Sample records for diltiazem

  1. Diltiazem

    ... used to treat high blood pressure and to control angina (chest pain). Diltiazem is in a class of medications called calcium-channel blockers. It works by relaxing the blood vessels so the heart does not have to pump ...

  2. Safety and Efficacy of Prehospital Diltiazem

    Jeffrey H Luk


    Full Text Available Introduction: Very few studies exist on the use of diltiazem in the prehospital setting. Some practitioners believe this medication is prone to causing hypotension in this setting. Our goals were to determine whether the prehospital administration of diltiazem induced hypotension and to evaluate the efficacy of the drug.Methods: Our two-tiered system is located in a suburban region of New Jersey with advanced life support (ALS care provided by fly-car units. The ALS units do not transport patients, and all of them are hospital based. The ALS providers are employed by the hospital system. In New Jersey, all ALS care requires online medical control, including the administration of diltiazem. We retrospectively reviewed patient care records for those who were believed to be in rapid atrial fibrillation and were given diltiazem in a suburban emergeny medical services system over a 22-month period. We examined the differences between heart rate (HR and blood pressure (BP on the initial evaluation and on arrival to the emergency department (ED. A hypotensive response was defined as a final systolic BP (SBP less than 90 mmHg and a drop in SBP of at least 10 mmHg. Diltiazem was considered effective if the ED HR was ,100 beats per minute (bpm or if it decreased [1]20%.Results: During the study period, 26,979 patients were transported. Of these patients, 2,488 had a documented rhythm of atrial fibrillation or atrial flutter. Of the 320 patients who received diltiazem, 42 patient encounters were excluded for incomplete data, yielding 278 patients for analysis. The average initial SBP was 139 mmHg and the average diastolic BP was 84 mmHg. The average diltiazem dosage was 16.7 mg. Two patients became hypotensive. The average initial HR was 154 bpm. On arrival to the ED, 33% of the patients had an HR , 100 bpm and 69% had a drop in HR [1] 20%. The overall efficacy of prehospital diltiazem was 73%.Conclusion: In the prehospital setting, diltiazem is associated

  3. Herbal carrier-based floating microparticles of diltiazem ...

    Various physicochemical properties of the floating microspheres were characterized, including ... Keywords: Diltiazem, Cardiac disease, Psyllium husk, Sodium alginate, Microsphere, Microparticle,. Controlled ..... solvent removal methods.

  4. Interactions between diltiazem and inhalation anaesthetics in the isolated heart.

    Carceles, M D; Miralles, F S; Laorden, M L; Hernandez, J


    It has been postulated that inhalation anaesthetics may interfere with calcium movement across cell membranes. We have evaluated the interaction between diltiazem and the inhalation anaesthetics halothane and isoflurane on sinus automaticity in the isolated right atrium (SAIRA). Isoflurane significantly reduced atrial rate at all concentrations tested. However, halothane produced only a small but significant decrease at the higher concentrations used (1-2 v/v%). Diltiazem modified the maximal negative chronotropic response to inhalation anaesthetics. Maximum depression of SAIRA was significantly greater in the presence of two different doses of diltiazem compared with exposure to halothane and isoflurane alone. These results suggest that inhalation anaesthetics may block the influx of extracellular calcium through voltage-dependent calcium channels inhibited by diltiazem.

  5. Effect of diltiazem on exercise capacity after heart transplantation.

    Varnado, Sara; Peled-Potashnik, Yael; Huntsberry, Ashley; Lowes, Brian D; Zolty, Ronald; Burdorf, Adam; Lyden, Elizabeth R; Moulton, Michael J; Um, John Y; Raichlin, Eugenia


    Sinus tachycardia (ST) is common after heart transplantation (HTx). The aim of the study was to evaluate the effect of diltiazem treatment during the first year after HTx on heart rate (HR), cardiac allograft function, and exercise capacity. From the total cohort, 25 HTx recipients started diltiazem treatment 4±2 weeks after HTx and continued it for at least 1 year (diltiazem group). Each study case was matched to a control. All patients underwent hemodynamic assessment and cardiopulmonary exercise test (CPET) at 1 year after HTx. HR decreased in the diltiazem group from 99±11 bpm to 94±7 bpm (P=.03) and did not change in the controls (98±11 bpm vs 100±13 bpm, P=.14). The difference between the groups at 1 year after HTx was significant (P=.04). In the diltiazem group left ventricular (LV), stroke volume and ejection fraction increased (48±16 vs 55±17 mL, P=.02, and 60%±10% vs 62%±12% P=.03, respectively) but did not differ from controls. E/E' decreased (10.7±2.7 vs 7.3±1.9, P=.003) while cardiac index was higher (3.5±0.8 vs 3.1±0.5; P=.05) in the diltiazem group at 1-year follow-up. The absolute peak VO2 (21±4 vs 18±6 mL/kg/min; P=.05) and normalized peak VO2 (73%±17% vs 58%±14%; P=.004) were significantly higher in the diltiazem group. This study showed that diltiazem treatment reduces ST, may improve cardiac allograft function and exercise tolerance during the first year after HTx. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Diltiazem and verapamil preferentially block inactivated cardiac calcium channels.

    Kanaya, S; Arlock, P; Katzung, B G; Hondeghem, L M


    Diltiazem has been proposed to act by blocking calcium channels of cardiac and smooth muscle since it has pharmacological [12-14] and clinical [10] effects that resemble those of verapamil, an agent that has been shown to block these channels [3]. However, block of the slow inward current by diltiazem has not been directly demonstrated. In fact, it has been suggested that diltiazem has an entirely different mechanism of action [7]. We therefore studied the blocking effects of diltiazem and verapamil on cardiac calcium channels by measuring the slow inward current in voltage-clamped ferret myocardium. Both drugs blocked the slow inward current in a use-dependent fashion, i.e. the block was enhanced by increased frequency of activating clamps and by more positive holding potentials. However, we found that short single activating clamps resulted in minimal block, whereas prolonging the clamp step progressively enhanced the blockade. Thus, a single long clamp caused as much blockade as a train of shorter pulses. These results demonstrate that diltiazem and verapamil block the slow inward current by binding to calcium channels in a state-dependent fashion, i.e. inactivated channels have a high affinity for the drugs, while rested and open channels have a lower affinity.

  7. Release Characteristics of Diltiazem Hydrochloride Wax-Matrix ...

    Michael Horsfall

    diltiazem hydrochloride-wax matrix granules with sintering. ... The drug release was by Higuchi controlled diffusion mechanism and it followed ... of plastic matrix tablets. Polymer films with different permeability have been .... More so, with increase in temperature and ..... characterization of ibuprofen-cetyl alcohol beads by.

  8. Preparation and characterization of diltiazem nanocapsules: Influence of various polymers

    Kumar G


    Full Text Available Nanocapsules are submicroscopic colloidal drug delivery system and are composed of an oily or an aqueous core surrounded by a thin polymeric membrane. Nanocapsules have recently generated lot of interest in the area of controlled release with availability of biocompatible and biodegradable polymers. Nanocapsules of diltiazem were prepared with an objective of achieving controlled release of the drug in order to reduce the frequency of administration of drug, to obtain more uniform plasma concentration, and to improve patient compliance. Diltiazem was chosen as the model drug, as it is widely used in the treatment of chronic conditions such as hypertension and angina which require prolonged therapy. Nanocapsules were prepared by the interfacial deposition technique by taking different concentrations of polymers and phospholipid mixture. Five best formulations were selected based on the encapsulation efficiency. The morphology of nanocapsules was assessed by scanning electron microscope and they were found to be smooth, spherical, and discrete. The particles followed normal size distribution with particle size in the range of 20 to 380 nm. In vitro release studies indicated prolonged release for all polymers for 48 hours, with polycaprolactone as the best polymer releasing about 95 to 98%. The formulations were stable at 4°C but unstable at 25°C, and hence recommended for storage in refrigeration. Thus, it can be concluded that nanocapsules are a useful technology for controlled release of diltiazem.

  9. Formulation and evaluation of floating matrix tablets of diltiazem hydrochloride

    Vinay D Gaikwad


    Full Text Available This study was performed to design floating tablets of diltiazem as a model drug for prolongation of gastric residence time. A simple visible spectrophotometric method was employed for the estimation of diltiazem at 236 nm and Beer′s law is obeyed in the concentration range of 2-20 mg/ml. Preformulation studies were carried out to optimize the ratios required for various grades of HPMC-SCMC and HPMC- Carbopol P934. Total 10 formulations (five each were prepared using HPMC (K4M. The prepared floating tablets were evaluated for hardness, weight variation, thickness, friability, drug content uniformity, buoyancy lag time, total floating time, water uptake (swelling index, and in vitro dissolution studies. SEM and stability studies were carried out only for best release formulations (A1 and B1. Among the five formulations with HPMC K4M and A1-A4 showed drug release ranging from 99.89 to 77.52%. Similarly five formulations with HPMC K4M and Carbopol P934 (B1-B4 showed drug release ranging from 97.9 to 80.35% in 0.1 N HCl dissolution medium. Formulations A1 and B1 gave maximum drug release upto 100% within 12 hrs. SEM for A1 and B1 formulations revealed that surface was smooth upto 4 hrs after that swelling and porosity of tablet increased indicating the diffusion and erosion mechanism of release.




    Full Text Available Objective: The main aim and objective of the work is to formulate immediate release tablets using different direct compression vehicles (DCV’S in different ratios. Methods: In the present study, design of oral immediate release tablets of Diltiazem hydrochloride by direct compression technique was carried out. Results: The main motive is to compare the dissolution profile of these formulations and conclude the best formulation which release drug at a faster rate . To determine the best fit dissolution profile for the dosage forms. Diltiazem hydrochloride tablets were formulated by using microcrystalline cellulose (diluent, potato starch, acacia (binder and magnesium stearate (lubricant. The granules were compressed into tablets and were subjected to dissolution studies. The dissolution profile of the formulation F2 was found to have better dissolution rate compared to others. Conclusion: The Invitro dissolution studies of all the formulations were conducted and the results were obtained, it was concluded that formulation F2 was the best with fast release of drug compared to others.

  11. Development and evaluation of microporous osmotic tablets of diltiazem hydrochloride.

    Bathool, Afifa; Gowda, D V; Khan, Mohammed S; Ahmed, Ayaz; Vasudha, S L; Rohitash, K


    Microporous osmotic tablet of diltiazem hydrochloride was developed for colon targeting. These prepared microporous osmotic pump tablet did not require laser drilling to deliver the drug to the specific site of action. The tablets were prepared by wet granulation method. The prepared tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan coating process. The incorporation of sodium lauryl sulfate (SLS), a leachable pore-forming agent, could form in situ delivery pores while coming in contact with gastrointestinal medium. The effect of formulation variables was studied by changing the amounts of sodium alginate and NaCMC in the tablet core, osmogen, and that of pore-forming agent (SLS) used in the semipermeable coating. As the amount of hydrophilic polymers increased, drug release rate prolonged. It was found that drug release was increased as the concentration of osmogen and pore-former was increased. Fourier transform infrared spectroscopy and Differential scanning calorimetry results showed that there was no interaction between drug and polymers. Scanning electron microscopic studies showed the formation of pores after predetermined time of coming in contact with dissolution medium. The formation of pores was dependent on the amount of pore former used in the semipermeable membrane. in vitro results showed acid-resistant, timed release at an almost zero order up to 24 hours. The developed osmotic tablets could be effectively used for prolonged delivery of Diltiazem HCl.

  12. Development and evaluation of microporous osmotic tablets of diltiazem hydrochloride

    Afifa Bathool


    Full Text Available Microporous osmotic tablet of diltiazem hydrochloride was developed for colon targeting. These prepared microporous osmotic pump tablet did not require laser drilling to deliver the drug to the specific site of action. The tablets were prepared by wet granulation method. The prepared tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan coating process. The incorporation of sodium lauryl sulfate (SLS, a leachable pore-forming agent, could form in situ delivery pores while coming in contact with gastrointestinal medium. The effect of formulation variables was studied by changing the amounts of sodium alginate and NaCMC in the tablet core, osmogen, and that of pore-forming agent (SLS used in the semipermeable coating. As the amount of hydrophilic polymers increased, drug release rate prolonged. It was found that drug release was increased as the concentration of osmogen and pore-former was increased. Fourier transform infrared spectroscopy and Differential scanning calorimetry results showed that there was no interaction between drug and polymers. Scanning electron microscopic studies showed the formation of pores after predetermined time of coming in contact with dissolution medium. The formation of pores was dependent on the amount of pore former used in the semipermeable membrane. in vitro results showed acid-resistant, timed release at an almost zero order up to 24 hours. The developed osmotic tablets could be effectively used for prolonged delivery of Diltiazem HCl.

  13. The solubility-modulated osmotic pump: in vitro/in vivo release of diltiazem hydrochloride.

    McClelland, G A; Sutton, S C; Engle, K; Zentner, G M


    A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem.HCl as a model drug. Diltiazem.HCl has an aqueous solubility greater than 590 mg/ml (37 degrees C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ml; 37 degrees C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of greater than 80% of an initial diltiazem.HCl load. Devices were prepared with cores that contained diltiazem.HCl and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of approximately 75% of the initial diltiazem.HCl load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

  14. Acute coronary hemodynamic effects of equihypotensive doses of nisoldipine and diltiazem

    H. Suryapranata (Harry); P.W.J.C. Serruys (Patrick); A.L. Soward; J. Planellas; G. Vanhaleweyk; P.G. Hugenholtz (Paul)


    textabstractThe hemodynamic effects of nisoldipine and diltiazem were investigated in two groups of patients undergoing investigation for suspected coronary artery disease. Emphasis was placed on the coronary hemodynamic changes. Approximately equihypotensive doses of these two calcium channel block

  15. Rapid reversal of life-threatening diltiazem-induced tetany with calcium chloride.

    Vinson, D R; Burke, T F; Sung, H M


    We describe a patient who developed tetany with sudden respiratory arrest after the infusion of intravenous diltiazem. The administration of calcium chloride rapidly resolved the patient's tetany with prompt recovery of respiratory function, averting the need for more aggressive airway management and ventilatory support. The emergency physician should be aware that life-threatening tetany may accompany the administration of intravenous diltiazem and that calcium chloride may be a rapid and effective remedy.

  16. Cisplatin-Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model.

    Naples, James G; Parham, Kourosh


    To evaluate whether the calcium-channel blocker diltiazem has protective effects against cisplatin-induced ototoxicity in a mouse model. Original basic science in vivo investigation. Academic setting: Otolaryngology-Head and Neck Surgery laboratory at University of Connecticut Health Center. Thirty-nine female CBA/J mice. Pure tone- or click-evoked auditory brainstem responses (ABRs) were recorded in CBA/J mice to determine auditory thresholds. All mice had baseline ABRs recorded. They were then given a single cisplatin bolus (14 mg/kg), followed by 5 consecutive days of intratympanic diltiazem or saline control. Follow-up thresholds were recorded on days 7, 14, and 21 postcisplatin. Tone-evoked ABRs evaluated the otoprotective effect of 2-mg/kg diltiazem in 9 mice, and dose effect was examined in response to click-evoked ABR with 2- or 4-mg/kg diltiazem in 2 groups of 15 mice. Saline-treated ears had significantly elevated tone-evoked auditory thresholds when compared with diltiazem-treated ears (P = .038) on day 7 postcisplatin only. Click-evoked ABR thresholds were significantly elevated in saline-treated ears versus diltiazem-treated ears for the 2-mg/kg group (P = .001) and 4-mg/kg group (P = .011) on days 7, 14, and 21 postcisplatin. Intratympanic diltiazem has significant protective effects against cisplatin ototoxicity at 2 and 4 mg/kg. This is the first in vivo study to demonstrate that diltiazem offers a potentially novel therapy for cisplatin-induced ototoxicity. © American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.

  17. Circulatory Support with Venoarterial ECMO Unsuccessful in Aiding Endogenous Diltiazem Clearance after Overdose

    Erin N. Frazee


    Full Text Available Introduction. In cardiovascular collapse from diltiazem poisoning, extracorporeal membrane oxygenation (ECMO may offer circulatory support sufficient to preserve endogenous hepatic drug clearance. Little is known about patient outcomes and diltiazem toxicokinetics in this setting. Case Report. A 36-year-old woman with a history of myocardial bridging syndrome presented with chest pain for which she self-medicated with 2.4 g of sustained release diltiazem over the course of 8 hours. Hemodynamics and mentation were satisfactory on presentation, but precipitously deteriorated after ICU transfer. She was given fluids, calcium, vasopressors, glucagon, high-dose insulin, and lipid emulsion. Due to circulatory collapse and multiorgan failure including ischemic hepatopathy, she underwent transvenous pacing and emergent initiation of venoarterial ECMO. The peak diltiazem level was 13150 ng/mL (normal 100–200 ng/mL and it remained elevated at 6340 ng/mL at hour 90. Unfortunately, the patient developed multiple complications which resulted in her death on ICU day 9. Conclusion. This case describes the unsuccessful use of ECMO for diltiazem intoxication. Although past reports suggest that support with ECMO may facilitate endogenous diltiazem clearance, it may be dependent on preserved hepatic function at the time of cannulation, a factor not present in this case.

  18. Effects of diltiazem on myocardial perfusion abnormalities during exercise in patients with hypertrophic cardiomyopathy

    Sugihara, Hiroki; Taniguchi, Yoko; Ito, Kazuki [Kyoto Prefectural Univ. of Medicine (Japan)] [and others


    The effect of diltiazem on myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM) was evaluated by exercise myocardial {sup 201}Tl single photon emission computed tomography (SPECT). Exercise myocardial SPECT was performed before and 8 weeks after oral administration of diltiazem (180 mg/day) in 20 patients with HCM who showed transient perfusion defects on exercise myocardial {sup 201}Tl SPECT under control conditions. SPECT images were divided into 17 segments. The {sup 201}Tl perfusion defects were visually scored and evaluated as the defect score. The transient dilation index was calculated as an index of subendocardial ischemia. Improvement of the defect score was demonstrated in 15 patients after the administration of diltiazem. The mean defect score decreased significantly from 9.90{+-}5.17 to 5.50{+-}4.89 (p<0.0001). Although 16 of 20 patients showed an abnormal transient dilation index before diltiazem treatment, 16 showed improvement and 13 of these normalized after diltiazem therapy. The mean transient dilation index decreased from 1.16{+-}0.10 to 1.02{+-}0.09 (p<0.0001). In conclusion, diltiazem prevents or diminishes myocardial ischemia in patients with HCM. (author)


    L. K. Omray


    Full Text Available Gastro retentive drug delivery system of diltiazem hydrochloride was designed and evaluated for its effectiveness for the management of mild to moderate hypertension. Gastro retentive drug delivery system were prepared using polyvinyl alcohol and sodium carboxy methyl cellulose as the polymers and sodium bicarbonate as a gas generating agent for the reduction of floating lag time. Gastro retentive drug delivery system tablets were prepared by wet granulation method by compression in tablet compression machine. Formulations DL1, DL2, DL3, DL4 and DL5 were developed which differed in the ratio of polyvinyl alcohol and sodium carboxy methyl cellulose polymers. All the formulations were evaluated for hardness, weight variation, friability, drug content, swelling index, buoyancy studies and in vitro drug release study. In vitro drug release study was performed using United State Pharmacopoeia 23 type 2 dissolution test apparatus employing paddle stirrer at 50 r/pm. Dissolution medium was 900 ml of 0.1N hydrochloric acid at 37ºC ± 3ºC. Formulations DL3 was found to be better as compared to other formulation.

  20. Pharmacokinetics of diltiazem hydrochloride delay-onset sustained-release pellet capsules in healthy volunteers

    Xi-Qing Yan


    Full Text Available The pharmacokinetics (PK of ordinary tablets and sustained release capsules of diltiazem hydrochloride in human clinical trials had been studied. The PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules, a new dosage form, has not been reported, although it is very important to clinical use. In this paper, we investigated the PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules and the food influence in Chinese healthy volunteers. The PK parameters indicated that the diltiazem hydrochloride delay-onset sustained-release pellet capsules appeared marked characteristics of delayed and controlled release. An opened-label, randomized and parallel clinical trial was conducted in 36 Chinese healthy volunteers with single oral dose (90 mg, 180 mg or 270 mg and a multiple oral dose (90 mg d-1×6 d administration. The effect of food on the PK of one single oral dose (360 mg was investigated in 24 healthy Chinese volunteers. Plasma diltiazem concentration was determined by reversed-phase high-performance liquid chromatography (RP-HPLC and the main pharmacokinetic parameters were analyzed by PKSolver (Ver 2.0. All clinical studies were conducted in the Clinical Pharmacological Center (No. JDX1999064 of Xiangya Hospital Affiliated Central South University, China. The PK parameters suggested that the new formulation had marked characteristics of delayed and controlled release of diltiazem, and food intake did not alter significantly diltiazem pharmacokinetic parameters.Embora a farmacocinética (PK do cloridrato de diltiazem nas formas de comprimidos de liberação imediata e cápsulas de liberação modificada em ensaios clínicos já tenha sido relatada, a pesquisa da PK do cloridrato de diltiazem na forma de cápsulas com peletes de liberação retardada e sustentada ainda é muito importante. Neste trabalho, propusemos avaliar a farmacocinética do cloridrato de diltiazem administrado através desta nova forma

  1. Effects of diltiazem on skinned skeletal muscle fibers of the African clawed toad.

    Ishizuka, T; Endo, M


    To examine the effects of diltiazem and its l-cis isomer (which possesses only a weak Ca++-antagonistic action) on the contractile system and the sarcoplasmic reticulum of skeletal muscle, we used skinned fibers isolated from iliofibularis muscle of the African clawed toad, Xenopus laevis. Diltiazem showed the following effects: an increase in the Ca++ sensitivity of the contractile system, a decrease in the maximal tension developed in a saturating concentration of Ca++, an inhibition of Ca++ uptake by the sarcoplasmic reticulum, an inhibition of Ca++ release from the sarcoplasmic reticulum by caffeine, and an increase in the Ca++ permeability of the sarcoplasmic reticulum membrane. The effects of the l-cis isomer were similar to those of diltiazem, and the potencies of the two substances were nearly equal, except with respect to the effect on the Ca++ release induced by caffeine: the l-cis isomer potentiated this type of Ca++ release. Diltiazem's effects on amphibian skinned skeletal muscle fibers may not be related qualitatively or quantitatively to the Ca++-antagonistic actions of the drug on mammalian cardiac and smooth muscles. The pharmacological spectrum of diltiazem on skinned skeletal muscle fibers is similar to that of some local anesthetics.

  2. Biodegradable microparticulate drug delivery system of diltiazem HCl

    Manish Kumar Gupta


    Full Text Available The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w. In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing

  3. Amiloride and diltiazem inhibition of microsomal and mitochondrial Na+ and Ca2+ transport.

    Sordahl, L A; LaBelle, E F; Rex, K A


    Amiloride, a K+-sparing diuretic, and diltiazem, a Ca2+ channel antagonist, have both been reported to inhibit Na+ transport-associated processes in different subcellular membrane systems. In this report, similar inhibitory effects of both agents are demonstrated on Na+-induced Ca2+ release from rabbit heart mitochondria and on Na+ uptake in a kidney medulla microsomal preparation. Both amiloride and diltiazem produce 50% inhibition of Na+ uptake in kidney microsomes at the same concentrations. Heart mitochondrial Na+-induced Ca2+ release was 50% inhibited by 6 microM diltiazem and 200 microM amiloride. No effects of either agent on mitochondrial respiratory activity were observed. The results suggest a specific effect of both drugs on a Na+-binding site associated with an antiport exchange process. These data also extend previous observations suggesting the use of these agents as tools to define further ion transport mechanisms in biological membranes.

  4. Activity of diltiazem and nifedipine in some animal models of depression.

    Kostowski, W; Dyr, W; Puciłowski, O


    The effect of two calcium channel inhibitors, diltiazem and nifedipine in animal models of depression: a) behavioral despair test and b) behavioral deficit produced by uncontrollable footshock was investigated. Additionally, the influence of both drugs on mouse killing (muricide) behavior induced by chronic isolation was studied. Both drugs given in single doses increased the active behavior of rats in behavioral despair test. Nifedipine but not diltiazem was partially effective in the test when administered chronically (14 days). Both drugs also attenuated stress-induced behavioral depression in the open field and forced swim test. Diltiazem was markedly more active in the former whereas nifedipine in the latter test. Neither compound influenced killing behavior in muricidal rats. Our data support the notion that calcium channel inhibitors may possess antidepressant activity, although there appear to exist certain differences in their scope of action depending on the model applied.

  5. The Role of Diltiazem enriched with Zinc sulphate in Anal Fissure

    Hamoudi Mosah Alsumbouly


    Full Text Available Chronic anal fissure has traditionally been treated surgically. Initial enthusiasm for chemical sphincterotomy has waned because of poor outcomes with glyceryltrinitrate ointment. In this study the use of topical 2% diltiazem enriched with 2% Zinc sulphate ointment has been investigated as an alternative method of chemical sphincterotomy. To evaluate the effectiveness and safety of combined ointment of 2% diltiazem enriched with Zinc sulphate in the treatment of anal fissure, and to analyze the relationship between healing duration of the treatment, and the number of applications. A prospective observational study of 55 patients diagnosed with anal fissure that began treatment with three groups; control group A; using Vaseline ointment (15 cases, group B; (15 cases topical diltiazem ointment 2%, and group C; (20 cases using combined ointment diltiazem 2% enriched with Zinc sulphate 2% , between August and December 2012. Diltiazem and zinc sulphate ointment was prepared in the Pharmacy Service. Effectiveness and safety were assessed by regular visits as an outpatient management and a telephone survey conducted with each patient within 8 weeks of treatment, adding it to the patient\\s clinical records. Variables were analyzed including healing, adverse effects, duration of treatment and number of applications, among others. Follow-up was carried out for up to 3 months until complete recovery of the fissure. A total of 55 patients were included in the study , 50% of anal fissure cases were healed especially group C. Recovery occurred in 15% of patients with anal fissure in group B and in 3% of patients with anal group A. 50 % of patients fissure were cured who underwent treatment for a month or more. Treatment of chronic anal fissures with 2% diltiazem ointment enriched with Zinc sulphate 2% for two months has avoided surgery in nearly 50 % of patients, with few adverse effects. [J Intercult Ethnopharmacol 2013; 2(3.000: 173-176

  6. Successful treatment of polymedicamentous poisoning with metoprolol, diltiazem and cilazapril

    Radovanović Milan R.


    Full Text Available Introduction. Poisoning caused by drugs with cardiodepressive effects is an urgent condition in medicine which is associated with high mortality rate regardless of modern therapeutic methods. Accidental or intentional poisoning whit these drugs produces heart activity depression and cardiovascular collapse as consequences. Current therapy for severe poisoning caused by beta-blockers and calcium channel blockers includes both unspecific and specific antidote therapy whit glucagon, as well as application of adrenergic drugs, calcium, phosphodiesterase inhibitors and hyperinsulinemia/euglycemia therapy. However, even whit the application of these drugs, prompt measures of unspecific detoxication therapy and cardiopulmonary reanimation are crucial for survival of patients with severe poisoning. Case report. A 28-year-old female patient was hospitalized for cardiogenic shock and altered state of conscioussnes (Glasgow coma score = 4, caused by acute poisoning with 2 g of metoprolol (Presolol®, 1.8 g of diltiazem (Cortiazem® and 50 mg of cilazapril (Zobox®. Prolonged cardiopulmonary resuscitation was applied during the first 16 hours of hospitalization, including administration of crystaline solutions (8 L, 17 mg of adrenaline, 4 mg of atropine, 4 mg of glucagone and 1.6 g of dopamine, with electro-stimulation by temporary pacemaker and mechanical ventilation. In a defined time period, normalized state of consciousness was registered, mechanical ventilation was stopped and normal heart activity and hemodynamic stability were accomplished. During hospitalization the patient was treated for mild pneumonia and after ten days, completely recovered, was released and sent to home treatment. Conclusion. Prompt measures of cardiopulmonary resuscitation and multidisciplinary treatment in intensive care units significantly increase the chances of complete recovery of a patient with severe poisoning caused by drugs with cardiodepressive efects.

  7. Development and validation of a dissolution test for diltiazem hydrochloride in immediate release capsules

    Taciane Ferreira Mendonça


    Full Text Available This work describes the development and validation of a dissolution test for 60 mg of diltiazem hydrochloride in immediate release capsules. The best dissolution in vitro profile was achieved using potassium phosphate buffer at pH 6.8 as the dissolution medium and paddle as the apparatus at 50 rpm. The drug concentrations in the dissolution media were determined by UV spectrophotometry and HPLC and a statistical analysis revealed that there were significant differences between HPLC and spectrophotometry. This study illustrates the importance of an official method for the dissolution test, since there is no official monograph for diltiazem hydrochloride in capsules.

  8. Diltiazem in acute myocardial infarction treated with thrombolytic agents : a randomised placebo-controlled trial

    Boden, WE; van Gilst, WH; Scheldewaert, RG; Starkey, IR; Carlier, MF; Julian, DG; Whitehead, A; Bertrand, ME; Col, JJ; Pedersen, OL; Lie, KI; Santoni, JP; Fox, KM


    Background Diltiazem reduces non-fatal reinfarction and refractory ischaemia after non-Q-wave myocardial infarction, an acute coronary syndrome similar to the incomplete infarction that occurs after successful reperfusion. We postulated that this agent would reduce cardiac events in patients after a

  9. Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations

    Christrup, Lona Louring; Bonde, J; Rasmussen, S N


    Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr r...

  10. Effects of verapamil and diltiazem on gastric emptying in normal subjects.

    Yavorski, R T; Hallgren, S E; Blue, P W


    It has been suggested that calcium-channel blockers may delay gastric emptying by inhibiting gastric smooth muscle contraction. Most reports in man, however, reveal no significant delay in gastric emptying after using nifedipine; other calcium-channel blockers have not been studied in humans to date. We studied the effects of verapamil and diltiazem on solid-phase gastric emptying in 10 healthy volunteers. Each subject underwent a radionuclide gastric emptying determination (1) without preadministered medication, (2) after verapamil 80 mg orally every 6 hr for 10 doses, and (3) after diltiazem 60 mg by mouth given as one dose. Results revealed no significant difference in gastric emptying rates after pretreatment with verapamil or diltiazem when compared with no premedication (P greater than 0.37). We conclude that verapamil and diltiazem do not significantly delay gastric emptying in normal subjects. These data may be of clinical significance when prescribing calcium-channel blockers to patients with diseases associated with altered gastric emptying.

  11. The haemodynamic effects of nifedipine, verapamil and diltiazem in patients with coronary artery disease. A review

    A.L. Soward; G.L.J. Vanhaleweyk; P.W.J.C. Serruys (Patrick)


    textabstractOf the 3 most widely used calcium antagonists--nifedipine, verapamil and diltiazem--nifedipine is the most potent arterial vasodilator. Increases in cardiac output and coronary blood flow following nifedipine administration result in part from the afterload reduction. Reflex adrenergic s

  12. Severe Diltiazem Poisoning Treated with Hyperinsulinaemia-Euglycaemia and Lipid Emulsion

    Nadine Monteiro


    Full Text Available Introduction. Calcium channel blockers (CCBs drugs are widely used in the treatment of cardiovascular diseases. CCB poisoning is associated with significant cardiovascular toxicity and is potentially fatal. Currently, there is no specific antidote and the treatment of CCB poisoning is supportive; however, this supportive therapy is often insufficient. We present a clinical case of severe diltiazem poisoning and the therapeutic approaches that were used. Case Report. A 55-year-old male was admitted to the intensive care unit (ICU after voluntary multiple drug intake, including extended release diltiazem (7200 mg. The patient developed symptoms of refractory shock to conventional therapy and required mechanical ventilation, a temporary pacemaker, and renal replacement therapy. Approximately 17 hours after drug intake, hyperinsulinaemia-euglycaemia with lipid emulsion therapy was initiated, followed by progressive haemodynamic recovery within approximately 30 minutes. The toxicological serum analysis 12 h after drug ingestion revealed a diltiazem serum level of 4778 ng/mL (therapeutic level: 40–200 ng/mL. Conclusions. This case report supports the therapeutic efficacy of hyperinsulinaemia-euglycaemia and lipid emulsion in the treatment of severe diltiazem poisoning.

