency. No decrease in the neuronal surviving was observed either by HAE or by its fractions. The present data indicate that C. sativum exert sleep-prolonging action without major neurotoxic effect.

  9. Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials

    Metra, Marco; Eichhorn, Eric; Abraham, William T.; Linseman, Jennifer; Böhm, Michael; Corbalan, Ramon; DeMets, David; De Marco, Teresa; Elkayam, Uri; Gerber, Michael; Komajda, Michel; Liu, Peter; Mareev, Vyacheslev; Perrone, Sergio V.; Poole-Wilson, Philip; Roecker, Ellen; Stewart, Jennifer; Swedberg, Karl; Tendera, Michal; Wiens, Brian; Bristow, Michael R.


    Aims Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy. Methods and results The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre

  10. Prolonged Pregnancy: Methods, Causal Determinants and Outcome

    Olesen, Annette Wind

    Summary Prolonged pregnancy, defined as a pregnancy with a gestational length of 294 days or more, is a frequent condition. It is associated with an increased risk of fetal and maternal complications. Little is known about the aetiology of prolonged pregnancy. The aims of the thesis were 1...

  11. Prenatal risk indicators of a prolonged pregnancy

    Olesen, Annette Wind; Westergaard, Jes Grabow; Olsen, Jørn


    BACKGROUND: Few prenatal risk factors of prolonged pregnancy, a pregnancy of 42 weeks or more, are known. The objective was to examine whether sociodemographic, reproductive, toxicologic, or medical health conditions were associated with the risk of prolonged pregnancy. METHODS: Data from the Dan...

  12. Neostigmine does not prolong the duration of analgesia produced by caudal bupivacaine in children undergoing urethroplasty

    Bhardwaj N


    Full Text Available Context : Neostigmine extends the duration of analgesia produced by caudal bupivacaine in children. Aims : To study the effect of different doses of caudal neostigmine on the duration of postoperative analgesia. Settings and Design : A randomized, double-blind study was conducted in 120 boys aged 1-12 years undergoing urethroplasty under combined general and caudal anesthesia. Materials and Methods : Children were administered 1.875 mg/kg bupivacaine alone (Group B, or with 2, 3 or 4 µg/kg of neostigmine (groups BN 2 , BN 3 or BN 4 respectively as caudal drug (0.75 ml/kg. Children with a pain score of 4 or more (OPS and NRS postoperatively were administered rescue analgesic. Time to first analgesic and the number of analgesic doses administered in the 24h were recorded. Statistical Analysis : Parametric data were analyzed using ANOVA. Kaplan-Meier survival curves for the time to first analgesic administration were plotted and compared using log rank analysis. Chi-square test was used to analyze the incidence data. Results : The median [IQR] time to first analgesic in Group B (540 [240-1441] min was similar to that in Groups BN 2 (450 [240-720], BN 3 (600 [360-1020] and BN 4 (990 [420-1441]. Significantly more patients in Groups B (9 [34.6%] and BN 4 (13 [44.8%] required no supplemental analgesic for 24h than those in Groups BN 2 and BN 3 (4 [13.8%] and 4 [13.3%]. The number of analgesic doses required in 24h in the four groups was similar. Conclusion : Addition of neostigmine to 1.875 mg/kg of caudal bupivacaine did not prolong the analgesia following urethroplasty in children.

  13. Continuous Fluoxetine Administration Prevents Recurrence of Pulmonary Arterial Hypertension and Prolongs Survival in Rats%持续氟西汀干预预防大鼠实验性肺动脉高压复发并改善生存率

    王君钰; 朱少平; 赵金平; 周雪峰; 徐明


    To investigate the short-term and long-term therapeutic effects of fluoxetine on monocrotaline-induced pulmonary arterial hypertension (PAH) and associated pathophysiologic alterations in PAH models. Methods: A total of 196 rats were randomly distributed into three groups. Long-term fluoxetine treatment group (M+F, n = 62) received a single subcutaneous injection of monocrotaline (MCT, 60 mg/kg) for three weeks and then were treated with fluoxetine (10 mg/kg) once daily by gavage in the following nine weeks. Short-term fluoxetine treatment group (M/F, n = 70) were treated with fluoxetine only for three weeks. The third group (MCT,n=46) were treated only with normal saline. The fourth group (Saline, n=18) was a normal control group. Morphometric changes, pulmonary arterial pressure (PAP), percent wall thick ness (PWT), right ventricular hypertrophy index (RVHI), and serotonin transporter (5-HTT) expressions were detected at various times during the 12-week observation; furthermore, survival analysis in each group was also performed until week 12. Results: ① A recurrence of the com pletely reversed PAH and aggravation of right ventricular hypertrophy was observed six weeks after fluoxetine withdrawal in M/F group, while no signs of such a recurrence and aggravation was observed in M+F group; ?5-HTT protein levels were significantly raised in M/F group af ter fluoxetine discontinuation, which was paralleled with the severity of PAH;however, no up-regulation.of 5-HTT was found in M + F group. Conclusion: Fluoxetine is effective in reversing MCT-induced pulmonary vascular remodeling and ameliorating right ventricular hypertophy in rats, which is associated with inhibition of overexpression of 5-HTT. Continuous fluoxetine administration is more effective than short-term administration in prolonging survival in rats with PAH.%目的:观察氟西汀对野百合碱(MCT)所致的大鼠肺动脉高压(PAH)的近期和远期疗效及伴随的病理生理学变化.方法:

  14. Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.

    Tsirigotis, P; Papanikolaou, N; Elefanti, A; Konstantinou, P; Gkirkas, K; Rontogianni, D; Siafakas, N; Karakitsos, P; Roilides, E; Dimitriadis, G; Zerva, L; Meletiadis, J


    Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

  15. Salivary stimulation by prolonged release of pilocarpine using films in diabetic rats.

    Jesús Rodríguez


    Full Text Available Introduction: The local use of prolonged drug delivery in the oral cavity provides many advantages, i.e., it increases pharmacologic actions in the desired local site, allows smaller doses and reduces adverse effects. Pilocarpine is a cholinergic drug approved by the FDA for treating glandular hypofunction; however, the adverse effects associated with it limit its use. Objective: To evaluate cytotoxicity of films in adherent fibroblasts and their ability to release pilocarpine in vivo for a prolonged time in the oral cavity of diabetic rats and its effect on salivary flow.Methods: Chitosan and Hydroxypropylmethylcellulose (Methocel K4MCR films were prepared in 1% acetic acid and pilocarpine was added under magnetic stirring. Cytotoxicity of films was evaluated in adherent fibroblasts HS27 and assessed by neutral red technique. The sialogogue effect of films was evaluated on the floor of the mouth of diabetic rats. Later, histopathological analysis was performed using hematoxylin and eosin and Masson’s trichrome stains. Results: Films were biocompatible and had 96% cell viability. It was possible to increase stimulation of salivary flow in diabetic rats (6.36±0.987mg/hr compared to the control group (0.5±0.06mg/hr. The histopathological analysis did not show inflammatory infiltrate in the area where films were placed. Conclusion: Films were biocompatible and had high cell viability. Also, they considerably increased salivary flow in diabetic rats, without triggering an inflammatory infiltrate in the area which indicates that it is a biocompatible product for sustained release and safe for pilocarpine administration.

  16. Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures.

    Lagae, Lieven


    An historical overview is provided regarding the use of benzodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in-hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the available data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures.

  17. In-hospital cardiac arrest is associated with use of non-antiarrhythmic QTc-prolonging drugs

    De Bruin, Marie L; Langendijk, Pim N J; Koopmans, Richard P


    AIMS: QTc interval-prolonging drugs have been linked to cardiac arrhythmias, cardiac arrest and sudden death. In this study we aimed to quantify the risk of cardiac arrest associated with the use of non-antiarrhythmic QTc-prolonging drugs in an academic hospital setting. METHODS: We performed...... a case-control study in which patients, for whom intervention of the advanced life support resuscitation team was requested for cardiac arrest between 1995 and 2003 in the Academic Medical Centre, Amsterdam, were compared with controls regarding current use of non-antiarrhythmic QTc-prolonging drugs......-prolonging drugs (42/140). The risk was more pronounced in patients receiving doses > 1 defined daily dose (OR 2.5, 95% CI 1.1, 5.9), patients taking > 1 QTc-prolonging drug simultaneously (OR 4.8, 95% CI 1.6, 14) and patients taking pharmacokinetic interacting drugs concomitantly (OR 4.0, 95% CI 1.2, 13...

  18. Seminal vesicles and diabetic neuropathy: ultrasound evaluation after prolonged treatment with a selective phosphodiesterase-5 inhibitor.

    La Vignera, S; Condorelli, R A; Vicari, E; Lotti, F; Favilla, V; Morgia, G; Maggi, M; Calogero, A E


    We have previously reported that infertile patients with diabetes mellitus (DM) have a particular ultrasound features of the seminal vesicles (SV) characterized by higher fundus-to-body ratio and lower pre- and post-ejaculatory difference in body antero-posterior diameter (APD). Based on these premises the aim of the present study was to investigate possible ultrasound SV changes in infertile patients with DM and diabetic neuropathy (DN), after prolonged administration of tadalafil (TAD) (a specific phosphodiesterase-5 inhibitor). To accomplish this, 20 infertile patients with symptomatic DN and erectile dysfunction were selected and arbitrarily divided into two groups which were assigned to: daily administration of 5 mg TAD for 3 months (Group A) (n = 10) and administration of placebo (Group B) (n = 10). All patients underwent to scrotal and prostate-vesicular transrectal ultrasound evaluation and semen analysis (Laboratory Manual for the Examination and Processing of Human Semen, WHO, 2010) before and after treatment. The following SV US parameters were recorded: (i) body APD; (ii) fundus APD; (iii) parietal thickness of the right and left SVs; and (iv) number of polycyclic areas within both SVs. We then calculated the following parameters: (i) fundus/body (F/B) ratio; (ii) difference of the parietal thickness between the right and the left SV and (iii) pre- and post-ejaculatory APD difference. In addition, we also evaluated the SV ejection fraction. Group A patients showed a significant reduction in F/B ratio and higher pre- and post-ejaculatory body SV APD difference compared with baseline or Group B after 3 months. These patients showed also a significant increase in SV ejection fraction and a significant improvement of the total sperm count, progressive motility, seminal levels of fructose, leucocytes and ejaculate volume. In conclusion, these results suggest that infertile DM patients with DN and erectile dysfunction had an improvement of ultrasound features

  19. Sugammadex rescue following prolonged rocuronium neuromuscular blockade with ‘recurarisation’ in a patient with severe renal failure

    Lobaz, Steven; Sammut, Mario; Damodaran, Anand


    We describe our experience of a 71-year-old patient with severe renal failure, who exhibited an unusually prolonged rocuronium-induced neuromuscular blockade (>4 h) and apparent recurarisation, following emergency rapid sequence induction (RSI). At the end of operation, 45 min post induction, train-of-four (TOF) testing had been 4/4 prior to wake up. No respiratory effort was seen 150 min postinduction, despite further neostigmine/glycopyrrolate and repeat TOF 4/4. The patient was resedated and transferred to the intensive care unit (ICU). At 180 min postinduction, fade was evident on TOF, suggestive of rocuronium reblockade. At 285 min, the patient was extubated safely following sugammadex administration and discharged uneventfully from the ICU. An important lesson to recognise is the potential for extremely prolonged neuromuscular blockade following rocuronium in patients with severe renal failure, particularly when using the higher doses (1.2 mg/kg) required for RSI, and that TOF in such cases may not be reliable in detecting residual blockade. PMID:23396837

  20. Daily Oxygen/O3 Treatment Reduces Muscular Fatigue and Improves Cardiac Performance in Rats Subjected to Prolonged High Intensity Physical Exercise

    C. Di Filippo


    Full Text Available Rats receiving daily intraperitoneal administration of O2 and running on a treadmill covered an average distance of 482.8 ± 21.8 m/week as calculated during 5-week observation. This distance was increased in rats receiving daily intraperitoneal administration of an oxygen/O3 mixture at a dose of 100; 150; and 300 μg/kg with the maximum increase being +34.5% at 300 μg/kg and still present after stopping the administration of oxygen/O3. Oxygen/O3 decreased the mean arterial blood pressure (−13%, the heart rate (−6%, the gastrocnemius and cardiac hypertrophy, and fibrosis and reduced by 49% the left ventricular mass and relative wall thickness measurements. Systolic and diastolic functions were improved in exercised oxygen/O3 rats compared to O2 rats. Oxygen/O3 treatment led to higher MPI index starting from the dose of 150 μg/kg (p<0.05 and more effective (+14% at a dose of 300 μg/kg oxygen/O3. Oxygen/O3 dose-dependently increased the expression of the antioxidant enzymes Mn-SOD and GPx1 and of eNOS compared to the exercised O2 rats. The same doses resulted in decrease of LDH levels, CPK, TnI, and nitrotyrosine concentration in the heart and gastrocnemius tissues, arguing a beneficial effect of the ozone molecule against the fatigue induced by a prolonged high intensity exercise.

  1. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

    Boogerd, W; vd Sande, J J; Moffie, D


    Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL.

  2. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

    Boogerd, W; vd Sande, J J; Moffie, D


    Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL. Images PMID:3225584

  3. Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia

    Christina Bognet


    Full Text Available Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL solutions, with or without epinephrine 5 µg/mL (1:200,000 in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001 or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001. Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.

  4. Administrating Solr

    Mohan, Surendra


    A fast-paced, example-based guide to learning how to administrate, monitor, and optimize Apache Solr.""Administrating Solr"" is for developers and Solr administrators who have a basic knowledge of Solr and who are looking for ways to keep their Solr server healthy and well maintained. A basic working knowledge of Apache Lucene is recommended, but this is not mandatory.

  5. Hidratación oral continua o a dosis fraccionadas en niños deshidratados por diarrea aguda Oral rehydration in continuous administration or in fractionated doses in dehydrated children with acute diarrhea

    Felipe Mota-Hernández


    means, standard deviations and medians, according the distribution of simple and relative frequencies. Results. The mean stool output in the AL group was 11.0±7.5 g/kg/h; as compared to 7.1±7.4 in the FD group (p=0.03. ORS intake, rehydration time, and mean diuresis values were similar in both groups (p>0.05. Six patients in the AL group and five in the FD group had high stool output (>10 g/kg/h, that improved after administration of rice starch solution. One patient in the AL group and two in the FD group had persistent vomiting that improved with gastroclisis. No patient required intravenous rehydration. Conclusions. These results suggest that ORS administration ad libitum under supervision, is a technique as safe and effective as the fractionated doses technique, for the treatment of dehydrated children due to acute diarrhea.

  6. Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

    Attema-de Jonge, M.E. (Milly Ellen)


    Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability

  7. QT Prolongation due to Graves’ Disease

    Zain Kulairi


    Full Text Available Hyperthyroidism is a highly prevalent disease affecting over 4 million people in the US. The disease is associated with many cardiac complications including atrial fibrillation and also less commonly with ventricular tachycardia and fibrillation. Many cardiac pathologies have been extensively studied; however, the relationship between hyperthyroidism and rate of ventricular repolarization manifesting as a prolonged QTc interval is not well known. Prolonged QTc interval regardless of thyroid status is a risk factor for cardiovascular mortality and life-threatening ventricular arrhythmia. The mechanism regarding the prolongation of the QT interval in a hyperthyroid patient has not been extensively investigated although its clinical implications are relevant. Herein, we describe a case of prolonged QTc in a patient who presented with signs of hyperthyroidism that was corrected with return to euthyroid status.

  8. Hippocampal Abnormalities in Prolonged Febrile Seizures

    J Gordon Millichap


    Full Text Available Apparent diffusion coefficient (ADC measurements were used to characterize hippocampal edema within 5 days of a prolonged febrile seizure (PFS in a study at Great Ormond Street Hospital, London, UK.

  9. MRI Abnormalities After Prolonged Febrile Seizures

    J Gordon Millichap


    Full Text Available The clinical, radiologic, and laboratory findings of 17 Asian patients with encephalopathy following a prolonged febrile seizure were reviewed retrospectively at Kameda Medical Center, and other centers in Japan and San Francisco, USA.

  10. QT Prolongation due to Graves' Disease

    Deol, Nisha; Tolly, Renee; Manocha, Rohan; Naseer, Maliha


    Hyperthyroidism is a highly prevalent disease affecting over 4 million people in the US. The disease is associated with many cardiac complications including atrial fibrillation and also less commonly with ventricular tachycardia and fibrillation. Many cardiac pathologies have been extensively studied; however, the relationship between hyperthyroidism and rate of ventricular repolarization manifesting as a prolonged QTc interval is not well known. Prolonged QTc interval regardless of thyroid status is a risk factor for cardiovascular mortality and life-threatening ventricular arrhythmia. The mechanism regarding the prolongation of the QT interval in a hyperthyroid patient has not been extensively investigated although its clinical implications are relevant. Herein, we describe a case of prolonged QTc in a patient who presented with signs of hyperthyroidism that was corrected with return to euthyroid status. PMID:28154763

  11. Administrative Circulars

    Département des Ressources humaines


    Administrative Circular N° 2 (Rev. 2) - May 2004 Guidelines and procedures concerning recruitment and probation period of staff members This circular has been revised. It cancels and replaces Administrative Circular N° 2 (Rev. 1) - March 2000. Administrative Circular N° 9 (Rev. 3) - May 2004 Staff members contracts This circular has been revised. It cancels and replaces Administrative Circular N° 9 (Rev. 2) - March 2000. Administrative Circular N° 26 (Rev. 4) - May 2004 Procedure governing the career evolution of staff members This circular has also been revised. It Administrative Circulars Administrative Circular N° 26 (Rev. 3) - December 2001 and brings up to date the French version (Rev. 4) published on the HR Department Web site in January 2004. Operational Circular N° 7 - May 2004 Work from home This circular has been drawn up. Operational Circular N° 8 - May 2004 Dealing with alcohol-related problems...

  12. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    Oranje Bob


    Full Text Available Abstract Background Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life. Methods/Design Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s and at least one benzodiazepine derivative for the last three months before inclusion. Exclusion criteria: currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin® 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4

  13. [Histopathological studies of the rat pancreas after prolonged treatment with imuran. Preliminary findings].

    Mansi, C; Savarino, V; Picciotto, A; Testa, R; Dabove, L; Gismondi, C; Celle, G


    The AA. have studied the pathological effects on the pancreas of rats after chronic administration of azathioprine (AZA) in different doses. The most significant lesions are flattening of duct epitelium and the presence of protein plugs in the ducts. These pancreatic lesions are significantly more frequent in rate treated with higher doses than in controls and so are dose-dependent.

  14. Quality of drug label information on QT interval prolongation

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H;


    characteristics (SPC) of recently approved medicinal products. METHODS: Drug labels of products centrally approved in Europe between 2006 and 2012 were screened. Of drugs including the term 'QT' in the SPC, the message on QT-prolongation ('no prolongation'/'unclear drug-QT association'/'possibly QT......-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. RESULTS: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT......-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT...

  15. Left Ventricular Function After Prolonged Exercise in Equine Endurance Athletes

    Flethøj, M.; Schwarzwald, C. C.; Haugaard, M. M.;


    Background: Prolonged exercise in human athletes is associated with transient impairment of left ventricular (LV) function, known as cardiac fatigue. Cardiac effects of prolonged exercise in horses remain unknown. Objectives :To investigate the effects of prolonged exercise on LV systolic...