  13. Pharmacokinetics and Comparative Bioavailability of Two Diltiazem Tablet Formulations in Healthy Volunteers

    Simin Dadashzadeh


    Full Text Available The pharmacokinetic parameters and bioavailability of diltiazem following a single oral administration of a generic diltiazem 60 mg tablet (Sobhan Pharmaceuticals, Iran were compared to those of a reference product (Entrydil, Orion Pharmaceuticals, Finland. Twelve healthy male volunteers received a single oral dose of either formulation following overnight fasting in a double blind, randomized, crossover study. Blood samples were collected at selected times during 24 h and diltiazem plasma concentrations were determined with a sensitive HPLC method. Individual pharmacokinetic parameters, t1/2, t1/2(abs, K, Ka, Tmax, Cmax, Vd/F, Cl/F, AUC0-24 and AUC0-∞ were calculated. No significant differences were observed in pharmacokinetic parameters between two formulations. The 90% confidence intervals for the test/reference geometric mean ratios of Cmax, AUC0-24 AUC0-∞ and Cmax/AUC0-∞ were within the conventional bioequivalence range of 0.8 - 1.25. In-vitro parameters of mean dissolution time (MDT and time for 70 % dissolution (T70 were also determined. There was a significant difference between the MDT for two dosage forms (p<0.0001. It was concluded that despite of a higher dissolution rate, the test product of diltiazem is bioequivalent to the reference product with respect to the rate and extent of absorption.

  14. Use of micellar mobile phases for the chromatographic determination of clorazepate, diazepam, and diltiazem in pharmaceuticals.

    Gil-Agustí, M; Carda-Broch, S; García-Alvarez-Coque, M C; Esteve-Romero, J


    An ODS-2 column, a micellar mobile phase of high elution strength containing 0.1M sodium dodecyl sulfate and 3% (v/v) butanol, and ultraviolet detection at 230 nm are used for the determination of either of two benzodiazepines (clorazepate and diazepam) and a benzothiazepine (diltiazem) in pharmaceuticals. The procedure is shown to be competitive against conventional chromatography with methanol-water mobile phases, especially for diltiazem. The composition of the micellar mobile phase is selected using a predictive strategy based on an accurate retention model and assisted by computer simulation. Calibration graphs are linear at least in the 2.5 to 20 microg/mL, 4 to 20 microg/mL, and 5 to 40 microg/mL ranges for clorazepate, diazepam, and diltiazem, respectively. The intra- and interday repeatabilities (%) are clorazepate (1.7, 5.2), diazepam (0.43, 3.7), and diltiazem (0.36, 3.1). Limits of detection are well below the concentrations of the drugs found in the commercial pharmaceutical preparations analyzed. The drug contents evaluated with the proposed procedure are compared with the declared contents given by the manufacturers. The achieved percentages of label claim are usually between 95 and 104%.

  15. Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats.

    Erbas, Oytun; Yilmaz, Mustafa


    Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone.


    王晓峰; 由广旭; 皮绍文; 秦永文


    To investigate the effects of angiotensin converting enzyme inhibitor captopril, calcium channel blocker diltiazem and β-adrenoceptor antagonist dobutamine on the permeability of rat aortic endothelial monolayers.Methods Trauma-free isolation by Chen et al was adopted in the culture of rat aortic endothelial cells. Rat aortic endothelial cells were seeded on the nitrocellulose microporous filters. Eight days after seeding, the monolayers could be used for measuring the permeability. Before being perfused, monolayers were treated with captopril, diltiazem and dobutamine for 4 hours successively. The prepared filters were mounted on the Boydon chambers and perfused with hyperlipemia containing FITC-labeled albumin. The fluid filtering through the monolayers and the filter was collected and the albumin concentration was measured. At the same time, cholesterol, triglyceride, lipoprotein A and lipoprotein B concentrations of the collected fluid were also measured by ELISA.Results The above three drugs decreased the permeability of aortic endothelial cell monolayers to water, cholesterol, triglyceride lipoprotein A and lipoprotein B significantly. Dobutamine had more significant effects than the other two drugs. But diltiazem worked well in the clearance of albumin, while the other two drugs had no obvious effect.Conclusion Captopril, diltiazem and dobutamine may decrease the infiltration of lipids and lipoproteins into the subendothelial space, thus they can be used to prevent and ameliorate atherosclerosis.

  17. Interaction of rivaroxaban with amiodarone, verapamil and diltiazem in patients with atrial fibrillation: terra incognita

    S. N. Bel'diev


    Full Text Available Currently there are no generally accepted guidelines for the use of rivaroxaban together with amiodarone, verapamil or diltiazem in patients with creatinine clearance (CrCl<80 ml/min. Some researchers suggest that in renal failure amiodarone, verapamil and diltiazem contribute to a significant increase in plasma concentrations of rivaroxaban that is accompanied by increased risk of bleeding. According to preliminary calculations, it seems rational to reduce the dose of rivaroxaban when co-administered with these drugs: to 15 mg/day in patients with ClCr 50-79 ml/min and to 10 mg/day in patients with ClCr<50 ml/min.

  18. Efficacy of diltiazem as an adjunct to lignocaine in intravenous regional anesthesia

    Puneet Khanna


    Full Text Available Background: Various adjuncts have been used with lignocaine to decrease tourniquet pain and prolong post-operative analgesia during intravenous regional anesthesia (IVRA. Calcium-channel blockers potentiate the analgesic effect of local anesthetics. This study was designed to evaluate the efficacy of diltiazem as an adjunct to lignocaine in IVRA with respect to tourniquet tolerance, perioperative analgesia, and quality of anesthesia. Methods: In this prospective, randomized, and double-blind study, 40 patients (American Society for Anesthesiologists grade I/II undergoing elective hand surgery under IVRA were assigned into two groups of 20 each and administered IVRA either with lignocaine 3 mg/kg (group Lignocaine (L or lignocaine 3 mg/kg plus diltiazem 0.2 mg/kg (group Lignocaine-Diltiazem (LD with normal saline (total volume-40 ml. Hemodynamic parameters, onset of the complete sensory blockade, motor blockade, and intraoperative (tourniquet pain and post-operative Visual Analogue Scale scores, total intraoperative and consumption of post-operative fentanyl intraoperative were recorded. Results: Sensory block was established in 2.5±0.688 min in group LD verses 5.60±0.851 min in group L. Motor blockade was established in 8.65±0.933 min in group LD and 13.46±0.604 min in group L. The mean VAS scores >3 were attained early at 30 min (3.1±0.912 in group L. Patients in group L requested early rescue analgesic at 30±8.633 min compared with 49.64±7.958 min in group LD. Conclusions: Diltiazem as an adjunct to lignocaine provided enhanced intraoperative and post-operative analgesia without any significant side effects.

  19. Evaluation of gum damar as a novel microencapsulating material for ibuprofen and diltiazem hydrochloride

    Morkhade D; Joshi S


    A natural gum, damar was investigated as a novel microencapsulating material for sustained drug delivery. Microparticles were prepared by oil-in-oil emulsion solvent evaporation method. Ibuprofen and diltiazem hydrochloride were used as model drugs. Microparticles were evaluated for particle size, encapsulation efficiency and in vitro drug release kinetics. Images of the microparticles were obtained by bright field microscopy. The effect of different gum:drug ratios and solubility of drug on ...

  20. Design and in vitro evaluation of controlled release alginate beads of diltiazem hydrochloride

    D.Nagasamy Venkatesh; A.Kalaivani; Kritika D.Kalro; Lalitha Chintha; James Tharani; M.K. Samanta; B.Suresh


    Objective:Oral slow and sustained release drug delivery system can release their drug content with a controlled manner,producing a desirable blood serum level,reduction in drug toxicity and improving the patient compli-ance by prolonging dosing intervals.The major drawback of orally administered drug like diltiazem as a calcium channel blocker for the treatment of angina pectoris,arrhythmia and hypertension.Its has higher aqueous solu-bility and shorter elimination half-life.Methods:To overcome these drawbacks associated with diltiazem,an attempt has been made to develop a sustained release dosage form of diltiazem embedded alginate microbeads by ionotropic gelation technique employing various concentrations of polymer and keeping the drug concentra-tion constant.Results:The beads were characterized for its particle size,drug content and in vitro release stud-ies.The results revealed that the surface adhering drug was found to release immediately and a steady state of release was obtained up to 12 h from all the batches.The results indicated there was an inverse relationship be-tween the concentration of alginate and drug release.The drug release was found to follow non-fickian diffusion obeying first order kinetics.Conclusion:The developed alginate microbeads offered a sustained release of dilti-azem.Hence,the formulated microbeads were found to be potential,cost effective,possess satisfactory in vitro release studies.

  1. Combination of tadalafil and diltiazem attenuates renal ischemia reperfusion-induced acute renal failure in rats.

    El-Sisi, Alaa E; Sokar, Samia S; Abu-Risha, Sally E; Ibrahim, Hanaa A


    Life threatening conditions characterized by renal ischemia/reperfusion (RIR) such as kidney transplantation, partial nephrectomy, renal artery angioplasty, cardiopulmonary bypass and aortic bypass surgery, continue to be among the most frequent causes of acute renal failure. The current study investigated the possible protective effects of tadalafil alone and in combination with diltiazem in experimentally-induced renal ischemia/reperfusion injury in rats. Possible underlying mechanisms were also investigated such as oxidative stress and inflammation. Rats were divided into sham-operated and I/R-operated groups. Anesthetized rats (urethane 1.3g/kg) were subjected to bilateral ischemia for 30min by occlusion of renal pedicles, then reperfused for 6h. Rats in the vehicle I/R group showed a significant (p˂0.05) increase in kidney malondialdehyde (MDA) content; myeloperoxidase (MPO) activity; TNF-α and IL-1β contents. In addition significant (p˂0.05) increase in intercellular adhesion molecule-1(ICAM-1) content, BUN and creatinine levels, along with significant decrease in kidney superoxide dismutase (SOD) activity. In addition, marked diffuse histopathological damage and severe cytoplasmic staining of caspase-3 were detected. Pretreatment with combination of tadalafil (5mg/kg bdwt) and diltiazem (5mg/kg bdwt) resulted in reversal of the increased biochemical parameters investigated. Also, histopathological examination revealed partial return to normal cellular architecture. In conclusion, pretreatment with tadalafil and diltiazem combination protected against RIR injury.

  2. Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening.

    Carosati, Emanuele; Budriesi, Roberta; Ioan, Pierfranco; Ugenti, Maria P; Frosini, Maria; Fusi, Fabio; Corda, Gaetano; Cosimelli, Barbara; Spinelli, Domenico; Chiarini, Alberto; Cruciani, Gabriele


    With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

  3. Effect of solvent type on retardation properties of diltiazem HCl form liquisolid tablets.

    Adibkia, Khosro; Shokri, Javad; Barzegar-Jalali, Mohammad; Solduzian, Mohammad; Javadzadeh, Yousef


    Liquisolid technique is a new approach to formulate sustained release dosage forms. It seems that the solubility of an active ingredient in solvent plays an important role in drug release profile. The aim of present study was to investigate the effect of solvent type on diltiazem hydrochloride release profile from liquisolid compacts. To examine aforementioned idea, the drug solubility was studied in several conventional nonvolatile solvents. Liquisolid formulations of diltiazem HCl in the different solvents were prepared and their release profiles were also obtained. Effect of aging on the hardness and drug release profile was studied as well. X-ray crystallography and differential scanning calorimetry (DSC) were used to investigate the formation of any complex between drug and carrier or any crystallinity changes during the manufacturing process. The results showed that diltiazem HCl had lowest solubility in polysorbate 20. Highest amount was devoted to polysorbate 80 and propylene glycol. Type of nonvolatile solvent and its physicochemical properties as well as solubility of the drug in the applied solvent found to have important role on release profile of the drug from liquisolid compacts. Hardness and dissolution profile of the drug were not affected by aging. Amorphous form was obtained during the process of liquisolid formulation. It follows that the optimized new technique can be used to prepare sustained release formulations of water-soluble drugs.


    D’souza A


    Full Text Available In this study buccoadhesive bilayered tablets of Diltiazem HCl (DTZ were prepared in order to improve the bioavailability by the avoidance of hepatic first-pass metabolism, and to prevent frequent administration. Bilayered Tablets containing fixed amount of Diltiazem HCl (DTZ were prepared by direct compression method using polymers like hydroxyl propyl methyl cellulose (HPMC K4M, HPMC K15M, HPMC K100M in combination with backing layer of ethyl cellulose and evaluated for physicochemical properties, swelling, bioadhesive strength, in vitro permeation studies, in vitro drug release and possible interaction between ingredients. The physicochemical properties, swelling index, surface pH, bioadhesive strength, in vitro drug release and in vitro permeation studies were found to be dependent on the grade and proportion of buccoadhesive material used. The dissolution of Diltiazem HCl from all the prepared tablets into phosphate buffer (pH 6.8 was controlled for 6 hrs and followed non-Fickian release mechanism. Lower release rates were observed for formulations containing higher concentration of higher viscosity grade of HPMC. FTIR and DSC studies revealed the absence of significant interaction between DTZ and the selected bioadhesive materials. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of DTZ relative to orally administered drug.

  5. Effects of chlorthalidone and diltiazem on myocardial ischemia in elderly patients with hypertension and coronary artery disease

    Serro-Azul João Batista


    Full Text Available OBJETIVE: Antihypertensive therapy with thiazides decreases coronary events in elderly patients. However, the influence of diuretics on myocardial ischemia has not been fully investigated. The aim of this study was to compare the effect of chlorthalidone and diltiazem on myocardial ischemia. METHODS: Following a randomized, double-blind, crossover protocol, we studied 15 elderly hypertensive patients aged 73.6±4.6 years with myocardial ischemia. All patients had angiographically documented coronary artery disease. We measured patients using 48- hour ambulatory electrocardiogram monitoring and exercise testing. After a 2-week period using placebo, patients received chlorthalidone or diltiazem for 4 weeks. RESULTS: Both treatments lowered systolic and diastolic blood pressures. The number of ischemic episodes on ambulatory electrocardiogram recordings was reduced with the use of chlorthalidone (2.5±3.8 and diltiazem (3.2±4.2 when compared with placebo (7.9±8.8; p<0.05. The total duration of ischemic episodes was reduced in both treatments when compared with placebo (chlorthalidone: 19.2±31.9min; diltiazem: 19.3±29.6min; placebo: 46.1±55.3min; p<0.05. CONCLUSION: In elderly hypertensive patients with coronary artery disease, chlorthalidone reduced myocardial ischemia similarly to diltiazem. This result is consistent with epidemiological studies and suggests that reduction of arterial blood pressure with thiazide therapy plays an important role in decreasing myocardial ischemia.

  6. Effects of diltiazem on transmembrane potential and current of right ventricular papillary muscle of ferrets.

    Kanaya, S; Katzung, B G


    We studied the effects of diltiazem on electrical properties of isolated ferret right ventricular papillary muscles. By using standard microelectrode recording techniques and current clamp and voltage clamp protocols (single sucrose gap method), we measured action potential variables, depolarization-induced automaticity, slow (or second) inward current (Isi) and time-dependent and isochronal (1 sec) outward current. Resting potential was unaffected at all concentrations studied (from 2 nM-11 microM). At concentrations below 2 microM and at slow rates of stimulation (0.5 Hz), a small reduction of overshoot and prolongation of the action potential duration at 80% of full repolarization were observed. At concentrations of 2.2 microM or greater, marked use-dependent reductions of overshoot and plateau duration were observed that reversed with rest. Depolarization-induced automaticity was selectively suppressed at less negative diastolic potentials. In voltage clamp studies, peak Isi was markedly diminished over the concentration range studied (50% inhibitory concentration, 0.5 microM), but the current-voltage relation for Isi was not shifted on the voltage axis. The diminution in Isi was strongly use-dependent and voltage-dependent. Diltiazem (1.1 microM) had small effects on outward currents. Steady-state (isochronal) outward current and the time-dependent outward current were both reduced by 10 to 20% over the entire voltage range. Diltiazem is a potent inhibitor of the slow inward current in ventricular muscle. Its interaction with slow channel receptors appears to be strongly modulated by the state of the channels.

  7. Influence of diltiazem on the behavior of zolpidem-treated mice in the elevated-plus maze test.

    Cui, X-Y; Zhao, X; Chu, Q-P; Chen, B-Q; Zhang, Y-H


    The present study was undertaken to investigate the effect of diltiazem, a L-type calcium channel blocker (CCB), on the behavior of zolpidem-treated mice in the elevated plus-maze (EPM). Atypical benzodiazepine zolpidem significantly increased the percentage of open arm entries without influencing the total entries and total distance and average speed at the dose of 5 mg/kg (p.o.). Co-administration of zolpidem (2 mg/kg, p.o.) and diltiazem (5, 10 and 20 mg/kg, p.o.) significantly increased both the time spent and arm entries in the open arms without influencing the total entries and spontaneous activity notwithstanding that zolpidem at dose up to 2 mg/kg (p.o.) and diltiazem at dose up to 20 mg/kg (p.o.) did not show any effects on mice behavior in EPM. Zolpidem also attenuated the anxiogenic effect of 1-(3-Chlorophenyl)piperazine (mCPP, 0.7 mg/kg, i.p.) and 5-hydroxytryptophan (5-HTP, 30 mg/kg, i.p.). Even though the zolpidem at 1 mg/kg and diltiazem at 5 mg/kg were ineffective on mCPP-induced anxiety, respectively, the co-administration of zolpidem (1 mg/kg, i.p.) and diltiazem (5 mg/kg, p.o.) showed inhibitory effect on mCPP-induced anxiety in mice. These results suggested that diltiazem, a L-type CCB may augment the anxiolytic-like effect of zolpidem and also indicated that calcium channel modulation maybe involved in the anxiolytic-like properties of zolpidem.

  8. The effect of verapamil and diltiazem on cardiac stimulant effect of adrenaline and calcium chloride on isolated frog heart

    Lakhavat Sudhakar, Naveen Kumar T, Tadvi NA, Venkata Rao Y


    Full Text Available Background: Calcium channel blockers block voltage dependent L-type of calcium channel and thus reduce the frequency of opening of these channels in response to depolarization. The result is a marked decrease in transmembrane calcium current associated with long lasting relaxation of vascular smooth muscle, reduction in contractility in cardiac muscle, decrease in pacemaker activity in the SA node and decrease in conduction velocity in the AV node. Among Calcium channel blockers verapamil, is cardio selective, nifedipine is vascular smooth muscle selective, while diltiazem exhibits intermediate selectivity. Methods: In the present study, the effect of two Ca++ channel blocker, Verapamil and Diltiazem were compared on the isolated frog heart by using adrenaline & calcium chloride as standard on frog heart contractility. Results and conclusion: Adrenaline and calcium chloride increased the amplitude of contraction of isolated perfused frog heart. The L- type of Ca2+ channel blockers verapamil and diltiazem produced dose dependent (2mg, 4mg, 8mg, and 16mg reduction in the amplitude of contraction produced by calcium chloride in isolated perfused frog heart. There was no statistical significant difference (p > 0.05 between the inhibitory effect of diltiazem and verapamil on calcium chloride induced contraction of isolated frog heart.

  9. Control of the light-regulated current in rod photoreceptors by cyclic GMP, calcium, and l-cis-diltiazem.

    Stern, J H; Kaupp, U B; MacLeish, P R


    The effect of calcium ions on the cGMP-activated current of outer segment membrane was examined by the excised-patch technique. Changes in the extracellular calcium concentration had marked effects on the cGMP-activated current, while changes in intracellular calcium concentration were ineffective. Changes in calcium concentration in the absence of cGMP had little, if any, effect on membrane conductance. These results suggest that both intracellular cGMP and extracellular calcium can directly affect the conductance underlying the light response in rod cells. The pharmacological agent l-cis-diltiazem reversibly inhibited the cGMP-activated current when applied to the intracellular side of an excised patch. When superfused over intact rod cells, l-cis-diltiazem reversibly blocked much of the normal light response. The isomer, d-cis-diltiazem, did not significantly affect either patches or intact rod cells. Thus, the light-regulated conductance has binding sites for both calcium and cGMP that may interact during the normal light response in rod cells and a site specific for l-cis-diltiazem that can be used to identify and further study the conductance mechanism.

  10. Factorial design approach for optimization of floating microspheres of diltiazem hydrochloride

    Mangal Singh Panwar


    Full Text Available The aim of this study was to perform optimization of floating microspheres of diltiazem hydrochloride for the prolongation of gastric residence time. The microspheres were prepared by a nonaqueous solvent evaporation method using polycarbonate. A full factorial design was applied to optimize the formulation. Preliminary studies revealed that the concentration of polymer and stirring speed significantly affected the characteristics of floating microspheres. The optimum batch of microsphere exhibited smooth surfaces with good flow and packing properties, prolonged sustained drug release, remained buoyant for more than 10 h, high entrapment efficiency up to 97% w/w. Scanning electron microscopy confirmed the hollow structure with particle size in the order of 190 μm. The studies revealed that the increase in concentration of polycarbonate increased the drug release from the floating microspheres. The results of two third full factorial design revealed that the concentration of polycarbonate (X1 and stirring speed (X2 significantly affected drug entrapment efficiency, percentage release.

  11. Taro corms mucilage/HPMC based transdermal patch: an efficient device for delivery of diltiazem hydrochloride.

    Sarkar, Gunjan; Saha, Nayan Ranjan; Roy, Indranil; Bhattacharyya, Amartya; Bose, Madhura; Mishra, Roshnara; Rana, Dipak; Bhattacharjee, Debashis; Chattopadhyay, Dipankar


    The aim of this work is to examine the effectiveness of mucilage/hydroxypropylmethylcellulose (HPMC) based transdermal patch (matrix type) as a drug delivery device. We have successfully extracted mucilage from Colocasia esculenta (Taro) corms and prepared diltiazem hydrochloride incorporated mucilage/HPMC based transdermal patches using various wt% of mucilage by the solvent evaporation technique. Characterization of both mucilage and transdermal patches has been done by several techniques such as Molisch's test, organoleptic evaluation of mucilage, mechanical, morphological and thermal analysis of transdermal patches. Skin irritation test is studied on hairless Albino rat skin showing that transdermal patches are apparently free of potentially hazardous skin irritation. Fourier transform infrared analysis shows that there is no interaction between drug, mucilage and HPMC while scanning electron microscopy shows the surface morphology of transdermal patches. In vitro drug release time of mucilage-HPMC based transdermal patches is prolonged with increasing mucilage concentration in the formulation.


    Birajdar Ganesh


    Full Text Available The objective behind present study was to formulate and evaluate sustained release tablet of Diltiazem hydrochloride by using different polymers by melt granulation technology and to study the effect of various concentrations of polymers on release rate from tablet. Tablets were prepared using bees wax, carnauba wax, paraffin wax as release ratardent polymers. The drug and excipient compatibility study was done by FTIR method using KBr pellet method. The granules prepared by melt granulation technique evaluated for characterization such as bulk density, tapped density, hausners ratio, angle of repose, cars index all granules shows good flow property. The tablet of Diltiazem HCL evaluated for characterization such as hardness, friability, weight variation and content uniformity all tablets shows sufficient hardness and friability shows that tablets are having sufficient strength. All results were satisfactory. The in vitro drug release studies for the prepared formulation were conducted for a period of 12 h using an EDT 08LX dissolution tester USP Type - II apparatus (rotating paddle set at 100 rpm and a temperature of 37 ± 0.5°C formulation was placed in the 900 ml of the medium. For first 2 h tablet was placed in 1.2 pH acidic medium which was replaced with 7.4 pH phosphate buffer for remaining 10 h. From the dissolution study and comparative graph it was concluded that increase in concentration of wax shows decrease in drug release from tablet. Batch F3 shows 99.84 % drug release at 12 h. In vitro release data of optimized formulations (Batch F3 was fitted to various kinetic models like zero order, first order, Higuchi, korsmeyer-peppas and pass Higuchi model as it has highest r2 value (0.955 among all models.

  13. Analytical Characterization of two new related impurities of Diltiazem by High Resolution Mass spectrometry and NMR techniques096

    Jagadeesh Narkedimilli


    Full Text Available Diltiazem (DTZ is an optically active calcium channel blocker having a benzodiazepine structure. Two impurities (referred as DTZ-I and DTZ-II were detected with area percentages ranging from 0.1% to 0.15% during the impurity profile study of Diltiazem hydrochloride drug substance. A simple isocratic high performance liquid chromatographic method (HPLC and liquid chromatography–mass spectrometry (LC–MS were used for the detection. The impurities were isolated by preparative column chromatography. Analytical information from nuclear magnetic resonance and mass spectral data of the potential impurities revealed their structures as 2-(4-methoxyphenyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (DTZ-I and 2-(4-methoxyphenyl-4-oxo-5-vinyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (DTZ-II. Impurity identification, isolation and structure elucidation were discussed.

  14. Modification of late radiation response of rat salivary glands by pentoxifylline and diltiazem

    Suh, Hyun Suk; Yang, Kwang Mo; Kang, Yun Kyung [College of Medicine, Inje Univ., Seoul (Korea, Republic of)


    To elucidate me effects of pentoxifylline and diltiazem on the late response of the salivary glands of the rat after irradiation. Sixteen Sprague-Dawley rats were divided into 4 groups: (a) irradiation alone (b) irradiation with pentixifylline (PTX) (c) irradiation with diltiazem (DTZ) (d) irradiation with both PTX and OT2, Irradiation was given in a single fraction of 16 Gy using 4 MV photon energy through an anterior port encompassing the left side of the salivary gland leaving the right side of salivary gland as a control. PTX, 20 mg/kg and/or OT2, 50 mg/kg were infused intraperitoneally before irradiation. Two rats from each group were sacrificed on the 10th week and the rest was sacrificed on the 16th week after irradiation. Histopathologic examinations were undertaken for each section and the proportion of vacuolated cells out of the total number of cells under light microscopic fields was calculated. The statistical significance in the difference of the proportion of the vacuolated cells among the experimental groups was evaluated by a x{sup 2}-test. Irradiated salivary glands of the 10th week group revealed markedly increased number of vacuolated cells compared to those of unirradiated control. The proportion of vacuolated cells was significantly reduced in both the PTX qroup (p vaJue=0.001) and the combined PTX and DTX group compared to those of irradiation alone group. The DTZ alone group did not reveal the significant reduction of vacuolated cells compared to those of irradiation alone group (p value, >0.05). The 16th week groups revealed similar findings to those of the 10th week group, but the degree of chronic inflammatory cell infiltrates and interstitial fibrosis was increased and the number of acinar cells was reduced compared to those of the 10th week group. PTX significantly reduced the late radiation response of salivary glands, but DTZ did not reduce the same degree as PTX did. Taking the positive results of this study into consideration, it

  15. Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation.

    Wang, Yi-xi; Li, Jia-li; Wang, Xue-ding; Zhang, Yu; Wang, Chang-xi; Huang, Min


    Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation. A total of 126 renal transplant patients were enrolled. All the patients received CsA (2-4 mg·kg(-1)·d(-1)), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes. In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered. MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.

  16. Wax beads as cushioning agents during the compression of coated diltiazem pellets.

    Vergote, G J; Kiekens, F; Vervaet, C; Remon, J P


    Placebo particles were mixed with film-coated diltiazem pellets to evaluate them as cushioning agents during tabletting in order to protect the film coat from damage. The cushioning properties of alpha-lactose monohydrate granules, microcrystalline cellulose pellets and wax/starch beads were evaluated by comparing the dissolution profile of the coated pellets before and after compression (compression force 10 kN). Only the tablet formulations containing wax/starch beads provided protection to the film coat. However, the dissolution rate of tablets formulated with waxy maltodextrin/paraffinic wax placebo beads was too slow as the tablets did not disintegrate. Adding 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads to the formulation was the optimal amount of cushioning beads to provide sufficient protection for the film coat and yield disintegrating tablets. Using a compression simulator, the effect of precompression force and compression time on the dissolution rate was found to be insignificant. The diametral crushing strength of tablets containing 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads was about 25.0 N (+/-0.3 N), with a friability of 0.4% (+/-0.04%). This study demonstrates that adding deformable wax pellets minimizes the damage to film-coated pellets during compression.

  17. [Diltiazem versus intravenous nitroglycerin in the treatment of unstable angina pectoris. A randomized study].

    Castro, P; Corbalán, R; Vergara, I; Kunstmann, S


    Prognosis of unstable angina pectoris is related to admission EKG changes and prompt symptom control. The aim of this study was to compare the clinical effects of intravenous diltiazem (DTZ) or nitroglycerin (NTG) in patients with unstable angina pectoris. We studied 43 patients admitted to the hospital with a history of rest angina within the last 48 hours, associated with EKG evidence of ischemia. All subjects received intravenous heparin and oral aspirin, 23 were randomly assigned to receive intravenous DTZ and 20 to receive intravenous NTG. Both groups had similar baseline features and the endpoints of treatment were recurrence of angina, myocardial infarction, death during hospitalization and secondary side effects. Treatment with DTZ, when compared to NTG, resulted in a significant reduction of recurrent angina (8.7 and 59% respectively; p bradicardia with DTZ (28% of patients). In each group, one patient had a myocardial infarction and one patient died. It is concluded that intravenous DTZ reduces myocardial ischemia to a greater extent than NTG and can be safely used in patients with unstable angina pectoris.

  18. Design and development of controlled porosity osmotic tablet of diltiazem hydrochloride

    Sadhana R Shahi


    Full Text Available The present work aims towards the design and development of extended release formulation of freely water-soluble drug diltiazem hydrochloride (DLTZ based on osmotic technology by using controlled porosity approach. DLTZ is an ideal candidate for a zero-order drug delivery system because it is freely water-soluble and has a short half-life (2-3 h. Sodium chloride (Osmogen was added to the core tablet to alter the solubility of DLTZ in an aqueous medium. Cellulose acetate (CA and sorbitol were used as semipermeable membrane and pore former, respectively. The effect of different formulation variables namely concentration of osmogen in the core tablet, % pore former, % weight gain, pH of the dissolution medium and agitation intensity on the in vitro release was studied. DLTZ release was directly proportional to % pore former and inversely proportional to % weight gain. The optimized formulation (F8 delivered DLTZ independent of pH and agitation intensity for 12 h at the upper level concentration of % pore former (25% w/w and middle level concentration of % weight gain (6% w/w. The comparative study of elementary osmotic pump (EOP and controlled porosity osmotic pump revealed that it superior than conventional EOP and also easier and cost effective to formulate.

  19. Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem.

    Leboeuf, J; Lamar, J C; Massingham, R; Ponsonnaille, J


    1. The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5 mg kg-1 i.v.) and those of verapamil and diltiazem (0.2 mg kg-1 i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2. The four drugs caused a bradycardia with the following order of potency: bepridil greater than CERM 11888 greater than diltiazem greater than verapamil. 3. All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order: verapamil much greater than diltiazem greater than bepridil greater than CERM 11888. 4. Verapamil and diltiazem did not affect conduction or the RP in atria while bepridil weakly slowed the former and markedly increased the latter. CERM 11888 caused a lengthening of RP but this was a delayed effect. 5. In the ventricle, bepridil and CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV. Verapamil and diltiazem had no significant effects at the ventricular level. 6. Our results confirm that the main sites of action of calcium antagonists are the SA and AV nodes. Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of bepridil.

  20. Formulation and in vitro evaluation of taste-masked oro-dispersible dosage form of diltiazem hydrochloride

    Swati Changdeo Jagdale


    Full Text Available Diltiazem hydrochloride is a calcium channel blocker generally indicated for the treatment of angina and hypertension, and it is extensively metabolized due to the hepatic metabolism. Formulation of diltiazem hydrochloride into an oro-dispersible dosage form can provide fast relief with higher bioavailability. The bitter taste of the drug should be masked to formulate it in a palatable form. In the present work, an attempt was made to mask the taste by complexation technique, with a formulation into an oro-dispersible dosage form, using superdisintegrants Doshion P544, crospovidone (CP and sodium starch glycolate (SSG. The complexes of diltiazem hydrochloride with β-CD (1:1 molar ratio were prepared by kneading, co-evaporation, co-grounding, freeze-drying and melting methods. Phase solubility showed stability constant 819.13M-1. Prepared inclusion complexes were evaluated for taste masking and characterized by I.R, XRD, DSC. Using the drug β-CD complex, oro-dispersible tablets were prepared and evaluated for hardness, friability, weight variation, thickness, disintegrating time (DT, dissolution rate and taste. Formulations with 4 % Doshion, 8 % CP and 4 % SSG showed DT of 0.54, 0.35 and 1.23 minutes, respectively.O cloridrato de diltiazem é bloqueador do canal de cálcio geralmente indicado para o tratamento de angina e de hipertensão e é extensamente biotransformado devido ao metabolismo hepático. A formulação do cloridrato de diltiazem em orodispersão pode prover rápida liberação com maior biodisponibilidade. O sabor amargo do fármaco deve ser mascarado para ser formulado em forma palatável. No presente trabalho tentou-se mascarar o sabor pela técnica de complexação, com uma orodispersão, usando superdesintegrantes, como Doshio P544, crospivodina (CP e glicolato de amido sódico (SSG. Os complexos de cloridrato de diltiazem com β-CD (razão molar 1:1 foram preparados por mistura, coevaporação, comoagem, liofilização e m

  1. Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKvl.4 channel currents expressed in Xenopus oocytes

    Dong ZHANG; Shi-min WANG; Hui CHEN; Xue-jun JIANG; Sheng-ping CHAO


    Alm: TO investigate the effects of diltiazem. an L-type calcium channel blocker, and propafenone, a sodium channel blocker,on the inactivation and recovery kinetics of fKvl.4.a potassium channel that generates the cardiac transient outward potassium current.Methods:The cRNA for fKv1.4△ N-rerminal deleted mutant of the flerret Kvl.4 potassium channel.was injected into Xenopusoocytes to express the fKv1.4△N channel in these cells. Currents were recorded using a two electrode voltage clamp technique. Results: Diltiazem(10 to 1000 μmol/L)inhibited the fKv1.4△N channel in a frequency-dependent,voltage-dependent,and concerttration-dependent manneh Suggesting an open channel block.The ICso was 241.04±23.06 μmol/L for the fKvl.4&N channel(at+50mY).and propafenone(10 to 500 μmol/L)showed a similar effect(IC50=103.68±10.13 μmol/L).After application of diltiazem and propafenone, fKv1.4AN inactivation was bi-exponential.with a faster drug-induced inactivation and a slower C-type inactivation.Diltiazem increased the C-type inactivation rate and slowed recovery in fKv1.4△N channels.Howeve, propafenone had no effect on either the slow inactivation time constant or the recovery.Conclusion:Diltiazem and propafenone accelerate the inactivation of the Kvl.4AN channeI by binding to the open state of the channel.Unlike propafenone, diltiazem slows the recovery of the Kv1.4AN channel.

  2. Sphincter-Preserving Therapy with Topical 2% Diltiazem for Chronic Anal Fissure: Our Experience

    Manish Swarnkar


    Full Text Available Background: Chronic anal fissure is a common problem across the world treated largely by surgical methods. Studies have demonstrated the efficacy of topical agents like Glyceryl Trinitrate (GTN in anal fissure but it has been shown to have side effects like headache and dizziness. There is a need for a pharmacological therapy for fissure which has fewer side effects. Hence, this study was taken up to assess the efficacy and adverse effects of topical 2% Diltiazem (DTZ gel. Aim & Objectives: To assess the efficacy and side effect of topical treatment with 2% DTZ gel in patient with chronic anal fissure. Material and Methods: Consecutive fifty adult patients with symptomatic chronic anal fissure attending the surgery clinic were enrolled in the study form February 2014- July 2014 and they were treated with regular topical application of 2% DTZ cream. Patients were followed up at regular intervals for symptomatic relief and healing of fissure. Results: In our study postdefecatory pain, bleeding and irritation were significantly reduced after 2week of therapy and a th primary healing rate of 86% (43 out of 50 at 6 week of therapy. The primary side-effects of 2% DTZ gel appeared to be perianal dermatitis and pruritis ani in 14% cases. Conclusion: Topical 2% DTZ gel is an effective agent in the treatment of chronic anal fissure. The need for hospital stay is abolished; psychological and financial burden on the patient is reduced. With a healing rate close to 90%, topical DTZ can be easily advised as the first line of treatment of chronic anal fissure.

  3. Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen.

    Abdul, Mansoor; Hoosein, Naseema


    MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.

  4. Effect of diltiazem on skeletal muscle 3-O-methylglucose transport in bacteremic rats

    Westfall, M.V.; Sayeed, M.M.


    This study examined whether alterations in cellular Ca2+ regulation contribute to previously observed changes in skeletal muscle sugar transport during bacteremia. Fasted male rats received saline (control) or bacteria (4 X 10(10) Escherichia coli/kg) intraperitoneally. Twelve hours later, basal and insulin-mediated 3-O-methylglucose (3MG) transport was measured in isolated soleus muscles. Measurements of 3MG transport in the presence of cytochalasin b or at a low temperature (0.5 degree C) indicated that altered sugar transport in bacteremic rat muscles was not due to nonspecific membrane permeability changes. To determine the role of Ca2+ in the pathogenesis of altered sugar transport during bacteremia, rats were treated with the Ca2+ antagonist diltiazem (DZ, 0.6-2.4 mg/kg) at various times (0, 0 + 7.5, 10 h) after saline or bacterial injection. In bacteremic rats given 2.4 mg/kg DZ at 10 h, basal and insulin-mediated transport were similar to control values. This dose of DZ had little effect on control muscles. The addition of 20 microM DZ to the incubation media did not affect basal or insulin-mediated 3MG transport in bacteremic rat muscles. Addition of the Ca2+ agonist BAY K 8644 to the incubation media had no effect on sugar transport in bacteremic rat muscles but caused alterations in control rat muscles that were comparable to those observed in bacteremia. These results suggest that alterations in Ca2+ regulation could contribute to the previously observed changes in sugar transport in skeletal muscles from bacteremic rats.

  5. Comparison Between Diltiazem and Cedilanid-D on Ventricular Rate Control of Atrial Fibrillation and Their Effect on Atrioventricular Conduction System

    Zhu liguang; Mohammad AL Mamun


    Objectives This randomized study was designed to compare the safety and efficacy of intravenous diltiazem versus intravenous cedilanid-D (deslanoside) for ventricular rate control in patients with atrial fibrillation (AF). Analysis of the effect on conduction system of these drugs was also performed.Methods Forty three patients with AF were randomly assigned to receive intravenous therapy with 0.25mg/kg diltiazem (n= 21) or 0.4mg cedilanid-D (n= 22). If not effective at 120 minutes (< 20% decrease in pretreatment ventricular rate or can not convert to sinus rhythm= another dose of diltiazem or 0.2mg cedilanid-D was administered. Blood pressure and electrocardiographic recordings were performed before and after 5,10, 20, 30, 60 minutes of drug administration. Further recordings were performed at 120 minutes in noneffective patients, and at 180 minutes in patients who received second time drug administration. To evaluate the effect on conduction system of these two drugs by measuring PA, AH and HV intervals using His bundle electrogram test another nineteen sinus rhythm patients were randomized to diltiazem (n=9) and cedilanid (n=10) group. His bundle electrogram recordings were performed before and after 5, 10, 20 and 30 minutes of drug administration. Statistical significance was assessed with the use of t test, Fisher's exact test, ANOVA and LSD methodology. Results At baseline and after 5,10, 20, 30, 60 minutes of drug administration the heart rates (mean±SD) were(133±15), (92±20), (87±22), (85 ±20), (85 ±21), (85 ±23)beats/minute in diltiazem group respectively and( 140±21 ), ( 122±24),(118±25), (110±26), (112±25), (110±28) beats/minute in cedilanid-D group respectively. Heart rate reduction was higher in diltiazem group than cedilanid group during 5 (41±20 vs 17±14,P < 0.01); 10(46±21 vs 22±20, P<0.01); 20 (48±21 vs 29±22,P<0.01 ); 30(48±22 vs 27±22, P<0.01 ) and 60 minutes (48±23 vs 29±24, P< 0.05). Both drugs had no effect

  6. A Prospective Randomized Trial of Diltiazem Gel and Glyceryl Trinitrate Ointment on Treatment of Chronic Anal Fissure

    M Akhondi-Meybodi


    Methods: This semi-experimental study consisted of sixty six outpatients (34 females and 32 males with chronic anal fissure, who referred to the gastroenterology clinic. Patients were randomly classified into two groups. Group A received GTN ointment (0.03%, whereas group B was treated with Diltiazem gel (2%. The treatment was administered twice daily for 8 weeks. Healing and side-effects were recorded to be compared after 8 weeks. Results: In group A, the anal fissure was thoroughly healed within 53.3% of patients, moderately healed for 6.7% of patients and not healed in 25.8% of patients. Moreover, side-effects were noted in 15(46.9% patients (P= 0.482. Two (6.2% patients had intolerable headache and discontinued the study, 11 (34.3% patients suffered from headache and 2 patients (6.2% were reported to have orthostatic hypotension. In group B, healing occurred in 21(67.7% out of 31 patients and 1 (3.2% case of headache was noted(P= 0.0001. Conclusion: The present study has demonstrated that topical diltiazem can be preferable to GTN owing to the absence of side-effects.


    Madhu Lata


    Full Text Available OBJECTIVE: To compare the efficacy, associated side effects in short term as well as long term use of topical Diltiazem and topical GTN in the management of chronic anal fissure. MATERIAL AND METHODS: Out patients records of 231 patients with chronic anal fissure who reported to hospital from August 2011 to August 2014 and treated were randomly selected for both types of management of which 118 patients had received topical 2% diltiazem and 113 were treated with 0.2% glyceryl trinitrate topical ointment thrice daily for 6 weeks. They were assessed at the time of presentation, then at the end of 1st week, 3rd week and at the end of 6th week of treatment. Records of patients with anal fissure due to other diseases like inflammatory bowel disease, malignancy, sexually transmitted diseases, previous treatment with local ointment or surgery, patients who required anal surgery for any concurrent disease like hemorrhoids, pregnant women, patients with significant cardiovascular conditions and patients who did not turned up for follow up were excluded. Signs and symptoms and side-effects were noted at the given time. RESULTS: The study results are comparable to national figures and other studies. CONCLUSION: Topical application of both the ointments, 2% Diltiazem and 0.2% Glyceryl trinitrate observed to be quite effective in treatment of chronic fissure in Ano. However, topical Diltiazem is preferred to topical glyceryl trinitrate due to its lesser side effects and long term better control

  8. Effect of Diltiazem on Coronary Artery Flow and Myocardial Perfusion in Patients With Isolated Coronary Artery Ectasia and Either Stable Angina Pectoris or Positive Myocardial Ischemic Stress Test.

    Ozcan, Ozgur Ulas; Atmaca, Yusuf; Goksuluk, Huseyin; Akbulut, Irem Muge; Ozyuncu, Nil; Ersoy, Nedret; Erol, Cetin


    Isolated coronary artery ectasia (CAE) may be associated with stable or unstable coronary events despite the absence of epicardial coronary stenosis. Impaired coronary flow dynamics and myocardial perfusion have been demonstrated in stable patients with ectatic coronary arteries. We aimed to assess whether epicardial flow and tissue-level perfusion would be improved by diltiazem in myocardial regions subtended by the ectatic coronary arteries in patients with isolated CAE. A total of 60 patients with isolated CAE were identified of 9,780 patients who underwent elective coronary angiography. Patients were randomized to 5 mg of intracoronary diltiazem or saline. Coronary blood flow of the microvascular network was assessed using myocardial blush grade (MBG) technique. The thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count (TFC) were used to assess epicardial coronary flow. MBG (from 2.4 to 2.6, p = 0.02), TIMI flow grades (from 2.4 to 2.8, p flow grade; and from 35 to 33, p = 0.43 for TFC). Diltiazem provided amelioration of the altered coronary flow dynamics, which was suggested as the pathophysiological influence of CAE. In conclusion, the favorable effects of the diltiazem on myocardial perfusion were observed at both epicardial and tissue levels.

  9. Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

    Ismail, Basma; deKemp, Rob A; Croteau, Etienne; Hadizad, Tayebeh; Burns, Kevin D; Beanlands, Rob S; DaSilva, Jean N


    ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8-10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18-20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

  10. The effect of pH and Polymer type on Release of Diltiazem HCl from hydrophilic matrices

    J. Akbari, Ph.D.


    Full Text Available AbstractBackground and Purpose: Oral administrations have been used for many years as a main method comparing to other methods. Sustained release techniques have been a great interest recently. Matrix polymers are one of the ways used to prepare a sustained-release drug and are most widely used to prepare the controlled-release drugs. Cellulose derivatives are the most common ones. Solubilities of some drugs are pH-dependent due to their acidic or basic nature. Diltiazem Hydrochloride due to having a pH-dependent solubility is a suitable model to investigate the effect of pH and also to prepare pH-independent formulations.Materials and Methods: In the present study, an attempt was made to form pH-independent formulations using HPMC, lactose, CAP and organic acids in different ratios. The physicochemical properties of tablets prepared (including weight uniformity, hardness, tensile strength, friability and assay were investigated. Rate of drug release was studied using USP I at pH 1.2 and 7.2, and sampling was done in the time of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8. The drug release data were analyzed according to four kinetics models.Results: Drug release profile in acid free formulations showed that it was higher in the acidic medium. 50% replacement of HPMC with CAP and 1:1 ratio with drug release was pH-independent. Studying the formulations containing organic acids; citric acid and polymer with 1:1 and 2:1 ratios; ascorbic acid and polymer with 1:1 and 2:1 ratios and tartaric acid with 1:1 and 2:1 ratios showed their pH independent release characteristics.Conclusion: These results showed the effect of combination of polymers and organic acids on drug release and its kinetic. Thus, the micro-environmental conditions for the dissolution and diffusion of diltiazem HCl were almost kept constant. The release of diltiazem HCl from tablets composed of HPMC and organic acids was found to be pH-independent.

  11. Diltiazem como alternativa ao betabloqueador na angiotomografia de artérias coronárias Diltiazem as an alternative to beta-blocker in coronary artery computed tomography angiography

    Carlos Eduardo Rochitte


    Full Text Available FUNDAMENTO: A redução da frequência cardíaca (FC na angiografia por tomografia das artérias coronarianas (ATCCor é fundamental para a qualidade de imagem. A eficácia dos bloqueadores de cálcio como alternativas para pacientes com contraindicações aos betabloqueadores não foi definida. OBJETIVOS: Comparar a eficácia na redução da FC e variabilidade RR do metoprolol e diltiazem na ATCCor. MÉTODOS: Estudo prospectivo, randomizado, aberto, incluiu pacientes com indicação clínica de ATCCor, em ritmo sinusal, com FC>70bpm e sem uso de agentes que interferissem com a FC. Cinquenta pacientes foram randomizados para grupos: metoprolol IV 5-15 mg ou até FC≤60 bpm(M, e diltiazem IV 0,25-0,60mg/kg ou até FC≤60 bpm (D. Pressão arterial (PA e FC foram aferidas na condição basal, 1min, 3min e 5min após agentes, na aquisição e após ATCCor. RESULTADOS: A redução da FC em valores absolutos foi maior no grupo M que no grupo D (1, 3, 5min, aquisição e pós-exame. A redução percentual da FC foi significativamente maior no grupo M apenas no 1 min e 3 min após início dos agentes. Não houve diferença no 5 min, durante a aquisição e após exame. A variabilidade RR percentual do grupo D foi estatisticamente menor do que a do grupo M durante a aquisição (variabilidade RR/ FC média da aquisição. Um único caso de BAV, 2:1 Mobitz I, revertido espontaneamente ocorreu (grupo D. CONCLUSÃO: Concluímos que o diltiazem é uma alternativa eficaz e segura aos betabloqueadores na redução da FC na realização de angiografia por tomografia computadorizada das artérias coronarianas. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0BACKGROUND: Reducing heart rate (HR in CT angiography of the coronary arteries (CTACor is critical to image quality. The effectiveness of calcium channel blockers as alternatives for patients with contraindications to beta-blockers has not been established. OBJECTIVES: To compare the efficacy in the

  12. An Overview of Analytical Determination of Diltiazem, Cimetidine, Ranitidine, and Famotidine by UV Spectrophotometry and HPLC Technique

    Nighat Shafi


    Full Text Available This review article recapitulates the analytical methods for the quantitative determinations of diltiazem and three H2 receptor antagonists (cimetidine, ranitidine, and famotidine by one of the spectroscopic technique (UV spectrophotometery and separation technique such as high-performance liquid chromatography (HPLC. The clinical and pharmaceutical analysis of these drugs requires effective analytical procedures for quality control, pharmaceutical dosage formulations, and biological fluids. An extensive survey of the literature published in various analytical and pharmaceutical chemistry-related journals has been compiled in its review. A synopsis of reported spectrophotometric and high-performance liquid chromatographic methods for individual drug is integrated. This appraisal illustrates that majority of the HPLC methods reviewed are based on the quantitative analysis of drugs in biological fluids, and they are appropriate for therapeutic drug monitoring purpose.

  13. Design and evaluation of pH sensitive multi-particulate systems for chronotherapeutic delivery of Diltiazem hydrochloride

    Shivakumar H


    Full Text Available A pH sensitive multi-particulate system intended to approximate the chronobiology of angina pectoris is proposed for colonic targeting. The system comprising of Eudragit S-100 coated pellets was designed for chronotherapeutic delivery of diltiazem hydrochloride. The drug loaded core pellets were produced by aqueous extrusion spheronization technique using microcrystalline cellulose as a spheronizing aid and PVP K 30 as a binder. Different coat weights of Eudragit S-100 were applied to the drug loaded pellets in an automatic coating machine to produce the pH sensitive coated pellets. Scanning electron microscopy revealed that the core pellets were discrete, spherical, or oval with a slightly rough surface whereas the coated pellets were covered with a uniform and continuous acrylic film. Optical microscopic image analysis portrayed that the values of aspect ratio and pellet circularity were close to 1.0, indicating the core pellets were almost spherical in shape. The friability with glass spheres was below 1.0%, signifying the core pellets produced were sufficiently hard. In vitro dissolution studies of the coated pellets performed following pH progression method showed that the drug release from the coated pellets depended on the coat weights applied and pH of the dissolution media. Since, diltiazem hydrochloride is a drug, which exhibits a high solubility, it would be possible to minimize drug release from the coated pellets below pH 7.0, and effectively release the drug at colonic pH only with higher coat loads (15-20% weight gain.

  14. Comparison of captopril (0.5%) cream with diltiazem (2%) cream for chronic anal fissure: a prospective randomized double-blind two-centre clinical trial.

    Ala, S; Enayatifard, R; Alvandipour, M; Qobadighadikolaei, R


    This study compared the efficacy of topical captopril with topical diltiazem in the treatment of chronic anal fissure (CAF). Fifty patients aged between 15 and 75 years with CAF were included in a prospective randomized, double-blind clinical trial. They were randomly allocated to either captopril (0.5%) cream or diltiazem (2%) cream in a dose of 2 cm of cream on the perianal skin every 12 h for 8 weeks. The intensity of pain upon defaecation was evaluated every 10 days using a visual analogue scale. Bleeding on defaecation, pruritus and the presence of perianal irritation were also recorded before and during the trial. The average pain scores were lower in the diltiazem group on the 20th and 30th days. From day 40 to the end of the trial the average pain scores of the two groups did not differ significantly. There were no significant differences in bleeding or perianal irritation between the groups, but the incidence of pruritus was considerably higher in the captopril group, and at the end of the trial 45.8% of the patients in this group still suffered from pruritus. Topical captopril and diltiazem were found to be equally effective in the management of pain, bleeding and perianal irritation due to CAF, but due to the high incidence of pruritus observed with topical captopril this medication is not recommended for the treatment of CAF. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

  15. Differential blockade of rat α3β4 and α7 neuronal nicotinic receptors by ω-conotoxin MVIIC, ω-conotoxin GVIA and diltiazem

    Herrero, Carlos J; García-Palomero, Esther; Pintado, Antonio J; García, Antonio G; Montiel, Carmen


    Rat α3β4 or α7 neuronal nicotinic acetylcholine receptors (AChRs) were expressed in Xenopus laevis oocytes, and the effects of various toxins and non-toxin Ca2+ channel blockers studied. Nicotinic AChR currents were elicited by 1 s pulses of dimethylphenylpiperazinium (DMPP, 100 μM) applied at regular intervals.The N/P/Q-type Ca2+ channel blocker ω-conotoxin MVIIC inhibited α3β4 currents with an IC50 of 1.3 μM; the blockade was non-competitive and reversible. The α7 currents were unaffected.At 1 μM, ω-conotoxin GVIA (N-type Ca2+ channel blocker) inhibited by 24 and 20% α3β4 and α7 currents, respectively. At 1 μM, ω-agatoxin IVA (a P/Q-type Ca2+ channel blocker) did not affect α7 currents and inhibited α3β4 currents by only 15%.L-type Ca2+ channel blockers furnidipine, verapamil and, particularly, diltiazem exhibited a preferential blocking activity on α3β4 nicotinic AChRs.The mechanism of α3β4 currents blockade by ω-conotoxins and diltiazem differed in the following aspects: (i) the onset and reversal of the blockade was faster for toxins; (ii) the blockade by the peptides was voltage-dependent, while that exerted by diltiazem was not; (iii) diltiazem promoted the inactivation of the current while ω-toxins did not.These data show that, at concentrations currently employed as Ca2+ channel blockers, some of these compounds also inhibit certain subtypes of nicotinic AChR currents. Our data calls for caution when interpreting many of the results obtained in neurons and other cell types, where nicotinic receptor and Ca2+ channels coexist. PMID:10455287

  16. Sustained Release of Diltiazem Hydrochloride from Cross-linked Biodegradable IPN Hydrogel Beads of Pectin and Modified Xanthan Gum.

    Giri, T K; Choudhary, C; Alexander, A; Ajazuddin; Badwaik, H; Tripathy, M; Tripathi, D K


    Interpenetrating polymer network hydrogel beads of pectin and sodium carboxymethyl xanthan were prepared by ionotropic gelation with Al(+3) ions and covalent cross-linking with glutaraldehyde for sustained delivery of diltiazem hydrochloride. Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning colorimetry and scanning electron microscopy were used to characterise the hydrogel beads. The swelling of the hydrogel and the release of drug were relatively low in pH 1.2 buffer solutions. However, higher swelling and drug release were observed in pH 6.8 buffer solutions. The carboxyl functional groups of hydrogels undergo ionisation and the osmotic pressure inside the beads increases resulting in higher swelling and drug release in higher pH. The release of drug depends on concentration of polymer, amount and exposure time of cross-linker and drug content in the hydrogel matrices. The present study indicated that the hydrogel beads minimised the drug release in pH 1.2 buffer solutions and to prolong the drug release in pH 6.8 buffer solutions.

  17. Sustained release of diltiazem hydrochloride from cross-linked biodegradable IPN hydrogel beads of pectin and modified xanthan gum

    T K Giri


    Full Text Available Interpenetrating polymer network hydrogel beads of pectin and sodium carboxymethyl xanthan were prepared by ionotropic gelation with Al +3 ions and covalent cross-linking with glutaraldehyde for sustained delivery of diltiazem hydrochloride. Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning colorimetry and scanning electron microscopy were used to characterise the hydrogel beads. The swelling of the hydrogel and the release of drug were relatively low in pH 1.2 buffer solutions. However, higher swelling and drug release were observed in pH 6.8 buffer solutions. The carboxyl functional groups of hydrogels undergo ionisation and the osmotic pressure inside the beads increases resulting in higher swelling and drug release in higher pH. The release of drug depends on concentration of polymer, amount and exposure time of cross-linker and drug content in the hydrogel matrices. The present study indicated that the hydrogel beads minimised the drug release in pH 1.2 buffer solutions and to prolong the drug release in pH 6.8 buffer solutions.

  18. Development and characterization of sustain release gastro retentive floating microsphere of diltiazem hydrochloride for the treatment of hypertension

    Mangal S Panwar


    Full Text Available Gastroretentive drug delivery systems are the systems, which are retained in the stomach for a longer period and thereby improve the bio-availability of drugs. Diltiazem hydrochloride (DTZ HCl, is a calcium channel blocker, an antihypertension and antianginal drug, DTZ HCl undergoes an extensive biotransformation, mainly through cytochrome P-450 CYP3A, which results in <4% of its oral dose being excreted unchanged in urine. Suffers from poor bio-availability (~30-40% owing to an important first pass metabolism. It has an elimination half-life of 3.5 h and an absorption zone from the upper intestinal tract. Thus, the present work is aimed to formulate sustain release floating microsphere of DTZ HCl for gastroretentive drug delivery system. Floating microsphere were prepared using nonaqueous solvent evaporation method using polycarbonate, chitosan, ethyl cellulose, hydroxypropyl methycellulose and acrycoat as materials in various quantities, in varying ratio to formulate 20 formulations of the floating microsphere. Observations of all formulations for physical characterization had shown that, all of them comply with the specification of official pharmacopoeias and/or standard reference. It was observed that microsphere of batch F3 followed the results obtained, it was concluded that the formulation 98.72% F3 is the best formulations as the extent of drug release was found to be around 99.81% at the desired time 12 h.

  19. Pluronic lecithin organogel (PLO) of diltiazem hydrochloride: effect of solvents/penetration enhancers on ex vivo permeation.

    Parhi, Rabinarayan; Suresh, Podilam; Pattnaik, Subasini


    In the present study, pluronic lecithin organogel (PLO) of diltiazem hydrochloride (DZH) was developed by taking different ratios of organic phase to aqueous phase (1:3, 1:4, and 1:5) with varying concentration of soya lecithin (20, 30, and 40 % w/w) in organic phase (isopropyl myristate, IPM) and pluronic (20, 25, and 30 % w/w) in aqueous phase, respectively, and characterized for in vitro parameters and ex vivo permeation study. The results of in vitro parameters were found to be within permissible limit and all the PLOs were physically stable at refrigeration and ambient temperature. The influence of phase ratio and different concentrations of soya lecithin on DZH release from the PLOs was found to be significant (p < 0.05), whereas the influences of different concentrations of pluronic were insignificant. The effect of different solvents/penetration enhancers viz. IPM, propylene glycol (PG), dimethyl sulphoxide (DMSO), and D-limonene, in combination and alone, on the permeation of DZH across the dorsal skin of rat was studied. Among all, formulation containing IPM (PLO6) exhibited highest flux of 147.317 μg/cm(2)/h. Furthermore, histopathology section of treated skin sample illustrated that lipid bilayer disruption was the mechanism for the DZH permeation. The above results indicated that PLO6 may serve as a promising alternative delivery system for DZH in the effective treatment of hypertension.

  20. Some variables affecting the characteristics of Eudragit E-sodium alginate polyelectrolyte complex as a tablet matrix for diltiazem hydrochloride.

    Yusif, Rehab Mohammad; Abu Hashim, Irhan Ibrahim; El-Dahan, Marwa Salah


    Eudragit E (EE)-sodium alginate (SA) polyelectrolyte complexes (PECs) were prepared at pH 4 and 5.8 using sodium alginate of high (SAH) and low viscosity (SAL). The optimum EE-SA complexation mass ratio was determined using viscosity measurements. Interactions between EE and SA in PECs were characterized by Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Diltiazem hydrochloride (DTZ HCl) tablets were prepared using the prepared EE-SA PECs and their physical mixtures at different ratios as matrices. Tablets were evaluated for swelling characteristics and in vitro drug release. Tablets containing EE-SAH physical mixtures of ratios (1.5:1 and 1:3) as matrices were effective in achieving sustained release of DTZ HCl, where the percent drug released was significantly (p < 0.05) decreased compared to that from tablets either containing the same ratios of EE-SAL physical mixtures or the preformed EE- -SAH and EE-SAL PECs.

  1. Modulation of drug release rate of diltiazem-HCl from hydrogel matrices of succinic acid-treated ispaghula husk.

    Gohel, M C; Amin, A F; Chhabaria, M T; Panchal, M K; Lalwani, A N


    The feasibility of using succinic acid-treated ispaghula husk in matrix-based tablets of diltiazem-HCl was investigated. The sample prepared using 4:1 weight ratio of ispaghula husk to succinic acid showed improved swelling and gelling. A 3(2) factorial design was employed to investigate the effect of amount of succinic acid-treated ispaghula husk and dicalcium phosphate (DCP) on the percentage of the drug dissolved in 60, 300, and 480 min from the compressed tablets. The results of multiple linear regression analysis revealed that the significance of the amount of succinic acid-treated ispaghula husk was greater in magnitude than that of the amount of DCP in controlling the drug release. Acceptable batches were identified from a contour plot with constraints on the percentage drug released at the three sampling times. A mathematical model was also evolved to describe the entire dissolution profile. The results of F-test revealed that the Higuchi model fits well to the in vitro dissolution data. The tablets showed considerable radial and axial swelling in distilled water. Succinic acid-treated ispaghula husk can be used as an economical hydrophilic matrixing agent.

  2. Vasorreactividad a adenosina en los pacientes con hipertensión pulmonar arterial: Prevalencia y respuesta clínica, funcional y hemodinámica al tratamiento con diltiazem Acute vasodilatador test using adenosine in patients with pulmonary arterial hypertension: Prevalence and clinical, functional and hemodynamic response after diltiazem treatment



    Full Text Available La Hipertensión Pulmonar Arterial (HAP es una entidad grave y progresiva. El estudio hemodinámica (EH permite certificar el diagnóstico y evaluar la vasorreactividad mediante adenosina. Los pacientes vaso-reactivos podrían responder a terapia con diltiazem. No existe información nacional al respecto. En nuestro programa todo paciente con sospecha de HAP es sometido a EH diagnóstico y de vasorreactividad. Los positivos son tratados con diltiazem y seguidos semestralmente según capacidad funcional (CF y con test de caminata. Al 6º mes se efectúa un 2º EH. Entre 2003-2008, 6/54 (11% de los pacientes con HAP fueron vasorreactivos. Todas mujeres, 45 ± 14 años, 4 con HPA idiopática, 4 en CFIII y 2 en CFII. A los 2 años, todos mejoraron clínicamente. La distancia recorrida aumentó significativamente en los meses 12 y 24 en 83 y 87 m respectivamente. Todas las variables hemodinámicas mejoraron. La terapia con diltiazem es efectiva en los pacientes vaso-reactivos lo que justifica usar el test de vasorreactividad.Pulmonary arterial hypertension (PAH is a severe and progressive disease. Invasive hemodynamic study (HS is required to confirm the diagnosis of PAH and to perform the vasodilator test (VT with adenosine. Vasodilator acute responders (VAR may have a sustained benefit with diltiazem. There is not national information regarding these issues. All patients with probable PAH were evaluated with HS and VT. VAR were treated with diltiazem and followed up with functional class score (FC and 6 minute walk test. After 6 months, a second HS was performed. Results: Between 2003 and 2008, 6/54 (11% were VAR. All were women, 45 ± 14 years oíd, 4 with idiopathic PAH, 4 in FCIII and 2 in FCII. After two years of treatment, all patients clinically improved. Walked distance significantly increased by 83 and 87 m at month 12 and 24 respectively. Hemodynamic parameters also improved. Therapy with diltiazem is effective in VAR patients supporting

  3. Calcificación idiopática de ganglios basales (síndrome de Fahr y discinesias tardías tratadas con Diltiazem.

    E Moral del Olmo


    Full Text Available Se describe un caso de discinesias bucolinguo-masticatorias en un Síndrome de Fahr (Calcificación Idiopática de los ganglios basales, Trastornos del Movimiento, Anormalidades neuropsiquiátricas y Metabolismo del fósforo y calcio normal, revisándose la literatura y discutiéndose la buena respuesta de ambos, Síndrome de Fahr y discinesia tardía, al tratamiento con diltiazem a dosis de 90 mg/día.

  4. Diltiazem enhances food intake and gastrointestinal function in rats%地尔硫卓增强大鼠的摄食及胃消化功能

    王丽娜; 李胜利; 李创宏; 张晨旭; 袁慧; 李新平


    The present study was to investigate the effects of diltiazem, a ghrelin receptor agonist, on food intake and gastrointestinal functions in rats. Rats were intragastrically administered with diltiazem solution (daily 16 mg/kg, 30 mg/kg or 80 mg/kg, 30 d), and the rats with saline as control. To detect the effects of diltiazem on food intake and body weight, the average daily food intake and body weight were recorded, and the serum metabolic hormones of plasma growth hormone (GH) and neuropeptide Y (NPY) were tested by radioimmunoassay. By means of the spectrophotometer and the modified Men's method, the effects of diltiazem on rat's gastrointestinal function and pepsin activity were tested, respectively. In addition, the gastric juice's acidity of rats was detected by titra-tion and the secretion amount was calculated. The results showed that the food intake and body weight were maximally promoted by diltiazem at the dose of 30 mg/kg daily (30 d). The average daily food intake and body weight were significantly increased, and the serum concentrations of GH and NPY were also remarkably increased in diltiazem-treated groups compared with those in control group. The results also showed that the gastric emptying rate, gastric acid secretion and the activity of pepsin were significantly increased in diltiazem-treated group compared with those in control group. These results suggest that diltiazem induces enhancement of eating, in the same time, it can also stimulate the gastrointestinal function and regulate growth of rat.%本文旨在研究ghrelin受体激动剂地尔硫卓对大鼠摄食及胃肠功能的影响.实验通过给大鼠灌胃低、中、高浓度(每天16 mg/kg、30 mg/kg或80 mg/kg,30d)的地尔硫卓溶液,灌胃等体积生理盐水为对照组,记录大鼠日均摄食量和日均体重增加量,运用放射免疫法测定大鼠血清中生长激素(growth hormone,GH)及神经肽Y(neuropeptide Y,NPY)的浓度,以检测地尔硫卓对大鼠摄食量及

  5. A novel micellar per aqueous liquid chromatographic method for simultaneous determination of diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum.