  16. Neuroimmune Effects of Inhaling Low Dose Sarin


    affect these responses. This was further confirmed by the observation that intracerebroventricular administration of pyridostigmine and edrophonium...intracerebroventricularly) into the brain. These results also suggested that subcutaneous administration of pyridostigmine bromide at doses

  17. Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse.

    Park, Man Young; Kim, Eun Yeob; Lee, Young Ho; Kim, Woojae; Kim, Ku Sang; Sheen, Seung Soo; Lim, Hong Seok; Park, Rae Woong


    The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems. Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed. A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p data seem to be essential to adverse drug reaction surveillance in future.

  18. Lack of experimental evidence to support mcr-1-positive escherichia coli strain selection during oral administration of colistin at recommended and higher dose given by gavage in weaned piglets.

    Viel, Alexis; Henri, Jérôme; Perrin-Guyomard, Agnès; Laroche, Julian; Couet, William; Grégoire, Nicolas; Laurentie, Michel


    In this study, we assessed the selective effect of colistin orally administered to healthy weaned piglets harbouring an intestinal mcr-1-positive Escherichia coli strain. Maximum recommended dose and a higher dose often used in European pig farms were given by gavage. No selection of the mcr-1-positive strain was observed in our controlled conditions whatever the dose. Further investigations in real farming conditions seem necessary. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  19. Effect of prolonging radiation delivery time on retention of gammaH2AX

    Duzenli Cheryl


    Full Text Available Abstract Background and purpose Compared to conventional external beam radiotherapy, IMRT requires significantly more time to deliver the dose. Prolonging dose delivery potentially increases DNA repair which would reduce the biological effect. We questioned whether retention of γH2AX, a measure of lack of repair of DNA damage, would decrease when dose delivery was protracted. Materials and methods Exponentially growing SiHa cervical carinoma cells were irradiated with 6 MV photons in a water tank using a VarianEX linear accelerator. Cells held at 37°C received 2 Gy in 0.5 min and 4 Gy in 1 min. To evaluate effect of dose delivery prolongation, 2 and 4 Gy were delivered in 30 and 60 min. After 24 h recovery, cells were analyzed for clonogenic survival and for residual γH2AX as measured using flow cytometry. Results Increasing the dose delivery time from 0.5 or 1 min to 30 or 60 min produced a signficant increase in cell survival from 0.45 to 0.48 after 2 Gy, and from 0.17 to 0.20 after 4 Gy. Expression of residual γH2AX decreased from 1.27 to 1.22 relative to background after 2 Gy and 1.46 to 1.39 relative to background after 4 Gy, but differences were not statistically significant. The relative differences in the slopes of residual γH2AX versus dose for acute versus prolonged irradiation bordered on significant (p = 0.055, and the magnitude of the change was consistent with the observed increase in surviving fraction. Conclusion These results support the concept that DNA repair underlies the increase in survival observed when dose delivery is prolonged. They also help to establish the limits of sensitivity of residual γH2AX, as measured using flow cytometry, for detecting differences in response to irradiation.

  20. Administrative Reform

    Plum, Maja

    Through the example of a Danish reform of educational plans in early childhood education, the paper critically addresses administrative educational reforms promoting accountability, visibility and documentation. Drawing on Foucaultian perspectives, the relation between knowledge and governing...... of administrative technology, tracing how the humanistic values of education embed and are embedded within ‘the professional nursery teacher' as an object and subject of administrative practice. Rather than undermining the humanistic potential of education, it is argued that the technology of accounting...

  1. Phentolamine mesylate: It′s role as a reversal agent for unwarranted prolonged local analgesia

    Harpreet Singh Grover; Anil Gupta; Neha Saksena; Neha Saini


    Administration of local anesthesia is an integral procedure prior to dental treatments to minimize the associated pain. It is learned that its effect stays more than the time required for the dental procedure to be completed. This prolonged soft tissue anesthesia (STA) can be detrimental, inconvenient, and unnecessary. Phentolamine mesylate, a Food and Drug Administration-approved drug essentially serves the purpose of faster recovery from numbness at the site of local anesthesia. This articl...

  2. Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, tolerability and cardiac repolarization in healthy subjects.

    Rabinovich-Guilatt, Laura; Elgart, Anna; Erisson, Lavi; Willsie, Sandra K; Tessler, Shoshi; Barnett-Griness, Ofra; Pande, Amitkumar; Spiegelstein, Ofer


    Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects. Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated. AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration-effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience. Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen. © 2015 The British Pharmacological Society.

  3. Prolonged spring oestrus in mares: The use of progestogens with specific reference to proligestone

    Holst, W. van der; Laar, P. H. van; Oldenkamp, E. P.


    The problems of prolonged spring oestrus in mares, which is often associated with multifollicular ovaries (MFO), are described in the context of the need to produce foals early in the year. The results obtained, in terms of pregnancy and time of ovulation, after the intramuscular administration of a

  4. 口服不同剂量胆碱在肉鸡血液中的代谢动力学研究%Different-Dose Pharmacokinetic Study of Choline Chloride in Broiler by Oral Administration

    王斯佳; 蔡辉益; 刘国华; 闫海洁


    This experiment was conducted to compare the pharmacokinetics of choline chloride in broiler after oral administration at different doses. Twelve 9-week-old Arbor Acres male broilers were randomly divided into 3 groups with 4 birds in each group, and fed choline at 0, 200 and 400 mg/kg ( on basis of choline chloride) , respectively. The blood sample of each experimental bird was collected at 1, 2, 3, 4, 8, 12, 24, 36 and 48 h, respectively, and the serum choline concentration was analyzed by ion chromatography. The pharmaco-kinetics parameters were calculated by WinNonlin 5.2 using non-compartment model. The results showed that the serum choline concentration in birds fed no exogenous choline was stable during the 48 h. The pharmacoki-netics of choline chloride at different doses was significantly different, for both Vz/F and CL/F (P<0.01), with their regression between the serum choline concentration and time being linear respectively. The Tmax, Cmax, t1/2, AUMC, Vz/F and CL/F were 8. 0 h, 399. 88 mg/kg, 7. 60 h, 5 979. 06 mg/( kg · h), 876.99 L/kg and 83. 27 mg/( kg · h ) respectively for the dose of 200 mg/kg group, and 8. 0 h, 445.88 mg/kg, 9.91 h, 1 0899.78 mg/( kg·h) , 318.43 L/kg, 21.22 mg/( kg·h) respectively for the the dose of 400 mg/kg group, with the choline at 200 mg/kg being more bioavailable. In conclusion, only in-creasing of choline chloride dosage can not achieve the purpose of improving the rate of choline bioavailability.%本试验旨在采用药代动力学的研究手段,探索胆碱在肉鸡血液中的吸收代谢规律。选用12只9周龄的爱拔益加( AA)肉公鸡,随机分为3组,每组4只鸡,按体重分别单次口服氯化胆碱200和400 mg/kg(以胆碱计算),并设空白对照组。采取血样,对血样中的胆碱浓度进行离子色谱法的测定,并用药代动力学处理软件WinNonlin 5.2采用非房室模型计算药代动力学参数。结果显示,空白对照组内源胆碱的合成水平基本稳定;不同给

  5. Blind method of clustering for the evaluation of the dose received by personnel in two methods of administration of radiopharmaceuticals; Metodo ciego de clusterizacion para la evaluacion de la dosis recibida por el personal en dos metodos de administracion de radioformacos

    VerdeVelasco, J. M.; Gonzalez Gonzalez, M.; Montes Fuentes, C.; Verde Velasco, J.; Gonzalez Blanco, F. J.; Ramos Pacho, J. A.


    The difficulty for the injection of drugs marked with radioactive isotopes while syringe is located within the lead protector does that in many cases staff do it chooses to use the syringe outside the lead protector, increasing therefore the dose of radiation received. In our service raises the possibility of using a different methodology, channeling a pathway through a catheter, which allows administer, in all cases, with the syringe within the lead guard. We will check if significant differences can be seen both in the dose absorbed by the staff as in the time it takes to perform the administration of the drug using the method proposed compared injection without guard. (Author)

  6. Direct nose-brain transport of benzoylecgonine following intranasal administration in rats.

    Chow, H H; Anavy, N; Villalobos, A


    after iv administration up to 30 min following dosing. We conclude than nasally administered benzoylecgonine was transported directly from the nasal cavity to the brain and that the significant increase in brain levels was sustained for a prolonged period of time. Factors contributing to the observed differences in the nose-brain transport of cocaine and benzoylecgonine are discussed.

  7. A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience

    Gallimore, Andrew R.; Strassman, Rick J.


    The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel “alternate universe,” often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient “beings.” The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects—less than 20 min—militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent. PMID:27471468

  8. A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience

    Andrew Robert Gallimore


    Full Text Available The state of consciousness induced by N,N-dimethyltryptamine (DMT is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel alternate universe, often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient beings. The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects—less than 20 minutes—militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modelling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anaesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent.

  9. A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience.

    Gallimore, Andrew R; Strassman, Rick J


    The state of consciousness induced by N,N-dimethyltryptamine (DMT) is one of the most extraordinary of any naturally-occurring psychedelic substance. Users consistently report the complete replacement of normal subjective experience with a novel "alternate universe," often densely populated with a variety of strange objects and other highly complex visual content, including what appear to be sentient "beings." The phenomenology of the DMT state is of great interest to psychology and calls for rigorous academic enquiry. The extremely short duration of DMT effects-less than 20 min-militates against single dose administration as the ideal model for such enquiry. Using pharmacokinetic modeling and DMT blood sampling data, we demonstrate that the unique pharmacological characteristics of DMT, which also include a rapid onset and lack of acute tolerance to its subjective effects, make it amenable to administration by target-controlled intravenous infusion. This is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. Simulations of our model demonstrate that this approach will allow research subjects to be induced into a stable and prolonged DMT experience, making it possible to carefully observe its psychological contents, and provide more extensive accounts for subsequent analyses. This model would also be valuable in performing functional neuroimaging, where subjects are required to remain under the influence of the drug for extended periods. Finally, target-controlled intravenous infusion of DMT may aid the development of unique psychotherapeutic applications of this psychedelic agent.

  10. Administrative Ecology

    McGarity, Augustus C., III; Maulding, Wanda


    This article discusses how all four facets of administrative ecology help dispel the claims about the "impossibility" of the superintendency. These are personal ecology, professional ecology, organizational ecology, and community ecology. Using today's superintendency as an administrative platform, current literature describes a preponderance of…

  11. Prolonged acute hepatitis A mimicking autoimmune hepatitis

    Rintaro Mikata; Osamu Yokosuka; Fumio Imazeki; Kenichi Fukai; Tatsuo Kanda; Hiromitsu Saisho


    AIM: We report a case with a prolonged course of hepatitisA, with alanine aminotransferase (ALT) higher than 500 IU/Lfor more than 2 mo.METHODS: A middle-aged woman had an elevated IgG level of more than 2 000 mg/dL, positive arti-nudear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), but no evidence of persistent hepatitis A virus (HAV) infection. Liver biopsy findings were compatible with prolonged acute hepatitis, although acute onset of autoimmune hepatitis could not be ruled out.RESULTS: It was assumed that she developed a course of hepatitis similar to autoimmune hepatitis triggered by HAV infection. Ursodeoxycholic acid (UDCA) treatment was initiated and a favorable outcome was obtained. CONCLUSION: We describe a case of a middle-aged woman who showed a prolonged course of acute hepatitis A mimicking autoimmune hepatitis. Treatment with UDCAproved to be effective.

  12. Safety information on QT-interval prolongation

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H;


    Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approve......) was moderate (kappa 0.434). However, the agreement in expected clinical decisions based on the product labels was much higher (kappa 0.673). The US drug label tends to be more explicit, especially when it considers absence of QT effects....

  13. Urinary excretion of L-carnitine, acetyl-L-carnitine, propionyl-L-carnitine and their antioxidant activities after single dose administration of L-carnitine in healthy subjects

    Yu Cao


    Full Text Available The urine excretion of L-carnitine (LC, acetyl-L-carnitine (ALC and propionyl-Lcarnitine (PLC and their relations with the antioxidant activities are presently unknown. Liquid L-carnitine (2.0 g was administered orally as a single dose in 12 healthy subjects. Urine concentrations of LC, ALC and PLC were detected by HPLC. Superoxide dismutase (SOD, total antioxidative capacity (T-AOC, malondialdehyde (MDA and nitrogen monoxidum (NO activities were measured by spectrophotometric methods. The 0~2 h, 2~4 h, 4~8 h, 8~12 h, 12~24 h excretion of LC was 53.13±31.36 µmol, 166.93±76.87 µmol, 219.92±76.30 µmol, 100.48±23.89 µmol, 72.07±25.77 µmol, respectively. The excretion of ALC was 29.70±14.43 µmol, 80.59±32.70 µmol, 109.85±49.21 µmol, 58.65±18.55 µmol, and 80.43±35.44 µmol, respectively. The urine concentration of PLC was 6.63±4.50 µmol, 15.33±12.59 µmol, 15.46±6.26 µmol, 13.41±11.66 µmol and 9.67±7.92 µmol, respectively. The accumulated excretion rate of LC was 6.1% within 24h after its administration. There was also an increase in urine concentrations of SOD and T-AOC, and a decrease in NO and MDA. A positive correlation was found between urine concentrations of LC and SOD (r = 0.8277 or T-AOC (r = 0.9547, and a negative correlation was found between urine LC excretions and NO (r = -0.8575 or MDA (r = 0.7085. In conclusion, a single oral LC administration let to a gradual increase in urine L-carnitine excretion which was associated with an increase in urine antioxidant enzymes and the total antioxidant capacities. These data may be useful in designing therapeutic regimens of LC or its analogues in the future.A excreção urinária de L-carnitina (LC, acetil-L-carnitina (ALC e propionil-L-carnitine (PLC e as suas relações com as atividades antioxidantes são presentemente desconhecidos. Líquido de L-carnitina (2,0 g foi administrada por via oral como uma dose única em 12 indivíduos saudáveis. As concentra

  14. A comparative study of pharmacokinetics, urinary excretion and tissue distribution of platinum in rats following a single-dose oral administration of two platinum(IV) complexes LA-12 (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) and satraplatin (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum(IV).

    Sova, Petr; Mistr, Adolf; Kroutil, Ales; Semerád, Martin; Chlubnová, Hana; Hrusková, Veronika; Chládková, Jirina; Chládek, Jaroslav


    This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P platinum after the doses of 150 mg and 300 mg/kg (P platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. In conclusion, this

  15. Cellular mechanism of the QT prolongation induced by sulpiride.

    Lee, Hyang-Ae; Kim, Ki-Suk; Park, Sang-Joon; Kim, Eun-Joo


    In this study, the authors investigated the electrophysiological effect of sulpiride on cardiac repolarization using conventional microelectrode recording techniques in isolated canine Purkinje fibers and a whole-cell patch clamp technique in transiently transfected cells with the hERG, KCNQ1/KCNE1, KCNJ2, and SCN5A cDNA and in rat cardiac myocytes for I(Ca). In studies of action potential duration, 10 microM, 100 microM, 300 microM, and 1 mM sulpiride prolonged action potential duration in a concentration-dependent manner. In studies of cardiac ion channels, sulpiride did not significantly affect I(Na), I(Ca), I(Ks), I(K1), except for I(Kr). Sulpiride dose-dependently decreased the hERG tail current. It is considered that the prolonged action potential duration by sulpiride was mainly the result of inhibition of the hERG channel. The data suggest that the clinical use of sulpiride is reasonable within therapeutic plasma concentrations, but all patients taking this drug should be cautiously monitored for clinical signs of long-QT syndrome and severe arrhythmia.

  16. Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports.

    Hasnain, Mehrul; Vieweg, W Victor R; Howland, Robert H; Kogut, Christopher; Breden Crouse, Ericka L; Koneru, Jayanthi N; Hancox, Jules C; Digby, Geneviève C; Baranchuk, Adrian; Deshmukh, Anand; Pandurangi, Ananda K


    Recently, both the manufacturer of quetiapine and the US Food and Drug Administration warned healthcare providers and patients about quetiapine-induced QTc interval prolongation and torsade de pointes (TdP) when using this drug within the approved labeling.  We reviewed the case-report literature and found 12 case reports of QTc interval prolongation in the setting of quetiapine administration. There were no cases of quetiapine-induced TdP or sudden cardiac death (SCD) among patients using quetiapine appropriately and free of additional risk factors for QTc interval prolongation and TdP. Among the 12 case reports risk factors included female sex (nine cases), coadministration of a drug associated with QTc interval prolongation (eight cases), hypokalemia or hypomagnesemia (six cases) quetiapine overdose (five cases), cardiac problems (four cases), and coadministration of cytochrome P450 3A4 inhibitors (two cases). There were four cases of TdP. As drug-induced TdP is a rare event, prospective studies to evaluate the risk factors associated with QTc prolongation and TdP are difficult to design, would be very costly, and would require very large samples to capture TdP rather than its surrogate markers. Furthermore, conventional statistical methods may not apply to studies of TdP, which is rare and an 'outlier' manifestation of QTc prolongation. We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, TdP, and SCD so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as quetiapine.

  17. Mast cell leukemia with prolonged survival on PKC412/midostaurin.

    Xu, Xiangdong; Kreisel, Friederike H; Frater, John L; Hassan, Anjum


    Mast cell leukemia (MCL) is a rare and aggressive form of systemic mastocytosis. There are approximately 50 reported cases since 1950s. MCL is refractory to cytoreduction chemotherapy and the average survival is only six months. We report a MCL case in a 71 year-old woman with high tumor load at the initial presentation in 2005, who did not respond to either interleukin-2 or dasatinib therapy. After enrolled in a clinical trial of PKC412 (or Midostaurin) with a daily dose of 100 mg, the patient responded well to PKC412 and became transfusion independent in three months. Since then, her disease had been stably controlled. This is the first report of a high-tumor-load MCL case which achieved prolonged survival (101 months) by PKC 412. The 101-month overall survival is the longest among reported MCL cases in the English literature.

  18. Prolonged treatment of refractory status epilepticus in a child.

    Sahin, M; Riviello, J J


    Barbiturate anesthesia, which is commonly used for refractory status epilepticus, is an effective treatment, but with many significant complications. The relationship between the duration of this extreme therapy and the ultimate outcome of refractory status epilepticus has not been well studied. We report a 7-year-old girl who presented with refractory status epilepticus secondary to presumed encephalitis with a focal lesion on cranial magnetic resonance imaging. She was treated for 70 days with high-dose antiepileptic drugs and recovered with a residual seizure disorder. This case suggests that, if the status epilepticus is due to a reversible cause such as encephalitis, neurologic recovery may occur despite this very prolonged course of extreme therapy.

  19. Prolonged remission of leukemia associated with polycythemia vera.

    Hazani, A; Tatarsky, I; Barzilai, D


    A patient with polycythemia vera (PV) received successive treatment by phlebotomies, radioactive phosphorus, myleran and cyclophosphamide. Sixteen years after the diagnosis, he developed acute myeloblastic leukemia. A complete remission was achieved following two courses of COAP (cyclophosphamide, vincristine, Cytosine Arabinoside, and prednisone) therapy. Four months later, while still in leukemic remission, he became mildly polycythemic again and the treatment with phlebotomies and cyclophosphamide was resume. The patient has subsequently been in complete remission of leukemia for over three years and his polycythemia is controlled by small doses of cyclophosphamide. This appears to be a unique case of such a prolonged remission of leukemia in the course of PV, with a return to a mild polycythemia state.


    Suzanne Schneider


    Full Text Available Prolonged exercise may compromise immunity through a reduction of salivary antimicrobial proteins (AMPs. Salivary IgA (IgA has been extensively studied, but little is known about the effect of acute, prolonged exercise on AMPs including lysozyme (Lys and lactoferrin (Lac. Objective: To determine the effect of a 50-km trail race on salivary cortisol (Cort, IgA, Lys, and Lac. Methods: 14 subjects: (6 females, 8 males completed a 50km ultramarathon. Saliva was collected pre, immediately after (post and 1.5 hrs post race ( 1.5. Results: Lac concentration was higher at 1.5 hrs post race compared to post exercise (p0.05. IgA concentration, secretion rate, and IgA/Osm were lower 1.5 hrs post compared to pre race (p<0.05. Cort concentration was higher at post compared to 1.5 (p<0.05, but was unaltered from pre race levels. Subjects finished in 7.81 ± 1.2 hrs. Saliva flow rate did not differ between time points. Saliva Osm increased at post (p<0.05 compared to pre race. Conclusions: The intensity could have been too low to alter Lys and Lac secretion rates and thus, may not be as sensitive as IgA to changes in response to prolonged running. Results expand our understanding of the mucosal immune system and may have implications for predicting illness after prolonged running.

  1. Offentlig administration

    Nielsen, Elof Nellemann; Rehr, Preben René

    En undervisningsbog der henvender sig til administrationsbacheloruddannelsen. Kapitlerne er inddelt efter modulerne på uddannelsen og indeholder derfor elementer af administration, forvaltning, økonomistyring, innovation, samfundsvidenskabelige metoder og politisk styrede organisationer.......En undervisningsbog der henvender sig til administrationsbacheloruddannelsen. Kapitlerne er inddelt efter modulerne på uddannelsen og indeholder derfor elementer af administration, forvaltning, økonomistyring, innovation, samfundsvidenskabelige metoder og politisk styrede organisationer....

  2. Pharmacokinetics of high doses of cyanocobalamin administered by intravenous injection for 26 weeks in rats.

    Nava-Ocampo, Alejandro A; Pastrak, Aleksandra; Cruz, Tony; Koren, Gideon


    1. High doses of vitamin B12 (cyanocobalamin) may be therapeutically effective to treat neurological alterations secondary to a wide range of disease states. The aim of the present study was to evaluate the effect of dose and repeated administration on the pharmacokinetics of cyanocobalamin in rats. 2. Forty-eight rats were randomly assigned to receive 1, 5, 25 or 100 mg/kg cyanocobalamin for 182 days (26 weeks). Cyanocobalamin plasma levels were quantified by HPLC on days 1, 85 and 182 of treatment and were analysed by means of non-compartment pharmacokinetic (PK) analysis. In addition, population PK analysis was used to fit cyanocobalamin plasma concentrations to time by means of a two-compartment model for intravascular administration. 3. The half-life of cyanocobalamin ranged from approximately 20 to 50 min, clearance ranged from 4.5 to 9 mL/min and the volume of distribution at steady state ranged from 140 to 470 mL. A statistically significant negative relationship existed between the dose of cyanocobalamin and the normalized area under the plasma concentration-time curve (AUC). This non-linearity was not exhibited in population PK analysis. No evidence of toxicity was observed. 4. At very high and prolonged doses (up to 100 mg/kg for 26 weeks), intravascular administration of cyanocobalamin in rats follows a two-compartment kinetic model and cyanocobalamin undergoes extensive extravascular distribution. The negative relationship between dose and normalized AUC is compatible with possible saturation of tubular reabsorption, thus increasing renal clearance at higher doses.

  3. Carotid Baroreflex Function During Prolonged Exercise

    Raven, P. B.


    Astronauts are often required to work (exercise) at moderate to high intensities for extended periods while performing extra-vehicular activities (EVA). Although the physiologic responses associated with prolonged exercise have been documented, the mechanisms involved in blood pressure regulation under these conditions have not yet been fully elucidated. An understanding of this issue is pertinent to the ability of humans to perform work in microgravity and complies with the emphasis of NASA's Space Physiology and Countermeasures Program. Prolonged exercise at a constant workload is know to result in a progressive decrease in mean arterial pressure (MAP) concomitant with a decrease in stroke volume and a compensatory increase in heart rate. The continuous decrease in MAP during the exercise, which is related to the thermoregulatory redistribution of circulating blood volume to the cutaneous circulation, raises the question as to whether there is a loss of baroreflex regulation of arterial blood pressure. We propose that with prolongation of the exercise to 60 minutes, progressive increases on central command reflect a progressive upward resetting of the carotid baroreflex (CBR) such that the operating point of the CBR is shifted to a pressure below the threshold of the reflex rendering it ineffectual in correcting the downward drift in MAP. In order to test this hypothesis, experiments have been designed to uncouple the global hemodynamic response to prolonged exercise from the central command mediated response via: (1) continuous maintenance of cardiac filling volume by intravenous infusion of a dextran solution; and (2) whole body surface cooling to counteract thermoregulatory cutaneous vasodialation. As the type of work (exercise) performed by astronauts is inherently arm and upper body dependent, we will also examine the physiologic responses to prolonged leg cycling and arm ergometry exercise in the supine positions with and without level lower body negative

  4. Pharmacokinetics of biapenem injection after single dose administration in healthy volunteers%单次注射比阿培南在健康人体的药代动力学

    朱燕; 张曼; 李天云; 肖永红; 吕媛; 魏敏吉; 张朴; 康子胜; 刘燕; 梁军; 张薇


    Objective To study the pharmacokinetic of biapenem injec-tion in healthy volunteers and provide reference for clinical applica-tion. Methods Twelve healthy volunteers were enrolled and a single dose of 150, 300, 600 mg of biapenem was administered intravenously in Latin square design. The drug concentrations of biapenem in plasma and in urine were determined by HPLC method. Pharmacokinetic parameters of biapenem were generated with DAS software. Results The plasma concentration - time curves of biapenem conformed to a 2 - compartment pharmarcokinetic model. The main pharmacokinetics parameters of three different dosages (150, 300, 600 mg) were as follows; Cmax were (8.49±1.03),(16.31 ±1.83), (34.51 ±3.74)mg ? L-1;Tmax were (1.00±0.00)h; t1/2β were (1.08 ±0.80), (0.89 ±0.14), (0.93 ± 0.08)h; AUC0-t were (13.49 ± 2.29), (28. 91 ± 4. 92), (60. 85 ± 8.72) mg·L-1·h and CL were (11.09 ± 1.58), (10.54 ± 1.85), (9. 98 ±1.39) L·h-1·kg-1, respectively. Urinary recoveries were 61.9%, 62.1%, 62.8% in 12 h after drug administration, respectively. Conclusion The plasma concentration - time curve of bia-penem fits two compartment model, the pharmacokinetic parameters pro-portionate linearly to the dosages. All the subjects are well - tolerant.%目的 研究注射用比阿培南(碳青霉烯类抗生素)在健康人群单次给药药代动力学.方法 用分层随机、三交叉、拉丁方设计、空腹给药的试验方法,12名健康受试者单次静脉滴注比阿培南150,300,600 mg,HPLC法测定给药后血、尿药物浓度,DAS软件计算药代动力学参数.结果 受试者静滴比阿培南150,300,600 mg后药代动力学参数如下,Cmas分别是(8.49±1.03),(16.31±1.83),(34.51±3.74) nmg·L-1;Tmax均为(1.00±0.00) h;t1/2β分别为(1.08±0.80),(0.89±0.14),(0.93±0.08)h;AUC0-t分别(13.49±2.29),(28.91±4.92),(60.85±8.72) mg· L-1· h;CL分别是(11.09±1.58),(10.54±1.85),(9.98±1.39) L·h-1·kg-1.12 h尿排出率分别为61.9%,62.1

  5. Continuous epidermal growth factor receptor-tyrosine kinase inhibitor administration in primary lung adenocarcinoma patients harboring favorable mutations with controlled target lung tumors dose not hinder survival benefit despite small new lesions

    Ping-Chih Hsu


    Conclusion: Continuous EGFR-TKI administration in favorable EGFR-mutative lung adenocarcinoma patients with controlled primary tumors did not hinder the survival benefit, despite the appearance of new lesions.

  6. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy.

    Kaminskas, Lisa M; McLeod, Victoria M; Ryan, Gemma M; Kelly, Brian D; Haynes, John M; Williamson, Mark; Thienthong, Neeranat; Owen, David J; Porter, Christopher J H


    Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10-13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30-50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity.

  7. [Effect of the dose of estradiol and long-term administration of the hormone on the proliferative activity of the epithelium of the cavity, glandular epithelium and stroma of the white rat uterus].

    Ivasenko, I N; Prianishnikov, V A


    The duration of S-sphase of the cell cycle in uterine epithelial and stroma tissues of ovariectomised rats, treated with two doses of estradiol-17 beta for 4 days, was estimated by the double labeling technique using H3 -and C14-thymidine. Estrogen treatment induced cyclical changes of S-phase duration in the uterine cell compartments, with maximal values at 72 and 24 hours for 1mcg and 1 mg of estradiol. resp. The high dose of estradiol induced five-fold reduction of the mitotic and labeling indices in luminal epithelium in contrast to the effect of the low dose. In the rat glandular epithelium and stroma cells mitotic and labeling indices are not influenced by eith of the estrogen dosis.

  8. [Prolonged pain in neonates: retrospective analysis].

    Lilla, Michèle; Stadelman-Diaw, Corinne; Ramelet, Anne-Sylvie


    Infants hospitalised in neonatology are inevitably exposed to pain repeatedly. Premature infants are particularly vulnerable, because they are hypersensitive to pain and demonstrate diminished behavioural responses to pain. They are therefore at risk of developing short and long-term complications if pain remains untreated. Compared to acute pain, there is limited evidence in the literature on prolonged pain in infants. However, the prevalence is reported between 20 and 40 %. This single case study aimed to identify the bio-contextual characteristics of neonates who experienced prolonged pain. This study was carried out in the neonatal unit of a tertiary referral centre in Western Switzerland. A retrospective data analysis of seven infants' profile, who experienced prolonged pain ,was performed using five different data sources. The mean gestational age of the seven infants was 32weeks. The main diagnosis included prematurity and respiratory distress syndrome. The total observations (N=55) showed that the participants had in average 21.8 (SD 6.9) painful procedures that were estimated to be of moderate to severe intensity each day. Out of the 164 recorded pain scores (2.9 pain assessment/day/infant), 14.6 % confirmed acute pain. Out of those experiencing acute pain, analgesia was given in 16.6 % of them and 79.1 % received no analgesia. This study highlighted the difficulty in managing pain in neonates who are exposed to numerous painful procedures. Pain in this population remains underevaluated and as a result undertreated.Results of this study showed that nursing documentation related to pain assessment is not systematic.Regular assessment and documentation of acute and prolonged pain are recommended. This could be achieved with clear guidelines on the Assessment Intervention Reassessment (AIR) cyclewith validated measures adapted to neonates. The adequacy of pain assessment is a pre-requisite for appropriate pain relief in neonates.

  9. Napping and Human Functioning during Prolonged Work


    alternative to napping is prolonged wakefulness. Polyphasic sleep , with frequent naps rather than a single sleep period per 24 hours, is natural for both the...very young and for the aged. It is not practiced by most adults, perhaps because of societal demands. Possibly a polyphasic sleep schedule could be...Functioning 1.2 Scope of this Chapter 2. REVIEW OF LITERATURE 2.1 Partial Sleep Deprivation Studies 2.2 Nap Studies: Four Nap Factors Affecting Performance

  10. Prolonged grief: setting the research agenda

    Rita Rosner


    Full Text Available Background: Prolonged grief disorder is proposed for the International Classification of Diseases (ICD-11, though it was rejected as a diagnosis for DSM-5. Objective: This review outlines findings and defines important areas for future research viewed from a lifespan perspective. Results: The development and psychometric evaluation of measures for the new diagnosis is paramount, specifically for children and adolescents. Treatments need to be adapted for specific subgroups and research findings have to be disseminated into various professional settings.

  11. Prolonged Paralysis Following Emergent Cesarean Section with Succinylcholine Despite Normal Dibucaine Number.

    Ellison, Matthew; Grose, Brian; Howell, Stephen; Wilson, Colin; Lenz, Jackson; Driver, Richard


    Prolonged paralysis due to a quantitative or qualitative deficiency of pseudocholinesterase activity is an uncommon but known side effect of succinylcholine. We describe a patient who experienced prolonged paralysis following administration of succinylcholine for general anesthesia and endotracheal intubation for an emergent cesarean section despite laboratory evidence of normal enzyme function. The patient required mechanical ventilation in the intensive care unit for several hours following surgery. The patient was extubated following return of full muscle strength and had a good outcome. The enzyme responsible for the metabolism of succinylcholine, pseudocholinesterase, was determined to be low in quantity in this patient but was functionally normal. This low level, by itself, was unlikely to be solely responsible for the prolonged paralysis. The patient likely had an abnormal pseudocholinesterase enzyme variant that is undetectable by standard laboratory tests.

  12. Prolonged ulcerative laryngitis: a new disease entity.

    Hsiao, Tzu-Yu


    Over the last decade, a new disease entity, prolonged ulcerative laryngitis (PUL), with unique clinical presentation and prolonged disease course, has been recognized. Until now, very few studies dealing with this disease have been reported in the literature. From 1999 to 2008, we analyzed clinical data from a series of 39 PUL patients who were treated with an observational approach without implementing specific treatments. This disease affects adults, predominantly females. The age of patients in our series ranged from 26 to 76 years with a median of 49.5 years. This disease is characterized by ulcers and signs of acute inflammation on the membranous portion of the vocal folds with a prolonged clinical course. The recovery times of patients ranged from 4 to 20 weeks with an average of 9.4 weeks. The data in this study may reflect a natural history of this disease. PUL seems to be a self-limited disease, but the etiology of this disease is unknown. Specific infections or systemic inflammatory processes involving the larynx must be ruled out before diagnosis, and conservative treatments are suggested.

  13. Database Administrator

    Moore, Pam


    The Internet and electronic commerce (e-commerce) generate lots of data. Data must be stored, organized, and managed. Database administrators, or DBAs, work with database software to find ways to do this. They identify user needs, set up computer databases, and test systems. They ensure that systems perform as they should and add people to the…

  14. Database Administrator

    Moore, Pam


    The Internet and electronic commerce (e-commerce) generate lots of data. Data must be stored, organized, and managed. Database administrators, or DBAs, work with database software to find ways to do this. They identify user needs, set up computer databases, and test systems. They ensure that systems perform as they should and add people to the…

  15. Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children.

    Ashrafi, Mahmoud Reza; Khosroshahi, Nahid; Karimi, Parviz; Malamiri, Reza Azizi; Bavarian, Behrouz; Zarch, Anoushiravan Vakili; Mirzaei, Mehdi; Kompani, Farshid


    A Prolonged convulsive seizure is the most common neurological medical emergency with poor outcome. An ideal anticonvulsant should be easy-to-use, effective, and safe, and it should also have a long-lasting effect. Benzodiazepines, give via the intravenous or rectal route have generally been used as first-line drugs. In small children, IV access can be difficult and time consuming. Midazolam is a potent anticonvulsant and is rapidly absorbed from the rectal, nasal, and buccal mucosa. Our aim was to evaluate the efficacy and usability of buccal midazolam in controlling seizures in children with acute prolonged seizures, by comparing it with rectal diazepam. Ninety-eight patients were enrolled, with 49 patients in each treatment group. In the buccal midazolam group, 42 (88%) patients were controlled in less than 4 min of drug administration, and all of the patients were controlled within 5 min of drug administration. In the rectal diazepam group, 24 (49%) patients were controlled in less than 4 min and 40 (82%) patients were controlled within 5 min of drug administration. The time for drug administration and drug effect was significantly less with buccal midazolam than with rectal diazepam (p valuediazepam group, 7 (14%) parents were satisfied. Buccal midazolam was significantly more acceptable than rectal diazepam (p valuediazepam but more convenient to use in the controlling acute prolonged seizures in children, especially in situations in which there is a difficulty in gaining IV access, for example, in infants.

  16. Prolonging β-lactam infusion: a review of the rationale and evidence, and guidance for implementation.

    MacVane, Shawn H; Kuti, Joseph L; Nicolau, David P


    Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT>MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.

  17. Dose and timing requirements for immunogenicity of viral poultry vaccine antigen: investigations of emulsion-based depot function.

    Jansen, Theo; Hofmans, Marij P M; Theelen, Marc J G; Manders, Frans G A; Schijns, Virgil E J C


    The release requirements for vaccine antigens delivered by adjuvants with presumed depot function are poorly understood. Water-in-oil (W/O) emulsions are routinely used in many poultry vaccines. They strongly activate antibody production, and are regarded as a depot from which antigens are slowly released, resulting in prolonged antigen residence. However, from earlier studies we concluded that W/O adjuvant activity is partly based on the immunostimulatory activity of the oil phase. Here we assess the dose and regimen requirements for viral antigen in immunization experiments in chickens. Three-week-old to 4-week-old White Leghorn chickens were repeatedly injected with inactivated infectious bursal disease virus antigen over 48 days. Our aim was to compare the antibody responses in repeatedly injected animals, receiving fractioned doses of antigen, with the responses in animals receiving only one injection of the full dose of antigen formulated in either a W/O emulsion or in saline. We observed that repeated administration of small amounts of antigen results in a gradual increase of specific humoral immune responses during the immunization regimen. Immunization with a higher first dose evoked an early higher antibody response, which, however, reached a similar plateau level at the end of the regimen. When compared with lower first-dose regimens, a slow decline of serum antibody titre 2 weeks after the end of antigen injections indicated that repeated injection of small doses of antigen indeed mimics the efficacy of depot-forming adjuvants. All regimens of fractioned antigen in saline, however, proved less effective, when compared with a single-dose vaccination of the cumulative amount of antigen formulated in a W/O emulsion. From our data we confirm that W/O emulsions are very effective vaccine vehicles for improving antigen-specific humoral responses in chickens, owing to a combination of antigen residence-prolonging activity and direct immune stimulation.




    We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different dos

  19. Dose dependence and temporal evolution of the T1 relaxation time and MRI contrast in the rat brain after subcutaneous injection of manganese chloride.