    Li, Ning; Li, Chun-lan; Lu, Ning-wei; Dong, Yu-ming


    A novel micellar per aqueous liquid chromatographic method was investigated to simultaneously determine diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum. Separation and determination of the analytes were performed on a Pinnacle II Cyano column as the stationary phase using the mobile phase consisted of aqueous solution (4.15×10(-2) mol/L sodium dodecyl sulfate and 0.02 mol/L sodium dihydrogen phosphate) with 10% (v/v) of 1-propanol at pH 7.0. This method was validated by linearity, lower limit of quantification, extraction recovery, stability, precision, and accuracy. The main analytical parameters were linearity (r>0.9950), intra- and inter-day precisions (intra-day RSD 2.2-3.5%, and inter-day RSD 3.7-9.5%), lower limit of quantification (20 ng mL(-1) for isosorbide mononitrate, metoprolol tartrate and diltiazem hydrochloride). The extraction recovery was 63.3% (0.1 μg/mL), 65.6% (1.0 μg/mL), and 69.5% (25 μg/mL) for isosorbide mononitrate; 65.1% (0.1 μg/mL), 69.5% (1.0 μg mL) and 73.5% (2.5 μg/mL) for metoprolol tartrate; 67.1% (0.1 μg/mL), 68.8% (1.0 μg/mL) and 73.8 % (2.5 μg/mL) for diltiazem hydrochloride. The relative error of stability was <6.4% at the room temperature for 24h, <3.8% at 4 °C for 1 week, <4.6% at -20 °C for 1 month, and <6.7% for freeze/thaw cycles (n=3). The results indicated that the proposed method was rapid, sensitive, and accurate for determination of the three antianginal drugs in human serum. The possible separation mechanism of the method was also discussed, and a model of separation mechanism for the analytes was established.

  6. Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

    Meyer Rebecca C


    Full Text Available Abstract Background Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood. Methods We used Western blot procedures to test whether in vivo TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits α1, α2, α3, α5, β3, and γ2 at 3 h, 6 h, 24 h, and 7 days post-injuy. We then used pre-injury injections of MK-801 to block calcium influx through the NMDA receptor, diltiazem to block L-type voltage-gated calcium influx, or diazepam to enhance chloride conductance, and re-examined the protein expressions of α1, α2, α3, and γ2, all of which were altered by TBI in the first study and all of which are important constituents in benzodiazepine-sensitive GABA-A receptors. Results Western blot analysis revealed no injury-induced alterations in protein expression for GABA-A receptor α2 or α5 subunits at any time point post-injury. Significant time-dependent changes in α1, α3, β3, and γ2 protein expression. The pattern of alterations to GABA-A subunits was nearly identical after diltiazem and diazepam treatment, and MK-801 normalized expression of all subunits 24 hours post-TBI. Conclusions These studies are the first to demonstrate that GABA-A receptor subunit expression is altered by TBI in vivo, and these alterations may be driven by calcium-mediated cascades in hippocampal neurons. Changes in GABA-A receptors in the hippocampus after TBI may have far-reaching consequences considering their essential importance in maintaining inhibitory balance and their extensive impact on neuronal function.

  7. Novel buccal adhesive tablets using Aloe vera L and Sinapis alba--a promising option for improved bioavailability of diltiazem hydrochloride.

    Sudhakar, Yajaman; Bandyopadhyay, A K


    In the current investigation, white mustard mucilage from whole seeds of Sinapis alba was evaluated for its physical properties and compared with the other mucoadhesive polymers such as hydroxy propyl methylcellulose 5Cps and Carbopol 934P. Further, methanol precipitable solids from whole leaves of Aloe Vera L were used as permeation enhancer. To achieve improved bioavailability of diltiazem, novel buccal adhesive tablets (NBATs) in cup and core fashion designed to achieve unidirectional release towards mucosa were prepared in a three-stage process using specially fabricated punches. The adhesive cups were studied for its shear, tensile, and peel strengths by specially designed apparatus using excised ruminant and porcine buccal mucosa as model substrates. Ex vivo permeation studies in a Franz diffusion cell were conducted through porcine buccal mucosa. Fourier transform infrared spectroscopy studies and differential scanning calorimetry thermographs showed no remarkable interactions. Histopathological studies showed no remarkable damage of buccal mucosa by the NBATs. In vivo studies were conducted on anaesthetized male New Zealand albino rabbits, estimated by reversed-phase high-performance liquid chromatography, and the pharmacokinetics were compared with the oral and intravenous bolus injection. NBATs exhibited a Cmax 74.6 ng/mL, Tmax 3.5 h, t(1/2) 4.36 h. The NBATs prevented salivary scavenging effect and exhibited 82.1% bioavailability.

  8. A randomized, single-center double-blinded trial on the effects of diltiazem sustained-release capsules in patients with coronary slow flow phenomenon at 6-month follow-up.

    Lun Li

    Full Text Available OBJECTIVE: The aim of this study is to observe the chronic effects of diltiazem release capsules on patients with coronary slow flow (CSF phenomenon. METHODS: From 2004 to 2009, 80 consecutive patients with chest pain and normal coronary arteries evidenced by coronary angiography and CSF were included in this randomized, double-blind, placebo-controlled trial. CSF patterns were evaluated by the corrected TIMI frame count. Patients were randomly assigned at 1:1 ratio to diltiazem sustained-release capsules treatment group (Dil, 90 mg twice daily or placebo control group. Holter, liver and kidney function, treadmill exercise test, coronary angiography and left ventricular angiography were measured at baseline and after 6 months. The incidence of cardiovascular events (re-admission or progress in coronary heart disease, myocardial infarction, malignant arrhythmia or cardiac death was evaluated during the 6 months follow up. RESULTS: Thirty-nine patients in control and 40 patients in Dil group completed the 6 months follow-up. There was no medication induced drug withdraw during follow up. Left ventricular ejection fraction was similar between the 2 groups at baseline and during follow up. Heart rate was significantly lower in Dil group than in control group and there was no symptomatic bradycardia and II and III degree atrioventricular conduction block in both groups. Significant improvement was observed in the onset of chest pain, treadmill exercise test and coronary blood flow in Dil group while these parameters remained unchanged in control group at the end of 6 months follow up. The incidence of cardiovascular events was similar between the two groups. CONCLUSION: Diltiazem slow-release capsules improved coronary blood flow and alleviated angina in patients with CSF. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TCC-11001864.

  9. 地尔硫卓在颅内动脉狭窄支架置入术中的应用%Application of diltiazem in stent implantation for intracranial artery stenosis

    潘晓华; 刘国荣; 李月春; 王宝军; 崇奕; 姜长春


    目的:对比分析地尔硫卓和尼莫通在颅内动脉狭窄支架置入术中、术后预防和治疗血管痉挛以及对血压调控的疗效。方法:选择2013年3月至2014年12月间经全脑血管造影后明确颅内动脉狭窄的缺血性脑血管病,需进行支架置入术治疗的患者84例,按照随机分配的原则分为地尔硫卓组和尼莫通组,术中及术后24 h给予上述两种药物微量泵入,术中若出现血管痉挛,地尔硫卓组给予微导管注射地尔硫卓缓解痉挛,而尼莫通组则加大尼莫通泵入量,若术中出现血压升高,地尔硫卓组给予静脉注射地尔硫卓,尼莫通组给予加大尼莫通泵入量。记录两组药物对于血管痉挛的预防效果,以及出现血管痉挛后的治疗效果及痉挛缓解的时间,出现血压升高后,两组的降压效果及血压下降的时间,以及药物的不良反应。术前始至术后24 h给予持续心电、血压、血氧监测。结果:两组患者在预防血管痉挛方面差异无统计学意义,但在术中出现血管痉挛及血压升高时,地尔硫卓组在解除血管痉挛及降压效果及时间方面优于尼莫通组。结论:地尔硫卓可用于颅内动脉狭窄支架置入术中及术后预防血管痉挛。地尔硫卓在术中解除血管痉挛及迅速控制血压方面疗效优于尼莫通组。%Objective:To comparatively analyze the efficacy of Diltiazem and Nimodipine in the prevention and treatment of vasospasm in stent implantation for intracranial artery stenosis during and after the operation , and in the regulation on blood pressure .Method:Intracranial artery ste-nosis patients with ischemic cerebrovascular disease verified by cerebral angiography were consecutively reviewed from March 2013 to March 2014. Among all of them, 84 patients who had the necessity to be given the treatment of stent implantation were randomly assigned into the Diltiazem group and the Nimotop group

  10. Clinical analysis of diltiazem hydrochloride combined with nitroglycerin in the treatment of unstable angina pectoris%盐酸地尔硫和硝酸甘油联合治疗不稳定型心绞痛的效果

    柳青; 李慧芳; 刘丽凤; 董瓅瑾


    Objective To observe the efficacy of injection of diltiazem hydrochloride combined with nitroglycerin in the treatment of unstable angina pectoris. Methods 101 patients with unstable angina pectoris in our hospital were randomly divided into test group (re =51) and control group (re = 50) . The test group was administered with diltiazem hydrochloride in combination with nitroglycerin while the control group was given nitroglycerin alone. After 48 hours, the two groups of patients were observed and compared in terms of anginal attacks, heart rate, Prt, Qrto, 01 interval time, blood pressure, myocardial oxygen consumption index, blood routine, blood biochemical index. JvesultS Ihere was no death, no complications or significant arrhythmias and hemodynamic changes. After treatment, the heart rate and myocardial oxygen consumption index of the test group decreased more significantly ( P < 0. 05 ) than in the control group. PR interval and QT interval of the test group were slightly longer than those of the control group, but without significant difference. Conclusion Injection of diltiazem hydrochloride combined with nitroglycerin in the treatment of unstable angina pectoris patients induces no serious adverse rectons and can effectively relieve angina,significantly reduce myocardial oxygen con- sumption and provide better myocardial protection.%目的 观察注射用盐酸地尔硫和硝酸甘油联合治疗不稳定型心绞痛的临床疗效.方法 选择我院住院的101例不稳定型心绞痛患者,随机分为实验组(n=51) 和对照组( n=50),对照组单用硝酸甘油,实验组应用硝酸甘油和盐酸地尔硫联合治疗.观察并比较两组患者用药48 h对心绞痛发作次数、心率、PR间期、QRS时限、QT间期、血压、心肌耗氧指标、血常规、血生化等指标.结果 两组均无并发症,无死亡,并且血流动力学的改变及心律失常的发生率差别均无统计学意义.实验组治疗后心率

  11. Effect of phentolamine and diltiazem on pulmonary artery hypertension in exacerbations of chronic obstructive pulmonary disease patients with chronic cor pulmonale%酚妥拉明联合地尔硫(卓)对慢性肺心病急性加重期肺动脉高压的疗效观察

    付松泉; 王莉; 刘圳奋; 路婷; 王丽红


    Objective To evaluate the effects of phentolamine and diltiazem on pulmonary artery hypertension in exacerbations of patients with chronic cor pulmonale caused by chronic obstructive pulmonary disease(COPD). Methods One hundred and twenty-five patients with COPD compicated with cor pulmonale were randomly divided into routine group ( n = 35), phentolamine group( n = 30), diltiazem group( n = 30) and phentolamine+ diltiazem group( n = 30). Four groups were given routine treatment and phentolamine group was given phentolamine(10 mg) intravenous infusion by micro pump(0.4- 0.6 mg/h), diltiazem group was given oral diltiazem supplement (30 mg, three times a day),phentolamine+ diltiazem group was given phentolamine (10 mg) intravenous infusion by micro pump and oral diltiazem supplement (30 mg, three times a day). Change of brain natriuretic peptide(BNP) and mean artery pulmonary artery pressure(mPAP) after 14 days were measured. Results In treatment groups,BNP and mean pulmonary artery pressure decreased significantly after 14 days of treatment compared with those before treatment in the same group and routine group (all P <0.05). mPAP in routine group(55.2±6.5)mmHg vs (48.6±8. 2) mmHg( P <0. 05),BNP (602.9± 96. 6) pg/L vs (416.2 ± 43.7) pg/L( P <0.05) ; mPAP in phentolamine group(57. 3 ± 6.8) mmHg vs (42.1±9.6) mmHg( P <0. 05),BNP(628.2±89.1) pg/L vs (356.1±37.9) pg/L( P <0.01);mPAP in diltiazem group(56.2±6.1) mmHg vs (43.4±8. 9) mmHg( P <0.05) ,BNP(612. 7±87. 4) pg/L vs (382. 9±37.5) pg/L( P < 0.01) ; mPAP in phentolamine+diltiazem group(58.3±6.7) mmHg vs (30.5±7.7) mmHg( P<0.01) ,BNP(644. 6± 98.3) pg/L vs (286.5±33.4) pg/L( P <0.01). Further extremely significant downregulation of BNP expression and mean pulmonary artery pressure were observed in phentolamine and diltiazem group after the following 14 days'treatment. Conclusion Phentolamine and diltiazem can adjust the synthesis and secretion of BNP,and the treatment can

  12. 银丹心脑通软胶囊联合地尔硫(草)治疗冠状动脉痉挛的临床观察%Clinical therapeutic effect of Yindan Xin Nao Tong combined with diltiazem in treating coronary artery spasm

    何建新; 徐丹苹


    Objectives To observe the clinical therapeutic effect of Yindan Nao Xin Tong combined with diltiazem in treating coronary artery spasm (CAS). Methods A total of 68 patients were randomly divided into 2 groups (36 patients in treatment group and 32 in control group). Patients of both groups were treated with diltiazem, antiplatelet medicine and statins after being diagnosed as CAS. Treatment group was treated with Yindan Xin Nao Tong along with the medicines taken by control group. Yindan Xin Nao Tong was 0.4 g per pill, taken orally 3 pills per dose and 3 doses per day. After being treated for 3 months, a followed up was conducted to both groups to record the frequency of chest pain and distress, as well as rechecking the level of blood lipids and lab data of adenosine 201 nuclide myocardial perfusion imaging. Results After 3 months, the occurrence rates of chest pain and the levels of blood lipids in treatment group were significantly better than before treating and control group (P<0.05). Result of adenosine 201 nuclide myocardial perfusion imaging indicated that significant effective rate and total effective rate of treatment group were significantly higher than those of control group [50.00% (18/36) vs. 18.75% (6/32) , P<0.05; 97.22% (35/36) vs. 87.50% (28/32), P <0.05]. Conclusions Yindan Xin Nao Tong combined with diltiazem in treating CAS is safe, reliable and worthy of further study.%目的 观察银丹心脑通软胶囊联合地尔硫(革)治疗冠状动脉痉挛的临床疗效.方法 将68例患者按完全随机化分组方法分为治疗组36例和对照组32例,两组患者在诊断为冠状动脉痉挛后开始以地尔硫革、抗血小板及他汀类药物调脂治疗为主的联合治疗.治疗组在对照组基础上加服银丹心脑通软胶囊,每日3次,每次3粒口服,规格0.4 g每粒.3个月后随访,记录患者的胸痛或胸闷发作的频次(次/个月);复查血脂水平;复查腺苷201核素灌注心肌显像负荷试验.结果

  13. Bioadhesive drug delivery system of diltiazem hydrochloride for ...

    1Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, 3Department of ... (including oral/buccal, nasal, vaginal or rectal) ... membrane and drug delivery device for extended .... The time required for complete.

  14. Спектрофотометриски, потенциометриски и HPLC квантитативни постапки за определување на Diltiazem во Aldizem препарати

    Gjorgjeska, Biljana


    Diltiazem е антималарик,антихипертензив и антиангиналник од групата на калциумовите антагонисти, деривати на бензодиазепините. Извршено е одрдување на Diltiazem во Aldizem препаратите со спектрофотометриско мерење на абсорбанцата во метанол на 242nm, потенциометриска титрација со перхлорна киселина во неводена средина, реверзно фазна HPLC во колона од типот Ultrapac LiChrosorb RP 18,5 микрометри со UV детекција....

  15. The Effect of Diltiazem and Nifedipine on the Rate of Metabolism of Midazolam


    is more selective for blocking the calcium channels in smooth muscle and therefore has a less depressant effect on the heart. ( Katzung , 1998). Calcium...divided into three different subtypes, ( L , T and N ). The L-type calcium voltage sensitive channel predominates in cardiac and smooth muscle ( Katzung ...nanometers under spectral analysis, which is how it derives its name ( Katzung 1998). The P-450 enzymes are the major catalysts of drug biotransformation


    Gupta Khemchand


    Full Text Available The major objective of this study was to use pectin (high methoxylated in combination with guar gum to control the burst effect by promoting gelation and also to examine the release pattern of guar-pectin matrices. Guar gum has long been used to prepare matrix tablets. But its uncontrolled rate of hydration and initial slow gelling results into undesirable burst effect. Various combination of drug: polymer ratios were tried, out of which the ratio 1:2 yielded best results. The ratio of gaur: pectin in the polymer blend which gave best results was found to be 1:1.The effects of various diluents on the drug release were also determined at the same polymer level. The matrix tablet were prepared by wet granulation method using distilled water, were subjected to physical characterization and in vitro release studies. Release kinetics was evaluated by using USP apparatus type II at 100 rpm in 900 ml of acidic dissolution medium ( pH 1.2 for two hours, followed by 900 ml phosphate buffer dissolution medium (pH 6.8.The in-vitro drug release study revealed that (batch F3 combining pectin with guar gum sustained the drug release for 10 hours (87.54±2.36% release. Fitting the in-vitro drug release data to Korsmeyer-Peppas equation indicated that diffusion along with erosion could be the mechanism of drug release. At the same polymer level the order of release fell in the following manner lactose, avicel pH 101, starch and Emcompress®. It was concluded from the study that guar-pectin binary polymeric matrix system is an interesting alternative for preparing sustained release tablets.

  17. Formulation and In vitro/In vivo Evaluation of Sustained Release ...



    Jul 15, 2013 ... Purpose: To develop and optimise sustained release (SR) matrix tablets of diltiazem ... Diltiazem HCl is a water soluble calcium-channel ... K15M CR, on contact with dissolution media or ..... Government of India, New Delhi.

  18. Drug: D03830 [KEGG MEDICUS

    Full Text Available D03830 Drug Diltiazem malate (USAN); Tiamate (TN) C22H26N2O4S. C4H6O5 548.1829 548.6053 D03830...036 Calcium channel blocking drugs map07037 Antiarrhythmic drugs Anatomical Therapeutic Chemical (ATC) classification [BR:br0830...LOCKERS WITH DIRECT CARDIAC EFFECTS C08DB Benzothiazepine derivatives C08DB01 Diltiazem D03830... Diltiazem malate (USAN) USP drug classification [BR:br08302] Cardiovascular Agents Calcium Cha...nnel Blocking Agents Diltiazem D03830 Diltiazem malate (USAN) Target-based classification of drugs [BR:br083

  19. Curative effect of diltiazem for treatment of patients with ischemic cardiomyopathy and angina pectoris%地尔硫(艹卓)革治疗缺血性心肌病患者心绞痛疗效观察

    申文祥; 牛锁成; 党瑜华


    目的 探讨口服地尔硫(艹卓)治疗缺血性心肌病(ICM)患者心绞痛(ICM-AP)的临床疗效.方法 72例ICM-AP患者随机分为两组,对照组30例给予常规抗心绞痛、纠正心衰治疗,地尔硫(艹卓)组42例在以上常规治疗基础上给予地尔硫(艹卓)15~30 mg,每日4次,分别于9:00、15:00、21:00、3:00时间点口服.疗程2周.对比观察两组心绞痛改善程度和心电图变化,以及药物对心率、血压和心功能的影响.结果 地尔硫(艹卓)组治疗心绞痛的临床总有效率高于对照组(P<0.05),两组心功能改善等级比较差异无统计学意义(P>0.05),两组血压比较差异无统计学意义(P>0.05),地尔硫(艹卓)组心率低于对照组(P<0.05).结论 口服地尔硫(艹卓)治疗ICM-AP安全有效.

  20. Effect of diltiazem on the time-response relationship of vecuronium%地尔硫(艹卓)对维库溴铵肌松时效的影响

    强铭; 周钦海; 傅诚章


    目的:探讨地尔硫(艹卓)对维库溴铵肌松时效的影响.方法:30例ASA Ⅰ~Ⅱ级择期手术的全麻患者,随机分为3组,每组10例.3组患者均行静脉快速诱导气管内插管,Ⅰ组静注芬太尼5 μg/kg,异丙酚2 mg/kg,和维库溴铵0.1 mg/kg(2×ED95)诱导,气管插管;Ⅱ组先缓慢静注地尔硫(艹卓)0.05 mg/kg,3 min后静注与Ⅰ组同等剂量的诱导用药,气管插管.Ⅲ组先缓慢静注地尔硫(艹卓)0.1 mg/kg,3 min后静注与Ⅰ组同等剂量的诱导用药,气管插管.Ⅱ、Ⅲ组中,静注地尔硫(艹卓)3 min后收缩压下降15%以上的病例不纳入研究,每组各选10例参与研究.3组均以异丙酚维持麻醉,用Biometer加速度仪监测肌松情况.结果:Ⅰ组的无反应期为(26.5±5.5)min,Ⅱ、Ⅲ组的无反应期分别为(35.2±4.2)min和(36.4±7.2)min,Ⅱ、Ⅲ组明显延长于Ⅰ组(P<0.01),而Ⅱ组与Ⅲ组间无统计学差异;Ⅰ组的临床作用时间为(37.4±5.8)min,Ⅱ、Ⅲ组的临床作用时间分别为(48.5±4.4)min和(54.5±8.9)min,Ⅱ、Ⅲ组显著长于Ⅰ组(P<0.01),Ⅱ组短于Ⅲ组,但无统计学意义:起效时间与恢复指数各组间无统计学差异.结论:地尔硫(艹卓)能延长维库溴铵的无反应期与临床作用时间.

  1. Secondary prevention with calcium antagonists after acute myocardial infarction

    Hansen, J F


    Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival...

  2. Capsicum

    ... concern. Some medications for high blood pressure include captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), ramipril (Altace), ... drugs. Some medications for high blood pressure include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem ( ...

  3. Effects of calcium antagonists on hypertension and diastolic function



  4. In vitro and in vivo effects of R023-6152 on heart mitochondrial calcium and energy metabolism.

    Medh, J D; Rex, K A; Benedict, C R; Sordahl, L A


    Previous studies have shown that Ca2+ channel antagonists in all chemical classes can inhibit Na(+)-induced CA2+ release from mitochondria. The effects of R023-6152, a new thiazepinone Ca2+ channel antagonist, on isolated rabbit heart mitochondrial Ca2+ transport and respiratory activity were compared with those of diltiazem. Heart mitochondria were also isolated and assayed from dogs treated in vivo with either R023-6152 or diltiazem. The results indicate that R023-6152 produces half-maximal inhibition of Na(+)-induced Ca2+ release from isolated mitochondria at relatively the same concentrations (10-30 microM) as diltiazem but also produces inhibition of mitochondrial Ca2+ uptake and state 3 respiration at concentrations (25-100 microM), at which diltiazem has no effect. The greater lipophilicity of R023-6152 in gaining access to and inhibiting the phosphate transporter in the mitochondrial membrane as compared with that of diltiazem may explain these results. Heart mitochondria isolated from dogs treated with diltiazem and R023-6152 exhibited lower rates of state 3 respiration as compared with controls. We suggest that this may result from a reduction in transsarcolemmal Ca2+ flux causing a down-regulation in mitochondrial dehydrogenase activity and not from any direct intracellular effects of the two drugs.

  5. Anti-ischaemic efficacy of L-propionylcarnitine--a promising novel metabolic approach to ischaemia?

    Bartels, G L; Remme, W J; Holwerda, K J; Kruijssen, D A


    L-propionylcarnitine, a naturally occurring derivative of L-carnitine, essential for mitochondrial fatty acid transport and high-energy phosphate exchange, acutely reduces myocardial ischaemia and improves ischaemia-induced cardiac dysfunction following intravenous administration. This randomized, crossover study was designed to compare the long-term anti-ischaemic effects of oral L-propionylcarnitine with diltiazem in patients with stable, exercise-induced angina. After a 2-week washout phase of anti-anginal medication and a 2-week single-blind placebo period, 46 patients were included in the study, 23 of whom received 1500 mg L-propionylcarnitine daily for 6 weeks, and 23 diltiazem (180 mg daily for 3 weeks, followed by 360 mg daily for 3 weeks), crossing over to the other treatment after a 1-week washout period. Three patients on L-propionylcarnitine and two on diltiazem discontinued. Both treatments resulted in comparable exercise duration (582 +/- 35 s and 588 +/- 33 s, mean +/- SEM), time to 0.1 mV ST depression (436 +/- 38 s and 465 +/- 36 s), and increase in time to 0.1 mV ST depression from baseline (20% and 28%), L-propionylcarnitine and diltiazem, respectively. Diltiazem decreased the rate-pressure product at rest and exercise, L-propionylcarnitine did not. Both compounds significantly reduced ST depression at maximal exercise [23% (L-propionylcarnitine) vs 35% (diltiazem), P propionylcarnitine]. Diltiazem increased the time to onset of angina by 22%. In contrast, no significant changes occurred with L-propionylcarnitine. During the study, anginal attacks were reduced by 70% and 57%, and nitroglycerin consumption decreased by 57% and 70%, L-propionylcarnitine and diltiazem, respectively. Thus, both L-propionylcarnitine and (high-dose) diltiazem result in anti-ischaemic effects and decrease anginal attacks in daily life. Although the effect of diltiazem on exercise-induced ischaemia appears more pronounced than that of L-propionylcarnitine, this novel

  6. Prevention of Pazopanib-Induced Prolonged Cardiac Repolarization and Proarrhythmic Effects

    Tulay Akman


    Full Text Available Background: Pazopanib (PZP may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6. The first group (normal group received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP, to the normal group and to the second group (control-PZP+SP group; 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca, to the third group (PZP+metoprolol group; and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat, to the fourth group (PZP+diltiazem group. One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I. Results: The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001. Conclusion: Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.

  7. In vivo and ex vivo evaluation of L-type calcium channel blockers on acid beta-glucosidase in Gaucher disease mouse models.

    Ying Sun

    Full Text Available Gaucher disease is a lysosomal storage disease caused by mutations in acid beta-glucosidase (GCase leading to defective hydrolysis and accumulation of its substrates. Two L-type calcium channel (LTCC blockers-verapamil and diltiazem-have been reported to modulate endoplasmic reticulum (ER folding, trafficking, and activity of GCase in human Gaucher disease fibroblasts. Similarly, these LTCC blockers were tested with cultured skin fibroblasts from homozygous point-mutated GCase mice (V394L, D409H, D409V, and N370S with the effect of enhancing of GCase activity. Correspondingly, diltiazem increased GCase protein and facilitated GCase trafficking to the lysosomes of these cells. The in vivo effects of diltiazem on GCase were evaluated in mice homozygous wild-type (WT, V394L and D409H. In D409H homozygotes diltiazem (10 mg/kg/d via drinking water or 50-200 mg/kg/d intraperitoneally had minor effects on increasing GCase activity in brain and liver (1.2-fold. Diltiazem treatment (10 mg/kg/d had essentially no effect on WT and V394L GCase protein or activity levels (<1.2-fold in liver. These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses.

  8. 雷诺嗪与阿替洛尔、氨氯地平或地尔硫(艹卓)联合用药对重度慢性心绞痛患者运动耐量和心绞痛发作频率的影响随机对照试验%Effects of Ranolazine With Atenolol,Amlodipine,or Diltiazem on Exercise Tolerance and Angina Frequency in Patients With Severe Chronic Angina A randomized controlled trial

    Bernard R.Chaitman; Carl J.Pepine; John O.Parker; MUDr Jaroslav Skopal; Galina Chumakova; Jerzy Kuch; Whedy Wang; Sandra L.Skettino; Andrew A.Wolff



  9. Study of the recrystallization in coated pellets - effect of coating on API crystallinity.

    Nikowitz, Krisztina; Pintye-Hódi, Klára; Regdon, Géza


    Coated diltiazem hydrochloride-containing pellets were prepared using the solution layering technique. Unusual thermal behavior was detected with differential scanning calorimetry (DSC) and its source was determined using thermogravimetry (TG), X-ray powder diffraction (XRPD) and hot-stage microscopy. The coated pellets contained diltiazem hydrochloride both in crystalline and amorphous form. Crystallization occurs on heat treatment causing an exothermic peak on the DSC curves that only appears in pellets containing both diltiazem hydrochloride and the coating. Results indicate that the amorphous fraction is situated in the coating layer. The migration of drugs into the coating layer can cause changes in its degree of crystallinity. Polymeric coating materials should therefore be investigated as possible crystallization inhibitors.

  10. Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation.

    Ulimoen, Sara R; Enger, Steve; Carlson, Jonas; Platonov, Pyotr G; Pripp, Are H; Abdelnoor, Michael; Arnesen, Harald; Gjesdal, Knut; Tveit, Arnljot


    Rate control of atrial fibrillation (AF) is a main treatment modality. However, data are scarce on the relative efficacy of calcium channel blockers and β blockers or between drugs within each class. The purpose of the present study was to compare the effect of 4 rate-reducing, once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF in an investigator-blind cross-over study. Diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, and carvedilol 25 mg/day were administered for 3 weeks in a randomized sequence. The 24-hour heart rate was measured using Holter monitoring, and arrhythmia-related symptoms were assessed using the Symptom Checklist questionnaire before randomization and on the last day of each treatment period. The 24-hour mean heart rate was 96 ± 12 beats/min at baseline (no treatment), 75 ± 10 beats/min with diltiazem, 81 ± 11 beats/min with verapamil, 82 ± 11 beats/min with metoprolol, and 84 ± 11 beats/min with carvedilol. All drugs reduced the heart rate compared to baseline (p <0.001 for all). The 24-hour heart rate was significantly lower with diltiazem than with any other drug tested (p <0.001 for all). Compared to baseline, diltiazem significantly reduced both the frequency (p <0.001) and the severity (p = 0.005) of symptoms. In contrast, verapamil reduced symptom frequency only (p = 0.012). In conclusion, diltiazem 360 mg/day was the most effective drug regimen for reducing the heart rate in patients with permanent AF. Arrhythmia-related symptoms were reduced by treatment with the calcium channel blockers diltiazem and verapamil, but not by the β blockers.

  11. Aspects on the treatment of experimentally induced coronary artery disease

    L.M. Sassen


    textabstractIn this thesis some therapeutic aspects of experimentally induced coronary artery disease are being highlighted. In chapter 2 the effects of the Ca2 • antagonist diltiazem on the progression of coronary and aortic atherosclerosis in pigs is being studied. So far, studies on the

  12. Formulation of Sustained-Release Matrix Tablets Using Cross ...


    JSS College of Pharmacy, JSS University, Mysore, Karnataka-570015, India. Abstract. Purpose: To develop sustained release matrix tablets of diltiazem hydrochloride (DTZ) using ... channel blocker that is widely prescribed for ..... appearance of new peaks which were absent ... penetration of dissolution media into the.

  13. Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations

    Hugtenburg, J.G.; Mathy, M.-J.; Boddeke, H.W.G.M.; Beckeringh, J.J.; Van Zwieten, P.A.


    In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly

  14. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy.

    Ambler, Geoffrey R; Chaitow, Jeffrey; Rogers, Maureen; McDonald, David W; Ouvrier, Robert A


    A 6-year-old boy with improving juvenile dermatomyositis (JDM) developed severe and debilitating calcinosis, unresponsive to diltiazem and probenecid. Alendronate produced dramatic improvement within 1 month and by 12 months calcinosis had virtually resolved. The response was followed by bone mineral content measurements.

  15. Inhibitory effects of calcium channel blockers on thyroid hormone uptake in neonatal rat cardiomyocytes

    F.A. Verhoeven; E.P.C.M. Moerings (Ellis); J.M.J. Lamers (Jos); G. Hennemann; T.J. Visser (Theo); M.E. Everts (Maria)


    textabstractThe effects of the Ca2+ channel blockers verapamil, nifedipine, and diltiazem on triiodothyronine (T3) and thyroxine (T4) uptake were tested in cultured cardiomyocytes from 2-day-old rats. Experiments were performed at 37 degrees C in medium with 0.5% BSA for [125I]T3 (

  16. Drotaverine interacts with the L-type Ca(2+) channel in pregnant rat uterine membranes.

    Tömösközi, Zsuzsanna; Finance, Olivier; Arányi, Péter


    The effect of the isoquinoline derivative, drotaverine on the specific binding of [(3)H]nitrendipine and [(3)H]diltiazem to pregnant rat uterine membranes was examined. Drotaverine inhibited the specific [(3)H]nitrendipine and [(3)H]diltiazem bindings with IC(50) values of 5.6 and 2.6 microM, respectively. Saturation studies showed that diltiazem caused a significant increase in the maximum binding density without changing the K(D) of [(3)H]nitrendipine while drotaverine increased both the K(D) and the B(max) of [3H]nitrendipine. The dissociation kinetics of both [3H]nitrendipine and [(3)H]diltiazem were accelerated by drotaverine. These results suggest that drotaverine has a negative allosteric interaction with the binding sites for 1,4-dihydropyridines and 1,5-benzothiazepines on the L-type Ca(2+) channel in pregnant rat uterine membranes, which may have implications as to the potential usefulness of this drug in aiding child delivery.

  17. Myocardial perfusion abnormality and effects of Ca channel blockers on myocardial ischemia in patients with hypertrophic cardiomyopathy

    Taniguchi, Yoko [Kyoto Prefectural Univ. of Medicine (Japan)


    The purpose of this study was to investigate the frequency of myocardial ischemia and characteristic regions of myocardial hypoperfusion during stress in patients with hypertrophic cardiomyopathy. Furthermore, the effects of Ca channel blocker (verapamil, diltiazem) on myocardial ischemia were studied. One hundred patients with hypertrophic cardiomyopathy underwent exercise {sup 201}Tl SPECT. Sixty-eight patients had one or more {sup 201}Tl abnormalities. Of the 68 patients with {sup 201}Tl abnormalities, 56 had reversible {sup 201}Tl abnormalities and 12 had fixed defect. {sup 201}Tl abnormalities were frequently distributed in the anterior and posterior areas of junction between the ventricular septum and the free wall and the apex. Of the 56 patients with reversible {sup 201}Tl abnormalities, 40 patients underwent one more exercise {sup 201}Tl SPECT after 8 weeks of oral administration of verapamil or diltiazem. The {sup 201}Tl defect was visually scored as the defect score. Transient dilation index was calculated as an index of subendocardial ischemia. The mean defect score decreased significantly from 9.80{+-}4.35 to 5.50{+-}4.63 after verapamil and from 9.90{+-}5.17 to 5.50{+-}4.89 after diltiazem. Mean transient dilation index decreased from 1.20{+-}0.12 to 1.08{+-}0.09 after treatment with verapamil and from 1.16{+-}0.10 to 1.02{+-}0.09 after treatment with diltiazem. (K.H.)

  18. Synergy between verapamil and other multidrug -resistance modulators in model membranes

    Madeleine Castaing; Alain Loiseau; Athel Cornish-Bowden


    Various cationic lipophilic compounds can reverse the multidrug resistance of cancer cells. Possible interaction between these compounds, which are known as modulators, has been assessed by measuring leakage of Sulphan blue from anionic liposomes, induced both by verapamil alone and by verapamil in combination with diltiazem, quinine, thioridazine or clomipramine. An equation was derived to quantify the permeation doses and Hill coefficients of the drugs and mixtures between them by simultaneous fitting of the experimental data. The interaction was tested by two methods, the competition plot and the isobole method; both showed synergy between verapamil and each of diltiazem, quinine and thioridazine. The dose factor of potentiation for verapamil determined within membranes was 4.0 ± 0.4 with diltiazem, 3.2 ± 0.4 with quinine and 2.4 ± 0.3 with thioridazine. The results suggest that the effectiveness of reversing multidrug resistance may be increased with modulators such as verapamil and diltiazem that have a much greater effect in combination than what would be expected from their effects when considered separately.

  19. Effects of Losartan on acute atrial electrical remodeling

    李悦; 李为民; 薛竟宜; 韩薇; 杨树森; 谷宏越


    Background Atrial electrical remodeling (AER) contributes to the maintainance of atrial fibrillation (AF). This study was to compare the effects of Losartan with those of Diltiazem on tachycardia-induced acute AER in rabbits.Methods Twenty-one rabbits paced with maximal atrial capture rate for 3 hours in the right atrium (RA) were randomly divided into saline group, Diltiazem group and Losartan group. After autonomic blockage, we measured atrial effective refractory period (AERP), AERP rate adapting feature, AERP dispersion and RA conduction time at basic cycle lengths (BCLs) of 200 ms and 150 ms at baseline, 0.5 hour, 1 hour, 2 and 3 hours after rapid atrial pacing. Results In the saline group, there was a prompt decrease in AERP as a result of rapid atrial pacing, and AERP200 and AERP150 were shortened sharply within 0.5 hour of pacing (30.2±10.5 ms and 24.1±9.1 ms, respectively). The AERP did not change dramatically in the Diltiazem and Losartan groups. In the saline group, the value of (AERP200-AERP150)/50 ms in high RA was 0.17±0.08 at baseline and became significantly smaller at 0.5 hour (0.08±0.06), 1 hour (0.09±0.06), 2 hours (0.08±0.04) and 3 hours (0.09±0.05) (all P<0.05), suggesting a reduction of rate adaptation of AERP. The value of (AERP200-AERP150)/50 ms in high RA did not change during the 3 hours of pacing in both Diltiazem and Losartan groups. In the saline group, AERP dispersion increased significantly at 2 and 3 hours (P<0.05). However, Diltiazem could not prevent the increase of AERP dispersion at 3 hours (P<0.05). During Losartan infusion, the AERP dispersion was no longer increased after rapid atrial pacing. There was no significant difference in RA conduction time among the three groups.Conclusion Like calcium antagonist Diltiazem, Losartan could prevent AERP shortening and preserve rate adaptation of AERP after rapid atrial pacing. Losartan is more effective than Diltiazem in inhibiting the increase of AERP dispersion.

  20. 地尔硫卓与硝普钠治疗自发性颅内出血患者高血压的疗效比较

    沈涛; 何先弟


    Objective To compare the effectiveness and safety of diltiazem and sodium nitroprusside for blood pressure management in patients with spontaneous intracerebral hemorrhage. Methods 42 patients were divided into 2 groups:group diltiazem(n=22)and group sodium nitroprusside (n=20). The changes of BP and adverse reaction were all observed. Results There was no significant difference in the management of blood pressure in the two groups (P>0.05),and there was significant difference in the incidence of hypotension in the two groups (P0.05)。但两组低血压发生率差异有显著性(P<0.05)。结论地尔硫卓及硝普钠均能有效控制自发性颅内出血患者的高血压,但地尔硫卓安全性较硝普钠高。

  1. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    Contreras, E; Tamayo, L; Amigo, M


    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  2. Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine

    Glossmann, H.; Ferry, D.R.; Goll, A.; Rombusch, M.


    Radiolabeled Ca2+ antagonists (1,4-dihydropyridines, verapamil, and D-cis-diltiazem) were used to study voltage-operated Ca2+ channels in different excitable tissues. The concept of three subtypes of Ca2+ channels, represented by brain, heart, and skeletal-muscle isoreceptors for 1,4-dihydropyridines, is developed. The three subtypes are characterized by a variety of criteria. Despite the biochemical differences between the subtypes, they have the same Mr in situ by target-size analysis (Mr approximately equal to 180,000, when evaluated by (/sub 3/H)nimodipine). The concept of the metalloprotein nature of the channel and the interaction of channel drugs with the Me2+ binding sites of the ionic pore is demonstrated. Distinct but interacting drug-receptor sites of the Ca2+ channel are found by direct labeling as well as indirectly by drug competition studies. The authors distinguish between the 1,4-dihydropyridine site, the verapamil site, and the D-cis-diltiazem site. Each receptor site can exist in high and low-affinity state; the distribution of receptor sites in these states is regulated by temperature, ions, and drugs. The concept of intrinsic activity of drugs to stabilize the high-affinity state is exemplified for the 1,4-dihydropyridines. A change in the channel architecture is induced by binding of D-cis-diltiazem to its drug receptor site. This is proven by target-size analysis of the channel in situ. Partially purified t-tubule membranes from skeletal muscle are an extremely rich source of Ca2+ channel drug-receptor sites. The stoichiometry was determined in this preparation and found to be four verapamil:two 1,4-dihydropyridine:one D-cis-diltiazem site. A novel Ca2+ channel probe, (/sup 125/I)iodipine (2,200 Ci/mmol), was synthetized, and the properties of this ligand are presented.

  3. Study of SCN Neurochemistry using In Vivo Microdialysis in the Conscious Brain: Correlation with Circadian Activity Rhythms.


    and calcium channel blockers avoid damage to the nuclei [coordinates: anterior/posterior (AP) = (diltiazem HCI 200 tiM, verapamil 200 pM, cinnarizine ...significantly affected by calcium channel with serotonin during the dark phase (starting at 03.00 h) blockers (N-type, cinnarizine and flunarizine and L...synthesis and cycle. Perfusion with 5 p.M TIX for 60 min during the light degradation [ 15-201 on behavioral and endocrine rhythms phase (starting at

  4. Transmembrane pH-gradient liposomes to treat cardiovascular drug intoxication.

    Bertrand, Nicolas; Bouvet, Céline; Moreau, Pierre; Leroux, Jean-Christophe


    Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no specific antidotes to treat pharmacological overdoses. They act by capturing the drug in situ, thereby restricting distribution in tissues. In the clinic, the only systems used for that purpose are parenteral lipid emulsions, which are relatively inefficient in terms of uptake capacity. In this study, we investigated long-circulating liposomes with a transmembrane pH gradient as treatment for diltiazem intoxication. The unique ion-trapping properties of the vesicles toward ionizable compounds were exploited to sequester the drug in the bloodstream and limit its pharmacological effect. After in vitro optimization of the formulation, the in vivo scavenging properties of the liposomes were demonstrated by examining the drug's pharmacokinetics. The reduced volume of distribution and increased area under the plasma concentration versus time curve in animals treated with liposomes indicated limited tissue distribution. The vesicles exerted a similar but more pronounced effect on deacetyl-diltiazem, the principal active metabolite of the drug. This in vivo uptake of both drug and metabolite altered the overall pharmacological outcome. In rats receiving an intravenous bolus of diltiazem, the liposomes tempered the hypotensive decline and maintained higher average blood pressure for 1 h. The detoxifying action of liposomes was even stronger when the rats received higher doses of the drug via perfusion. In conclusion, the present work provided clear evidence that liposomes with a transmembrane pH gradient are able to change the pharmacokinetics and pharmacodynamics of diltiazem and its metabolite and confirmed their potential as efficient detoxifying nanocarriers.

  5. A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery

    Zaheeda Khan


    Full Text Available A Multilayered Multidisk Tablet (MLMDT comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC and ethylcellulose (EC granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL (1st barrier layer and hydroxypropylmethylcellulose (HPMC (HBL1 and HBL2 as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery.

  6. Interaction between inhalational anaesthetics and enoximone on isolated heart muscle.

    Miralles, F S; Carceles, M D; Laorden, M L


    1. The present study describes the effects of halothane or isoflurane on enoximone activity in the isolated left atria of the rat. 2. Concentration-response curves were obtained for the positive inotropic effects of enoximone on electrically stimulated left atria. 3. Enoximone significantly (P < 0.01) increased the contractile force (56% maximum) with all the concentrations tested (10(-9) -10(-3) M). 4. When halothane (1.5% v/v) was present in the organ bath, the maximum effect obtained with enoximone (9%) was significantly lower than that obtained with enoximone alone. 5. Similar results were obtained with enoximone in the presence of halothane plus diltiazem. Isoflurane (1.5% v/v) did not significantly modify the maximum effect obtained with enoximone alone. 6. The administration of diltiazem antagonized the positive inotropic effects of enoximone in the presence of isoflurane or halothane. 7. These results shows that halothane, but not isoflurane, decreased the potency of enoximone on the isolated left atria and suggests that this effect may be mediated by the blocking of the influx of extracellular calcium through voltage-dependent calcium channels inhibited by diltiazem.

  7. Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis.

    Ting-Wei Mu


    Full Text Available A lysosomal storage disease (LSD results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum-associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil-both US Food and Drug Administration-approved hypertension drugs-partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient-derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely alpha-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety.

  8. Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1,4- and 1,5-benzodiazepines in cerebrocortical neurons.

    Katsura, Masashi; Shibasaki, Masahiro; Kurokawa, Kazuhiro; Tsujimura, Atsushi; Ohkuma, Seitaro


    The aim of this study is to examine how sustained exposure to two 1,4-benzodiazepines (BZDs) with different action period, diazepam and brotizolam, and a 1,5-BZD, clobazam, affects L-type high voltage-gated calcium channel (HVCC) functions and its mechanisms using primary cultures of mouse cerebral cortical neurons. The sustained exposure to these three BZDs increased [(45)Ca2+] influx, which was due to the enhanced [(45)Ca2+] entry through L-type HVCCs but not through of Cav2.1 and Cav2.2. Increase in [(3)H]diltiazem binding after the exposure to these three BZDs was due to the increase in the binding sites of [(3)H]diltiazem. Western blot analysis showed increase of Cav1.2 and Cav1.3 in association with the increased expression of alpha2/delta1 subunit. Similar changes in [(3)H]diltiazem binding and L-type HVCC subunit expression were found in the cerebral cortex from mouse with BZD physical dependence. These results indicate that BZDs examined here have the potential to increase L-type HVCC functions mediated via the enhanced expression of not only Cav1.2 and Cav1.3 but also alpha2/delta1 subunit after their sustained exposure, which may participate in the development of physical dependence by these BZDs.

  9. Effects of first and second generation calcium channel blockers on diastolic function of the failing hamster heart: relationship with coronary flow changes.

    Beaucage, Pierre; Massicotte, Julie; Boileau, Jean-François; Dumont, Louis


    Calcium channel blockers (CCBs) have variable efficacy in the treatment of heart failure. We hypothesized that modulation of left ventricular diastolic pressure (LVDP) may play a role in the variable efficacy of CCBs in this condition. Isolated perfused hearts from 200- to 250-day-old UM-X7.1 cardiomyopathic hamsters (failing hearts) and age-matched Syrian hamsters (normal hearts) were studied. After recording of heart rate, coronary flow (CF), LVDP and left ventricular systolic pressure (LVSP), hearts were exposed either to verapamil or diltiazem (1 nM-10 microM), mibefradil (1 nM-1 microM) or clentiazem (1 nM-10 microM). Mechanical increase in CF (+2 to +10 ml/min) was carried out using a roller pump. Mechanically-augmented flow led to an increase in coronary perfusion pressure (+40 to +90 mm Hg), LVSP (+5 to +40 mm Hg) and LVDP (+5 to +25 mm Hg). CCBs-induced increment of coronary flow led to a difference in their cardiac response. In normal hearts, the negative inotropic response was more important with diltiazem and verapamil. Failing hearts did not demonstrate increased inotropic sensitivity to first-generation CCBs. On the contrary, at clinically relevant concentrations, verapamil resulted in the most pronounced impairment of LVDP followed by diltiazem while mibefradil and clentiazem, at clinically relevant concentrations, preserved LVDP. Such findings provide an additional explanation for the variable efficacy of CCBs in heart failure.

  10. An innovative matrix controlling drug delivery produced by thermal treatment of DC tablets containing polycarbophil and ethylcellulose.

    Caviglioli, Gabriele; Baldassari, Sara; Cirrincione, Paola; Russo, Eleonora; Parodi, Brunella; Gatti, Paolo; Drava, Giuliana


    An innovative matrix, produced by thermal treatment on direct compression (DC) tablets containing polycarbophil (POL) and ethylcellulose (EC), identified as matrix forming polymers, and able to control the release of diltiazem hydrochloride, was developed. At pH 7.2, 72 ± 1.2% (w/w) of drug loaded was released in 25 h, mostly at constant rate. This swellable and unerodible matrix controls drug release by an anomalous transport mechanism. The modifications induced by the thermal treatment are irreversible and can be used to control and characterize the matrix. A 3-component constrained mixture design allowed the investigation of the experimental domain in which the matrix forms and the computation of a mathematical model that can be used to optimize the formulation properties. The release rate can be modulated (0.032-0.064% drug released/min) through the choice of suitable treatment conditions and tablet composition. The maximum amount of diltiazem hydrochloride released by zero-order kinetics, at the lowest release rate, occurs for POL:EC ratio in the range of 1:1-2:3 with 20-30% of diluent. The tablets are able to load up to 50% (w/w) of diltiazem hydrochloride without losing their properties. A stability study performed on a selected formulation containing DTZ showed stability for at least 2.7 years at RT conditions.

  11. The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices.

    Asare-Addo, Kofi; Conway, Barbara R; Larhrib, Hassan; Levina, Marina; Rajabi-Siahboomi, Ali R; Tetteh, John; Boateng, Joshua; Nokhodchi, Ali


    The evaluation of the effects of different media ionic strengths and pH on the release of hydrochlorothiazide, a poorly soluble drug, and diltiazem hydrochloride, a cationic and soluble drug, from a gel forming hydrophilic polymeric matrix was the objective of this study. The drug to polymer ratio of formulated tablets was 4:1. Hydrochlorothiazide or diltiazem HCl extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2-7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic strength of the media was varied over a range of 0-0.4M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. The K4M, K15M and K100M tablets however withstood the effects of media ionic strength and showed a decrease in drug release to occur with an increase in ionic strength. For example, drug release after the 1h mark for the K100M matrices in water was 36%. Drug release in pH 1.2 after 1h was 30%. An increase of the pH 1.2 ionic strength to 0.4M saw a reduction of drug release to 26%. This was the general trend for the K4M and K15M matrices as well. The similarity factor f2 was calculated using drug release in water as a reference. Despite similarity occurring for all the diltiazem HCl matrices in the pH 1.2 media (f2=64-72), increases of ionic strength at 0.2M and 0.4M brought about dissimilarity. The hydrochlorothiazide tablet matrices showed similarity at all the ionic strength tested for all polymers (f2=56-81). The values of f2 however reduced with increasing ionic strengths. DSC hydration results explained the hydrochlorothiazide release from their HPMC matrices. There was an increase in

  12. Hypothyroid state reduces calcium channel function in 18-day pregnant rat uterus.

    Parija, S C; Mishra, S K; Raviprakash, V


    Hypothyroidism significantly reduced the mean amplitude and increased the mean frequency of spontaneous rhythmic contractions in 18 day pregnant rat uterus. Nifedipine (10(-12)-10(-9) M) and diltiazem (10(-10)-10(-6) M) caused concentration related inhibition of the myogenic responses of the uterine strips obtained from both pregnant and hypothyroid state. However, nifedipine was less potent (IC50:2.11 x 10(-11) M) in pregnant hypothyroid state as compared to pregnant control (IC50: 3.1 x 10(-12) M). Similarly, diltiazem was less potent (IC50: 3.72 x 10(-9) M) in inhibiting the uterine spontaneous contractions in hypothyroid than in pregnant rat uterus (IC50:5.37 x 10(-10) M). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction and K(+)-stimulated 45Ca2+ influx was observed with these calcium channel antagonists in uterus obtained from hypothyroid pregnant rats compared to the controls. Nifedipine-sensitive influx of 45Ca(2+)-stimulated either by K+ (100 mM) or by Bay K8644 (1,4-dihydro-2,6-methyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-9) M) was significantly less in uterine strips from hypothyroid rats compared to controls. The results suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

  13. Depolarization-stimulated /sup 42/K+ efflux in rat aorta is calcium- and cellular volume-dependent

    Magliola, L.; Jones, A.W.


    The purpose of this study was to investigate the factors controlling membrane permeability to potassium of smooth muscle cells from rat aorta stimulated by depolarization. The increase /sup 42/K+ efflux (change in the rate constant) induced by depolarization (application of high concentrations of potassium chloride) was inhibited significantly by the calcium antagonists diltiazem and nisoldipine. Parallel inhibitory effects on contraction were observed. Diltiazem also inhibited potassium-stimulated /sup 36/Cl- efflux. The addition of 25-150 mM KCl to normal physiologic solution stimulated /sup 42/K+ efflux in a concentration-dependent manner. Diltiazem suppressed potassium-stimulated /sup 42/K+ efflux approximately 90% at 25 mM KCl and approximately 40% at 150 mM KCl. The ability of nisoldipine to inhibit /sup 42/K+ efflux also diminished as the potassium chloride concentration was elevated. The component of efflux that was resistant to calcium antagonists probably resulted from a decrease in the electrochemical gradient for potassium. Cellular water did not change during potassium addition. Substitution of 80 and 150 mM KCl for sodium chloride produced cellular swelling and enhanced potassium-stimulated /sup 42/K+ efflux compared with potassium chloride addition. The addition of sucrose to prevent cellular swelling reduced efflux response to potassium substitution toward that of potassium addition. A hypoosmolar physiologic solution produced an increase in the /sup 42/K+ efflux and a contracture that were both prevented by the addition of sucrose. We concluded that the depolarization-mediated /sup 42/K+ efflux has three components: one is calcium dependent; a second is dependent on cellular volume; and a third is resistant to inhibition by calcium antagonists.


    A. A. Kirichenko


    Full Text Available Aim. To study efficacy and tolerability of antihypertensive therapy with enalapril (Berlipril®, Berlin-Chemie AG/Menarini Group and diltiazem (Altiazem® PP, Berlin-Chemie AG/Menarini Group in postmenopausal women with arterial hypertension (HT and climacteric disorders.Material and methods. 60 postmenopausal women (aged 56,8±3,9 y.o. with HT of 1-3 degrees were included into the study. They were split in two groups. Patients of the first group (30 people received enalapril (Berlipril® 20 mg/daily, patients of the second group (30 people – diltiazem (Altiazem® PP 180-360 mg/daily. Observation period was 6 months. Ambulatory blood pressure monitoring (ABPM was performed before treatment and after 3 weeks, 1, 3 and 6 months of therapy. Climacteric syndrome severity and urodynamic disorders was estimated as well as psychic status according to score of depression and anxiety.Results. Office and ambulance blood pressure decreased after 6 months of therapy in all patients of both groups. A number of complaints on headache and giddiness reduced significantly. Severity of climacteric syndrome also decreased. Enalapril (Berlipril® monotherapy and especially combined therapy with hydrochlorothiazide led to aggravation of urodinamic disorders. On the contrary both monotherapy with diltiazem (Altiazem® PP or its combination with hydrochlorothiazide had positive effect on urodinamics. Both therapies reduced depression and anxiety levels significantly.Conclusion. All spectrum of pharmacology effects should be taken into account during antihypertensive therapy of patients with climacteric disorders.

  15. Release kinetics of coated, donut-shaped tablets for water soluble drugs.

    Kim, C J


    Coated, donut-shaped tablets (CDST) were designed to achieve parabolic and linear drug release profiles. When rapidly erodible polymers (HPMC E3, HPC, PEG8000, PEOs (Mw=100000 and 200000)) were used, the release profiles of diltiazem HCl from the tablets becomes parabolic whereas zero-order release was achieved by using slowly erodible polymers (HPMC E5, HPMC E15, PEO (Mw=300000)). Drug release from the rapidly erodible polymers was governed by the pure erosion of the polymer while both polymer erosion and drug diffusion controlled drug release from the slowly erodible polymers. As drug loading was increased from 10% to 39% w/w, the drug release rate from CDST based on HPMC E3 became faster and parabolic whereas that from CDST based on HPMC E5 was linear. The slowly erodible polymer (HPMC E5) provided parabolic release profiles when drug loading was greater than 49% w/w. In this case, drug release mechanisms likely shifted from a combination of polymer erosion and drug diffusion to pure polymer erosion due to the enhancement of polymer erosion by faster influx of water. As drug solubility decreased from 61.6% w/v (diltiazem HCl), 1.0% w/v (theophylline), to 0.5% w/v (nicardipine HCl), the drug release rate from CDST based on HPMC E3 decreased due to polymer erosion mechanism but there was little difference in release rate from CDST based on HPMC E5 due to the greater contribution of drug diffusion to drug release kinetics along with polymer erosion. As expected, the drug release rate of diltiazem HCl from HPMC E3 and E5 was significantly influenced by stirring rate and hole size.

  16. Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study.

    Jennifer Settergren

    Full Text Available PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased. METHODS: Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed. RESULTS: OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23. Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58-0.68. Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78. Mean DDD (SD for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149 compared to patients on statin monotherapy 127 (93, (p<0.001. CONCLUSIONS: Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy

  17. Antianxiety actions of Ca2+ channel antagonists with Vogel-type conflict test in rats.

    Matsumoto, Y; Kataoka, Y; Watanabe, Y; Miyazaki, A; Taniyama, K


    We examined the effects of various derivatives of Ca2+ channel antagonists in a modified rat Vogel-type conflict model. Flunarizine (10 and 20 mg/kg), nicardipine (20 mg/kg), and verapamil (20 mg/kg), given as single i.p. injections, significantly increased punished lickings by 50-110%. Chronic administration of diltiazem, at 20 mg/kg i.p. for 8 days, a dose ineffective with a single i.p. injection, produced a significant anticonflict action. The possibility that Ca2+ channel antagonists have anxiolytic action should be considered.

  18. Resolution of sustained narrow complex ventricular tachycardia and tachycardia-induced cardiomyopathy in a Quarter Horse following quinidine therapy.

    Stern, Joshua A; Doreste, Yamir R; Barnett, Susan; Lahmers, Sunshine M; Baumwart, Ryan D; Seino, Kathy K; Bonagura, John D


    Sustained narrow-QRS tachycardia of three months duration and left ventricular systolic dysfunction were identified in a fifteen-year-old Quarter Horse. No underlying cause for the tachyarrhythmia was found and no predisposing structural cardiac lesions were evident by echocardiography. Intravenous diltiazem and lidocaine were administered without achieving successful conversion of the arrhythmia. Oral quinidine therapy converted the tachyarrhythmia to sinus rhythm. Ventricular systolic dysfunction and chamber dilatation subsequently resolved. As with other species, echocardiographic features of dilated cardiomyopathy can be tachycardia-induced and may resolve following successful control of heart rate and rhythm. Published by Elsevier B.V.

  19. Heparin/heparan sulfates bind to and modulate neuronal L-type (Cav1.2) voltage-dependent Ca2+ channels

    Garau, Gianpiero; Magotti, Paola; Heine, Martin


    M), integrating their enthalpic and entropic binding contributions. Interaction between heparin and recombinant as well as native full-length neuronal Cav1.2α1 channels was confirmed using the heparin–agarose pull down assay. Whole cell patch clamp recordings in HEK293 cells transfected with neuronal Cav1...... rate and led to appearance of long-lasting bursts in the same manner as treatment with the inhibitor of L-VDCC diltiazem. Thus, heparan sulfate proteoglycans may bind to and regulate L-VDCC inactivation and network activity....

  20. Colchicine modulates oxidative stress in serum and neutrophil of patients with Behçet disease through regulation of Ca²⁺ release and antioxidant system.

    Korkmaz, Selma; Erturan, Ijlal; Nazıroğlu, Mustafa; Uğuz, Abdulhadi Cihangir; Ciğ, Bilal; Övey, Ishak Suat


    Behçet disease (BD) is a chronic, inflammatory, and multisystemic condition with an uncertain pathogenesis. One of the major immunologic findings in BD pathogenesis is increase in activity of neutrophil. An increase in the cytosolic free Ca²⁺[Ca²⁺](i) concentration that induces Ca²⁺ signaling is an important step that participates in the neutrophil activation and reactive oxygen species production that leads to tissue damage in body cells. We aimed to investigate the effects of colchicine on oxidative stress and Ca²⁺ release in serum and neutrophil of BD patients with active and inactive periods. Twelve Behçet patients (6 active and 6 inactive) and 6 control subject were included in the study. Disease activity was considered by clinical findings. Serum and neutrophil samples were obtained from the patients and control subjects. Neutrophils from patients with active BD were divided into three subgroups and were incubated with colchicine, verapamil + diltiazem, and colchicine + verapamil + diltiazem, respectively. Erythrocyte sedimentation rate, leucocytes counts, serum C-reactive protein, neutrophil, and serum lipid peroxidation and intracellular Ca²⁺ release levels were higher in active and inactive groups than in the control group, although their levels were lower in active group than in inactive group. However, neutrophil Ca²⁺ release levels were decreased in colchicine, verapamil + diltiazem, and colchicine + verapamil + diltiazem groups group compared to active group. Serum glutathione, vitamin A, vitamin E, and β-carotene concentrations were lower in active and inactive groups than in the control group, although serum vitamin E and β-carotene concentrations were higher in the inactive group than in the active group. Neutrophil and serum glutathione peroxidase activity within the three groups did not change. In conclusion, we observed the importance of Ca²⁺ influx into the neutrophils and oxidative stress in the pathogenesis and

  1. Paroxysmal Supraventricular Tachycardia: Pathophysiology, Diagnosis, and Management.

    Al-Zaiti, Salah S; Magdic, Kathy S


    Paroxysmal supraventricular tachycardia (PSVT) is a well-known and thoroughly studied clinical syndrome, characterized by regular tachycardia rhythm with sudden onset and abrupt termination. Most patients present with palpitations and dizziness, and their electrocardiogram demonstrates a narrow QRS complex and regular tachycardia with hidden or inverted P waves. PSVT is caused by re-entry due to the presence of inhomogeneous, accessory, or concealed conducting pathways. Hemodynamically stable patients are treated by vagal maneuvers, intravenous adenosine, diltiazem, or verapamil, hemodynamically unstable patients are treated by cardioversion. Patients with symptomatic and recurrent PSVT can be treated with long-term drug treatment or catheter ablation.

  2. Clopidogrel: A possible exacerbating factor for psoriasis

    Vikram K Mahajan


    Full Text Available A 64-year-old man developed palmoplantar pustulosis eventuating into palmoplantar pustular psoriasis following treatment with diltiazem, atenolol, aspirin and atorvastatin for suspected coronary artery disease (CAD. Treatment for psoriasis, stopping atenolol and substituting aspirin with clopidogrel did not benefit. Subsequently, he stopped all his drugs and did not develop psoriasis or symptoms/signs of CAD. Re-challenge with oral clopidogrel precipitated his skin lesions. This case has implications for patients having psoriasis and cardiovascular comorbidity where clopidogrel/ticlopidine or aspirin may not be a useful alternative.

  3. Effects of L-type Ca2+ channel antagonists on in vitro excystment of Paragonimus ohirai metacercariae induced by sodium cholate.

    Ikeda, Teruaki


    The inhibitory effects of L-type Ca2+ channel antagonists on Na cholate-induced in vitro excystment (CIIE) of Paragonimus ohirai metacercariae were studied. At concentrations of 10 microM, nicardipine and nimodipine inhibited CIIE completely and by approximately 92%, respectively. Nitrendipine and (+/-)-verapamil inhibited CIIE by about one half and one third, respectively. Nifedipine and diltiazem did not inhibit CIIE significantly. At higher concentrations, nitrendipine at 20 microM completely inhibited CIIE, and (+/-)-verapamil at 40 microM inhibited CIIE by 93%. Nifedipine and diltiazem inhibited CIIE only slightly and little, respectively, even at 40 microM. Complete inhibition by nicardipine at 10 microM required preincubation of metacercariae with the antagonist for 15 min. The inhibitory effects of nicardipine and nimodipine were reversible, and most of the nimodipine-treated metacercariae could excyst within 1 h after being washed, but the nicardipine-treated ones started to excyst 1 h after washing. Nicardipine suppressed the active movement of encysted juveniles evoked by Na cholate, whereas nimodipine did not suppress this significantly. These results suggested that L-type Ca2+ channels appeared to be involved in CIIE of P. ohirai metacercariae and that the inhibitory effect of the channels was due primarily to factors other than the inhibition of muscular activity, probably involving the secretion and release of enzymes lytic against the metacercarial cyst wall.

  4. Hypertrophic cardiomyopathy and their therapeutic management in a Lhasa apso dog

    Deepak K. Kashyap

    Full Text Available Case history and observation: A male, 3 years old Lhasa Apso dog was presented with the history of haematemesis, dehydration, exercise intolerance, poor appetite, lethargy, cough, seizures and syncope for more than 3 weeks. Lateral roentgenogram revealed enlarged heart. Based on radiographic examination alongwith history of seizures and syncope the condition was diagnosed as hypertrophic cardiomyopathy. Treatment: The dog was treated with oral diltiazem @ 1.5 mg/kg body weight, ramipril @ 0.5 mg/kg body weight and frusemide @ 2 mg/kg body weight orally along with fluid therapy. Clinical improvement was noticed from third day. Improvement in appetite and physical activity with complete alleviation of clinical signs was observed by continued diltiazem (1.5 mg/kg, orally and ramipril (0.5 mg/kg. Result: It was reported that the dog continued to improve and became much brighter and active over next 25 days. Post treatment radiograph showed nearly normal size of the heart suggestive of clinical recovery. Conclusion: Thus it is conclude that hypertrophic cardiomyopathy can be comfortably managed by medicinal therapy in canines. [Vet. World 2012; 5(8.000: 493-494

  5. Risk-based approach for systematic development of gastroretentive drug delivery system.

    Mirani, A G; Patankar, S P; Kadam, V J


    The research envisioned was the development of diltiazem hydrochloride effervescent floating matrix tablet using a risk-based approach. Preliminarily, the in vitro drug release profile was derived which theoretically simulated the in vivo condition after oral administration. Considering this as a rationale, the formulation development was initiated with defining the quality target product profile (QTPP) and critical quality attributes (CQAs). The preliminary studies were conducted to screen material attributes and process parameters followed by their risk assessment studies to select the plausible factors affecting the drug product CQAs, i.e., floating lag time and drug release profile. A 3(2) full factorial design was used to estimate the effect of the amount of swelling polymer (X 1) and gas-generating agent (X 2) on percent drug release (Q t1h and Q t8h) and floating lag time. Response and interaction plots were generated to examine the variables. Selection of an optimized formulation was done using desirability function and further validated. The model diagnostic plots represent the absence of outliers. The optimized formula obtained by the software was further validated, and the result of drug release and floating lag time was close to the predicted values. In a clear and concise way, the current investigations report the successful development of an effervescent floating matrix tablet for twice daily administration of diltiazem hydrochloride.