    Shazeeb, Mohammed Salman; Sotak, Christopher H


    Divalent manganese ion (Mn(2+)) is a widely used T(1) contrast agent in manganese-enhanced MRI studies to visualize functional neural tracts and anatomy in the brain in vivo. In animal studies, Mn(2+) is administered at a dose that will maximize the contrast, while minimizing its toxic effects. In rodents, systemic administration of Mn(2+) via intravenous injection has been shown to create unique MRI contrast in the brain at a maximum dose of 175 mg kg(-1). However, intravenous administration of Mn(2+) results in faster bioelimination of excess Mn(2+) from the plasma due to a steep concentration gradient between plasma and bile. By contrast, following subcutaneous injection (LD(50) value = 320 mg kg(-1)), Mn(2+) is released slowly into the bloodstream, thus avoiding immediate hepatic elimination resulting in prolonged accumulation of Mn(2+) in the brain via the choroid plexus than that obtained via intravenous administration. The goal of this study was to investigate MRI dose response of Mn(2+) in rat brain following subcutaneous administration of Mn(2+). Dose dependence and temporal dynamics of Mn(2+) after subcutaneous injection can prove useful for longitudinal in vivo studies that require brain enhancement to persist for a long period of time to visualize neuroarchitecture like in neurodegenerative disease studies. Copyright © 2012 Wiley Periodicals, Inc.

  20. Comparative pharmacokinetics of fluralaner in dogs and cats following single topical or intravenous administration.

    Kilp, Susanne; Ramirez, Diana; Allan, Mark J; Roepke, Rainer Ka


    Bravecto™ Chewable Tablets for Dogs, containing fluralaner as active ingredient, is an innovative treatment for flea and tick infestations that provides safe, rapid and long acting efficacy after a single oral administration in dogs. Topically applied fluralaner provides similar safe, rapid and long acting efficacy, both in dogs and in cats. The pharmacokinetic profile of fluralaner was evaluated in dogs and in cats following either topical or intravenous administration. Twenty four dogs and 24 cats received three different topical doses, with the mid-dose based on the respective minimum recommended dose, and one intravenous dose. Plasma samples were collected for 112 days and fluralaner concentrations were quantified using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated using non-compartmental methods. In dogs, fluralaner was readily absorbed from the topical administration site into the skin, subjacent tissues and blood. Fluralaner plasma concentrations showed an apparent plateau between ~ day 7 and 63, with individual tmax seen within this time period. After the plasma plateau, concentrations declined slowly and were quantifiable for more than 12 weeks. In cats, fluralaner was readily systemically absorbed from the topical administration site, reaching maximum concentrations (Cmax) in plasma between 3 and 21 days post administration, after which concentrations declined slowly, and were also quantifiable for more than 12 weeks. Systemic exposure, as shown by Cmax and the area under the concentration versus time curve from time 0 to the last measurable concentration (AUC(0→t)) increased proportionally with dose in both species. Following intravenous administration fluralaner showed a relatively high apparent volume of distribution (Vz), a low plasma clearance (Cl), a long terminal half-life (t1/2) and a long mean residence time (MRT); thereby demonstrating

  1. Prolonged latent schistosomiasis diagnosed 38 years after infestation in a HIV patient.

    Payet, Barry; Chaumentin, Gilles; Boyer, Michelle; Amaranto, Paula; Lemonon-Meric, Claire; Lucht, Frederic


    We report a case of Schistosoma mansoni bilharziasis in a HIV patient 38 y after leaving an endemic region. A viable S. mansoni egg on a liver biopsy sample was diagnostic. Despite severe concomitant immunodeficiency the effective treatment was a single dose of praziquantel. Worms' intravascular longevity and the role of immunodeficiency as a possible factor in eggs retention after such prolonged latent schistosomiasis are discussed.

  2. Effectiveness of Cognitive Processing Therapy and Prolonged Exposure in the Department of Veterans Affairs.

    Rutt, Benjamin T; Oehlert, Mary E; Krieshok, Thomas S; Lichtenberg, James W


    Objective This study evaluated the effectiveness of cognitive processing therapy and prolonged exposure in conditions reflective of current clinical practice within the Veterans Health Administration. Method This study involved a retrospective review of 2030 charts. A total of 750 veterans from 10 U.S. states who received cognitive processing therapy or prolonged exposure in individual psychotherapy were included in the study (participants in cognitive processing therapy, N = 376; participants in prolonged exposure, N = 374). The main dependent variable was self-reported posttraumatic stress disorder symptoms as measured by total scores on the Posttraumatic Stress Disorder Checklist. The study used multilevel modeling to evaluate the absolute and relative effectiveness of both treatments and determine the relationship between patient-level variables and total Posttraumatic Stress Disorder Checklist scores during treatment. Results Cognitive processing therapy and prolonged exposure were equally effective at reducing total Posttraumatic Stress Disorder Checklist scores. Veterans who completed therapy reported significantly larger reductions in the Posttraumatic Stress Disorder Checklist than patients who did not complete therapy. There were no significant differences in the improvement of posttraumatic stress disorder symptoms with respect to age and three racial/ethnic groups (Caucasian, African American, and Hispanic). Conclusions Cognitive processing therapy and prolonged exposure were shown to be effective in conditions highly reflective of clinical practice and with a highly diverse sample of veterans. Challenges related to dropout from trauma focused therapy should continue to be researched.

  3. The administration of a single dose of a multivalent (DHPPiL4R vaccine prevents clinical signs and mortality following virulent challenge with canine distemper virus, canine adenovirus or canine parvovirus

    Stephen Wilson


    In conclusion, we demonstrated that a single administration of a minimum titre, multivalent vaccine to dogs of six weeks of age is efficacious and prevents clinical signs and mortality caused by CAV-1 and CDV; prevents clinical signs and significantly reduces virus shedding caused by CAV-2; and prevents clinical signs, leucopoenia and viral excretion caused by CPV.

  4. Topological evolution of self-induced silicon nanogratings during prolonged femtosecond laser irradiation

    Golosov, E.V.; Kolobov, Y.R. [Belgorod State University, Belgorod (Russian Federation); Ionin, A.A.; Kudryashov, S.I.; Novoselov, Y.N.; Seleznev, L.V.; Sinitsyn, D.V. [Russian Academy of Sciences, P.N. Lebedev Physical Institute, Moscow (Russian Federation); Ligachev, A.E. [A.M. Prokhorov General Physics Institute, Moscow (Russian Federation); Makarov, S.V. [Russian Academy of Sciences, P.N. Lebedev Physical Institute, Moscow (Russian Federation); National Research Nuclear University, MEPHI, Moscow (Russian Federation)


    Gradual evolution of self-induced silicon surface topology from one-dimensional ridge-like to two-dimensional spike-like nanogratings and then to isotropic sets of micro-columns was observed by evenly increasing IR and UV femtosecond laser irradiation dose. This topological evolution exhibits clear indications of consequent melting and vaporization processes being set up during the prolonged laser irradiation. Monotonously decreasing cumulative IR and UV femtosecond laser-nanostructuring thresholds may indicate an increase of optical absorbance of the laser-nanostructured silicon surfaces versus the increasing laser dose, consistent with the consequent onset of the abovementioned thermal modification processes. (orig.)

  5. Prolonged labour as indication for emergency caesarean section

    Maaløe, Nanna; Sorensen, B L; Onesmo, R


    To audit the quality of obstetric management preceding emergency caesarean sections for prolonged labour.......To audit the quality of obstetric management preceding emergency caesarean sections for prolonged labour....

  6. Cesium-induced QT-interval prolongation in an adolescent.

    O'Brien, Catherine E; Harik, Nada; James, Laura P; Seib, Paul M; Stowe, Cindy D


    Alternative medicine is becoming increasingly popular, especially with terminally ill patients. Most alternative remedies have not been adequately studied or proven effective for the diseases for which they are promoted. In the worst cases, these therapies are harmful. We describe a 16-year-old girl with metastatic hepatocellular carcinoma who experienced cesium-induced QT-interval prolongation after the start of a cesium chloride-based alternative treatment regimen. She had received seven courses of chemotherapy, with a cumulative doxorubicin dose of 500 mg/m(2) over 5 months, resulting in minimal tumor regression. Against the advice of her oncologist, she abandoned traditional therapy and started an alternative regimen that included cesium chloride supplements. Two weeks later, the patient went to a local emergency department after experiencing two brief syncopal episodes. An electrocardiogram revealed occasional premature ventricular contractions, a QTc interval of 683 msec (normal range for females 450-460 msec), and R on T phenomenon. She was admitted to the hospital and later experienced monomorphic ventricular tachycardia, which resolved spontaneously. Lidocaine therapy was started, and the patient was transferred to a cardiac intensive care unit at our hospital. Her plasma cesium level was 2400 microg/dl (normal cesium level was 1800 microg/dl, and her QTc interval was 494 msec. According to the Naranjo adverse drug reaction probability scale, cesium was the probable cause of the patient's arrhythmia. In animal models, cesium chloride has induced cardiac arrhythmias, including torsade de pointes. It inhibits delayed rectifier potassium channels in the myocardium, causing delayed repolarization and QT-interval prolongation. Patients with cancer should be aware that alternative remedies may be harmful and ineffective. Because patients may be unlikely to self-report alternative remedies, health care providers should specifically ask their patients about any

  7. The role of trefoil factor family in apparently healthy subjects administrated gastroprotective agents for the primary prevention of gastrointestinal injuries from low-dose acetylsalicylic acid: a preliminary study.

    Kawai, Takashi; Takagi, Yu; Fukuzawa, Mari; Yamagishi, Tetsuya; Goto, Shinya


    It is well-known that acetylsalicylic acid induces gastrointestinal complication. Recently, trefoil factor family has been reported as a mucosal protective factor. We focused on trefoil factor family as one of defensive system for gastrointestinal injuries. The aim of this trial was to evaluate trefoil factor family levels in the serum of healthy subjects with low-dose acetylsalicylic acid. Low-dose acetylsalicylic acid with placebo or proton pump inhibitor or rebamipide were administered in 30 healthy subjects. Transnasal endoscopy was performed at 0, 24 h, 3 and 7 day. Changing of trefoil factor family (1,2,3) and numbers of gastric injuries were evaluated. The numbers of gastric injuries were significantly increased in the placebo group at 3 and 7 days. Injuries in the proton pump inhibitor group were not induced, in the rebamipide group were slightly induced. Trefoil factor family level in the placebo group were decreased in 3 and 7 days compared with prior to starting the trial. Trefoil factor family may have an important association with acetylsalicylic acid-induced gastrointestinal damage. Proton pump inhibitor and rebamipide prevented low-dose acetylsalicylic acid-induced gastrointestinal complications compared with the placebo group.

  8. Laryngotracheal Injury following Prolonged Endotracheal Intubation

    J. Mehdizadeh


    Full Text Available Background: Prolonged endotracheal intubation is a growing method for supporting ventilation in patients who require intensive care. Despite considerable advancement in endotracheal intubation, this method still has some complications; the most important is laryngo-tracheal injuries. Methods: Over a 2-year period, this retrospective study was conducted on 57 patients with history of prolonged intubation who were referred to the ENT Department of Amir Alam Hospital. For each patient, a complete evaluation including history, physical examination, and direct laryngoscopy and bronchoscopy was done under general anesthesia. Results: Fifty-seven patients (44 male; mean age, 23.014.7 years were studied. Mean intubation period was 15.88 days. The most common presenting symptom was dyspnea (62%. Head trauma was responsible for most cases of intubation (72.4%. The most common types of tracheal and laryngeal lesions were tracheal (56.9% and subglottic (55.2% stenosis, respectively. Mean length of tracheal stenosis was 0.810.83 cm. There was a statistically significant relationship between length of tracheal stenosis and intubation period (P=0.0001 but no relation was observed between tracheal stenosis and age, sex, and etiology of intubation (All P=NS. Among the glottic lesions, inter- arytenoids adhesion was the most common lesion (25.9%. No statistically significant relation was found between glottic and subglottic lesions and age, sex and intubation period (all P=NS. Length of stenosis and intubation period was significantly greater in tracheal/ subglottic lesions than those in glottic/ supraglottic lesions (all P=NS. Conclusion: After prolonged endotracheal intubation, laryngo-tracheal lesions had no relation with patient’s age, sex, and cause of intubation.There was direct relation between length of tracheal stenosis and intubation period. Glottic lesions were more commonly observed in head trauma patients. Lesion length and intubation

  9. [Prolonged acute pancreatitis after bone marrow transplantation].

    De Singly, B; Simon, M; Bennani, J; Wittnebel, S; Zagadanski, A-M; Pacault, V; Gornet, J-M; Allez, M; Lémann, M


    Acute pancreatitis is not infrequent after allogenic marrow transplantation. Several causes can predispose to pancreatitis, including Graft-Versus-Host Disease (GVHD), a condition which is probably underestimated. In the literature, few description of pancreatic GVHD can be found. Pancreatic GVHD diagnosis can be difficult if pancreatic involvement occurs without other typical manifestations of GVHD. We report the case of a woman, 54 years old, suffering from prolonged, painful pancreatitis two months after allogenic bone marrow transplantation for acute myeloid leucemia. Pancreatic GVHD diagnosis was performed after five weeks on duodenal biopsies despite the absence of diarrheoa. The patient dramatically improved within few days on corticosteroids.

  10. Prolonged parenteral nutrition after neonatal gastrointestinal surgery

    Estmann, Anne; Qvist, Niels; Husby, Steffen


    INTRODUCTION: Long-term treatment with parenteral nutrition (PN) may be essential for survival in infants after neonatal gastrointestinal surgery. It seemed well indicated in a population-based study to estimate the need for long-term PN and to characterize the infants that received TPN with regard...... to diagnosis and clinical course. METHODOLOGY: This study reviews the clinical course of infants with gastrointestinal disease (gastroschisis, intestinal atresia, omphalocele, volvulus, Hirschsprung's disease and necrotizing enterocolitis) with a prolonged need for parenteral nutrition in the Western part...

  11. Survival of soil bacteria during prolonged desiccation.

    Chen, M.; Alexander, M.


    A determination was made of the kinds and numbers of bacteria surviving when two soils were maintained in the laboratory under dry conditions for more than half a year. Certain non-spore-forming bacteria were found to survive in the dry condition for long periods. A higher percentage of drought-tolerant than drought-sensitive bacteria was able to grow at low water activities. When they were grown in media with high salt concentrations, bacteria generally became more tolerant of prolonged drought and they persisted longer. The percent of cells in a bacterial population that remained viable when exposed to drought stress varied with the stage of growth.

  12. Prolonged parenteral nutrition after neonatal gastrointestinal surgery

    Estmann, Anne; Qvist, Niels; Husby, Steffen


    INTRODUCTION: Long-term treatment with parenteral nutrition (PN) may be essential for survival in infants after neonatal gastrointestinal surgery. It seemed well indicated in a population-based study to estimate the need for long-term PN and to characterize the infants that received TPN with regard...... to diagnosis and clinical course. METHODOLOGY: This study reviews the clinical course of infants with gastrointestinal disease (gastroschisis, intestinal atresia, omphalocele, volvulus, Hirschsprung's disease and necrotizing enterocolitis) with a prolonged need for parenteral nutrition in the Western part...

  13. Toxicological evaluation of long-term intravenous administration of amitraz in horses

    Queiroz-Neto A.


    Full Text Available With the aim of determining the possible toxicity of amitraz after its prolonged use in horses, six English Thoroughbred horses received intravenous injections of amitraz (0.05, 0.10 or 0.15 mg/kg weekly for four months, constituting the experimental group. Eight other animals (control group, via the same route following the same drug administration schedule and period of time, received the vehicle, dimethylformamide. At the end of this period, blood was collected from all the animals, and a comparison was made of the means of the values obtained for the various blood analyses: complete hemogram, alkaline phosphatase, gamma-glutamyltransferase, blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, creatine phosphokinase, glucose, albumin, total protein, creatinine, Na+ , K+, Cl- and CO2. The results for the biochemical characteristics showed that only the mean value for urea of the animals submitted to treatment with amitraz was significantly different than the mean value obtained for the control group. The analyses of the hematological characteristics showed that no significant differences between groups were observed. Similarly, the measurement of blood electrolyte levels demonstrated that long-term treatment with amitraz did not cause significant changes in the variables analyzed. The results indicate that amitraz, given in the doses employed in this study, did not show signs of inducing toxic effects in vital organs, even after prolonged administration.

  14. A Case of Prolonged Cholestatic Hepatitis Induced by Azithromycin in a Young Woman

    Caterina Maggioli


    Full Text Available Azithromycin, a semisynthetic macrolides, is frequently prescribed for the treatment of middle ear and upper respiratory tract infections, bronchitis, and community-acquired pneumonia. This antibiotic is usually well tolerated, and a rapid resolving cholestatic hepatitis has been described up to now only in six patients all, except one, over 65 years of age. We here report the case of a prolonged cholestatic hepatitis after administration of azithromycin in a young woman with no history of liver disease.

  15. Sustained, low-dose intraperitoneal cisplatin improves treatment outcome in ovarian cancer mouse models.

    Ye, Hongye; Tanenbaum, Laura M; Na, Young Jeong; Mantzavinou, Aikaterini; Fulci, Giulia; del Carmen, Marcela G; Birrer, Michael J; Cima, Michael J


    Intraperitoneal (IP) chemotherapy for ovarian cancer treatment prolongs overall survival by 16 months compared to intravenous chemotherapy but is not widely practiced due to catheter-related complications and complexity of administration. An implantable, nonresorbable IP microdevice was used to release chemotherapeutic agent at a constant rate of approximately 1.3 μg/h in vitro and 1.0 μg/h in vivo. Studies conducted in two orthotopic murine models bearing human xenografts (SKOV3 and UCI101) demonstrate that continuous dosing reduces tumor burden to the same extent as weekly IP bolus drug injections. Treatment-induced toxicity was quantified via body weight loss and complete blood count. The microdevice resulted in significantly less toxicity than IP bolus injections, despite administration of higher cumulative doses (total area under the concentration-time curve of 3049 ng day/mL with the microdevice vs. 2118 ng-day/mL with IP bolus injections). This preclinical study supports the concept that reduced toxicity with similar efficacy outcomes can be achieved by continuous dosing in ovarian cancer patients currently treated with IP therapy.

  16. Involvement of bradykinin B2 and muscarinic receptors in the prolonged diuretic and antihypertensive properties of Echinodorus grandiflorus (Cham. & Schltdl.) Micheli.

    Prando, Thiago Buno Lima; Barboza, Lorena Neris; Araújo, Valdinei de Oliveira; Gasparotto, Francielly Mourão; de Souza, Lauro Mera; Lourenço, Emerson Luiz Botelho; Gasparotto Junior, Arquimedes


    Although Echinodorus grandiflorus (Cham. & Schltr.) Michel are used in Brazilian folk medicine as a diuretic drug, to date, no study has evaluated the mechanisms involved in this activity after prolonged administration in rats. Evaluate the possible mechanisms involved in the prolonged diuretic activity of ethanol soluble fraction obtained from Echinodorus grandiflorus (ES-EG) and to assess its relationship with hypotensive and antihypertensive activity using normotensive rats and those with renovascular hypertension (2K1C). The diuretic effects of ES-EG (30-300 mg/kg; p.o.) were compared with hydrochlorothiazide in a repeated-dose treatment for 7 days. The urinary volume and sodium, potassium, chloride, bicarbonate contents, conductivity, pH and density were estimated in sample collected in 24 h for 7 days. Plasma sodium, potassium, total protein, urea, creatinine, aldosterone, vasopressin, nitrite, acetylcholinesterase concentration and angiotensin converting enzyme (ACE) activity were measured in samples collected at the end of the experimental period (seventh day). Using pharmacological antagonists or inhibitors, the involvement of bradykinin, prostaglandin, acetylcholine and nitric oxide (NO) in ES-EG-induced diuresis was determined. In addition, activities of erythrocytary carbonic anhydrase and renal Na+/K+/ATPase were evaluated in vitro. ES-EG increased diuresis similarly to hydrochlorothiazide and also presented HCO3-sparing effects and increased serum nitrite levels. Moreover, the intraduodenal administration of ES-EG induces significant hypotensive and antihypertensive effects in 2K1C rats. Previous treatment with HOE-140, indometacin and atropine fully avoided the diuretic effect of ES-EG, and including L-NAME pre-administration, it prevented the hypotensive and hypertensive activity induced by ES-EG. In addition, the association between HOE-140 and atropine or indometacin and L-NAME fully inhibited the hypotensive and antihypertensive effects of ES

  17. Administrative contracts

    Vukićević-Petković Milica


    Full Text Available Administrative contracts are a special type of contract where usually one of the contracting parties is a public law body and which is concluded for the performance of public service and the realization of a public interest. They go a long way since its inception to its eventual final acceptance of all the legal systems. One of the enduring characteristics of this type of contract is their disquised or unnoticed existence. This is why only monitoring their development may lead to a complete understanding of the importance and essence of this institution as well as the need for its complete legal regulation.

  18. L-dopa dose and the duration and severity of dyskinesia in primed MPTP-treated primates.

    Kuoppamäki, M; Al-Barghouthy, G; Jackson, M J; Smith, L A; Quinn, N; Jenner, P


    Most patients with Parkinson's disease (PD) develop dyskinesia and other motor complications after prolonged L-dopa use. We now report on the relationship between L-dopa dose and the duration and severity of dyskinesia in L-dopa-primed MPTP-treated primates with marked nigral degeneration mimicking late stage PD. With increasing doses of L-dopa, locomotor activity increased and motor disability declined. The duration of dyskinesia following L-dopa administration increased dose-dependently, and showed a linear correlation with total locomotor activity. In addition, the time-course of dyskinesia paralleled closely that of locomotor activity in a dose-dependent manner. In contrast, severity of dyskinesia showed a non-linear correlation with total locomotor activity, low doses of L-dopa eliciting severe dyskinesia for short periods of time. The threshold for dyskinesia induction and the antiparkinsonian effects of L-dopa appear very similar in primed MPTP primates mimicking late stage PD. Reducing individual doses of L-dopa to avoid severe dyskinesia can markedly compromise the antiparkinsonian response. Our results extend the relevance of the dyskinetic MPTP-treated primate in studying the genesis of involuntary movements occurring in L-dopa treated patients with PD.

  19. How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

    Jamal, Janattul-Ain; Mueller, Bruce A; Choi, Gordon Y S; Lipman, Jeffrey; Roberts, Jason A


    Determining appropriate antibiotic dosing for critically ill patients receiving renal replacement therapy (RRT) is complex. Worldwide unstandardized and heterogeneous prescribing of RRT as well as altered patient physiology and pathogen susceptibility all cause drug disposition to be much different to that seen in non-critically ill patients. Significant changes to pharmacokinetic parameters, including volume of distribution and clearance, could be expected, in particular, for antibiotics that are hydrophilic with low plasma protein binding and that are usually primarily eliminated by the renal system. Antibiotic clearance is likely to be significantly increased when higher RRT intensities are used. The combined effect of these factors that alter antibiotic disposition is that non-standard dosing strategies should be considered to achieve therapeutic exposure. In particular, an aggressive early approach to dosing should be considered and this may include administration of a 'loading dose', to rapidly achieve therapeutic concentrations and maximally reduce the inoculum of the pathogen. This approach is particularly important given the pharmacokinetic changes in the critically ill as well as the increased likelihood of less susceptible pathogens. Dose individualization that applies knowledge of the RRT and patient factors causing altered pharmacokinetics remains the key approach for ensuring effective antibiotic therapy for these patients. Where possible, therapeutic drug monitoring should also be used to ensure more accurate therapy. A lack of pharmacokinetic data for antibiotics during the prolonged intermittent RRT and intermittent hemodialysis currently limits evidence-based antibiotic dose recommendations for these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Single Daily Dosing of Gentamicin: Pharmacokinetic Comparison of Two Dosing Methodologies for Postpartum Endometritis

    C. Liu


    Full Text Available Objective: We compared the pharmacokinetics of two methods for dosing gentamicin for the treatment of postpartum endometritis with the goal of achieving adequate peak serum concentrations (>12 mg/L and prolonged trough levels below 2 mg/L.

  1. Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism.

    Horiguchi, Masakuni; Miyauchi, Masanori; Neugebauer, Nichole M; Oyamada, Yoshihiro; Meltzer, Herbert Y


    Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15-21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

  2. Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole

    Kapp, D.S.; Wagner, F.C.; Lawrence, R.


    In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m/sup 2/. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.

  3. Metronomic Chemotherapy: Low Dose Less Toxicity Anticancer Strategy

    Anjan Khadka


    Full Text Available Metronomic chemotherapy is the frequent administration of chemotherapy drugs at doses below the maximum tolerated dose and with no prolonged drug‑free break. It thus achieves a sustained low blood level of the drug without significant toxic side‑effects. Metronomic therapy leads to sustained plasma concentration of the drug without significant toxic side‑effects and hence there is reduced need for supportive therapy. However in case of conventional therapy toxicity is a concern. Metronomic chemotherapy exerts both direct and indirect effects on tumor cells and their microenvironment. It can inhibit tumor angiogenesis, stimulate anticancer immune response and also induces tumor dormancy. Optimizing a metronomic anticancer therapy is still a challenging task. New strategies are being developed to combine metronomic chemotherapy with conventional chemotherapy, radiotherapy and/or targeted therapy. An important disadvantage of this type of regimen is the empiricism in finding the optimal ‘low‑dose’ and in monitoring therapeutic efficacy during the course of treatment.

  4. Lifetime Prolonging Algorithms for Underwater Sensor Networks

    GUO Zhong-wen; LI Zhi-wei; YU Lei


    Underwater acoustic modem technology has attained a level of maturity to support underwater acoustic sensor networks (UASNs) which are generally formed by acoustically connected sensor nodes and a surface station providing a link to an on-shore control center. While many applications require long-term monitoring of the deployment area, the battery-powered network nodes limit the lifetime of UASNs. Therefore, designing a UASN that minimizes the power consumption while maximizing lifetime becomes a very difficult task. In this paper, a method is proposed to determine the optimum number of clusters through combining an application-specific protocol architecture and underwater acoustic communication model so as to reduce the energy dissipation of UASNs. Deploying more sensor nodes which work alternately is another way to prolong the lifetime of UASNs. An algorithm is presented for selecting sensor nodes and putting them into operation in each round, ensuring the monitoring to the whole given area. The present results show that the algorithm can help prolong system lifetime remarkably when it is applied to other conventional approaches for sensor networks under the condition that the sensor node density is high.

  5. Prolonged energy harvesting for ingestible devices.

    Nadeau, Phillip; El-Damak, Dina; Glettig, Dean; Kong, Yong Lin; Mo, Stacy; Cleveland, Cody; Booth, Lucas; Roxhed, Niclas; Langer, Robert; Chandrakasan, Anantha P; Traverso, Giovanni


    Ingestible electronics have revolutionized the standard of care for a variety of health conditions. Extending the capacity and safety of these devices, and reducing the costs of powering them, could enable broad deployment of prolonged monitoring systems for patients. Although prior biocompatible power harvesting systems for in vivo use have demonstrated short minute-long bursts of power from the stomach, not much is known about the capacity to power electronics in the longer term and throughout the gastrointestinal tract. Here, we report the design and operation of an energy-harvesting galvanic cell for continuous in vivo temperature sensing and wireless communication. The device delivered an average power of 0.23 μW per mm(2) of electrode area for an average of 6.1 days of temperature measurements in the gastrointestinal tract of pigs. This power-harvesting cell has the capacity to provide power for prolonged periods of time to the next generation of ingestible electronic devices located in the gastrointestinal tract.

  6. Prolonged and post-term pregnancies: guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF).

    Vayssière, Christophe; Haumonte, Jean-Baptiste; Chantry, Anne; Coatleven, Frédéric; Debord, Marie Pascal; Gomez, Conchita; Le Ray, Camille; Lopez, Emmanuel; Salomon, Laurent J; Senat, Marie Victoire; Sentilhes, Loïc; Serry, Aurelie; Winer, Norbert; Grandjean, Hélène; Verspyck, Eric; Subtil, Damien


    ), without increasing the risk of either membrane rupture or maternal or neonatal infection (grade B). Used as a tampon or vaginal gel, prostaglandins E2 (PGE2) are an effective method of inducing labor (grade A). They can be used to induce labor successfully, regardless of cervical ripeness (grade A). If misoprostol is chosen, the lowest dose is to be preferred, starting with a vaginal dose of 25μg every 3-6h (grade A). For misoprostol, more powerful studies remain necessary for better defining the doses, routes of administration, tolerance and indications. Misoprostol at any dose is contraindicated in women with uterine scars (grade B). Placement of an intracervical Foley catheter is an effective mechanical means of inducing labor, with less uterine hyperstimulation than prostaglandins and no increase in the cesarean section rate (grade A). Nonetheless, as the risk of infection might be increased, this technique requires more robust evaluation before entering general practice (grade B). In cases of meconium-stained amniotic fluid, pharyngeal aspiration before delivery of the shoulders is not recommended (grade A). The team managing a post-term newborn with meconium-stained amniotic fluid at birth must know how to perform intubation and, if the intubation is not helpful, endotracheal aspiration (grade C) and ventilation with a mask. Routine endotracheal intubation of a vigorous newborn is not recommended (grade A).


    Division des ressources humaines


    N° 2 (Rev. 1) - March 2000Guidelines and procedures concerning recruitment and probation period of staff membersN° 9 (Rev. 2) - March 2000Staff members contractsN° 16 (Rev. 2) - January 2000TrainingN° 30 (Rev. 1) - January 2000Indemnities and reimbursements upon taking up appointment and termination of contractN° 32 - February 2000Principles and procedures governing complaints of harassmentThese circular have been amended (No 2, N° 9, N° 16 and N° 30) or drawn up (N° 32).Copies are available in the Divisional Secretariats.Note:\tAdministrative and operational circulars, as well as the lists of those in force, are available for consultation in the server SRV4_Home in the Appletalk zone NOVELL (as GUEST or using your Novell username and password), volume PE Division Data Disk.The Word files are available in the folder COM, folder Public, folder ADM.CIRC.docHuman Resources DivisionTel. 74128

  8. Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam.

    Chapman, Shira; Yaakov, Guy; Egoz, Inbal; Rabinovitz, Ishai; Raveh, Lily; Kadar, Tamar; Gilat, Eran; Grauer, Ettie


    Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 μg/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam 1mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning.

  9. Hyaluronidase inhibitors (sodium cromoglycate and sodium auro-thiomalate) reduce the local tissue damage and prolong the survival time of mice injected with Naja kaouthia and Calloselasma rhodostoma venoms.

    Yingprasertchai, Senee; Bunyasrisawat, Srisurat; Ratanabanangkoon, Kavi


    Experiments have been carried out to find potent inhibitors of hyaluronidases of Naja kaouthia (NK) and Calloselasma rhodostoma (CR) venoms with the aim of reducing local tissue damage and systemic toxicities caused by the venoms. Seven drugs/chemicals known to inhibit hyaluronidases were tested for their activity on venom enzymes. These were: sodium cromoglycate (SC), sodium aurothiomalate (SAT), apigenin, kaemferol, phenylbutazone, oxyphenbutazone and fenoprofen. The results showed that SC or SAT at 10 mM, completely inhibited the enzymes of both venoms. In in vivo experiments, SC or SAT, when incubated with NK venom prior to injection, significantly reduced edema and myonecrosis. In the case of CR venom, hemorrhage, in addition to edema and myonecrosis, was also significantly reduced. In the independent type experiment, SC or SAT were effective if injected within 1 min after the injection of venom. At longer time intervals of 3 and 10 min the inhibitors were effective in reducing some parameters of local tissue necrosis but the extent of inhibition was lower. SC and SAT at 256 and 195 microg/mouse, respectively, significantly prolonged the survival time of mice receiving lethal doses of NK. In the case of CR venoms, the two inhibitors not only prolonged the survival time but also prevented death of mice receiving lethal doses of the venom. The other inhibitors were poorly soluble in water and were studied only on enzyme inhibition and prolongation of survival time; they were mostly ineffective. Thus, SC and SAT when injected immediately at the sites of bites can reduce the systemic and local toxicity of NK and CR venoms. These results suggest that administration of these drugs at the site of venom injection may be useful in reducing venom-induced local tissue damage.

  10. Prolonged deficits in presynaptic serotonin function following withdrawal from chronic cocaine exposure as revealed by 5-HTP-induced head-twitch response in mice.

    Darmani, N A; Shaddy, J; Elder, E L


    Recent in vivo microdialysis studies have indicated that presynaptic deficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch response (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the dose- and time-response effects of this deficit. The HTR is considered to be a sensitive model for activation of central postsynaptic 5-HT2A receptors in rodents. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing, at 24 h following last injection, the treated mice received either 1) no cocaine; 2) their corresponding daily dose as challenge injection; or 3) a 10 mg/kg challenge dose. In a second series of experiments, extended abstinence studies were performed under the conditions of experimental protocols 1 and 2 for both 7- and 13-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 24, 48, 72 and 96 h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied following prolonged withdrawal from chronic cocaine exposure (0, 0.5, 5 and 10 mg/kg, twice daily for 7 and 13 days) at 24, 96 and 240 h abstinence. In experimental protocol 1 at 24 h abstinence in the 7 day exposure group, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenuated the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72 h abstinence. Although in the 13 day cocaine exposure groups (experimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96 h abstinence. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) in their corresponding pretreatment groups significantly reduced the behavior at diverse abstinence intervals in both 7- and 13-day exposure regimens relative to their chronically vehicle-treated controls which had received a vehicle challenge

  11. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Cros, C., E-mail: [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)


    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  12. [Sideroblastic anemia after prolonged linezolid therapy].

    Kakimoto, Tsunayuki; Nakazato, Tomonori; Miura, Reiko; Kurai, Hanako; Yamashita, Daisuke; Sagara, Yuko; Ishida, Akaru


    Linezolid is an effective and well-tolerated antibiotic for the treatment of infections caused by Gram-positive pathogens. Some reports have shown that linezolid treatment for more than 2 weeks has been associated with reversible bone marrow suppression, especially thrombocytopenia and anemia. We encountered a case of sideroblastic anemia following prolonged linezolid therapy in a laryngeal cancer patient. He received linezolid therapy for multiple abscesses due to MRSA. Before treatment, the Hb level was 12.5 g/dl and then slowly decreased to 5.9 g/dl for 2 months during treatment. Ringed sideroblasts were detected in the bone marrow. Linezolid was discontinued and the Hb level was slowly increased. This case was considered to reflect a rare complication of linezolid therapy.

  13. Multifactorial QT Interval Prolongation and Takotsubo Cardiomyopathy

    Michael Gysel


    Full Text Available A 71-year-old woman collapsed while working as a grocery store cashier. CPR was performed and an AED revealed torsades de pointes (TdP. She was subsequently defibrillated resulting in restoration of sinus rhythm with a QTc interval of 544 msec. Further evaluation revealed a diagnosis of Takotsubo Cardiomyopathy (TCM contributing to the development of a multifactorial acquired long QT syndrome (LQTS. The case highlights the role of TCM as a cause of LQTS in the setting of multiple risk factors including old age, female gender, hypokalemia, and treatment with QT prolonging medications. It also highlights the multifactorial nature of acquired LQTS and lends support to growing evidence of an association with TCM.

  14. Neurohumoral responses during prolonged exercise in humans

    Nybo, Lars; Nielsen, Bodil; Blomstrand, Eva


    in the hyperthermic trial, with a concomitant increase in perceived exertion (P brain had a small release of tryptophan (arteriovenous difference of -1.2 +/- 0.3 micromol/l), whereas a net balance was obtained during the two exercise trials. Both the arterial and jugular venous dopamine levels...... became elevated during the hyperthermic trial, but the net release from the brain was unchanged. During exercise, the O2/CHO was similar across trials, but, during recovery from the hyperthermic trial, the ratio decreased to 3.8 +/- 0.3 (P ...This study examined neurohumoral alterations during prolonged exercise with and without hyperthermia. The cerebral oxygen-to-carbohydrate uptake ratio (O2/CHO = arteriovenous oxygen difference divided by arteriovenous glucose difference plus one-half lactate), the cerebral balances of dopamine...

  15. Hepatoprotective Effect of Low Doses of Caffeine on CCl4-Induced Liver Damage in Rats.

    Cachón, Andrés Uc; Quintal-Novelo, Carlos; Medina-Escobedo, Gilberto; Castro-Aguilar, Gaspar; Moo-Puc, Rosa E


    Several studies have shown the hepatoprotective effect of the consumption of coffee and tea, which is mainly attributed to caffeine. Many experimental studies have demonstrated this effect; however, these studies used high caffeine doses that are not related to human consumption. The aim of this study was to evaluate the hepatoprotective effect of low doses of caffeine on carbon tetrachloride (CCl4)-treated rats. Low doses of caffeine (CAFF) 5 and 10 mg/kg (CAFF5 and CAFF10) were evaluated in chronic liver damage induced by CCl4 (0.75 mL/kg) in rats. CAFF treatment was administered once a day and CCl4 administration was twice weekly for 10 weeks. Liver function tests (biochemical markers) and functional (sleeping time) and histological (hematoxylin-eosin and Masson trichrome stains) parameters were carried out at the end of damage treatment. Daily treatments of CAFF5 and CAFF10 exhibited a hepatoprotective effect supported by a decrease of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) serum activities and bilirubin serum levels compared with control and also restored serum albumin levels and liver glutathione (GSH). Moreover, CAFF prevented CCl4-induced prolongation in pentobarbital sleeping time and a decrease of liver fibrosis and cell death. Our results demonstrated that low doses of CAFF exert a hepatoprotective effect against CCl4 -induced liver damage in rats.

  16. Trends in multidrug-resistant gram-negative bacilli and the role of prolonged β-lactam infusion in the intensive care unit.

    Guervil, David J; Chau, Terence


    Multidrug-resistant gram-negative bacilli are emerging threats in the intensive care unit setting worldwide. Extended-spectrum β-lactamases, AmpC β-lactamases, and carbapenem-resistant Enterobacteriaceae are increasing at an alarming rate, leaving limited therapeutic options. In addition, multidrug resistance among Pseudomonas aeruginosa and Acinetobacter baumannii has widely disseminated and become a frequent cause of nosocomial infections within many intensive care units. Therefore, resistance is increasing to all currently available antibiotics, including cephalosporins, penicillins, aztreonam, carbapenems, fluoroquinolones, and aminoglycosides. Some multidrug-resistant gram-negative bacteria remain susceptible to only a few antibiotics such as tigecycline, fosfomycin, and polymyxins. The steady trend of increasing resistance coupled with the lack of novel antibiotics targeting resistant gram-negative bacilli has forced clinicians to increasingly apply more aggressive dosing strategies, such as prolonged and continuous infusion of β-lactam antibiotics to address the challenges associated with these difficult-to-treat pathogens. Nurses who have a thorough understanding of antibiotic resistance patterns, infection control procedures, and appropriate antibiotic use and dosing regimens, particularly the method of administration, are essential in the battle to preserve the usefulness of antibiotics and prevent further antibiotic resistance.