  6. Azelnidipine inhibits Msx2-dependent osteogenic differentiation and matrix mineralization of vascular smooth muscle cells.

    Shimizu, Takehisa; Tanaka, Toru; Iso, Tatsuya; Kawai-Kowase, Keiko; Kurabayashi, Masahiko


    Vascular calcification is an active and regulated process that is similar to bone formation. While calcium channel blockers (CCBs) have been shown to improve outcomes in atherosclerotic vascular disease, it remains unknown whether CCBs have an effect on the process of vascular calcification. Here we investigated whether CCBs inhibit osteogenic differentiation and matrix mineralization of vascular smooth muscle cells induced by Msx2, a key factor of vascular calcification. Human aortic smooth muscle cells (HASMCs) were transduced with adenovirus expressing MSX2 and were treated with 3 distinct CCBs. Azelnidipine, a dihydropyridine subclass of CCBs, significantly decreased alkaline phosphatase (ALP) activity of Msx2-overexpressed HASMCs, whereas verapamil and diltiazem had no effect. Furthermore, azelnidipine, but not verapamil and diltiazem, significantly decreased matrix mineralization of Msx2-overexpressing HASMCs. Azelnidipine significantly attenuated the induction of ALP gene expression by Msx2, a key transcription factor in osteogenesis, while it did not reduce enzymatic activity of ALP. Furthermore, azelnidipine inhibited the ability of Msx2 to activate the ALP gene, but had no effect on Notch-induced Msx2 expression. Given that L-type calcium channels are equally blocked by these CCBs, our results suggest that azelnidipine inhibits the Msx2-dependent process of vascular calcification by mechanisms other than inhibition of calcium channel activity.

  7. Uso do clodronato endovenoso na calcinose difusa em uma criança com síndrome de superposição esclerose sistêmica e dermatomiosite Use of clodronate in extensive calcinosis in a child with systemic sclerosis and dermatomyositis overlap

    Gláucio R. Werner de Castro


    Full Text Available Os autores descrevem o caso de uma garota negra, com diagnóstico de síndrome de superposição dermatomiosite e esclerose sistêmica, que desenvolveu calcinose difusa, complicada por infecções secundárias e significativa limitação funcional de membros. Tratamento com colchicina, diltiazem e alendronato sódico não se mostrou eficaz no controle da calcinose, requerendo uso endovenoso bimestral de clodronato, que contribuiu para significativa melhora na cicatrização das úlceras cutâneas e na qualidade de vida.The authors report an Afro-Brazilian girl with systemic sclerosis and dermatomyositis overlap who evolved with extensive calcinosis, complicated by secondary infections and important disability. Treatment with colchicine, diltiazem and sodium alendronate was not effective in the control of calcinosis, requiring the use of bimonthly intravenous doses of clodronate that resulted in significant improvement in the healing of cutaneous ulcers and in the quality of life of the patient.

  8. Possible mechanism(s) for relaxant effects of Foeniculum vulgare on guinea pig tracheal chains.

    Boskabady, M H; Khatami, A; Nazari, A


    In a previous study the relaxant (bronchodilatory) effect of Foeniculum vulgare on isolated guinea pig tracheal chains was demonstrated. To study mechanisms responsible for this effect the present study evaluated the inhibitory effect of this plant on contracted tracheal chains of guinea pig. The relaxant effects of aqueous and ethanol extracts and an essential oil from Foeniculum vulgare were compared to negative controls (saline for aqueous extract and essential oil and ethanol for ethanol extract) and a positive control (diltiazem) using isolated tracheal chains of the guinea pig precontracted by 10 microM methacholine (group 1) and 60 mM KCl (group 2, n = 7 for each group). In the group 1, experiments diltiazem, ethanol extract, and essential oil from Foeniculum vulgare showed a significant relaxant effect on methacholine induced contraction of tracheal chains compared to those of negative controls (p Foeniculum vulgare. However with regard to the effect of KCl on calcium channels, the results indicated that the inhibitory effect of ethanol extracts and essential oil from Foeniculum vulgare on calcium channels is not contributing to their relaxant (bronchodilatory) effects on guinea pig tracheal chains. However the results suggest a potassium channel opening effect for this plant, which may contribute on its relaxant effect on guinea pig tracheal chains.

  9. [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.

  10. Dispersive liquid-liquid microextraction based on solidification of floating organic drop and high-performance liquid chromatography to the analysis of cocaine's major adulterants in human urine.

    Sena, Laís Cristina Santana; Matos, Humberto Reis; Dórea, Haroldo Silveira; Pimentel, Maria Fernanda; de Santana, Danielle Cristine Almeida Silva; de Santana, Fernando José Malagueño


    A simple method has been proposed for the determination of cocaine's major adulterants (caffeine, levamisole, lidocaine, phenacetin, diltiazem, and hydroxyzine) in human urine by dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFO) in combination with high-performance liquid chromatography - photodiode array detector (HPLC-PDA). The reversed-phase chromatographic separation was obtained with a column C18 extended (250×4.6mm; 5μm; 80Å) in gradient elution mode using acetonitrile-trifluoroacetic acid 0.026% (v,v) (pH=2.5) at 1mLmin(-1) as mobile phase, at 25°C, and detection at 235nm. The analysis time was 25min. This condition had the best resolution factors (>1.15), retention factors (>0.68), number of plates (>2094.9), and separation factors (>1.05) for all targets, indicating a good separation. The kind of extraction and dispersive solvent were investigated for unifactorial design. The buffer pH, the volume of extraction and disperser solvent, and the amount of salt were optimized for full factorial design. Under optimum conditions, human urine samples were alkalized with 0.5M sodium phosphate buffer (pH 10) and added to sodium chloride (20%m/v). Acetonitrile (150μL) and 1-dodecanol (30μL) were used as dispersive and extraction solvent, respectively. The method presented linear range of 312.5-3125ngmL(-1) to caffeine and levamisole and 187.5-1875ngmL(-1) to lidocaine, phenacetin, diltiazem, and hydroxyzine. The limit of quantification was 187.5ngmL(-1) to lidocaine, phenacetin, diltiazem, and hydroxyzine and 312.5ngmL(-1) for caffeine and levamisole. The recovery mean values were between 6.0 and 42.6%. The method showed good precision and accuracy, with within- and between-run relative standard deviation and relative error less than 15%. The samples were stable after freeze-thaw cycle and short-term room temperature stability tests. Besides, this method was satisfactorily applied in urine of cocaine users. It

  11. The role of external Ca²⁺ in the action of Ca²⁺-channel agonists and antagonists on isolated human thoracic arteries.

    Garaliene, V; Barsys, V; Giedraitis, S; Benetis, R; Krauze, A


    In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²⁺-channel agonists and antagonists by varying the external Ca²⁺ concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻⁷ to 10⁻⁴ M) were established by varying the external Ca²⁺ concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²⁺ concentration significantly increased arterial contraction, particularly at the lower Ca²⁺ (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻⁴ M concentrations by 55%, 55% and 44%, respectively, when the external Ca²⁺ corresponded to the physiological standard. Shifting to lower or higher Ca²⁺ concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow

  12. Medical image of the week: subcutaneous calcification in dermatomyositis

    Natt B


    Full Text Available A 36-year old woman was referred to our Interstitial Lung Disease (ILD clinic for evaluation of dyspnea. A high-resolution CT scan of the chest showed perivascular reticular and ground glass opacities with air trapping, consistent with non-specific interstitial pneumonitis (Figure 1. She was diagnosed with connective tissue associated ILD. On review of previous images extensive subcutaneous calcifications were seen (Figure 2. Calcinosis is an uncommon manifestation of dermatomyositis in adults (1. It is usually seen around areas of frequent trauma like the hands and elbows. In her case, a pelvic inflammatory disease may have been a trigger for this calcinosis. Calcinosis is a difficult complication to treat with some success seen with diltiazem, aluminum hydroxide, and even alendronate in children. Surgical excision may be required in some cases.

  13. [Vaughan Williams class IV antiarrhythmic drugs].

    Horie, M; Washizuka, T; Ikeguchi, S; Sasayama, S


    Vaughan Williams class IV antiarrhythmic drugs have Ca-channel blocking actions. Since L-type Ca-channels play key roles in regulating pulse conduction in atrioventricular node as well as in pathologically-depolarized myocardium, Ca-channel blockers known to modulate this type of Ca-channel (ICa,L) are used as antiarrhythmic agents. ICa,L channels have relatively high threshold potential (-40 mV) to activate and long-opening properties, and are enhanced by beta-adrenergic stimulation. Among three major ICa,L blockers, dihydropyridines such as nifedipine were found to bind to the channel from extracellular side. In contrast, verapamil and diltiazem interact with the channel from the cytoplasmic side, thereby causing rate-dependent block of ICa,L channels. This sideness of pharmacological action of the Ca-channel blockers determines an important therapeutic modality and their indication for tachyarrhythmias.

  14. Case Report: Coronary arterial spasm in single right coronary artery

    En-zhi JIA; Qi-jun SHAN; Zhi-jian YANG; Tie-bing ZHU; Lian-sheng WANG; Ke-jiang CAO; Wen-zhu MA


    We presented a case of anomalous single-coronary artery detected incidentally during routine coronary angiography. A 32-year-old male Chinese patient presented with recurrent pre-syncope and six episodes of syncope. Coronary angiography and coronary-computed tomography (CT)-angiography performed by a dual-source computed tomography (DSCT) revealed that the patient had a single large right coronary artery. A moderately large branch originated from the proximal part of the single right coronary artery and extended to the left, passing the anterior to the pulmonary artery, and divided into the anterior descending artery branch and circumflex branch at the base of the left auricular appendage. The episodes of the syncope were suspected to be caused by coronary arterial spasm, so this patient was on a regimen of 30 mg of diltiazem every 6 h and had no recurrence of syncope during follow-up.

  15. Lipoxygenase—mediated N—demethylation of imipramine and related tricyclic antidepressants

    HuJA; SajaM


    The ability of soybean lipoxygenase to mediate the N-demethylation of imipramine and related drugs in the presence of hydrogen peroxide was examined.Under optimal assay conditions,Vmax values of 14 to 18 mol formaldehyde·min-1·mol-1 enzyme were observed.An inhibition of formaldehyde and desipramine formation by nordihydroguaiaretic acid confirmed the lipoxygenase involvement.The blockade of the reaction by glutathione,dithiothreitol butylated hydroxyanisole (BHA) and butylated hydroxytoluene(BHT) indicated the generation of a free radical intermediate from imipramine.Desipramine,trimipramine,clomipramine,and diltiazem,but not amitriptyline and doxepin,were also oxidized,albeit at a lower rate.Collectively,the evidence gathered in this study suggests,for the first time,that tricyclic antidepressant drugs may undergo lipoxygenase-catalyzed N-demethylation.

  16. ACE inhibitors and calcium antagonists in the treatment of congestive heart failure

    Hansen, J F


    The increased mortality after myocardial infarction is related to the risk of reinfarction, sudden death, and the development and progression of heart failure; in congestive heart failure it is due to the progression of heart failure and sudden death. ACE inhibitors have been proven to prevent...... cardiovascular events, especially the progression of heart failure, in postinfarct patients with reduced ejection fraction and heart failure in the SAVE and AIRE trials. In patients with congestive heart failure, ACE inhibitor treatment has prevented cardiovascular death and reduced morbidity due to progressive...... heart failure in the SOLVD trials. In post-myocardial infarction patients, the calcium antagonist nifedipine did not affect mortality or morbidity; diltiazem improved prognosis in patients without congestive heart failure and in patients with non-Q-wave infarction; and verapamil improved prognosis...

  17. [Raynaud's phenomenon and calcium blocking agents. A preliminary open study with flunarizine].

    Centonze, V; Campanale, G; Vino, M; Caporaletti, P; Magrone, D; Russo, P; Di Bari, M; Loragno, V; Albano, O


    Raynaud's phenomenon (Raynaud's disease), an accessual vascular acrosyndrome characterised by an important constriction of distal arterioles, has still no specific pharmacological therapy. In the last years, the use of calcium-entry-blockers (nifedipine, diltiazem, verapamil, nicardipine), drugs able to control the contractility of the vessels, showed some positive results. Considering this data, we appraised the efficacy of flunarizine, another calcium-entry-blocker, in a preliminary study of 28 patients (23 females, 5 males, aged between 15 and 48 years) suffering from Raynaud's disease. Apart from a statistically insignificant improvement of subjective symptoms (i.e. acroparesthesias, cold extremities) flunarizine (10 mg/day for 1 month) did not have positive results. Finally, this drug caused some side-effects: drowsiness, increase of weight and appetite, but without a real necessity for withdrawal of therapy.

  18. Antioxidant effects of calcium antagonists in rat brain homogenates.

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T


    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  19. Diversity and intensity of adverse events in the treatment of hypertension with barnidipine.

    van der Velden, J W; Beudeker, H J; Nishi, M


    Calcium antagonists (CaAs) are divided into three structural classes, typically represented by verapamil, diltiazem and nifedipine. As a group, the principal (type I) adverse effects of these drugs relate to the pharmacological action of calcium channel blockade, namely vasodilation, and include dizziness, flushing, palpitations and peripheral oedema. The clinical safety of the new dihydropyridine CaA, barnidipine, has been assessed in more than 12 clinical trials, including 2041 patients who have been treated with one or more doses of barnidipine (dose of up to 50 mg). Adverse events with barnidipine are of mild to moderate intensity, most commonly of type I, occurring in the early phase of treatment. The incidence of serious adverse events and the rate of withdrawals are low. Hence, barnidipine is likely to be well tolerated in general clinical use.

  20. Receptor binding profile of Otilonium bromide.

    Evangelista, S; Giachetti, A; Chapelain, B; Neliat, G; Maggi, C A


    The interaction of Otilonium bromide (OB) with binding sites for 63 different receptors and ion channels in appropriate preparations has been investigated. Experiments were also performed in rat colon, the preferred tissue for OB 'in vivo' uptake after oral administration. Among the receptors investigated OB binds with sub microM affinity to muscarinic M1, M2, M4, M5 and PAF receptors and with microM affinity to the diltiazem binding site on L type Ca2+ channels. In the rat colon OB shows competitive interaction with the verapamil binding site on L type Ca2+ channels and with muscarinic M2 receptors with IC50 of 1020 and 1220 nM, respectively. These findings provide a molecular rationale to explain the spasmolytic action exerted by OB on intestinal smooth muscle. In particular, a combination of antimuscarinic and Ca2+ channel blocker properties seems to best account for the action of this compound.

  1. Practical aspects of apixaban use in clinical practice: continuing the theme

    S. N. Bel'diev


    Full Text Available Currently there are no generally accepted guidelines for the use of apixaban together with CYP3A4 and/or P-glycoprotein (P-gp inhibitors. Analysis of clinical and pharmacological studies suggests that apixaban dose should be reduced to 2.5 mg twice daily when co-administered with a strong CYP3A4 and P-gp inhibitors, such as azole antimycotics, HIV protease inhibitors and clarithromycin. However, it is preferred to avoid apixaban combination with strong CYP3A4 and P-gp inhibitors in patients with a creatinine clearance (CrCl <30 mL/min. According to preliminary calculations, apixaban dose should also be adjusted in patients with CrCl <70-80 ml/min, receiving less potent inhibitors of CYP3A4 and/or P-gp, such as diltiazem, naproxen, verapamil, amiodarone and quinidine. 

  2. The role of L-type calcium channels in the development and expression of behavioral sensitization to ethanol.

    Broadbent, Julie


    Behavioral sensitization is thought to play a significant role in drug addiction. L-type calcium channels have been implicated in sensitization to stimulant and opiate drugs but it is unclear if these channels also contribute to sensitization to ethanol. The effects of three L-type calcium channel blockers, nifedipine (1-7.5 mg/kg), diltiazem (12.5-50 mg/kg), and verapamil (12.5 and 25 mg/kg), on sensitization to ethanol (2 g/kg) were examined in DBA/2J mice. All three blockers reduced but did not prevent expression of sensitization. Only nifedipine blocked acquisition of sensitization. Nifedipine and verapamil decreased blood ethanol levels. The current findings suggest L-type calcium channels do not play a substantial role in sensitization to ethanol and that the neural mechanisms underlying sensitization to ethanol are distinct from those mediating sensitization to stimulants and opiates.

  3. Diabetic Nephropathy in Women With Preexisting Diabetes

    Ringholm, Lene; Damm, Julie Agner; Vestgaard, Marianne


    In women with preexisting diabetes and nephropathy or microalbuminuria, it is important to deliver careful preconception counselling to assess the risk for the mother and the foetus, for optimizing glycaemic status and to adjust medical treatment. If serum creatinine is normal in early pregnancy......, kidney function is often preserved during pregnancy, but complications such as severe preeclampsia and preterm delivery are still common. Perinatal mortality is now comparable with that in women with diabetes and normal kidney function. Besides strict glycaemic control before and during pregnancy, early...... and intensive antihypertensive treatment is important to optimize pregnancy outcomes. Methyldopa, labetalol, nifedipine and diltiazem are considered safe, whereas angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers should be stopped before or at confirmation of pregnancy...

  4. A mathematical model to predict the release of water-soluble drugs from HPMC matrices.

    Fu, X C; Wang, G P; Fu, C Y; Liang, W Q


    A mathematical model to predict the fraction of water-soluble drug released as a function of release time (t, h), HPMC concentration (CH, w/w), and volume of drug molecule (V, nm3) was derived with ranitidine hydrochloride, diltiazem hydrochloride, and ribavirin as model drugs. The model is log (M(t)/M(infinity)) = 0.5 log t-0.3322CH-0.2222V-0.2988 (n = 140, r = 0.9848), where M(t) is the amount of drug released at time t, M(infinity) is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using isoniazid and satisfactory results were obtained. The model can be used to predict the release fraction of various soluble drugs from HPMC matrices having different polymer levels.

  5. Isradipine and lacidipine: effects in vivo and in vitro on Trypanosoma cruzi epimastigotes.

    Núñez-Vergara, L J; Squella, J A; Bollo-Dragnic, S; Marín-Catalán, R; Pino, L; Díaz-Araya, G; Letelier, M E


    1. Isradipine and lacidipine, two new drugs that are members of the nitro-aryl-1,4-dihydropyridine family, produced inhibition of both growth cultures and oxygen consumption on epimastigotes of Trypanosoma cruzi Tulahuen strain, at micromolar concentrations. 2. Isradipine was found to be the most potent derivative in both, in growth cultures (I50 = 20.8 microM) and in vivo oxygen uptake (I50 = 31.1 microM). 3. Diltiazem and verapamil, two well-known calcium channel antagonists, lacked inhibitory activity, even at a 100 microM concentration. 4. The present findings indicate that the trypanocide effects exerted by isradipine and lacidipine are not related with a disruption of the calcium homeostasis of the parasite.

  6. Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update

    Bikash Medhi


    Full Text Available Surgical sphincterotomy reduces anal tone and sphincter spasm and promotes ulcer healing. Because the surgery is associated with the side effect of faecal incontinence, pharmacological agents to treat chronic anal fissure have been explored recently. Glyceryl trinitrate (GTN ointment (0.2% has an efficacy of up to 68% in healing chronic anal fissure, but it is associated with headache as the major and most common side effect. Though botulinum toxin injected into the anal sphincter healed over 80% of chronic anal fis-sures, it is more invasive and expensive than GTN therapy. Diltiazem ointment achieved healing of chronic anal fissure comparable to 0.2% GTN ointment but was associated with fewer side effects. Other drugs that have been tried are lidocaine, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil.

  7. Novel colon targeted drug delivery system using natural polymers

    Ravi V


    Full Text Available A novel colon targeted tablet formulation was developed using pectin as carrier and diltiazem HCl and indomethacin as model drugs. The tablets were coated with inulin followed by shellac and were evaluated for average weight, hardness and coat thickness. In vitro release studies for prepared tablets were carried out for 2 h in pH 1.2 HCl buffer, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid. The drug release from the coated systems was monitored using UV/Vis spectroscopy. In vitro studies revealed that the tablets coated with inulin and shellac have limited the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment. The study revealed that polysaccharides as carriers and inulin and shellac as a coating material can be used effectively for colon targeting of both water soluble and insoluble drugs.

  8. Protective effects of Ca2+ handling drugs against abnormal Ca2+ homeostasis and cell damage in myopathic skeletal muscle cells.

    Iwata, Yuko; Katanosaka, Yuki; Shijun, Zhu; Kobayashi, Yuko; Hanada, Hironori; Shigekawa, Munekazu; Wakabayashi, Shigeo


    Deficiency of delta-sarcoglycan (delta-SG), a component of the dystrophin-glycoprotein complex (DGC), causes skeletal muscular dystrophy and cardiomyopathy in BIO14.6 hamsters. Here, we studied the involvement of abnormal Ca2+ homeostasis in muscle degeneration and the protective effect of drugs against Ca2+ handling proteins in vivo as well as in vitro. First, we characterized the properties of cultured myotubes from muscles of normal and BIO14.6 hamsters (30-60 days old). While there were no apparent differences in the levels of expression of various Ca2+ handling proteins (L-type Ca2+ channel, ryanodine receptor, SR-Ca2+ ATPase, and Na+/Ca2+ exchanger), muscle-specific proteins (contractile actin and acetylcholine receptor), or DGC member proteins except SGs, BIO14.6 myotubes showed a high degree of susceptibility to mechanical stressors, such as cyclic stretching and hypo-osmotic stress as compared to normal myotubes, as evidenced by marked increases in creatine phosphokinase (CK) release and bleb formation. BIO14.6 myotubes showed abnormal Ca2+ homeostasis characterized by elevated cytosolic Ca2+ concentration, frequent Ca2+ oscillation, and increased 45Ca2+ uptake. These abnormal Ca2+ events and CK release were significantly prevented by Ca2+ handling drugs, tranilast, diltiazem, and FK506. The calpain inhibitor E64 prevented CK release, but not 45Ca2+ uptake. Some of these drugs (tranilast, diltiazem, and FK506) also exerted a significant protective effect for muscle degeneration in BIO14.6 hamsters and mdx mice in vivo. These observations suggest that elevated Ca2+ entry through sarcolemmal Ca2+ channels predominantly contributes to muscle degeneration and that the drugs tested here may have novel therapeutic potential against muscular dystrophy.

  9. Low-dose calcium antagonists reduce energy demand and cellular damage of isolated hearts during both ischemia and reperfusion.

    Becker, B F; Möbert, J


    Calcium antagonists may protect against postischemic reperfusion injury of the heart, but neither the time and mode of action leading to cardioprotection is resolved, nor is the generality of this effect proven. Accordingly, the functional and metabolic influence of four different Ca2+-antagonists (diltiazem, 3x10(-8) M; nifedipine, 3x10(-9) M; amlodipine, 3x 10(-9) M; barnidipine, 3x10(-11) M) was examined in preparations of guinea pig hearts (n=7/group) performing pressure-volume work after being subjected to low-flow ischemia (30 min) and reperfusion (35 min). The drugs were applied throughout the study at concentrations without negative inotropic or chronotropic effect, as would be mandatory for any therapeutic application, and without overt coronary dilatation. All calcium antagonists improved postischemic recovery of external heart work: from 42% in controls (post- vs. preischemic value) to 59% for diltiazem, 61% for nifedipine, 65% for amlodipine, and 73% for barnidipine (all Pbarnidipine (15% efficiency). Release of lactate dehydrogenase in the first 5 min of reperfusion, a sign of cell damage, increased from basal (65 mU/min) to 208 mU/min in controls. This increase was fully suppressed by all drugs tested. Myocardial release of lactate and of purine catabolites of adenine nucleotides (markers of anaerobic metabolism) was markedly reduced by Ca2+-antagonists. Interestingly, these metabolic effects were evident not only in the reperfusion phase, but already in the period of low-flow ischemia. Oxidative consumption of pyruvate was enhanced, whereas coronary flow and heart rate showed no postischemic effect of treatment. These findings on isolated guinea pig hearts suggest that Ca2+-antagonists generally improve postischemic pump function and aerobic metabolism without any requirements for negative inotropic action or coronary dilatation. The protective effects seemed to rely on an attenuation of both ischemic stress and reperfusion damage. This could

  10. In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates Avaliação in vitro do verapamil e de outros agentes moduladores em isolados de Plasmodium falciparum resistentes à cloroquina

    Carla M.S. Menezes


    Full Text Available Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility. Intrinsic antiplasmodial activity was observed from the lowest concentrations without a significant modulating action. Other reported modulating agents, such as the antipsychotic drug trifluoperazine and the antidepressants desipramine and imipramine, demonstrated similar responses under the same experimental conditions. Results suggest a much higher susceptibility of Brazilian strains, as well as an indifferent behaviour in relation to modulating agents.Verapamil foi ensaiado quanto ao efeito modulador em isolados brasileiros de Plasmodium falciparum resistentes à cloroquina. Outros agentes cardiovasculares, considerados como moduladores da resistência em malária e/ou em neoplasias multiresistentes a fármacos, como nifedipino, nitrendipino, diltiazem e propranolol foram ensaiados quanto ao mesmo efeito. Concentrações semelhantes às da terapia cardiovascular foram empregadas no ensaio de microtécnica de sensibilidade para fármacos antimaláricos. Atividade antiplasmódica intrínsica foi observada desde as menores concentrações, sem, entretanto, ocorrência de modulação significativa da resistência. Sob as mesmas condições experimentais, respostas semelhantes foram observadas para outros agentes moduladores conhecidos como o antipsicótico trifluoperazina e os antidepressivos desipramina e imipramina. Em conjunto, estes resultados sugerem alta sensibilidade e comportamento indiferente de cepas brasileiras ao efeito de agentes moduladores da resistência.

  11. A comparison of the cardioprotective effects of calcium antagonists from different classes upon ischaemic damage in the guinea-pig working heart.

    Hugtenburg, J G; Mathy, M J; Veldsema-Currie, R D; Boddeke, H W; Beckeringh, J J; van Zwieten, P A


    The cardioprotective effects of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and the coronary vasodilator dipyridamole were evaluated in the guinea-pig working heart with respect to cardiac function and high energy phosphate content after 45 min of global ischaemia and 25 min of reperfusion. All drugs, with the exception of dipyridamole, induced a negative inotropic effect, which resulted in a decrease of the aortic pressure (AoP), of its first derivative dAoP/dt and the cardiac output. To compare the anti-ischaemic effect of the calcium antagonists, concentrations were selected that reduced the dAoP/dt by 10% (EC10) and 30% (EC30), respectively. With the exception of nifedipine at the EC10 and bepridil and CERM 11956 at the EC30, perfusion with the calcium antagonists and dipyridamole (3 mumol/l) improved the recovery of contractile function after global ischaemia and reperfusion to a value between 60 and 80% of the controls in normoxic hearts. Pretreatment with nifedipine, verapamil, diltiazem, lidoflazine and mioflazine, but not with bepridil, CERM 11956 and dipyridamole led to slightly increased ATP levels in ischaemic hearts as compared to the control value in ischaemic hearts. After subsequent reperfusion for 25 min, for all drugs, ATP levels were further enhanced to 50% of the level in normoxic hearts; phosphocreatine levels reached normoxic values. In particular at the EC30, the effects of calcium antagonists on cardiac function varied in accordance with their known pharmacological and physiological profile. However, there appeared to exist no direct relationship between their beneficial effects on contractile activity and those on the levels of high energy phosphates after ischaemia and reperfusion.

  12. Detection of neural stem cells function in rats with traumatic brain injury by manganese-enhanced magnetic resonance imaging

    TANG Hai-liang; SUN Hua-ping; WU Xing; SHA Hong-ying; FENG Xiao-yuan; ZHU Jian-hong


    Background Previously we had successfully tracked adult human neural stem cells (NSCs) labeled with superparamagnetic iron oxide particles (SPIOs) in host human brain after transplantation In vivo non-invasively by magnetic resonance imaging (MRI). However, the function of the transplanted NSCs could not be evaluated by the method. In the study, we applied manganese-enhanced MRI (ME-MRI) to detect NSCs function after implantation in brain of rats with traumatic brain injury (TBI) In vivo.Methods Totally 40 TBI rats were randomly divided into 4 groups with 10 rats in each group. In group 1, the TBI rats did not receive NSCs transplantation. MnCl2-4H2O was intravenously injected, hyperosmolar mannitol was delivered to disrupt rightside blood brain barrier, and its contralateral forepaw was electrically stimulated. In group 2, the TBI rats received NSCs (labeled with SPIO) transplantation, and the ME-MRI procedure was same to group 1. In group 3, the TBI rats received NSCs (labeled with SPIO) transplantation, and the ME-MRI procedure was same to group 1, but diltiazem was introduced during the electrical stimulation period. In group 4, the TBI rats received phosphate buffered saline (PBS) injection, and the ME-MRI procedure was same to group 1.Results Hyperintense signals were detected by ME-MRI in the cortex areas associated with somatosensory in TBI rats of group 2. These signals, which could not be induced in TBI rats of groups 1 and 4, disappeared when diltiazem was introduced in TBI rats of group 3.Conclusion In this initial study, we mapped implanted NSCs activity and its functional participation within local brain area in TBI rats by ME-MRI technique, paving the way for further pre-clinical research.

  13. Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma

    Bevilacqua, M.; Vago, T.; Norbiato, G. (Servizio di Endocrinologia, Milano, (Italy))


    Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine ({sup 3}H)-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca{sup 2}{sup +} and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca{sup 2}{sup +}-containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37{degree}C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37{degree}C decreased the affinity of the binding; this effect was counteracted by the addition of Ca{sup 2}{sup +} to the medium. This result was consistent with a competition between Ca{sup 2}{sup +} and PC. The effect of PC incubation at 4{degree}C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca{sup 2}{sup +}.

  14. Development and validation of an HPLC-DAD method for simultaneous determination of cocaine, benzoic acid, benzoylecgonine and the main adulterants found in products based on cocaine.

    Floriani, Gisele; Gasparetto, João Cleverson; Pontarolo, Roberto; Gonçalves, Alan Guilherme


    Here, an HPLC-DAD method was developed and validated for simultaneous determination of cocaine, two cocaine degradation products (benzoylecgonine and benzoic acid), and the main adulterants found in products based on cocaine (caffeine, lidocaine, phenacetin, benzocaine and diltiazem). The new method was developed and validated using an XBridge C18 4.6mm×250mm, 5μm particle size column maintained at 60°C. The mobile phase consisted of a gradient of acetonitrile and ammonium formate 0.05M - pH 3.1, eluted at 1.0mL/min. The volume of injection was 10μL and the DAD detector was set at 274nm. Method validation assays demonstrated suitable sensitivity, selectivity, linearity, precision and accuracy. For selectivity assay, a MS detection system could be directly adapted to the method without the need of any change in the chromatographic conditions. The robustness study indicated that the flow rate, temperature and pH of the mobile phase are critical parameters and should not be changed considering the conditions herein determined. The new method was then successfully applied for determining cocaine, benzoylecgonine, benzoic acid, caffeine, lidocaine, phenacetin, benzocaine and diltiazem in 115 samples, seized in Brazil (2007-2012), which consisted of cocaine paste, cocaine base and salt cocaine samples. This study revealed cocaine contents that ranged from undetectable to 97.2%, with 97 samples presenting at least one of the degradation products or adulterants here evaluated. All of the studied degradation products and adulterants were observed among the seized samples, justifying the application of the method, which can be used as a screening and quantification tool in forensic analysis.

  15. Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

    Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo


    Purpose Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. Materials and Methods The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10-4 M levobupivacaine, 2×10-3 M ropivacaine, and 7×10-3 M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Results Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10-3 M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Conclusion Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic. PMID:24142661

  16. Defining the role of calcium channel antagonists in heart failure due to systolic dysfunction.

    Mahé, Isabelle; Chassany, Olivier; Grenard, Anne-Sophie; Caulin, Charles; Bergmann, Jean-François


    Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations. Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure. There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a 'class b' effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents. Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized

  17. Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy

    Salabei, Joshua K. [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202 (United States); Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202 (United States); Balakumaran, Arun [Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555‐0438 (United States); Frey, Justin C. [Department of Biology, University of Wisconsin-Eau Claire, Eau Claire, WI 54702 (United States); Boor, Paul J. [Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555‐0438 (United States); Treinen-Moslen, Mary [Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555‐0609 (United States); Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555‐0438 (United States); Conklin, Daniel J., E-mail: [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202 (United States); Division of Cardiovascular Medicine, University of Louisville, Louisville, KY 40202 (United States); Department of Biology, University of Wisconsin-Eau Claire, Eau Claire, WI 54702 (United States); Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555‐0438 (United States)


    Calcium channel blockers (CCBs) are important in the management of hypertension and limit restenosis. Although CCB efficacy could derive from decreased blood pressure, other mechanisms independent of CCB activity also can contribute to antiproliferative action. To understand mechanisms of CCB-mediated antiproliferation, we studied two structurally dissimilar CCBs, diltiazem and verapamil, in cultured rat vascular smooth muscle cells (VSMC). To elucidate CCB-independent effects, pure stereoisomers of verapamil (R-verapamil, inactive VR; S-verapamil, active, VS) were used. The effects of CCB exposure on cell viability (MTT reduction), cell proliferation ({sup 3}H-thymidine incorporation), VSMC morphology by light and transmission electron microscopy (TEM) and autophagy (LC3I/II, ATG5) were measured. In general, verapamil, VR or VS treatment alone (80 μM) appreciably enhanced MTT absorbance although higher concentrations (VR or VS) slightly decreased MTT absorbance. Diltiazem (140 μM) markedly decreased MTT absorbance (40%) at 120 h. VR or VS treatment inhibited {sup 3}H-thymidine incorporation (24 h) and induced cytological alterations (i.e., karyokinesis, enhanced perinuclear MTT deposition, accumulated perinuclear “vacuoles”). TEM revealed perinuclear “vacuoles” to be aggregates of highly laminated and electron-dense vesicles resembling autophagosomes and lysosomes, respectively. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation by Western blotting and by increased perinuclear LC3-GFP{sup +} puncta in verapamil-treated VSMC. Verapamil stereoisomers appeared to decrease perinuclear mitochondrial density. These observations indicate that antiproliferative effects of verapamil stereoisomers are produced by enhanced mitochondrial damage and upregulated autophagy in VSMC. These effects are independent of CCB activity indicating a distinct mechanism of action that could be targeted for more efficacious anti

  18. Effect of cytochrome P450 and aldo-keto reductase inhibitors on progesterone inactivation in primary bovine hepatic cell cultures.