  17. Epinephrine as adjuvant for propranolol produces a marked peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats.

    Tzeng, Jann-Inn; Pan, He-Jia; Liu, Kuo-Sheng; Chen, Yu-Wen; Chen, Yu-Chung; Wang, Jhi-Joung


    The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the relative potency was bupivacaine [2.05 (1.95-2.21) μmol/kg]>propranolol [9.21 (9.08-9.42) μmol/kg] (Ppropranolol or bupivacaine) at ED50 or ED95, respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED95 with epinephrine (0.012 μmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia.

  18. Pharmacokinetics of compound famotidine chewing tablets in Chinese healthy volunteers after a single oral dose administration%单剂量复方法莫替丁咀嚼片在健康人体的药代动力学

    刘丽京; 李素霞; 孙莉; 邓艳萍


    Objective To evaluate the pharmacokinetics of single dose of compound famotidine chewing tablets in Chinese healthy volunteers . Methods The study was designed as an open , randomized , parallel and single-dose single cycle study .Thirty healthy volunteers were divided into three groups .The drug concentrations of plasma sample from the vo-lunteers after taking 20 , 30 and 40 mg famotidine were determined by HPLC.The pharmacokine-tic parameters were calculated by 3P97 soft-ware.Results The healthy volunteers were given single dose of famoti-dine with 20, 30 and 40 mg, respectively.The main pharmacokinetic pa-rameters were as follows:Cmax were (68.94 ±15.34 ), (100.34 ±31.95 ), (98.82 ±42.87)ng? mL-1, tmax were (1.70 ±0.42), (1.75 ±0.35), (1.60 ±0.52 ) h, t1/2Ke were (2.88 ±0.48), ( 2.86 ±0.68 ), (3.61 ±0.42)h, AUC0-15 were (345.99 ±98.99), (448.50 ±104.02 ), (478.84 ±200.98 ) ng? h? mL-1.Conclusion The plasma concentra-tion-time curve fits one compartment model .The safe dose was 20-40 mg.%目的 评价中国健康志愿者单剂量口服复方法莫替丁咀嚼片后的药代动力学. 方法 按开放、随机、平行、单次、单周期试验设计. 30名健康受试者,男女各半,分为3组,分别单次口服复方法莫替丁咀嚼片20,30,40 mg后,用HPLC法测定血浆中法莫替丁的浓度,用3 P97软件计算药代动力学参数. 结果 单剂量口服复方法莫替丁咀嚼片后,20,30,40 mg组法莫替丁的主要药代动力学参数:Cmax分别为(68.94 ±15.34),(100.34 ±31.95),(98.82 ±42.87)ng? mL-1;tmax分别为( 1.70 ±0.42 ), ( 1.75 ±0.35 ), ( 1.60 ±0.52 ) h;t1/2Ke 分别为(2.88 ±0.48), ( 2.86 ± 0.68 ), ( 3.61 ± 0.42 ) h; AUC0-15 分 别 为(345.99 ±98.99),(448.50 ±104.02 ), (478.84 ±200.98 ) ng? mL-1 ? h.结论 复方法莫替丁咀嚼片的血药浓度-时间曲线符合一室模型,其剂量在20~40 mg是安全的.

  19. Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects

    Tay, Lee; Leon, Francisco; Vratsanos, George; Raymond, Ralph; Corbo, Michael


    The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes. PMID:17425783

  20. Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.

    Tang, Wei-Hua; Wang, Chao-Ping; Chung, Fu-Mei; Huang, Lynn L H; Yu, Teng-Hung; Hung, Wei-Chin; Lu, Li-Fen; Chen, Po-Yuan; Luo, Ching-Hsing; Lee, Kun-Tai; Lee, Yau-Jiunn; Lai, Wen-Ter


    Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.

  1. Design of novel injectable cationic microspheres based on aminated gelatin for prolonged insulin action.

    Morimoto, Kazuhiro; Chono, Sumio; Kosai, Tadashi; Seki, Toshinobu; Tabata, Yasuhiko


    The aim of this study was to prepare two types of injectable cationized microspheres based on a native gelatin (NGMS) and aminated gelatin with ethylenediamine (CGMS) to prolong the action of insulin. Release of rhodamin B isothiocyanate insulin from CGMS was compared with that from NGMS under in-vitro and in-vivo conditions. Lower release of insulin from CGMS compared with that from NGMS was caused by the suppression of initial release. The disappearance of 125I-insulin from the injection site after intramuscular administration by NGMS and CGMS had a biphasic profile in mice. Almost all the 125I-insulin had disappeared from the injection site one day after administration by NGMS. The remaining insulin at the injection site after administration by CGMS was prolonged, with approximately 59% remaining after one day and 16% after 14 days. The disappearance of CGMS from the injection site was lower than that of NGMS. However, the difference in these disappearance rates was not great compared with those of 125I-insulin from the injection site by NGMS and CGMS. The time course of disappearance of 125I-CGMS from the injection site was similar to that of 125I-insulin by CGMS. The initial hypoglycaemic effect was observed 1 h after administration of insulin by NGMS, thereafter its effect rapidly disappeared. The hypoglycaemic effect was observed 2-4 h after administration by CGMS and continued to be exhibited for 7 days. The prolonged hypoglycaemic action by CGMS depended on the time profiles of the disappearance of insulin from muscular tissues, which occurs due to the enzymatic degradation of CGMS.

  2. Effect of the dose and route of administration of butylscopolamine on the reduction of the artifacts associated with intestinal peristalsis in abdominal magnetic resonance; Efecto de la dosis y la via de administracion de butilescopolamina en la disminucion de los artefactors asociados al peristaltismo intestinal en la RM abdominal

    Dosda, R.; Marti-Bonmati, L. [Hospital Universitario Dr Peset. Valencia. Clinica Quiron. Valencia (Spain); Ronchera-Oms, C. [Hospital San Pablo-CEU. Moncada Valencia (Spain)


    To compare the effect of the route of administration (intravenous and oral) and the dose (40 mg and 80 mg) of butylscopolamine, determining its efficacy in reducing the noise associated with gastrointestinal movement in magnetic resonance (MR) images and the incidence and severity of associated adverse reactions. The present prospective, controlled, double-blind study included 80 patients who underwent abdominal MR. All the patients were given oral, high-density barium sulfate and were divided randomly into 4 groups of 20 patients each: a control group and 3 groups treated with 40 mg or 80 mg of oral butylscopolamine or 40 mg of intravenous butylscopolamine. Both the barium and the oral solutions were administered 25 to 30 minutes before the examination. the MR images were obtained with a STIR sequence (1487/100/44), and qualitative analysis of the noise was carried out using regions of interest situated in the background. The gastrointestinal noise was defined both by the mean and the standard deviation of the signal intensity of the air front of an behind the patient. The standard deviation of the air beside the patient was determined to confirm the absence of variations in noise inherent to MR. The adverse reactions to MR after 2 hours (immediate) and one day (late) were recorded. There were no significant differences among the groups with respect to sex, age or time interval between administration of the oral solution and the start of the sequence. The noise inherent to MR was not significantly different from one group to another (Student-Newman-Keuls test, p=0.71). Both the mean and the standard deviation of the intensity of the air situated in anteroposterior phase-encoding direction were significantly lower in the butylscopolamine groups than in the control group (Student-Newman-Keuls test, p=0.008). The most marked reduction was observed after the oral dose of 80 mg, followed by intravenous injection of 40 mg and the oral dose of 40 mg. Adverse reaction

  3. Intracerebroventricular administration of drugs.

    Cook, Aaron M; Mieure, Katherine D; Owen, Robert D; Pesaturo, Adam B; Hatton, Jimmi


    Intracerebroventricular drug administration is a method that bypasses the blood-brain barrier and other mechanisms that limit drug distribution into the brain, allowing high drug concentrations to enter the central compartment. Instillation of drugs directly into the ventricles of the brain must be done carefully and with full consideration of factors affecting the efficacy and safety of this route of administration. These factors include the osmolarity, pH, volume, and presence of preservatives and diluents of the drug solution being administered. Very few studies have formally investigated intraventricular therapies, and dosing recommendations may vary widely depending on the agent and the patient. Many antimicrobials have been given intraventricularly, although very few prospective studies have evaluated this strategy. There are wide variations among the reports regarding dosage regimens and the pharmacokinetics of the antimicrobials used. Guidance on appropriate formulations and their use is lacking. Clinicians should be aware of their patients' ongoing disease processes and neurologic status, as well as pertinent physiochemical properties of drugs when formulating them for intracerebroventricular administration; a high index of suspicion should be maintained when monitoring patients for adverse drug events after instillation.

  4. Pharmacokinetics of repeated sodium salicylate administration to laying hens: evidence for time dependent increase in drug elimination from plasma and eggs.

    Błażej Poźniak

    Full Text Available Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus salicylate (SA may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT, minimal plasma concentration (Cmin, C16h and elimination half-life (T1/2el of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment.

  5. Total ionizing dose effects of domestic SiGe HBTs under different dose rates

    Liu, Mo-Han; Lu, Wu; Ma, Wu-Ying; Wang, Xin; Guo, Qi; He, Cheng-Fa; Jiang, Ke; Li, Xiao-Long; Xun, Ming-Zhu


    The total ionizing radiation (TID) response of commercial NPN silicon germanium hetero-junction bipolar transistors (SiGe HBTs) produced domestically are investigated under dose rates of 800 mGy(Si)/s and 1.3 mGy(Si)/s with a Co-60 gamma irradiation source. The changes of transistor parameters such as Gummel characteristics, and excess base current before and after irradiation, are examined. The results of the experiments show that for the KT1151, the radiation damage is slightly different under the different dose rates after prolonged annealing, and shows a time dependent effect (TDE). For the KT9041, however, the degradations of low dose rate irradiation is higher than for the high dose rate, demonstrating that there is a potential enhanced low dose rate sensitivity (ELDRS) effect for the KT9041. The possible underlying physical mechanisms of the different dose rates responses induced by the gamma rays are discussed.

  6. Total ionizing dose effects of domestic SiGe HBTs under different dose rate

    Mo-Han, Liu; Wu-Ying, Ma; Xin, Wang; Qi, Guo; Cheng-Fa, He; Ke, Jiang; Xiao-Long, Li; Ming-Zhu, Xiong


    The total ionizing radiation (TID) response of commercial NPN silicon germanium hetero-junction bipolar transistors (SiGe HBTs) produced domestic were investigated under the dose rate of 800mGy(Si)/s and 1.3mGy(Si)/s with Co-60 gamma irradiation source, respectively. The changes of the transistor parameter such as Gummel characteristics, excess base current before and after irradiation are investigated. The results of the experiments shows that for the KT1151, the radiation damage have slightly difference under the different dose rate after the prolonged annealing, shows an time dependent effect(TDE). But for the KT9041, the degradations of low dose rate irradiation are more higher than the high dose rate, demonstrate that there have potential enhanced low dose rate sensitive(ELDRS) effect exist on KT9041. The underlying physical mechanisms of the different dose rates response induced by the gamma ray are detailed discussed.

  7. Prolonged pain and disability are common after rib fractures.

    Fabricant, Loic; Ham, Bruce; Mullins, Richard; Mayberry, John


    The contribution of rib fractures to prolonged pain and disability may be underappreciated and undertreated. Clinicians are traditionally taught that the pain and disability of rib fractures resolves in 6 to 8 weeks. This study was a prospective observation of 203 patients with rib fractures at a level 1 trauma center. Chest wall pain was evaluated by the McGill Pain Questionnaire (MPQ) pain rating index (PRI) and present pain intensity (PPI). Prolonged pain was defined as a PRI of 8 or more at 2 months after injury. Prolonged disability was defined as a decrease in 1 or more levels of work or functional status at 2 months after injury. Predictors of prolonged pain and disability were determined by multivariate analysis. One hundred forty-five male patients and 58 female patients with a mean injury severity score (ISS) of 20 (range, 1 to 59) had a mean of 5.4 rib fractures (range, 1 to 29). Forty-four (22%) patients had bilateral fractures, 15 (7%) had flail chest, and 92 (45%) had associated injury. One hundred eighty-seven patients were followed 2 months or more. One hundred ten (59%) patients had prolonged chest wall pain and 142 (76%) had prolonged disability. Among 111 patients with isolated rib fractures, 67 (64%) had prolonged chest wall pain and 69 (66%) had prolonged disability. MPQ PPI was predictive of prolonged pain (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.4 to 2.5), and prolonged disability (OR, 2.2; 95% CI, 1.5 to 3.4). The presence of significant associated injuries was predictive of prolonged disability (OR, 5.9; 95% CI, 1.4 to 29). Prolonged chest wall pain is common, and the contribution of rib fractures to disability is greater than traditionally expected. Further investigation into more effective therapies that prevent prolonged pain and disability after rib fractures is needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Pharmacokinetics of a florfenicol-tylosin combination after intravenous and intramuscular administration to beagle dogs.

    Kim, Eun-Young; Gebru, Elias; Lee, Joong-Su; Kim, Jong-Choon; Park, Seung-Chun


    A pharmacokinetic study of a commercial florfenicol-tylosin (2:1) combination product was conducted in six beagle dogs after intravenous (IV) and intramuscular (IM) administration at doses of 10 mg/kg (florfenicol) and 5 mg/kg (tylosin). Serum drug concentrations were determined by a validated high performance liquid chromatography (HPLC) using UV detection. A rapid and nearly complete absorption of both drugs with a mean IM bioavailability of 103.9% (florfenicol) and 92.6% (tylosin), prolonged elimination half-life, and high tissue penetration with steady state volume of distribution of 2.63 l/kg (florfenicol) and 1.98 l/kg (tylosin) were observed. Additional studies, including pharmacodynamic and toxicological evaluation are required before recommendations can be made regarding the clinical application of the product in dogs.

  9. Late-responding normal tissue cells benefit from high-precision radiotherapy with prolonged fraction delivery times via enhanced autophagy

    Yao, Qiwei; Zheng, Rong; Xie, Guozhu; Liao, Guixiang; Du, Shasha; Ren, Chen; Li, Rong; Lin, Xiaoshan; Hu, Daokun; Yuan, Yawei


    High-precision radiotherapy (HPR) has established its important role in the treatment of tumors due to its precise dose distribution. Given its more complicated delivery process, HPR commonly requires more fraction delivery time (FDT). However, it is unknown whether it has an identical response of prolonged FDT on different normal tissues. Our results showed that fractionated irradiation with prolonged FDTs (15, 36, and 50 minutes) enhanced cell surviving fractions for normal tissue cells compared with irradiation with an FDT of 2 minutes. However, the late-responding normal cell line HEI-OC1 was more responsive to prolonged FDTs and demonstrated higher surviving fractions and significantly decreased apoptosis and DNA damage compared to the acute-responding normal cell line HaCaT. Increased autophagy mediated via the ATM-AMPK pathway was observed in HEI-OC1 cells compared with HaCaT cells when irradiated with prolonged FDTs. Furthermore, treatment with the autophagy inhibitor 3-MA or ATM inhibitor KU55933 resulted in enhanced ROS accumulation and attenuation of the effect of prolonged FDT-mediated protection on irradiated HEI-OC1 cells. Our results indicated that late-responding normal tissue cells benefitted more from prolonged FDTs compared with acute-responding tissue cells, which was mainly attributed to enhanced cytoprotective autophagy mediated via the ATM/AMPK signaling pathway. PMID:25766900

  10. Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

    Devarakonda K


    Full Text Available Krishna Devarakonda,1 Terri Morton,1 Rachel Margulis,2 Michael Giuliani,3 Thomas Barrett4 1Clinical Pharmacology and Pharmacokinetics, 2Clinical Operations, 3Research and Development, 4Clinical Affairs, Mallinckrodt Inc., Hazelwood, MO, USA Background: XARTEMIS™ XR (formerly MNK-795 is a combination oxycodone (OC and acetaminophen (APAP analgesic with both immediate-release and extended-release (ER components (ER OC/APAP. The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets versus fasted conditions on the PK of ER OC/APAP was performed. Methods: This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48 were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP. Results: Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC] from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food. Conclusion: The findings from this study suggest that ER OC

  11. Clinical experience with daily doses of misonidazole

    Kogelnik, H.D.; Reinartz, G.; Szepesi, T.; Seitz, W.; Wurst, F.; Mamoli, B.; Wessely, P.; Stark, H.


    In this pilot study daily low doses of misonidazole (in the range of 1 to 2 g) up to cumulative doses between 7 and 19 g/m/sup 2/ were used. Serum levels were analysed at different times after administration and according to several dose regimens. We related the cumulative doses to the incidence and severity of the observed peripheral neuropathies. The aim was to find an effective daily low-dose schedule of misonidazole with a clinically acceptable incidence of side effects. Some impressive clinical responses were observed.

  12. Medication Administration Practices of School Nurses.

    McCarthy, Ann Marie; Kelly, Michael W.; Reed, David


    Assessed medication administration practices among school nurses, surveying members of the National Association of School Nurses. Respondents were extremely concerned about medication administration. Errors in administering medications were reported by 48.5 percent of respondents, with missed doses the most common error. Most nurses followed…

  13. [Successful induction of complete cytogenetic response with low-dose imatinib mesylate in an accelerated phase chronic myelogenous leukemia patient who developed severe bone marrow aplasia following standard-dose imatinib mesylate therapy].

    Nakazato, Tomonori; Suzuki, Kazuhito; Mihara, Ai; Sanada, Yukinari; Kakimoto, Tsunayuki


    A 58-year-old female presented with massive splenomegaly, leukocytosis and anemia. Bone marrow appearance was consistent with CML-AP, and t (9;22) (q34;q11) was detected on karyotyping. 600 mg daily imatinib mesylate (imatinib) was started and achieved complete hematological remission. However, pancytopenia was evident. Despite dose reduction and subsequent drug withdrawal, the pancytopenia worsened and she became transfusion dependent. Grade 4 pancytopenia persisted for 8 months after discontinuing imatinib. Bone marrow biopsy showed severe bone marrow aplasia with no morphological evidence of disease progression. Karyotyping showed minor cytogenetic response with no clonal evolution. Signs of hematological recovery appeared 8 months after stopping imatinib. The patient was re-started on imatinib at a dose of 100 mg/day. The dose was increased to 200 mg/day without hematological toxicity. Complete cytogenetic response (CCyR) was achieved 5 months after the re-administration of imatinib. The patient maintained CCyR with 200 mg of imatinib per day. Prolonged severe bone marrow aplasia has rarely been reported as a complication of imatinib therapy. This case also suggests that low-dose imatinib would be tolerable and effective for some CML patients who are intolerant of a standard dose of imatinib.

  14. A randomized, dose-ranging assessment of the immunogenicity and safety of a booster dose of a combined diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b (DTPw-HBV-IPV/Hib) vaccine vs. co-administration of DTPw-HBV/Hib and IPV vaccines in 12 to 24 months old Filipino toddlers.