    Lemley, C O; Wilson, M E


    Progesterone is required for maintenance of pregnancy, and peripheral concentrations of progesterone are affected by both production and inactivation. Hepatic cytochrome P450 (EC and aldo-keto reductase (EC enzymes play a pivotal role in the first step of steroid inactivation, which involves the addition of hydroxyl groups to various sites of the cyclopentanoperhydrophenanthrene nucleus. The current objective was to discern the proportional involvement of hepatic progesterone inactivating enzymes on progesterone decay using specific enzyme inhibitors. Ticlopidine, diltiazem, curcumin, dicumarol, and naproxen were used because of their selective inhibition of cytochrome P450s, aldo-keto reductases, and glucuronosyltransferases. Liver biopsies were collected from 6 lactating Holstein dairy cows, and cells were dissociated using a nonperfusion technique. Confluent wells were preincubated for 4 h with enzyme inhibitor and then challenged with progesterone for 1 h. Cell viability was unaffected by inhibitor treatment and averaged 84±1%. In control wells, 50% of the progesterone had been inactivated after a 1-h challenge with 5 ng/mL of progesterone. Preincubation with curcumin, ticlopidine, or naproxen caused the greatest reduction in progesterone inactivation compared with controls and averaged 77, 39, or 37%, respectively. Hydroxylation of 4-nitrophenol to 4-nitrocatechol in intact cells was inhibited by approximately 65% after treatment with curcumin or ticlopidine. Glucuronidation of phenol red or 4-nitrocatechol in intact cells was inhibited by treatment with curcumin, dicumarol, or naproxen. In cytoplasmic preparations, aldo-keto reductase 1C activity was inhibited by curcumin, dicumarol, or naproxen treatment. Microsomal cytochrome P450 2C activity was inhibited by treatment with curcumin or ticlopidine, whereas cytochrome P450 3A activity was inhibited by treatment with curcumin or diltiazem. The contribution of cytochrome P450 2C and

  19. Cooling device for bradycardia based on Peltier element for accurate anastomosis of off-pump coronary artery bypass grafting.

    Kuniyoshi, Yukio; Koja, Kageharu; Miyagi, Kazufumi; Shimoji, Mituyoshi; Uezu, Tooru; Arakaki, Katuya; Yamashiro, Satoshi; Mabuni, Katuhito; Senaha, Shigenobu


    Upon introducing off-pump coronary artery bypass grafting (CABG), the indications for CABG were expanded to include patients who previously had no operative indications. For accurate anastomosis, various devices and methods have been developed. Bradycardia is easily induced by drug administration. However, this method of achieving bradycardia also has adverse effects on cardiac function. We have developed a new device to decrease the heart rate by regional cooling of the sino-atrial node. The new device is incorporated with Peltier's element, which uses an electric charge to create a temperature gradient on both of its surfaces. In terms of the cooling ability of this device, its cooling surface is chilled from 25 degrees C to 0 degrees C within 30 s. During in vivo animal experiments, this device has been shown to decrease the myocardial temperature around the sino-atrial node to 15 degrees C and suppress sino-atrial node activity, resulting in bradycardia to 60 beats/min level. In summary, the simple and easily applicable device for local cooling in combination with the application of diltiazem for effective heart rate reduction may be very helpful for the surgeon and may avoid disadvantages for critically ill patients.

  20. Removal and seasonal variability of selected analgesics/anti-inflammatory, anti-hypertensive/cardiovascular pharmaceuticals and UV filters in wastewater treatment plant.

    Golovko, Oksana; Kumar, Vimal; Fedorova, Ganna; Randak, Tomas; Grabic, Roman


    Seasonal removal efficiency of 16 pharmaceuticals and personal care products was monitored in a wastewater treatment plant in České Budějovice, Czech Republic, over a period of 1 year (total amount of samples, n = 272). The studied compounds included four UV filters, three analgesics/anti-inflammatory drugs and nine anti-hypertensive/cardiovascular drugs. In most cases, elimination of the substances was incomplete, and overall removal rates varied strongly from -38 to 100%. Therefore, it was difficult to establish a general trend for each therapeutic group. Based on the removal efficiencies (REs) over the year, three groups of target compounds were observed. A few compounds (benzophenon-1, valsartan, isradipine and furosemide) were not fully removed, but their REs were greater than 50%. The second group of analytes, consisting of 2-phenylbenzimidazole-5-sulfonic acid, tramadol, sotalol, metoprolol, atenolol and diclofenac, showed a very low RE (lower than 50%). The third group of compounds showed extremely variable RE (benzophenon-3 and benzophenon-4, codeine, verapamil, diltiazem and bisoprolol). There were significant seasonal trends in the observed REs, with reduced efficiencies in colder months.

  1. Safrole-induced Ca2+ mobilization and cytotoxicity in human PC3 prostate cancer cells.

    Chang, H C; Cheng, H H; Huang, C J; Chen, W C; Chen, I S; Liu, S I; Hsu, S S; Chang, H T; Wang, J K; Lu, Y C; Chou, C T; Jan, C R


    The effect of the carcinogen safrole on intracellular Ca2+ mobilization and on viability of human PC3 prostate cancer cells was examined. Cytosolic free Ca2+ levels ([Ca2+]i) were measured by using fura-2 as a probe. Safrole at concentrations above 10 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 value of 350 microM. The Ca2+ signal was reduced by more than half after removing extracellular Ca2+ but was unaffected by nifedipine, nicardipine, nimodipine, diltiazem, or verapamil. In Ca2+-free medium, after treatment with 650 microM safrole, 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) failed to release Ca2+. Neither inhibition of phospholipase C with U73122 nor modulation of protein kinase C activity affected safrole-induced Ca2+ release. Overnight incubation with 0.65-65 microM safrole did not affect cell viability, but incubation with 325-625 microM safrole decreased viability. Collectively, the data suggest that in PC3 cells, safrole induced a [Ca2+]i increase by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion, and by inducing Ca2+ influx. Safrole can decrease cell viability in a concentration-dependent manner.

  2. Systematic approach to optimize a pretreatment method for ultrasensitive liquid chromatography with tandem mass spectrometry analysis of multiple target compounds in biological samples.

    Togashi, Kazutaka; Mutaguchi, Kuninori; Komuro, Setsuko; Kataoka, Makoto; Yamazaki, Hiroshi; Yamashita, Shinji


    In current approaches for new drug development, highly sensitive and robust analytical methods for the determination of test compounds in biological samples are essential. These analytical methods should be optimized for every target compound. However, for biological samples that contain multiple compounds as new drug candidates obtained by cassette dosing tests, it would be preferable to develop a single method that allows the determination of all compounds at once. This study aims to establish a systematic approach that enables a selection of the most appropriate pretreatment method for multiple target compounds without the use of their chemical information. We investigated the retention times of 27 known compounds under different mobile phase conditions and determined the required pretreatment of human plasma samples using several solid-phase and liquid-liquid extractions. From the relationship between retention time and recovery in a principal component analysis, appropriate pretreatments were categorized into several types. Based on the category, we have optimized a pretreatment method for the identification of three calcium channel blockers in human plasma. Plasma concentrations of these drugs in a cassette-dose clinical study at microdose level were successfully determined with a lower limit of quantitation of 0.2 pg/mL for diltiazem, 1 pg/mL for nicardipine, and 2 pg/mL for nifedipine.

  3. Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide.

    Turner, Stephen T; Boerwinkle, Eric; O'Connell, Jeffrey R; Bailey, Kent R; Gong, Yan; Chapman, Arlene B; McDonough, Caitrin W; Beitelshees, Amber L; Schwartz, Gary L; Gums, John G; Padmanabhan, Sandosh; Hiltunen, Timo P; Citterio, Lorena; Donner, Kati M; Hedner, Thomas; Lanzani, Chiara; Melander, Olle; Saarela, Janna; Ripatti, Samuli; Wahlstrand, Björn; Manunta, Paolo; Kontula, Kimmo; Dominiczak, Anna F; Cooper-DeHoff, Rhonda M; Johnson, Julie A


    To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.

  4. Microbial degradation of pharmaceuticals in estuarine and coastal seawater

    Benotti, Mark J. [Marine Sciences Research Center, Stony Brook University, Stony Brook, NY 11794-5000 (United States); Brownawell, Bruce J. [Marine Sciences Research Center, Stony Brook University, Stony Brook, NY 11794-5000 (United States)], E-mail:


    Microbial degradation rates were measured for 19 pharmaceuticals in estuarine and coastal surface water samples. Antipyrine, carbamazepine, cotinine, sulfamethoxazole, and trimethoprim were the most refractory (half-lives, t{sub 1/2} = 35 to >100 days), making them excellent candidates for wastewater tracers. Nicotine, acetaminophen, and fluoxetine were labile across all treatments (t{sub 1/2} = 0.68-11 days). Caffeine, diltiazem, and nifedipine were also and relatively labile in all but one of the treatments (t{sub 1/2} = 3.5-13 days). Microbial degradation of caffeine was further confirmed by production {sup 14}CO{sub 2}. The fastest decay of non-refractory compounds was always observed in more sewage-affected Jamaica Bay waters. Degradation rates for the majority of these pharmaceuticals are much slower than reported rates for small biomolecules, such as glucose and amino acids. Batch sorption experiments indicate that removal of these soluble pharmaceuticals from the water column to sediments is a relatively insignificant removal process in these receiving waters. - Microbial degradation rates were measured for 19 structurally variable pharmaceuticals in wastewater-impacted estuarine and coastal seawater.


    Franci Cesar


    Full Text Available Background. A variant form of angina pectoris (VAP is caused by coronary vessel spasm and occures in patients with and without varying degrees of obstructive coronary artery disease. Although the prognosis of VAP without significant organic stenosis is generally good, multivessel spasm is associated with a high risk of life-threatening abnormalities of rhythm and conduction.Patient and methods. We describe a patient who presented with prolonged chest pain, associated with hypotension, lost of consciousness, complete AV block and widespread ST segment elevations consistent with inferoanterior acute myocardial infarction. Urgent selective coronary angiography revealed spasms in right coronary artery and in left circumflex artery that were relieved by intracoronary injection of nitroglycerin. All coronary arteries were otherwise patient, without signs of atherosclerosis. The patient was treated with diltiazem and nitrates. She made a complete recovery and resumed her normal activities.Conclusions. Simultaneous multiple spasms of native coronary arteries represent a rare syndrome characterized by significantly higher incidence of potentially life-threatening arrhythmia. Less commonly, prolonged coronary spasm may mimic acute myocardial infarction. Modern management of acute coronary syndromes, including urgent coronarography, enables a prompt differentiation between prolonged coronary spasm and atherosclerotic coronary disease, warranting different treatment strategies. Medical treatment with nitrates and calcium channel blockers in most cases prevents recurrence of vasospasms and arrhythmias.

  6. The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function.

    Ya-Juan Wang


    Full Text Available High blood pressure (BP is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT of African Americans (P=0.01. This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.

  7. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

    Cipriani, A; Saunders, K; Attenburrow, M-J; Stefaniak, J; Panchal, P; Stockton, S; Lane, T A; Tunbridge, E M; Geddes, J R; Harrison, P J


    l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes. PMID:27240535

  8. Safety and Efficacy of Intracoronary Vasodilators in the Treatment of No-Reflow after Primary Percutaneous Intervention in Patients with Acute ST-Elevation Myocardial Infarction: A Literature Review

    Mostafa Dastani


    Full Text Available Introduction: The investigation of no-reflow phenomenon after Percutaneous Coronary Intervention (PCI in patients with acute ST-segment Elevation Myocardial Infarction (STEMI has therapeutic implications. Several vasodilators were administered through intracoronary injection to treat this phenomenon. We aimed to elucidate the risk factors, predictors, and long-term effects of no-reflow phenomenon, and to compare the effects of various vasodilators on re-opening the obstructed vessels. Materials and Methods: All the reviewed articles were retrieved from MEDLINE and Science Direct (up to October 2014. All no-reflow cases were determined through Thrombolysis in Myocardial Infarction grading (TIMI system. Results: Four articles were included, two of which mainly focused on risk factors, predictors, and long-term prognosis of no-reflow phenomenon, and its association with patient mortality and morbidity. The other two articles evaluated therapeutic interventions and compared their efficacy in treating no-reflow. Conclusion: Development of no-reflow in patients with STEMI after primary PCI is associated with low myocardial salvage by primary PCI, large scintigraphic infarct size, deteriorated left ventricle ejection fraction at six months, and increased risk of first-year mortality. During primary PCI, intracoronary infusion of diltiazem and verapamil can reverse no-reflow more effectively than nitroglycerin.

  9. Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat.

    Igreja, Bruno; Pires, Nuno Miguel; Bonifácio, Maria João; Loureiro, Ana Isabel; Fernandes-Lopes, Carlos; Wright, Lyndon Christopher; Soares-da-Silva, Patrício


    Hyperactivation of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. This study evaluated the efficacy of etamicastat, a dopamine-β-hydroxylase (DβH) inhibitor, in controlling high blood pressure in the spontaneously hypertensive rat (SHR), either alone or in combination with other classes of antihypertensives. SHRs were administered with etamicastat by gavage, and its pharmacodynamic and pharmacokinetic properties were evaluated. Etamicastat induced a time-dependent decrease in noradrenaline-to-dopamine ratios in the heart and kidney, and had no effect on catecholamine levels in the frontal cortex of SHRs. Cardiovascular pharmacodynamic effects following administration of etamicastat alone or in combination with other classes of antihypertensive drugs were assessed by telemetry. Etamicastat was evaluated in combination with captopril, losartan, hydrochlorothiazide, metoprolol, prazosin and/or diltiazem. Etamicastat monotherapy induced a dose-dependent reduction in blood pressure without reflex tachycardia. Combination therapy amplified the antihypertensive effects of all tested drugs. In conclusion, inhibition of peripheral DβH with etamicastat, as a monotherapy or combination therapy, may constitute a valid alternative treatment for high blood pressure.

  10. Enhancement of the 1-Octanol/Water Partition Coefficient of the Anti-Inflammatory Indomethacin in the Presence of Lidocaine and Other Local Anesthetics.

    Tateuchi, Ryo; Sagawa, Naoki; Shimada, Yohsuke; Goto, Satoru


    Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin (log P'IND) increases in the presence of lidocaine, and this is used as a physicochemical model for investigating polypharmacy. We examined the changes in log P'IND caused by clinically used local anesthetics-lidocaine, tetracaine, mepivacaine, bupivacaine, and dibucaine-and by structurally similar basic drugs-procainamide, imipramine, and diltiazem. The quantitative structure-activity relationship study of log P'IND showed that the partition coefficient values (log PLA) and the structural entropic terms (ΔSobs, log f) of the additives affect log P'IND. These results indicate that the local anesthetics and structurally similar drugs function as phase-transfer catalysts, increasing the membrane permeability of indomethacin via heterogeneous intermolecular association. Therefore, we expect that the potency of indomethacin, an acidic nonsteroidal anti-inflammatory drug, will be increased by concurrent administration of the other drugs.

  11. Taste effects of lingual application of cardiovascular medications.

    Zervakis, J; Graham, B G; Schiffman, S S


    Medications used to treat cardiovascular diseases such as congestive heart failure, high blood pressure, and arrhythmia, are prescribed extensively in Western countries. However, taste complaints are common side effects of many of these cardiovascular medications. Although clinical observations are helpful in determining potential taste problems from a medication, experimental studies are necessary to obtain quantitative data on taste. In the studies performed here, nine cardiovascular medications (labetalol HCl, captopril, diltiazem HCl, enalapril maleate, hydrochlorothiazide, propranolol HCl, mexiletine HCl, procainamide HCl, and propafenone HCl) were applied to the tongue in human volunteers to measure the direct effect of these drugs on taste receptors. The medications were applied topically to the tongue surface of both young and elderly subjects to mimic the situation in which the drug is secreted into the saliva. Detection thresholds ranged from 0.048 mM (propafenone) to 0.438 mM (procainamide). The detection thresholds of healthy elderly subjects did not significantly differ from young controls. The compounds tested had a predominantly bitter taste with other qualities as well. In addition, topical application of the medications to the tongue affected the taste of one or more taste stimuli, with medications differing in the pattern of taste effects exhibited. The mechanism of taste effects is not fully known, but the results of this study suggest one route may be due to medications' effect on peripheral taste receptors.

  12. Balanced discussion of second-generation antihistamines' data

    Boev R


    Full Text Available Rossen Boev,1 Jürgen WG Bentz2 1UCB Pharma, Bulle, Switzerland; 2UCB Pharma, Brussels, Belgium It is with interest that we read the paper “Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine” by Wang et al1, in which the authors provide insights into the burden of allergic diseases in the Asia-Pacific region. Unfortunately, we found that the review provides some unsubstantiated information, incorrect statements, and/or data inconsistencies as listed below.The abstract states that bilastine “has very low potential for drug–drug interactions”; however, the drug label lists interactions with ketoconazole, erythromycin, diltiazem, and other intestinal efflux transporters, leading to 2–3-fold increases in drug maximum serum concentration and area under the curve2. Also, food interactions decrease bilastine’s bioavailability by 30%, and the label recommendation is that it is taken 1 hour before or 2 hours after intake of food or fruit juice2. View the original article by Wang et al.

  13. Spinal pharmacology of tactile allodynia in diabetic rats

    Calcutt, Nigel A; Chaplan, Sandra R


    Rats develop tactile allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown.Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether tactile allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing.Dose-dependent inhibition of tactile allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the α2-adrenoceptor agonist dexmedetomidine, the μ-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX.No effect on tactile allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle.These data suggest that the tactile allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins. PMID:9421298

  14. Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

    Okwa, Iniviefien B; Akindele, Abidemi J; Agbaje, Esther O; Oshinuga, Oladoyin T; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O


    Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

  15. Degradation kinetics and pathways of three calcium channel blockers under UV irradiation.

    Zhu, Bing; Zonja, Bozo; Gonzalez, Oscar; Sans, Carme; Pérez, Sandra; Barceló, Damia; Esplugas, Santiago; Xu, Ke; Qiang, Zhimin


    Calcium channel blockers (CCBs) are a group of pharmaceuticals widely prescribed to lower blood pressure and treat heart diseases. They have been frequently detected in wastewater treatment plant (WWTP) effluents and downstream river waters, thus inducing a potential risk to aquatic ecosystems. However, little is known about the behavior and fate of CCBs under UV irradiation, which has been adopted as a primary disinfection method for WWTP effluents. This study investigated the degradation kinetics and pathways of three commonly-used CCBs, including amlodipine (AML), diltiazem (DIL), and verapamil (VER), under UV (254 nm) irradiation. The chemical structures of transformation byproducts (TBPs) were first identified to assess the potential ecological hazards. On that basis, a generic solid-phase extraction method, which simultaneously used four different cartridges, was adopted to extract and enrich the TBPs. Thereafter, the photo-degradation of target CCBs was performed under UV fluences typical for WWTP effluent disinfection. The degradation of all three CCBs conformed to the pseudo-first-order kinetics, with rate constants of 0.031, 0.044 and 0.011 min(-1) for AML, DIL and VER, respectively. By comparing the MS(2) fragments and the evolution (i.e., formation or decay) trends of identified TBPs, the degradation pathways were proposed. In the WWTP effluent, although the target CCBs could be degraded, several TBPs still contained the functional pharmacophores and reached peak concentrations under UV fluences of 40-100 mJ cm(-2).

  16. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

    Johannesen, L; Vicente, J; Mason, J W; Erato, C; Sanabria, C; Waite-Labott, K; Hong, M; Lin, J; Guo, P; Mutlib, A; Wang, J; Crumb, W J; Blinova, K; Chan, D; Stohlman, J; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G


    Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

  17. Calcinosis en Esclerosis Sistémica

    Tamara Caínzos Romero


    Full Text Available Paciente de 85 años diagnosticada de esclerosis sistémica con esclerodermia limitada de años de evolución con ANA positivos a título de 1:5120 patrón anticentrómero, antiScl-70 y anti-Jo negativos. Sus principales manifestaciones clínicas son: Raynaud grave y úlceras digitales a tratamiento con nifedipino y bosentán, hipertensión pulmonar leve, esclerodactilia y calcificación extensa de tejidos blandos en ambas manos, 4º dedo de mano derecha y 4º-5º dedos de mano izquierda, con deformidades en flexión bilaterales, que pueden observarse en estudios de radiografía simple de ambas manos. La calcinosis resulta del depósito de cristales de hidroxiapatita de calcio fundamentalmente. Aunque los resultados son, en general malos, se han utilizado diltiazem, colchicina y los AINES en los casos que se produce una reacción inflamatoria similar a la pseudogota, en los casos más graves es necesario recurrir a la cirugía.

  18. Characteristics of odorant elicited calcium fluxes in acutely-isolated chick olfactory neurons.

    Jung, Yewah; Wirkus, Eric; Amendola, Diedra; Gomez, George


    To understand avian olfaction, it is important to characterize the peripheral olfactory system of a representative bird species. This study determined the functional properties of olfactory receptor neurons of the chicken olfactory epithelium. Individual neurons were acutely isolated from embryonic day-18 to newborn chicks by dissection and enzymatic dissociation. We tested single olfactory neurons with behaviorally relevant odorant mixtures and measured their responses using ratiometric calcium imaging; techniques used in this study were identical to those used in other studies of olfaction in other vertebrate species. Chick olfactory neurons displayed properties similar to those found in other vertebrates: they responded to odorant stimuli with either decreases or increases in intracellular calcium, calcium increases were mediated by a calcium influx, and responses were reversibly inhibited by 100 microM L: -cis-diltiazem, 1 mM Neomycin, and 20 microM U73122, which are biochemical inhibitors of second messenger signaling. In addition, some cells showed a complex pattern of responses, with different odorant mixtures eliciting increases or decreases in calcium in the same cell. It appears that there are common features of odorant signaling shared by a variety of vertebrate species, as well as features that may be peculiar to chickens.

  19. Modification of intracellular free calcium in cultured A10 vascular smooth muscle cells by exogenous phosphatidic acid.

    Bhugra, Praveen; Xu, Yan-Jun; Rathi, Satyajeet; Dhalla, Naranjan S


    Exogenous phosphatidic acid (PA) was observed to produce a concentration-dependent increase in [Ca(2+)](i) in cultured A10 vascular smooth muscle cells. Preincubation of cells with sarcoplasmic reticulum Ca(2+)-ATPase inhibitors (cyclopiazonic acid and thapsigargin), a phospholipase C inhibitor (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), inositol 1,4,5-trisphosphate receptor antagonists (2-aminoethoxydiphenyl borate and xestospongin), and an activator of protein kinase C (PKC) (phorbol 12-myristate 13-acetate) depressed the PA-evoked increase in [Ca(2+)](i). Although EGTA, an extracellular Ca(2+) chelator, decreased the PA-induced increase in [Ca(2+)](i), sarcolemmal Ca(2+)-channel blockers (verapamil or diltiazem) did not alter the action of PA. On the other hand, inhibitors of PKC (bisindolylmaleimide I) and G(i)-protein (pertussis toxin) potentiated the increase in [Ca(2+)](i) evoked by PA significantly. These results suggest that the PA-induced increase in [Ca(2+)](i) in vascular smooth muscle cells may occur upon the activation of phospholipase C and the subsequent release of Ca(2+) from the inositol 1,4,5-trisphosphate-sensitive Ca(2+) pool in the sarcoplasmic reticulum. This action of PA may be mediated through the involvement of PKC.

  20. Effects of calcium channel antagonists on the induction of nitric oxide synthase in cultured cells by immunostimulants.

    Hattori, Y; Kasai, K; So, S; Hattori, S; Banba, N; Shimoda, S


    We investigated whether calcium channel antagonists would alter the induction of nitric oxide (NO) synthesis by bacterial lipopolysaccharide (LPS) alone or in combination with interferon-gamma (IFN gamma) in cultured J774 macrophages, rat vascular smooth muscle cells, rat renal mesangial cells, and rat cardiac myocytes. The induction of NO synthesis was determined by measuring nitrite, the stable end-product. The dihydropyridine calcium channel antagonists, nifedipine, manidipine, nitrendipine, benidipine, barnidipine, perdipine, and nilvadipine all reduced the LPS-induced nitrite production in a dose-dependent manner, each with a differing half-maximal inhibitory concentration, in cultured J774 macrophages. Nifedipine also inhibited nitrite production in vascular smooth muscle cells, mesangial cells, and cardiac myocytes. The half-maximal inhibitory concentrations of nifedipine were ranked as follows: smooth muscle cells < mesangial cells < cardiac myocytes. Diltiazem, at nontoxic concentrations, had no effect on the nitrite formation in the three cell types. Verapamil markedly increased the formation of nitrite in cardiac myocytes in response to LPS and IFN gamma, but not in vascular smooth muscle or mesangial cells. Exposure of cardiac myocytes to LPS and IFN gamma caused the expression of NO synthase mRNA that was significantly increased by verapamil. Thus, certain calcium channel antagonists modulate NO synthesis by altering the induction of NO synthase.

  1. [Influence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients].

    Yoshimoto, H; Takahashi, M; Saima, S


    Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.

  2. Drug hypersensitivity syndrome

    Rashmi Kumari


    Full Text Available Drug hypersensitivity syndrome (DHS is an adverse drug reaction commonly associated with the aromatic antiepileptic drugs (AEDs, viz., phenytoin (PHT, carbamazepine (CBZ, phenobarbital (PB, lamotrigine, primidone, etc. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol. Diagnosis of DHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic or collagen vascular disorders. The risk for developing hypersensitivity within 60 days of the first or second prescription in new users of PHT or CBZ was estimated to be 2.3-4.5 per 10,000 and 1-4.1 per 10,000, respectively. The syndrome is defined by the fever, skin rash, lymphadenopathy and internal organ involvement within the first 2-8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis and myositis. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Cross-reactivity among PHT, CBZ and PB is as high as 70%-80%. Management mainly includes immediate withdrawal of the culprit drug, symptomatic treatment and systemic steroids or immunoglobulins.


    Vaibhav Shukla


    Full Text Available Diltiazem HCl (DTZ is an antihypertensive agent that antagonizes the action of beta-1 receptor. DTZ when given orally is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect. DTZ undergoes extensive metabolism in which only 2% to 4% of the unchanged drug appears in the urine. Drugs which induce or inhibit hepatic microsomal enzymes may alter DTZ disposition. It has been reported that the absolute bioavailability of DTZ when given orally is 30-40%. The biological half-life of DTZ is 4-6 hour and the main site of absorption is proximal small intestine.The reduced bioavailability of DTZ may be because of transportation of dosage form from the region of absorption window to site where it is less absorbed. Therefore there was a need to increase gastroretention time of dosage form so that drug would be available at the site of absorption and results in improved bioavailability. A mucoadhesive nanoparticle delivery system was envisioned for DTZ as such a system when administered would adhere on the gastric mucosa for a prolong period of time and the drug would be available at the main site of absorption i.e. proximal small intestine resulting in enhanced bioavailability.

  4. Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers.

    Samak, Geetha; Gangwar, Ruchika; Meena, Avtar S; Rao, Roshan G; Shukla, Pradeep K; Manda, Bhargavi; Narayanan, Damodaran; Jaggar, Jonathan H; Rao, RadhaKrishna


    Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca(2+)-free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or CaV1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L-cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK.

  5. Prevalence of gingival overgrowth induced by antihypertensive drugs: A hospital-based study

    Saumiya Gopal


    Full Text Available Background: Gingival overgrowth (GO is a known side-effect of calcium channel blockers. Although there have been several case reports, few studies have examined the prevalence of nifedipine, diltiazem, and amlodipine. This study was conducted to determine the prevalence and risk factors for GO in patients treated with calcium channel blockers. Materials and Methods: A cross-sectional study was conducted in out patient Department of Medicine, Government Medical College, Calicut. 133 patients taking antihypertensives were examined for the presence of GO using two different indices: Vertical GO in 6 points around each tooth and horizontal Miranda-Brunet index in the interdental area. Gingival index (GI, plaque index, and probing depth were also evaluated. Results: The frequency of GO was significantly higher in nifedipine-treated cases than other drug groups. Frequency of GO was 75% for nifedipine, 31.4% for amlodipine and 25% for amlodipine + metoprolol. Higher gingival, plaque and calculus were observed in patients taking calcium channel blockers. Among the possible risk factors, only the GI showed a significant correlation with GO. Conclusions: Patients taking antihypertensives had poor oral hygiene. Patients taking nifedipine showed a higher frequency of GO. Gingival inflammation acts as a predisposing factor.

  6. Physicochemical characterisation and investigation of the bonding mechanisms of API-titanate nanotube composites as new drug carrier systems.

    Sipos, Barbara; Pintye-Hódi, Klára; Kónya, Zoltán; Kelemen, András; Regdon, Géza; Sovány, Tamás


    Titanate nanotube (TNT) has recently been explored as a new carrier material for active pharmaceutical ingredients (API). The aim of the present work was to reveal the physicochemical properties of API-TNT composites, focusing on the interactions between the TNTs and the incorporated APIs. Drugs belonging to different Biopharmaceutical Classification System (BCS) classes were loaded into TNTs: diltiazem hydrochloride (BCS I.), diclofenac sodium (BCS II.), atenolol (BCS III.) and hydrochlorothiazide (BCS IV.). Experimental results demonstrated that it is feasible for spiral cross-sectioned titanate nanotubes to carry drugs and maintain their bioactivity. The structural properties of the composites were characterized by a range of analytical techniques, including FT-IR, DSC, TG-MS, etc. The interactions between APIs and TNTs were identified as electrostatic attractions, mainly dominated by hydrogen bonds. Based on the results, it can be stated that the strength of the association depends on the hydrogen donor strength of the API. The drug release of incorporated APIs was evaluated from compressed tablets and compared to that of pure APIs. Differences noticed in the dissolution profiles due to incorporation showed a correlation with the strength of interactions between the APIs and the TNTs observed in the above analytical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Direct measurement of calcium transport across chloroplast inner-envelope vesicles

    Roh, M.H.; Shingles, R.; Cleveland, M.J.; McCarty, R.E. [Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biology


    The initial rate of Ca{sup 2+} movement across the inner-envelope membrane of pea (Pisum sativum L.) chloroplasts was directly measured by stopped-flow spectrofluorometry using membrane vesicles loaded with the Ca{sup 2+}-sensitive fluorophore fura-2. Calibration of fura-2 fluorescence was achieved by combining a ratiometric method with Ca{sup 2+}-selective minielectrodes to determine pCa values. The initial rate of Ca{sup 2+} influx in predominantly right-side-out inner-envelope membrane vesicles was greater than that in largely inside-out vesicles. Ca{sup 2+} movement was stimulated by an inwardly directed electrochemical proton gradient across the membrane vesicles, an effect that was diminished by the addition of valinomycin in the presence of K{sup +}. In addition, Ca{sup 2+} was shown to move across the membrane vesicles in the presence of K{sup +} diffusion potential gradient. The potential-stimulated rate of Ca{sup 2+} transport was slightly inhibited by diltiazem and greatly inhibited by ruthenium red. Other pharmacological agents such as LaCl{sub 3}, verapamil, and nifedipine had little or no effect. These results indicate that Ca{sup 2+} transport across the chloroplast inner envelope can occur by a potential-stimulated uniport mechanism.