    Quiambao, Beatriz; Van Der Meeren, Olivier; Kolhe, Devayani; Gatchalian, Salvacion


    As progress toward global poliovirus eradication continues, more and more countries are moving away from use of oral poliovirus vaccines (OPV) to inactivated poliovirus vaccines (IPV) in national vaccination schedules. Reduction of antigen dose in IPV could increase manufacturing capacity and facilitate the change from OPV to IPV. Combination vaccines reduce the number of injections required to complete vaccination, thus playing an important role in maintaining high vaccine coverage with good public acceptability. Three formulations of a combined, candidate hexavalent diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b conjugate vaccine (DTPw-HBV-IPV/Hib, GlaxoSmithKline Biologicals) differing only in IPV antigen content (full-dose, half-dose and one-third dose as compared with available stand-alone IPV vaccines), were evaluated when administered to healthy toddlers. Controls received separately administered licensed DTPw-HBV/Hib and IPV vaccines. Immunogenicity was assessed before and one month after vaccination. Safety and reactogenicity data were assessed for 30 d after vaccination. A total of 312 Filipino children were vaccinated in their second year of life. Each DTPw-HBV-IPV/Hib formulation was non-inferior to control in terms of pre-defined criteria for IPV immunogenicity. Post-vaccination GMTs against each poliovirus type were increased between 4.2- and 37.9-fold over pre-vaccination titers. Non-inferiority to other vaccine antigens was also demonstrated. The safety profile of the 3 DTPw-HBV-IPV/Hib formulations resembled licensed DTPw-HBV/Hib Kft and IPV in terms of the frequency and intensity of adverse reactions after vaccination. Further investigation of DTPw-HBV-IPV/Hib containing reduced quantity of IPV antigen for primary vaccination in infants is warranted. This study is registered at NCT number: NCT01106092.

  15. A randomized, dose-ranging assessment of the immunogenicity and safety of a booster dose of a combined diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b (DTPw-HBV-IPV/Hib) vaccine vs. co-administration of DTPw-HBV/Hib and IPV vaccines in 12 to 24 months old Filipino toddlers

    Quiambao, Beatriz; Van Der Meeren, Olivier; Kolhe, Devayani; Gatchalian, Salvacion


    As progress toward global poliovirus eradication continues, more and more countries are moving away from use of oral poliovirus vaccines (OPV) to inactivated poliovirus vaccines (IPV) in national vaccination schedules. Reduction of antigen dose in IPV could increase manufacturing capacity and facilitate the change from OPV to IPV. Combination vaccines reduce the number of injections required to complete vaccination, thus playing an important role in maintaining high vaccine coverage with good...

  16. Single-dose subcutaneous iodine-131-iodohippurate for determination of renal plasma flow

    Grant, M.E.; Herron, K.G.; MacDougall, M.L.; Preston, D.F.; Moore, W.V.; Wiegmann, T.B. (Department of Medicine, University of Kansas Medical Center, Kansas City (USA))


    Subcutaneous administration of a single dose of 131I-iodohippurate was used for determination of renal plasma flow (RPF) in 20 subjects during water diuresis. Slow release of tracer (200 microCi) permitted serial clearance measurements over 5 hr that were compared to standard, constant infusion, PAH clearance (mean 379.5 {plus minus} 34.9 ml/min/1.73 m2, range 50.9 to 696.3 ml/min/1.73 m2). RPF(Isotope) was 424.9 {plus minus} 30.3 ml/min/1.73 m2 (range 144.4 to 746.5 ml/min/1.73 m2) and highly correlated with RPFPAH (r = 0.883, p less than 0.0001). This technique permits prolonged studies of renal plasma flow under steady-state conditions without constant infusion.

  17. A comparative study of evaluate dose related feto-maternal effects of syntocinon during labor

    Farhin Radhanpuri


    Conclusions: There is significant reduction in the duration of labor by augmenting labor with slow low regulated dose of syntocinon drip, thus reducing the maternal exhaustion and morbidity due to prolonged labor. There is significant reduction in the operative interference like LSCS, vacuum and forceps delivery, thus reducing maternal morbidity associated with operative interference and anesthesia. It also reduces the cost of medical services. The incidence of fetal distress and LSCS for the same does not increase in the augmentation group, indicating that syntocinon can be safely used for the augmentation. At this time, much attention in the field of obstetrics is focused on attempting to reduce the rate of cesarean section, not only to reduce maternal morbidity, but to lower the cost of medical care. Our finding is that syntocinon administration can significantly reduce the cesarean section rate. [Int J Reprod Contracept Obstet Gynecol 2015; 4(5.000: 1344-1348

  18. Dose estimate for personal music players including earphone sensitivity and characteristic

    Hammershøi, Dorte; Ordoñez Pizarro, Rodrigo Eduardo; Christensen, Anders Tornvig


    Personal music players can expose their listeners to high sound pressure levels over prolonged periods of time. The risk associated with prolonged listening is not readily available to the listener, and efforts are made to standardize dose estimates that may be displayed for the user...

  19. Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity

    Thomsen, J J; Rentsch, R L; Robach, P


    The effects of recombinant human erythropoietin (rHuEpo) treatment on aerobic power (VO2max) are well documented, but little is known about the effects of rHuEpo on submaximal exercise performance. The present study investigated the effect on performance (ergometer cycling, 20-30 min at 80...

  20. Prolonged skin graft survival by administration of anti-CD80 monoclonal antibody with cyclosporin A

    Ossevoort, MA; Lorre, K; Boon, L; van den Hout, Y; de Boer, M; De Waele, P; Jonker, M; VandeVoorde, A


    Costimulation via the B7/CD28 pathway is an important signal for the activation of T cells. Maximal inhibition of T-cell activation and the induction of alloantigen-specific nonresponsiveness in vitro was achieved using anti-CD80 monoclonal antibody (mAb) in combination with cyclosporin A (CsA). Bas

  1. Prolonging sensor networks lifetime using convex clusters

    Payam Salehi


    Full Text Available Reducing the energy consumption of nodes in sensor networks and prolonging the network life time has been proposed as one of the most important challenges facing researchers in the field of sensor networks. Therefore, designing an energy-aware protocol to gather data from network level and transmitting it to sink is placed on the agenda at this paper. After presenting an analysis of the processes of clustering in sensory networks and investigating the effect of sending interval on the amount of energy consumption, We have shown that if the use of convex static casters be done such as all the communications within the cluster with the sending distance less than the optimal threshold, it Will help to increase the lifetime of nodes. also have shown that if we create a virtual backbone between cluster heads to transfer far cluster heads data from sink to sink , will has a significant impact on increasing the network lifetime. For this reason, a detailed discussion on how to determine the size of clusters and partitioning of the network environment to them is presented in Chapter 4.Simulation results show considerable improvement of the proposed algorithm.

  2. Persistent telomere cohesion triggers a prolonged anaphase.

    Kim, Mi Kyung; Smith, Susan


    Telomeres use distinct mechanisms (not used by arms or centromeres) to mediate cohesion between sister chromatids. However, the motivation for a specialized mechanism at telomeres is not well understood. Here we show, using fluorescence in situ hybridization and live-cell imaging, that persistent sister chromatid cohesion at telomeres triggers a prolonged anaphase in normal human cells and cancer cells. Excess cohesion at telomeres can be induced by inhibition of tankyrase 1, a poly(ADP-ribose) polymerase that is required for resolution of telomere cohesion, or by overexpression of proteins required to establish telomere cohesion, the shelterin subunit TIN2 and the cohesin subunit SA1. Regardless of the method of induction, excess cohesion at telomeres in mitosis prevents a robust and efficient anaphase. SA1- or TIN2-induced excess cohesion and anaphase delay can be rescued by overexpression of tankyrase 1. Moreover, we show that primary fibroblasts, which accumulate excess telomere cohesion at mitosis naturally during replicative aging, undergo a similar delay in anaphase progression that can also be rescued by overexpression of tankyrase 1. Our study demonstrates that there are opposing forces that regulate telomere cohesion. The observation that cells respond to unresolved telomere cohesion by delaying (but not completely disrupting) anaphase progression suggests a mechanism for tolerating excess cohesion and maintaining telomere integrity. This attempt to deal with telomere damage may be ultimately futile for aging fibroblasts but useful for cancer cells.

  3. [Prospective study of patients with prolonged fever].

    Calderón, E; Legorreta, J; Sztabinski, G; Hernández, M; Wilkins, A; Gómez, D; Dávila, A


    A prospective study was made in 283 patients who attended IMAN's Children's Hospital, with fever the main symptom. A clinical and paraclinical procedure was designed for the study of each patient. 112 patients were eliminated because they did not follow the established criteria. All patients had acute infectious diseases considered trivial; 85% were 3 weeks to 2 years of age. They all had an antibacterial treatment without precise diagnosis. It was considered that on admission the patients showed a normal course in the natural history of the basic disease. The study group included 171 patients 2 months to 13 years of age; 62.5% had fever due to infection, 12.2% to collagenopathies, 7% to neoplasias 5.2% to miscellaneous causes and 12.8% were not diagnosed. The most common infectious causes for prolonged fever were tuberculosis, upper respiratory infections, amoebic liver abscess, typhoid fever and malaria. Careful questioning and clinical examination were enough to enlighten diagnosis in more than 80% of the patients.


    Ah. Yusuf


    Full Text Available Introduction: Decision for cesarean section may lead to the stress for women in delivery. Stress response requires longer recovery time in post cesarean section patients. Most of patients who experience stress before and after surgical is associated with wound healing delay. When this condition continues, the wound will have a higher risk of infection. The objective of this study was to analyze correlation between stress and wound healing phase in post cesarean section patients. Method: A cross sectional design was used in this study. The population were women with cesarean section, both elective or emergency, in Delivery Room I RSU Dr. Soetomo Surabaya. Samples were recruited by using purposive sampling, with 28 samples who met to the inclusion criterias. The observed variables were stress and wound healing phase in post cesarean section patient. Stress data were collected by interview and wound healing measurement done by observation on the 3rd day post cesarean section. Result: The result showed that women with stress experience wound healing delay. The characteristic of wound healing delay was prolonged on inflammation phase, nevertheless there was presence of granulation tissue. Spearman’s rho correlation showed that correlation value r=0.675 with p=0.000. Discussion: It can be concluded that there was strong significant correlation between stress and wound healing phase in post cesarean section patients. It is important to give this information to the patients with cesarean section in order to prevent stress and delay in wound healing phase.

  5. Gluteal Compartment Syndrome After Prolonged Immobilisation

    H.L. Liu


    Full Text Available Muscles in the gluteal region are confined by distinct fascial attachments which can potentially result in compartment syndrome. A 74-year-old chronic drinker was admitted to the medical ward after being found drunk on the street. He noticed acute painful swelling of the right side of his buttock the following morning and recalled a slip and fall prior to his blackout. The whole right half of the buttock was tense with erythematous overlying skin. Examination revealed sciatic nerve palsy and myoglobinuria. Emergency fasciotomy and debridement were performed. Intra-operative pressure measurement confirmed a grossly elevated intra-compartmental pressure. Gluteal compartment syndrome is an extremely rare condition and has only been scantily documented previously in case reports. Early diagnosis is crucial but delay recognition is common from lack of knowledge of the condition and readily results in permanent sciatic nerve injury and acute renal shutdown from myoglobinuria. Awareness of the condition, early diagnosis and prompt exploration provide the only chance of avoiding these devastating consequences. Acute swelling diffusely affecting the whole or one side of the buttock, a history of trauma and prolonged local pressure impingement associated with pain out of proportion to the clinical signs should raise a suspicion of this rare condition.

  6. Prolonged Wars: A Post-Nuclear Challenge


    Garcia Marquez , Cuba in Angola: Operation Carlota (New York: Cuba Update), 128. Ian Grieg suggests that the USSR’s reasons for becoming involved in...specific groups. This political orientation was exemplified by the failure of the Parti Progressite Tchadien (PPT) (formed by Gabriel Lisette) to emerge as...1989), 18. 10.- Gabriel Lisette, a black colonial administrator of Guadeloupian descent, was elected to represent Chad in the French National Assembly

  7. Antitumor Activity and Prolonged Expression from a TRAIL-Expressing Adenoviral Vector

    Jeongwu Lee


    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL induces apoptosis in a variety of transformed cell lines, but generally spares most normal cells. Transduction by an adenoviral vector expressing human TRAIL cDNA (Ad.TRAIL-GFP resulted in both direct tumor cell killing as well as a potent bystander effect through presentation of TRAIL by transduced normal cells. Administration of Ad.TRAIL-GFP significantly prolonged survival of mice harboring either intracerebral glioblastomas or breast carcinoma-induced peritoneal carcinomatosis. Additionally, TRAIL induced prolonged transgene expression in normal tissue, presumably as a result of diminished immunemediated destruction of vector-transduced cells. Taken together, these data suggest that vector-mediated transduction of TRAIL may represent an effective strategy for cancer gene therapy.

  8. Fanconi syndrome due to prolonged use of low-dose adefovir

    Xiao-Bing Wang


    Full Text Available Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury.

  9. Improving medication administration safety in solid organ transplant patients through barcode-assisted medication administration.

    Bonkowski, Josesph; Weber, Robert J; Melucci, Joseph; Pesavento, Todd; Henry, Mitchell; Moffatt-Bruce, Susan


    Solid organ transplant recipients are prescribed a high number of medications, increasing the potential for medication errors. Barcode-assisted medication administration (BCMA) is technology that reduces medication administration errors. An observational study was conducted at an academic medical center solid organ transplant unit before and after BMCA implementation. Medication accuracy was determined and administration errors were categorized by type and therapeutic class of medication. A baseline medication administration error rate of 4.8% was observed with wrong dose errors representing 78% of the errors. During the post-BCMA period the medication administration error rate was reduced by 68% to 1.5% (P = .0001). Wrong dose errors were reduced by 67% (P = .001), and unauthorized medication administrations were reduced by 73%. Steroids were associated with the highest error rate. The results of this study suggest that routinely adopting BCMA has the potential to reduce medication administration errors in transplant patients.

  10. Morphological changes in liver of laboratory animals at prolonged intake of gold nanoparticles

    Pakhomy S.S.


    Full Text Available Aim: to evaluate the severity of morphological changes in the liver of laboratory animals with prolonged intake of pegilated gold nanoparticles of different sizes from 2 to 50 nm. Material and methods. The experiment was performed on 240 albino rats divided into 4 groups. The animals of experimental groups were orally administered the gold nanoparticles in a specific pattern. Results. Morphological changes in liver depend on the particle size and the duration of administration. Developing pathological changes in the liver are reversible, as evidenced by the gradual recovery of the liver structure 14 days after administration. Conclusion. The most significant changes in the liver were found in the experimental groups with a 30-day administration of 2 and 50 nm gold nanoparticles that show the size-dependent nature of their impact.

  11. Effects of administration of the standardized Panax ginseng extract G115 on hepatic antioxidant function after exhaustive exercise.

    Voces, J; Alvarez, A I; Vila, L; Ferrando, A; Cabral de Oliveira, C; Prieto, J G


    The effect of prolonged treatment with the standardized Panax ginseng extract G115 on the antioxidant capacity of the liver was investigated. For this purpose, rats that had received G115 orally at different doses for 3 months and untreated control rats were subjected to exhaustive exercise on a treadmill. A bell-shaped dose response on running time was obtained. The results showed that the administration of G115 significantly increases the hepatic glutathione peroxidase activity (GPX) and the reduced glutathione (GSH) levels in the liver, with a dose-dependent reduction of the thiobarbituric acid reactant substances (TBARS). After the exercise, there is reduced hepatic lipid peroxidation, as evidenced by the TBARS levels in both the controls and the treated animals. The GPX (glutathione peroxidase) and SOD (superoxide dismutase) activity are also significantly increased in the groups receiving G115, compared with the controls. The hepatic transaminase levels, ALT (Alanine-amino-transferase) and AST (Aspartate-amino-transferase), in the recuperation phase 48 h after the exercise, indicate a clear hepatoprotective effect related to the administration of the standardized Panax ginseng extract G115. At hepatic level, G115 increases the antioxidant capacity, with a marked reduction of the effects of the oxidative stress induced by the exhaustive exercise.

  12. Encephalitis with Prolonged but Reversible Splenial Lesion

    Alena Meleková


    Full Text Available Introduction: The splenium of the corpus callosum has a specific structure of blood supply with a tendency towards blood-brain barrier breakdown, intramyelinic edema, and damage due to hypoxia or toxins. Signs and symptoms of reversible syndrome of the splenium of the corpus callosum typically include disorientation, confusion, impaired consciousness, and epileptic seizures. Case report: A previously healthy 32-year-old man suffered from weakness, headache, and fever. Subsequently, he developed apathy, ataxia, and inability to walk, and therefore was admitted to the hospital. Cerebrospinal fluid showed protein elevation (0.9 g/l and pleocytosis (232/1 ul. A brain MRI showed hyperintense lesions in the middle of the corpus callosum. The patient was treated with antibiotics, and subsequently, in combination with steroids. Two months later, the hyperintense lesions in the splenium and the basal ganglia had disappeared. Almost seven months since his hospitalization in the Department of Neurology, the patient has returned to his previous employment. He now does not exhibit any mental changes, an optic edema and urological problems have improved. In addition, he is now actively engaged in sports. Conclusion: We have described a case of a 32-year-old man with confusion, ataxia, and inability to stand and walk. The man developed a febrile meningeal syndrome and a hyperintense lesion of the splenium, which lasted for two months. Neurological changes, optic nerve edema, and urinary retention have resolved over the course of seven months. We think that the prolonged but transient lesion of the splenium may have been caused by encephalitis of viral origin.

  13. Diaphragmatic energetics during prolonged exhaustive exercise.

    Manohar, M; Hassan, A S


    The present study was carried out to examine diaphragmatic O2 extraction and lactate and ammonia production during prolonged exhaustive exercise. Experiments were performed on nine healthy exercise-conditioned ponies in which catheters had been implanted in the phrenic vein previously. Blood-gas variables and lactate and ammonia concentrations were determined on simultaneously obtained arterial and phrenic-venous blood samples at rest and during 30 min of exertion at 15 mph + 7% grade (heart rate, 200 beats/min; approximately 90% of maximum). Arterial O2 tension and saturation were maintained near resting value but CO2 tension decreased markedly with exercise, and because of increased hemoglobin concentration, arterial O2 content rose. Concomitantly, phrenic venous O2 tension, saturation and content decreased markedly (23.6 +/- 1 mm Hg, 24.5 +/- 2%, 5.2 +/- 0.3 ml/dl at 3 min of exertion) and significant fluctuations did not occur as exercise duration progressed to 30 min. Diaphragmatic arteriovenous O2 content difference and O2 extraction rose from 4 +/- 0.3 to 16 +/- 0.5 ml/dl and from 30 +/- 3 to 75 +/- 1% at 3 min of exercise, and significant deviations did not occur as exercise duration progressed. Arterial lactate and ammonia levels increased during exercise, indicating their release from working limb muscles. Phrenic-venous values of lactate and ammonia did not exceed arterial values. Ponies sweated profusely and were unable to keep up with the belt speed in the last 4 to 5 min of exercise. Constancy of phrenic arteriovenous O2 content difference in exercise indicated ability to adjust perfusion in diaphragm so as to adequately meet its O2 needs.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Exceptionally prolonged tooth formation in elasmosaurid plesiosaurians

    Kear, Benjamin P.; Larsson, Dennis; Lindgren, Johan; Kundrát, Martin


    Elasmosaurid plesiosaurians were globally prolific marine reptiles that dominated the Mesozoic seas for over 70 million years. Their iconic body-plan incorporated an exceedingly long neck and small skull equipped with prominent intermeshing ‘fangs’. How this bizarre dental apparatus was employed in feeding is uncertain, but fossilized gut contents indicate a diverse diet of small pelagic vertebrates, cephalopods and epifaunal benthos. Here we report the first plesiosaurian tooth formation rates as a mechanism for servicing the functional dentition. Multiple dentine thin sections were taken through isolated elasmosaurid teeth from the Upper Cretaceous of Sweden. These specimens revealed an average of 950 daily incremental lines of von Ebner, and infer a remarkably protracted tooth formation cycle of about 2–3 years–other polyphyodont amniotes normally take ~1–2 years to form their teeth. Such delayed odontogenesis might reflect differences in crown length and function within an originally uneven tooth array. Indeed, slower replacement periodicity has been found to distinguish larger caniniform teeth in macrophagous pliosaurid plesiosaurians. However, the archetypal sauropterygian dental replacement system likely also imposed constraints via segregation of the developing tooth germs within discrete bony crypts; these partly resorbed to allow maturation of the replacement teeth within the primary alveoli after displacement of the functional crowns. Prolonged dental formation has otherwise been linked to tooth robustness and adaption for vigorous food processing. Conversely, elasmosaurids possessed narrow crowns with an elongate profile that denotes structural fragility. Their apparent predilection for easily subdued prey could thus have minimized this potential for damage, and was perhaps coupled with selective feeding strategies that ecologically optimized elasmosaurids towards more delicate middle trophic level aquatic predation. PMID:28241059

  15. Fatigue associated with prolonged graded running.

    Giandolini, Marlene; Vernillo, Gianluca; Samozino, Pierre; Horvais, Nicolas; Edwards, W Brent; Morin, Jean-Benoît; Millet, Guillaume Y


    Scientific experiments on running mainly consider level running. However, the magnitude and etiology of fatigue depend on the exercise under consideration, particularly the predominant type of contraction, which differs between level, uphill, and downhill running. The purpose of this review is to comprehensively summarize the neurophysiological and biomechanical changes due to fatigue in graded running. When comparing prolonged hilly running (i.e., a combination of uphill and downhill running) to level running, it is found that (1) the general shape of the neuromuscular fatigue-exercise duration curve as well as the etiology of fatigue in knee extensor and plantar flexor muscles are similar and (2) the biomechanical consequences are also relatively comparable, suggesting that duration rather than elevation changes affects neuromuscular function and running patterns. However, 'pure' uphill or downhill running has several fatigue-related intrinsic features compared with the level running. Downhill running induces severe lower limb tissue damage, indirectly evidenced by massive increases in plasma creatine kinase/myoglobin concentration or inflammatory markers. In addition, low-frequency fatigue (i.e., excitation-contraction coupling failure) is systematically observed after downhill running, although it has also been found in high-intensity uphill running for different reasons. Indeed, low-frequency fatigue in downhill running is attributed to mechanical stress at the interface sarcoplasmic reticulum/T-tubule, while the inorganic phosphate accumulation probably plays a central role in intense uphill running. Other fatigue-related specificities of graded running such as strategies to minimize the deleterious effects of downhill running on muscle function, the difference of energy cost versus heat storage or muscle activity changes in downhill, level, and uphill running are also discussed.

  16. Administration of Anesthesia

    ... a Surgeon What We Do Administration of Anesthesia Administration of Anesthesia Oral and maxillofacial surgeons are extensively ... Injury Wisdom Teeth Management Procedures Administration of Anesthesia Administration of Anesthesia Oral and maxillofacial surgeons are extensively ...

  17. Dermal administration of manganese porphyrin by iontophoresis.

    Ito, Fuminori; Imamura, Shinya; Asayama, Shoichiro; Kanamura, Kiyoshi; Kawakami, Hiroyoshi


    The present study describes a technique for dermal administration of cationic manganese porphyrin (Mn-porphyrin), an antioxidant with superoxide dismutase (SOD) activity, in hairless mouse. In general, the stratum corneum on the surface of the skin represents a barrier to passive diffusion of therapeutic agents by standard dermal administration. The present study investigated whether, dermal administration of Mn-porphyrin solution using iontophoresis, the electrical dermal administration technique, could overcome this barrier. We visually confirmed that Mn-porphyrin had penetrated to the reverse side of the hairless mouse skin after iontophoresis for a short period. With prolonged iontophoresis, the ratio of detectable Mn-porphyrin solution on the reverse side of the hairless mouse skin increased. In the future, this technique could provide an innovative approach for delivery of this antioxidant in intractable disease.

  18. Acute toxicity, histopathology, and coagulopathy in American kestrels (Falco sparverius) following administration of the rodenticie diphacinone

    Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Day, Daniel D.; Meteyer, Carol U.; Voler, Steven F.; Eisemann, John D.; Johnston, John J.


    The acute oral toxicity of the anticoagulant rodenticide diphacinone was found to be over 20 times greater in American kestrels (Falco sparverius; median lethal dose 96.8 mg/kg body weight) compared with Northern bobwhite (Colinus virginianus) and mallards (Anas platyrhynchos). Modest evidence of internal bleeding was observed at necropsy, although histological examination of heart, liver, kidney, lung, intestine, and skeletal muscle revealed hemorrhage over a wide range of doses (35.1-675 mg/kg). Residue analysis suggests that the half-life of diphacinone in the liver of kestrels that survived was relatively short, with the majority of the dose cleared within 7 d of exposure. Several precise and sensitive clotting assays (prothrombin time, Russell's viper venom time, thrombin clotting time) were adapted for use in this species, and oral administration of diphacinone at 50 mg/kg increased prothrombin time and Russell?s viper venom time at 48 and 96 h postdose compared with controls. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and generally corresponded with the onset of overt signs of toxicity and lethality. In view of the toxicity and risk evaluation data derived from American kestrels, the involvement of diphacinone in some raptor mortality events, and the paucity of threshold effects data following short-term dietary exposure for birds of prey, additional feeding trials with captive raptors are warranted to characterize more fully the risk of secondary poisoning.

  19. QT interval prolongation after Premature Ventricular Contractions (PVCs

    Mohammed Haroon Rashid


    Full Text Available Long QT syndrome (LQTS is an inherited ion channelopathy resulting in abnormal ventricular repolarization and abnormal prolongation of QT interval on the ECG. Syncope, fainting, cardiac arrest, and sudden death are common manifestations of LQTS. We present a case report that describes a patient with prolonged QT interval after extrasystoles and a family history of sudden cardiac deaths.

  20. Enhanced absorption of anthocyanins after oral administration of phytic acid in rats and humans.

    Matsumoto, Hitoshi; Ito, Kyoko; Yonekura, Kumiko; Tsuda, Takanori; Ichiyanagi, Takashi; Hirayama, Masao; Konishi, Tetsuya


    Many studies on the bioavailability of polyphenols have been reported. However, the relative urinary excretions of AC are also low, ranging from 0.004% to 0.1%. By contrast, other polyphenols show higher urinary excretion levels. Here, we studied the enhancing effects of phytic acid (IP6) on absorption of blackcurrant anthocyanins (BCAs) in rats and humans. In rats after oral administration of BCAs (as 241 mg of AC/kg body weight) in IP6 (0%, 0.25%, 0.5%, 1%, 2.5%) solution, the ACs recovery in urine was increased dependent on IP6 dose. These results suggest that the IP6 enhances gastrointestinal absorption of ACs. At the further analysis of IP6 enhancement effect in rat, whereas BCAs were normally passed through the stomach and duodenum within 2 h, in IP6 group, after 2-6 h post-administration, stomach and jejunum content's weights were specifically heavy, and large amounts of ACs were also detected in stomach, duodenum, and jejunum. These results suggested that the mixture of BCAs and IP6 reduced the gastrointestinal motility. Prolongation of ACs residue in gastrointestinal tract then caused the enhancing effects of IP6 on absorption of AC. In the human study, each subject was orally administrated a BCA beverage containing BCA concentrate (AC 4 mg/kg body weight), 1% of IP6, and 1% of sodium citrate as a pH stabilizer. Both the plasma level and the urinary excretion of AC were increased as compared to BCA administration without IP6. AC intake with IP6 may increase the bioavailability of AC to the comparative level as other polyphenols. Yet, phytic acid, being a strong chelator of important minerals, contributes to mineral deficiencies. An interference with iron uptake has been reported. Safety tests are therefore necessary before high dose IP6 can be used in foods.

  1. Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial

    Francine Foss


    Full Text Available Abstract Background Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD. Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130, including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. Methods Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m2 romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. Results Of the 32 patients (25 % with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment. The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m2 on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. Conclusions We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. Trial registration NCT00426764

  2. Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly

    Madsen, Michael; Fisker, Sanne; Feldt-Rasmussen, Ulla;


    OBJECTIVE: To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome. PATIENTS AND METHODS: Seventeen patients (6 women), mean age 46·3 years (range: 23...... correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age or body weight were found. CONCLUSIONS: (1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in patients with acromegaly, (2) serum...

  3. Gormezis Effect of Cells Response on the Prolonged Influension of Xenobiotics

    Sergey A. Sherstyuk


    Full Text Available This work has studied the cellular response of the animal in terms of prolongation of the experiment on white rats in the active, inactive and toxic doses by the action of xenobiotics domestic purposes at the cellular, subcellular and regulatory levels. Morphological changes have been detected in the number of blood cells in the dynamics of the experiment, the structural integrity and metabolic disorders phospholipids of cell membranes, a decrease in the level of cyclic nucleotides of organs of experimental animals and an increase of this substance in the blood plasma by the action of the stress modulator of the chemical nature.

  4. The in vivo study on the radiobiologic effect of prolonged delivery time to tumor control in C57BL mice implanted with Lewis lung cancer.

    Wang, Xin; Xiong, Xiao-Peng; Lu, Jiade; Zhu, Guo-Pei; He, Shao-Qin; Hu, Chao-Su; Ying, Hong-Mei


    High-precision radiation therapy techniques such as IMRT or sterotactic radiosurgery, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The purpose of this work is to explore the radiobiologic effect of prolonged fraction delivery time on tumor response and survival in vivo. 1-cm-diameter Lewis lung cancer tumors growing in the legs of C57BL mice were used. To evaluate effect of dose delivery prolongation, 18 Gy was divided into different subfractions. 48 mice were randomized into 6 groups: the normal control group, the single fraction with 18 Gy group, the two subfractions with 30 min interval group, the seven subfractions with 5 min interval group, the two subfractions with 60 min interval group and the seven subfractions with 10 min interval group. The tumor growth tendency, the tumor growth delay and the mice survival time were analyzed. The tumor growth delay of groups with prolonged delivery time was shorter than the group with single fraction of 18 Gy (P delivery time 30 min was longer than that of groups with prolonged delivery time 60 min P delivery time (P > 0.05). Compared to the group with single fraction of 18 Gy, the groups with prolonged delivery time shorten the mice survival time while there was no significant difference between the groups with prolonged delivery time 30 min and the groups with prolonged delivery time 60 min. The prolonged delivery time with same radiation dose shorten the tumor growth delay and survival time in the mice implanted with Lewis lung cancer. The anti-tumor effect decreased with elongation of the total interfractional time.

  5. Effects of systemic or topical administration of sodium selenite on early radiation effects in mouse oral mucosa

    Gehrisch, A. [Dept. of Radiotherapy and Radiooncology, Medical Faculty Carl Gustav Carus, Technical Univ. of Dresden (Germany); Doerr, W. [Dept. of Radiotherapy and Radiooncology, Medical Faculty Carl Gustav Carus, Technical Univ. of Dresden (Germany); Experimental Center, Medical Faculty Carl Gustav Carus, Technical Univ. of Dresden (Germany)


    Purpose: to quantify the effect of sodium selenite (selenium) on radiation-induced oral mucositis (mouse) after subcutaneous or topical administration. Material and methods: mucosal ulceration of the lower epithelium of mouse tongue was analyzed. Selenium (5 {mu}g) was applied subcutaneously (s.c.) or locally, 60 min or 30 min prior to irradiation, respectively. In combination with single-dose irradiation, a single selenium application was given. With daily fractionated irradiation (3 Gy/fraction) for 1 week (days 0-4), selenium was administered at all 5 days of irradiation. With ten fractions over 2 weeks, selenium was applied in week 1, week 2, or both. All fractionation protocols were terminated by graded test doses to generate full dose-effect curves. Results: in a single-dose control experiment, the ED{sub 50} (dose after which ulcer induction is expected in 50% of the mice) was 12.9 {+-} 1.6 Gy. Selenium increased the ED{sub 50} to 17.7 {+-} 2.6 Gy (s.c.; p = 0.0003) and 16.3 {+-} 3.0 Gy (local; p = 0.0104). The ED{sub 50} for test irradiation after 5 x 3 Gy was 7.4 {+-} 2.2 Gy. Subcutaneous administration of selenium resulted in an ED{sub 50} of 11.5 {+-} 2.0 Gy (p = 0.0015), local application yielded an ED{sub 50} of 10.0 {+-} 2.1 Gy (p = 0.0284). The ED{sub 50} for test irradiation after 10 x 3 Gy/2 weeks was 8.0 {+-} 1.7 Gy. Subcutaneous or local administration of selenium in week 1 yielded a significant increase in ED{sub 50} to 10.5 {+-} 1.0 Gy (p = 0.0069) and 10.7 {+-} 1.0 Gy (p = 0.0039), respectively. By clear contrast, selenium administration in week 2 had no significant effect. Administration in both weeks resulted in an ED{sub 50} of 9.1 {+-} 2.0 Gy (s.c.; p = 0.2747) and 9.7 {+-} 1.4 Gy (local; p = 0.0541). Conclusion: administration of sodium selenite during clinically relevant fractionated irradiation protocols has a significant effect during the initial treatment phase, i.e., week 1 in the mouse. Therefore, in clinical radiotherapy, the

  6. Prolonged remission maintenance in acute myeloid leukaemia.

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S


    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.

  7. Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.

    Francia, Giulio; Shaked, Yuval; Hashimoto, Kae; Sun, John; Yin, Melissa; Cesta, Carolyn; Xu, Ping; Man, Shan; Hackl, Christina; Stewart, Julie; Uhlik, Mark; Dantzig, Anne H; Foster, F Stuart; Kerbel, Robert S


    Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow-derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor-bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.

  8. Observation on Short-Term Intermittent Administration Dopamine at Low Doses on Patients With Severe Decompensated Heart Failure%小剂量多巴胺间歇短程应用治疗重度失代偿性心力衰竭观察



    Objective To explore the short-term intermittent administration dopamine at low doses on patients with severe decompensated heart failure. Methods 84 cases of severe patients with severe decompensated heart failure in our hospital were selected, random grouping, each of 42 cases. The routine group was treated with neuroendocrine antagonist, digitalis, diureticsand and other conventional treatmen. The study group was given a small dose of dopamine on the basis of the conventional group. The clinical effect and adverse reaction rate of the two groups were statistically analyzed. Results The clinical total effective rate of the study group was 88.1% better than that of the conventional group 66.7%,the difference between the two groups was significant (P0.05). Conclusion Usingshort-term intermittent administration dopamine at low doses on patients with severe decompensated heart failure, can significantly improve the clinical effect, and does not increase the incidence of adverse reactions.%目的:探究小剂量多巴胺间歇短程应用治疗重度失代偿性心力衰竭。方法选取我院收治的84例重度失代偿性心力衰竭患者,随机分组,各42例。常规组给予神经内分泌拮抗剂、洋地黄制剂及利尿剂等常规治疗。研究组于此基础上予小剂量以多巴胺治疗。统计两组患者临床效果及不良反应发生率。结果研究组临床总有效率88.1%,优于常规组66.7%,两组差异有统计学意义(P <0.05);两组患者不良反应发生率对比,差异无统计学意义(P >0.05)。结论采用小剂量多巴胺间歇短程治疗重度失代偿性心力衰竭患者,可提高其临床效果,且不会增加不良反应发生率,在临床研究中具有重要意义。

  9. The influence of a single and chronic administration of venlafaxine on tramadol pharmacokinetics in a rabbit model.

    Szkutnik-Fiedler, Danuta; Grabowski, Tomasz; Balcerkiewicz, Monika; Michalak, Michał; Pilipczuk, Irina; Wyrowski, Łukasz; Urjasz, Hanna; Grześkowiak, Edmund


    The combined use of tramadol with selective serotonin and norepinephrine reuptake inhibitors e.g. venlafaxine may be associated with serotonin syndrome. No previous studies exist examining the influence of a weak CYP2D6 inhibitor venlafaxine on the pharmacokinetics of tramadol. Therefore, the aim of this study was to determine the effect of a single and chronic administration of venlafaxine on the pharmacokinetics of tramadol using a rabbit model. Adult New Zealand white rabbits of both sexes (n=21) were used. Animals received 100mg of tramadol per os (one slow release tablet) and 75mg of venlafaxine (one prolonged release capsule), and were divided into four groups: control group - a single dose of tramadol alone, 1day group - a single dose of tramadol and venlafaxine, 7 and 14days groups - seven and fourteen days administration of venlafaxine once daily plus a single dose of tramadol on the last day of the study. Venlafaxine administration over a period of 7 and 14days resulted in faster elimination of tramadol compared to the control group: significantly higher values of k el, and lower values of t1/2kel and MRT for the 7 and 14days group were observed. Although no differences in bioavailability of tramadol were obtained. Using a rabbit model, there is no evidence that the combined administration of tramadol and venlafaxine may increase the plasma exposure of tramadol and therefore increase the risk of serotonin syndrome. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  10. Acute arterial thrombosis associated with inadvertent high dose of tranexamic acid

    Surjya Prasad Upadhyay


    Full Text Available Tranexamic acid (TA act as anti-fibrinolytic agent and is widely used to limit bleeding in clinical practice. Tranexemic acid bind with plasminogen and prevent its conversion to plasmin, which limits the fibrinolytic pathway, so there is a theoretical risk of increasing thrombosis with high or prolonged therapy with TA. We encountered a case of acute arterial thrombosis following inadvertent administration of high dose of TA. A 27-years-old male with no other co-morbidity was ordered intravenous 1 gm TA to control excessive bleeding from previous bladder injury, but by mistake, he received 10 gm of TA. The patient developed signs and symptoms of acute ischemia in the right lower limb, which was diagnosed as acute iliac arterial thrombosis by computed tomography (CT angiography. The patient was managed with systemic heparinization, fasciotomy for impending gangrene and other supportive care following which he recovered fully within a few days. Caution should be exercised for all prophylactic use, especially with high dosage or prolonged therapy with TA.

  11. Prolonged paradoxical reaction to antituberculous treatment after discontinuation of TNF-alpha- blocker therapy with adalimumab. Rare clinical documentation

    Falkenstern-Ge Roger Fei


    Full Text Available In the past decades, tumor necrosis factor alpha (TNF-a antagonist has been a milestone in the treatment of many chronic inflammatory disease