  8. Sudden cardiac death in a dog during Holter recording-R on T phenomenon.

    Gunasekaran, T; Sanders, R A


    A 6-year-old castrated male Golden Retriever was diagnosed with severe subaortic stenosis with severe left atrial enlargement and high heart rate due to atrial fibrillation. Treatment with digoxin and diltiazem to control ventricular response rate was initiated. Ambulatory electrocardiographic monitoring (Holter monitoring) was performed at the beginning of treatment and was repeated to evaluate the patient's response to drug therapy. Drug dose adjustments were made based on response to therapy as assessed by Holter monitoring. The dog experienced sudden death at home 19 days after beginning treatment while wearing the Holter monitor. Analysis of the Holter recording revealed marked increase in number and complexity of ventricular arrhythmias. A ventricular premature complex occurring on a T wave (R on T) was noted preceding the polymorphic ventricular tachycardia. This arrhythmia immediately degenerated into ventricular fibrillation followed by asystole. This case report describes the arrhythmia that preceded cardiac arrest and reviews the risk factors that could have potentiated the fatal arrhythmia in this dog. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Roles of extracellular Ca++ and calmodulin in roxatidine-stimulated secretion and synthesis of mucus by cultured rabbit gastric mucosal cells.

    Takahashi, S; Okabe, S


    We found that roxatidine stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells. In this study, we examined the roles of the extracellular Ca++ and calmodulin in these effects of roxatidine. Reduction of the extracellular Ca++ concentration decreased the roxatidine-induced increases in mucus secretion and synthesis by gastric mucosal cells. Roxatidine concentration-dependently promoted Ca++ influx and caused an increases in intracellular Ca++. After the addition of roxatidine, the increases in the secretion and synthesis reflected those in Ca++ influx and intracellular Ca++ concentration and then disappeared as Ca++ influx and intracellular Ca++ concentration returned to the control level. The roxatidine-stimulated Ca++ influx and intracellular Ca++ mobilization were abolished by reduction of the extracellular Ca++ concentration. Nifedipine and diltiazem inhibited both the effects of roxatidine, but even at 10 microM, the inhibition was partial. Furthermore, W-7 (a calmodulin antagonist) completely abolished the effects of roxatidine on mucus secretion and synthesis without causing a reduction of the stimulated Ca++ influx. Taken together, these results suggest that roxatidine promotes Ca++ influx through both voltage-sensitive Ca++ channels and other Ca++ entry gates and the subsequent intracellular Ca++ mobilization, leading to potentiation of mucus secretion and synthesis by rabbit gastric mucosal cells. In addition, Ca(++)-activated calmodulin may play a pivotal role in these stimulatory effects of roxatidine.

  10. Performance evaluation of the UV/H2O2 process on selected nitrogenous organic compounds: reductions of organic contents vs. corresponding C-, N-DBPs formations.

    Chen, Huei-Wen; Chen, Chia-Yang; Wang, Gen-Shuh


    The presence of various organic contaminants in water sources is of concern due to their direct threats to human health and potential to react with disinfectants to form carcinogenic byproducts including trihalomethanes, haloacetic acids and nitrosamines in finished water. This study applied both medium-pressure and low-pressure ultraviolet light coupled with hydrogen peroxide (UV/H2O2) to evaluate its efficacy for degradation of selected nitrogenous organic compounds and corresponding disinfection byproduct (DBP) formation. Six organic compounds were chosen as target precursors based on their nitrogen contents and molecular structures. The results showed that higher oxidation capacity resulted in better reduction of organic matters and DBP formation potentials (DBPFPs). However, insufficient contact time and oxidant doses could lead to a rise of DBPFPs in the early stages of UV/H2O2 reactions. A greater percentage removal was achieved for organic carbon than organic nitrogen after UV/H2O2 treatment, especially for compounds with complicated structure such as diltiazem. During the UV/H2O2 treatment, the intermediate products include tertiary amine, dimethyl amine (DMA) or DMA-like structures, which are N-nitrosodimethylamine (NDMA) precursors after chlorination or chloramination. Furthermore, it was observed that using dissolved organic nitrogen and DMA to predict NDMAFP could lead to biased conclusions because of the complex nature of nitrogenous matters in aqueous environments.

  11. Konjac glucomannan and konjac glucomannan/xanthan gum mixtures as excipients for controlled drug delivery systems. Diffusion of small drugs.

    Alvarez-Manceñido, Felipe; Landin, Mariana; Lacik, Igor; Martínez-Pacheco, Ramón


    Konjac glucomannan (KGM), alone or in combination with xanthan gum (XG), was evaluated as main component of systems capable of controlling the diffusion of small molecules with a view of their use in drug delivery. To provide the study with enough general character, KGM batches were obtained from the three main areas of excipient harmonization (Europe, USA and Japan). The rheological evaluation at physiological temperature of KGM (0.5%, w/v) aqueous dispersions, with or without XG at different ratios, showed significant variability among the three KGMs owing to differences in the acetylation degree. The Japanese and European varieties of KGM synergically interact with XG giving rise to gel formation; the synergism being maximum at a 1:1 ratio. By contrast, the American KGM does not show such effect forming only viscous solutions. Drug diffusion coefficients of theophylline and diltiazem HCl, with different molecular size and net charge, were evaluated in systems containing KGM/XG ratio 1:1. KGM/XG systems were more efficient than the XG alone dispersion for controlling drug diffusion of small molecules because of the gel formation. These results point out the potential of mixtures of some KGM types with XG to develop delivery systems capable of maintaining physical integrity and drug release control for up to 8-h period.

  12. Cardiac actions of phencyclidine in isolated guinea pig and rat heart: possible involvement of slow channels

    Temma, K.; Akera, T.; Ng, Y.C.


    The mechanisms responsible for the positive inotropic effect of phencyclidine were studied in isolated preparations of guinea pig and rat heart. In electrically paced left atrial muscle preparations, phencyclidine increased the force of contraction; rat heart muscle preparations were more sensitive than guinea pig heart muscle preparations. The positive inotropic effect of phencyclidine was not significantly reduced by a combination of phentolamine and nadolol; however, the effect was competitively blocked by verapamil in the presence of phentolamine and nadolol. Inhibition of the outward K+ current by tetraethylammonium chloride also produced a positive inotropic effect; however, the effect of tetraethylammonium was reduced by phentolamine and nadolol, and was almost insensitive to verapamil. The inotropic effect of phencyclidine was associated with a marked prolongation of the action potential duration and a decrease in maximal upstroke velocity of the action potential, with no change in the resting membrane potential. The specific (/sup 3/H)phencyclidine binding observed with membrane preparations from guinea pig ventricular muscle was saturable with a single class of high-affinity binding site. This binding was inhibited by verapamil, diltiazem, or nitrendipine, but not by ryanodine or tetrodotoxin. These results suggest that the positive inotropic effect of phencyclidine results from enhanced Ca/sup 2 +/ influx via slow channels, either by stimulation of the channels or secondary to inhibition of outward K/sup +/ currents.

  13. The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?

    Cheng, Jen-Kun; Chen, Chien-Chuan; Yang, Jia-Rung; Chiou, Lih-Chu


    Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.

  14. Brain death provokes very acute alteration in myocardial morphology detected by echocardiography: preventive effect of beta-blockers.

    Ferrera, René; Hadour, Guylaine; Tamion, Fabienne; Henry, Jean-Paul; Mulder, Paul; Richard, Vincent; Thuillez, Christian; Ovize, Michel; Derumeaux, Geneviève


    Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg). Treatments were administered intravenously 5 min before BD induction. Echocardiography (ATL-5000, 8 MHz) was performed to measure left ventricular (LV) dimensions and fractional shortening at baseline, during BD induction and 5 min and 15 min after BD. In controls, BD was immediately associated with an increase in wall thickness and a decrease in LV cavity dimension. This myocardial wall hypertrophy was completely prevented by β-blockers, but not with calcium- and alpha-blockers. Extensive myocardial interstitial edema was found in all groups, except in the β-blocker group. Myocardial wall hypertrophy was also prevented during a longer follow-up of 180 min after BD in β-blocker group as opposed to controls. In conclusion, BD is associated with an immediate and severe myocardial damage related to an important interstitial edema which is prevented by β-blockers.

  15. Multiple unit gastroretentive drug delivery systems: a new preparation method for low density microparticles.

    Streubel, A; Siepmann, J; Bodmeier, R


    The aim of this study was to develop a new preparation method for low density foam-based, floating microparticles and to demonstrate the systems' performance in vitro. Major advantages of the novel preparation technique include: (i) short processing times, (ii) no exposure of the ingredients to high temperatures, (iii) the possibility to avoid toxic organic solvents, and (iv) high encapsulation efficiencies close to 100%. Floating microparticles consisting of polypropylene foam powder, model drug [chlorpheniramine maleate (CPM), diltiazem HCl, theophylline or verapamil HCl] and polymer [Eudragit RS or polymethyl methacrylate (PMMA)] were prepared by soaking the microporous foam carrier with an organic solution of drug and polymer and subsequent drying. The effects of various formulation and processing parameters on the resulting in vitro floating behaviour, internal and external particle morphology, drug loading, in vitro drug release and physical state of the incorporated drug were studied. Good in vitro floating behaviour was observed in most cases and a broad variety of drug release patterns could be achieved by varying the drug loading and type of polymer. Interestingly, PMMA-based microparticles showed incomplete drug release with verapamil HCl. This restriction could be overcome by forming the free base of the drug prior to microparticle preparation. In contrast to the salt, the free base acted as a plasticizer for PMMA, resulting in sufficiently high diffusion coefficients and, consequently, complete drug release. The low density microparticles were compressed into rapidly disintegrating tablets in order to provide an administrable oral dosage form.

  16. Treatment of an Early Kaposi’s Sarcoma Case Post Kidney Transplantation by Sirolimus: A Case Report

    Farzaneh Najafi


    Full Text Available Kaposi᾽s sarcoma (KS can develop in 0.06% to 4.1% of kidney transplant recipients. Here we describe a case of 50-year-old man who developed KS a few months after kidney transplantation. After transplantation, he had delayed graft function and was managed by anti-thymocyte globulin (ATG for five days. At the discharge, his immunosuppressive therapy was prednisolone 20 mg/day, tTacrolimus (Pprograf® 4 mg/day, and mycophenolate mofetil (MMF 2 gr/day, while he also took Vvalcyte and diltiazem. Once diagnosed with KS, the Prograf® (tacrolimus  was replaced by prednisolone (5 mg/day and sirolimus (2 mg/day. Gradually the skin nodule on the patient arm disappeared, and the others nodule on the right his leg was decreased. It seems that the examination of skin should be a part of regular follow-up and dermatologist examination is recommended every 6 months.

  17. Chitosan-polycarbophil complexes in swellable matrix systems for controlled drug release.

    Lu, Z; Chen, W; Hamman, J H


    A prerequisite for progress in the design of novel drug delivery systems is the development of excipients that are capable of fulfilling multifunctional roles such as controlling the release of the drug according to the therapeutic needs. Although several polymers have been utilised in the development of specialised drug delivery systems, their scope in dosage form design can be enlarged through combining different polymers. When a polymer is cross-linked or complexed with an oppositely charged polyelectrolyte, a three-dimensional network is formed in which the drug can be incorporated to control its release. The swelling properties and release kinetics of two model drugs with different water solubilities (i.e. diltiazem and ibuprofen) from monolithic matrix tablets consisting of an interpolyelectrolyte complex between chitosan and polycarbophil are reported. Matrix tablets consisting of this polymeric complex without drug or excipients exhibited extremely high swelling properties that are completely reversible upon drying. The drug release from matrix systems with different formulations depended on the concentration of the chitosan-polycarbophil interpolyelectrolyte complex and approached zero order release kinetics for both model drugs. The chitosan-polycarbophil interpolyelectrolyte complex has demonstrated a high potential as an excipient for the production of swellable matrix systems with controlled drug release properties.

  18. Effect of aqueous extract of Ipomoea carnea leaf on isolated frog and mouse heart.

    Bachhav, K V; Burande, M D; Rangari, V D; Mehta, J K


    Ipomoea carnea fam. Convolvulaceae is a poisonous plant and its toxicity is supposed to be due to the cardiac and respiratory failure. The present paper describes the cardiac effect of aqueous extract of the fresh leaves of I. carnea using mouse and frog heart. The aqueous extract produced an initial blockade of isolated frog heart for 5-10 sec followed by dose dependent increase in both amplitude and rate that lasts up to 2 min. Atropine (1 microgram/ml) blocked the initial depressant phase and potentiated the stimulant effect of the aqueous extract. The dose dependent increase in cardiac contractility of aqueous extract was not altered by propranolol or calcium channel blockers like nifedipine or diltiazem. The decrease in sodium chloride concentration or increase in potassium chloride concentration or calcium chloride concentration in physiological salt solution inhibited the responses to aqueous extract while an increase in sodium chloride concentration or decrease in potassium chloride or calcium chloride concentration in physiological salt solution potentiated the responses to the aqueous extract of I. carnea. It may be suggested from the data that aqueous extract of I. carnea produces positive inotropic effect on isolate frog heart possibly by sodium extrusion or release of the intracellular calcium.

  19. Transamidation of carboxamides catalyzed by Fe(III) and water.

    Becerra-Figueroa, Liliana; Ojeda-Porras, Andrea; Gamba-Sánchez, Diego


    The highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is described. The reaction is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III), and the results show that the presence of water is crucial. The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. An example of its use is an intramolecular application in the synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one, which is the bicyclic core of diltiazem and structurally related drugs (Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr. Med. Chem. 2007, 14, 279-287). A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum. This methodology represents a significant improvement over other existing methods; it can be performed in air and with wet or technical grade solvents.

  20. [Beer-Fick criteria and generic drugs in Brazil].

    Gorzoni, Milton Luiz; Fabbri, Renato Moraes Alves; Pires, Sueli Luciano


    Determine, according to the Beer-Fick criteria, the prevalence of drugs potentially inappropriate for the elderly available as generic medication in Brazil. Analysis of the list of generic medications issued by " Diário Oficial da União" on July/12/2004 and of the page of the National Agency for Sanitary Surveillance (ANVISA) -, using the Beers-Fick criteria. From the list of 299 products 20 (6.7% of the total) included in the Beers-Fick criteria were analyzed, mainly in the categories of anxiolytics, platelet antiaggregants, antiallergics, anti-angina and vasodilators, antiarrythmics, antidepressants, antispasmodics, anti-hypertensive's, non steroid antinflammatories, antiulceratives and cardiac glycosides. These criteria do not include drugs such as cough suppressants, cinnarizine, diltiazem, piracetam, quinolones, xanthines, creams, ointments and ophthalmic solutions which are also present in the list of generic medication. The Beers-Fick criteria may prevent use of drugs potentially inappropriate for the elderly, however, it should be stressed that these criteria are not complete for Brazilian generic medications.

  1. [Management of muscle cramp: what's to be done?].

    Drouet, Alain


    Muscle cramp is characterized by involuntary, painful, visible contraction of a muscle (or a part of muscle) and is always associated with irregular repetitive firing of motor unit action potentials (200 à 300 Hz) which is caused by hyperexcitability of intramuscular terminal motor axons. It's a common condition in normal people, but most commonly in young people (pregnancy, exercise) and more in the elderly (50% after 65 years-old). A careful history and examination should allow the physician to determine the significance of cramp. ENMG and biological tests are needed in cases of severe symptoms (severity and frequency of cramps) and/or abnormal examination. Idiopathic and secondary (drug or metabolic disorders) cramps are the most common groups, but it's very important to search the motor unit diseases (neuropathy, radiculopathy, plexopathy, neuromyotonia, and a cramp fasciculation syndrome which can preceded ALS). The first goal in management of cramp is to determine if there is an underlying cause and the second to use physical measures (stretching), because, pharmacologic treatments have a moderate interest because of the potential of toxicity (quinine sulfate) or a little effectiveness (vitamin B complex, naftidrofuryl, and calcium channel blockers such as diltiazem, gabapentin). Isolated cramp doesn't need treatment.

  2. Combining other antihypertensive drugs with β-blockers in hypertension: a focus on safety and tolerability.

    Richards, Tiffany R; Tobe, Sheldon W


    Combining multiple classes of antihypertensive drugs together is one of the most important factors for achieving blood pressure control in most hypertensive patients. The benefits of combination therapy in comparison with monotherapy include: a synergistic enhancement of each drug's hypertensive effects and a potential reduction of side effects if each drug is used at a lower dose. Although long-acting dihydropyridine calcium channel blockers and β-blockers are a good fit for combination therapy, because of the risk of atrioventricular block and bradycardia, the combination of verapamil and β-blockers is not advised. In addition, the combination of higher-dose diltiazem and β-blockers is also not advised. β-blockers and diuretic agents as initial lone combination therapy are not the preferred combination to be used in uncomplicated hypertension. Using an angiotensin-converting enzyme inhibitor as initial combination therapy with most β-blockers is not recommended because of a lack of antihypertensive efficacy. Nebivolol, however, appears different in this regard and might provide an opportunity for combining these 2 classes of agents with proven cardiovascular benefits for better blood pressure control. Adding an α-blocker to a β-blocker is an effective combination.

  3. Critérios de Beers-Fick e medicamentos genéricos no Brasil Beer-Fick criteria and generic drugs in Brazil

    Milton Luiz Gorzoni


    Full Text Available OBJETIVO: Determinar a prevalência de fármacos potencialmente inapropriados para idosos em medicamentos genéricos brasileiros pelos critérios de Beers-Fick. MÉTODOS: Análise da lista de medicamentos genéricos publicada no Diário Oficial da União de 12 de julho de 2004 e copiada da página da Agência Nacional de Vigilância Sanitária (ANVISA -, utilizando-se os critérios de Beers-Fick. RESULTADOS: Contendo 299 produtos e/ou apresentações, a lista analisada apresentava 20 deles (6,7% do total incluídos nos critérios de Beers-Fick, concentrados nas categorias de ansiolíticos, antiagregantes plaquetários, antialérgicos, antiangionosos e vasodilatadores, antiarrítmicos, antidepressivos, antiespasmódicos, anti-hipertensivos, antiinflamatórios não esteroidais, antiulcerosos e glicosídeos cardíacos. Esses critérios não incluem fármacos como antitussígenos, cinarizina, diltiazem, piracetam, quinolonas, xantinas, cremes, pomadas e colírios que fazem parte dessa lista de medicamentos genéricos. CONCLUSÃO: Critérios de Beers-Fick são úteis para a prevenção do uso de fármacos potencialmente inapropriados em idosos, com a ressalva de que não são completos para medicamentos genéricos brasileiros.BACKGROUND: Determine, according to the Beer-Fick criteria, the prevalence of drugs potentially inappropriate for the elderly available as generic medication in Brazil. METHODS: Analysis of the list of generic medications issued by " Diário Oficial da União" on July/12/2004 and of the page of the National Agency for Sanitary Surveillance (ANVISA -, using the Beers-Fick criteria. RESULTS: From the list of 299 products 20 (6.7% of the total included in the Beers-Fick criteria were analyzed, mainly in the categories of anxiolytics, platelet antiaggregants, antiallergics, anti-angina and vasodilators, antiarrythmics, antidepressants, antispasmodics, anti-hypertensive's, non steroid

  4. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions.

    Scheen, André J


    Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally

  5. 1例急性心功能不全缓解患者的药学监护%Pharmaceutical care on one stable patient after acute heart failure attack

    张雅; 张亚同; 纪立伟; 胡欣


    One elder female patient was admitted to hospital due to acute exacerbation of chronic heart failure. She received the standard regime of chronic heart failure after the condition was stable. And her admission diagnoses were chronic heart failure with acute exacerbation, lung infection, acute exacerbation of chronic obstructive pulmonary disease, hypertension and type 2 diabetes. For the reason that the patient developed lower limb venous thrombus and pulmonary embolism, low molecular weight heparin and warfarin were used successively. Clinical pharmacist evaluated the rationality of the overlapping time of the low molecular weight heparin and warfarin, and adjusted the dosage of warfarin by measuring the INR values. Diltiazem was withdrawn because that diltiazem may elevate the blood concentration of warfarin. Considering that ACEI or ARB were the first-line therapy for heart failure, clinical pharmacists recommended switching felodipine to losartan, and the blood pressure was controlled well. The factors affecting the blood concentration of digoxin were analyzed, and clinical pharmacists reminded the patient to pay close attention to the symptoms of poisoning for avoiding digitalis toxicity, and offered discharge education to the patient, such as avoiding use of the drugs and foods that can affect the blood concentration of warfarin, monitoring blood pressure, blood glucose and INR values.%  1例老年女性患者,因慢性心力衰竭急性发作入院,入院诊断为慢性心功能不全急性发作、肺部感染、慢性阻塞性肺疾病急性发作、高血压Ⅲ级、2型糖尿病。因患者出现下肢静脉血栓及肺栓塞,先后使用低分子肝素和华法林治疗,临床药师评估了低分子肝素和华法林的重叠使用时间,并通过测量INR值调整华法林的用量;因地尔硫卓可能升高华法林的血药浓度,建议停用地尔硫卓;考虑到心衰患者首选ACEI或ARB类降压药,建议停用非洛地

  6. Determination of five antiarrhythmic drugs in human plasma by dispersive liquid-liquid microextraction and high-performance liquid chromatography.

    Jouyban, Abolghasem; Sorouraddin, Mohammad Hossein; Farajzadeh, Mir Ali; Somi, Mohammad Hossein; Fazeli-Bakhtiyari, Rana


    A fast and sensitive high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection was developed and validated for the simultaneous quantitation of five antiarrhythmic drugs (metoprolol, propranolol, carvedilol, diltiazem, and verapamil) in human plasma samples. It involves dispersive liquid-liquid microextraction (DLLME) of the desired drugs from 660 µL plasma and separation using isocratic elution with UV detection at 200 nm. The complete separation of all analytes was achieved within 7 min. Acetonitrile (as disperser solvent) resulting from the protein precipitation procedure was mixed with 100 µL dichloromethane (as an extraction solvent) and rapidly injected into 5 mL aqueous solution (pH 11.5) containing 1% (w/v), NaCl. After centrifugation, the sedimented phase containing enriched analytes was collected and evaporated to dryness. The residue was re-dissolved in 50 µL de-ionized water (acidified to pH 3) and injected into the HPLC system for analysis. Under the optimal conditions, the enrichment factors and extraction recoveries ranged between 4.4-10.8 and 33-82%, respectively. The suggested method was linear (r(2) ≥0.997) over a dynamic range of 0.02-0.80 µg mL(-1) in plasma. The intra- and inter-days relative standard deviation (RSD%) and relative error (RE%) values of the method were below 20%, which shows good precision and accuracy. Finally, this method was applied to the analysis of real plasma samples obtained from the patients treated with these drugs.

  7. The carcinogen safrole increases intracellular free Ca2+ levels and causes death in MDCK cells.

    Chen, Wei-Chuan; Cheng, He-Hsiung; Huang, Chun-Jen; Lu, Yih-Chau; Chen, I-Shu; Liu, Shiuh-Inn; Hsu, Shu-Shong; Chang, Hong-Tai; Huang, Jong-Khing; Chen, Jin-Shyr; Jan, Chung-Ren


    The effect of the carcinogen safrole on intracellular Ca2+ movement in renal tubular cells has not been explored previously. The present study examined whether safrole could alter Ca2+ handling in Madin-Darby canine kidney (MDCK) cells. Cytosolic free Ca2+ levels ([Ca2+]i) in populations of cells were measured using fura-2 as a fluorescent Ca2+ probe. Safrole at concentrations above 33 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 value of 400 microM. The Ca2+ signal was reduced by 90% by removing extracellular Ca2+, but was not affected by nifedipine, verapamil, or diltiazem. Addition of Ca2+ after safrole had depleted intracellular Ca(2+)-induced dramatic Ca2+ influx, suggesting that safrole caused store-operated Ca2+ entry. In Ca(2+)-free medium, after pretreatment with 650 microM safrole, 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) failed to release more Ca 2+. Inhibition of phospholipase C with 2 microM U73122 did not affect safrole-induced Ca2+ release. Trypan blue exclusion assays revealed that incubation with 650 microM safrole for 30 min did not kill cells, but killed 70% of cells after incubation for 60 min. Collectively, the data suggest that in MDCK cells, safrole induced a [Ca2+] increase by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C-independent fashion, and by inducing Ca2+ influx via store-operated Ca2+ entry. Furthermore, safrole can cause acute toxicity to MDCK cells.

  8. Independent [Ca2+]i increases and cell proliferation induced by the carcinogen safrole in human oral cancer cells.

    Huang, Jong-Khing; Huang, Chun-Jen; Chen, Wei-Chuan; Liu, Shiuh-Inn; Hsu, Shu-Shong; Chang, Hong-Tai; Tseng, Li-Ling; Chou, Chiang-Ting; Chang, Chih-Hung; Jan, Chung-Ren


    The effect of the carcinogen safrole on intracellular Ca2+ movement and cell proliferation has not been explored previously. The present study examined whether safrole could alter Ca2+ handling and growth in human oral cancer OC2 cells. Cytosolic free Ca2+ levels ([Ca2+]i) in populations of cells were measured using fura-2 as a fluorescent Ca2+ probe. Safrole at a concentration of 325 microM started to increase [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced by 40% by removing extracellular Ca2+, and was decreased by 39% by nifedipine but not by verapamil or diltiazem. In Ca2+-free medium, after pretreatment with 650 microM safrole, 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) barely induced a [Ca2+]i rise; in contrast, addition of safrole after thapsigargin treatment induced a small [Ca2+]i rise. Neither inhibition of phospholipase C with 2 microM U73122 nor modulation of protein kinase C activity affected safrole-induced Ca2+ release. Overnight incubation with 1 microM safrole did not alter cell proliferation, but incubation with 10-1000 microM safrole increased cell proliferation by 60+/-10%. This increase was not reversed by pre-chelating Ca2+ with 10 microM of the Ca2+ chelator BAPTA. Collectively, the data suggest that in human oral cancer cells, safrole induced a [Ca2+]i rise by causing release of stored Ca2+ from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion and by inducing Ca2+ influx via nifedipine-sensitive Ca2+ entry. Furthermore, safrole can enhance cell growth in a Ca2+-independent manner.

  9. Human-health pharmaceutical compounds in Lake Mead, Nevada and Arizona, and Las Vegas Wash, Nevada, October 2000-August 2001

    Boyd, Robert A.; Furlong, Edward T.


    The U.S. Geological Survey and the National Park Service conducted a reconnaissance study to investigate the occurrence of selected human-health pharmaceutical compounds in water samples collected from Lake Mead on the Colorado River and Las Vegas Wash, a waterway used to transport treated wastewater from the Las Vegas metropolitan area to Lake Mead. Current research indicates many of these compounds can bioaccumulate and may adversely affect aquatic organisms by disrupting physiological processes, impairing reproductive functions, increasing cancer rates, contributing to the development of antibiotic-resistant strains of bacteria, and acting in undesirable ways when mixed with other substances. These compounds may be present in effluent because a high percentage of prescription and non-prescription drugs used for human-health purposes are excreted from the body as a mixture of parent compounds and degraded metabolite compounds; also, they can be released to the environment when unused products are discarded by way of toilets, sinks, and trash in landfills. Thirteen of 33 targeted compounds were detected in at least one water sample collected between October 2000 and August 2001. All concentrations were less than or equal to 0.20 micrograms per liter. The most frequently detected compounds in samples from Las Vegas Wash were caffeine, carbamazepine (used to treat epilepsy), cotinine (a metabolite of nicotine), and dehydronifedipine (a metabolite of the antianginal Procardia). Less frequently detected compounds in samples collected from Las Vegas Wash were antibiotics (clarithromycin, erythromycin, sulfamethoxazole, and trimethoprim), acetaminophen (an analgesic and anti-inflammatory), cimetidine (used to treat ulcers), codeine (a narcotic and analgesic), diltiazem (an antihypertensive), and 1,7-dimethylxanthine (a metabolite of caffeine). Fewer compounds were detected in samples collected from Lake Mead than from Las Vegas Wash. Caffeine was detected in all samples

  10. Cloud computing and validation of expandable in silico livers

    Hunt C Anthony


    Full Text Available Abstract Background In Silico Livers (ISLs are works in progress. They are used to challenge multilevel, multi-attribute, mechanistic hypotheses about the hepatic disposition of xenobiotics coupled with hepatic responses. To enhance ISL-to-liver mappings, we added discrete time metabolism, biliary elimination, and bolus dosing features to a previously validated ISL and initiated re-validated experiments that required scaling experiments to use more simulated lobules than previously, more than could be achieved using the local cluster technology. Rather than dramatically increasing the size of our local cluster we undertook the re-validation experiments using the Amazon EC2 cloud platform. So doing required demonstrating the efficacy of scaling a simulation to use more cluster nodes and assessing the scientific equivalence of local cluster validation experiments with those executed using the cloud platform. Results The local cluster technology was duplicated in the Amazon EC2 cloud platform. Synthetic modeling protocols were followed to identify a successful parameterization. Experiment sample sizes (number of simulated lobules on both platforms were 49, 70, 84, and 152 (cloud only. Experimental indistinguishability was demonstrated for ISL outflow profiles of diltiazem using both platforms for experiments consisting of 84 or more samples. The process was analogous to demonstration of results equivalency from two different wet-labs. Conclusions The results provide additional evidence that disposition simulations using ISLs can cover the behavior space of liver experiments in distinct experimental contexts (there is in silico-to-wet-lab phenotype similarity. The scientific value of experimenting with multiscale biomedical models has been limited to research groups with access to computer clusters. The availability of cloud technology coupled with the evidence of scientific equivalency has lowered the barrier and will greatly facilitate model

  11. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology.

    Bhidayasiri, Roongroj; Fahn, Stanley; Weiner, William J; Gronseth, Gary S; Sullivan, Kelly L; Zesiewicz, Theresa A


    To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy? PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966-2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence. Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

  12. Comparison of contaminants of emerging concern removal, discharge, and water quality hazards among centralized and on-site wastewater treatment system effluents receiving common wastewater influent.

    Du, Bowen; Price, Amy E; Scott, W Casan; Kristofco, Lauren A; Ramirez, Alejandro J; Chambliss, C Kevin; Yelderman, Joe C; Brooks, Bryan W


    A comparative understanding of effluent quality of decentralized on-site wastewater treatment systems, particularly for contaminants of emerging concern (CECs), remains less understood than effluent quality from centralized municipal wastewater treatment plants. Using a novel experimental facility with common influent wastewater, effluent water quality from a decentralized advanced aerobic treatment system (ATS) and a typical septic treatment system (STS) coupled to a subsurface flow constructed wetland (WET) were compared to effluent from a centralized municipal treatment plant (MTP). The STS did not include soil treatment, which may represent a system not functioning properly. Occurrence and discharge of a range of CECs were examined using isotope dilution liquid chromatography-tandem mass spectrometry during fall and winter seasons. Conventional parameters, including total suspended solids, carbonaceous biochemical oxygen demand and nutrients were also evaluated from each treatment system. Water quality of these effluents was further examined using a therapeutic hazard modeling approach. Of 19 CECs targeted for study, the benzodiazepine pharmaceutical diazepam was the only CEC not detected in all wastewater influent and effluent samples over two sampling seasons. Diphenhydramine, codeine, diltiazem, atenolol, and diclofenac exhibited significant (ptreatment systems was generally not influenced by season. However, significant differences (pwater quality indicators were observed among the various treatment technologies. For example, removal of most CECs by ATS was generally comparable to MTP. Lowest removal of most CECs was observed for STS; however, removal was improved when coupling the STS to a WET. Across the treatment systems examined, the majority of pharmaceuticals observed in on-site and municipal effluent discharges were predicted to potentially present therapeutic hazards to fish.

  13. Calcium competes with zinc for a channel mechanism on the brush border membrane of piglet intestine.

    Bertolo, R F.P.; Bettger, W J.; Atkinson, S A.


    Interactions between Ca(+2) and Zn(+2) at the intestinal brush border membrane occur via unclear mechanisms. We hypothesized that Zn(+2) and Ca(+2) are transported across the brush border membrane via a multidivalent metal channel. Using brush border membrane vesicles (BBMV) prepared from intestines of 8 sow-fed piglets, we sought to determine whether Ca(+2) competes with Zn(+2) for uptake. Extravesicular Zn(+2) was removed with ethylenediamine-tetraacetic acid. Time curves of Zn(+2) and Ca(+2) uptake by BBMV were conducted with increasing concentrations of Ca(+2) and Zn(+2), respectively. Saturation curves compared kinetic parameters of Zn(+2) uptake with and without Ca(+2). In addition, Zn(+2) uptake was measured in the presence of various classical Ca(+2) channel modulators. Over 20 min, a 0.4x concentration of Zn(+2) lowered Ca(+2) uptake by vesicles, whereas a 30x concentration of Ca(+2) was necessary to lower Zn(+2) uptake. These data suggest that Ca(+2) has lower affinity than Zn(+2) for a brush border membrane transport protein. Kinetic parameters showed higher K(m) values with 4 or 15 mM Ca(+2) but unchanged J(max), suggesting competitive inhibition. The Ca(+2) channel blocking agents, La(+3), Ba(+2), verapamil, and diltiazem, inhibited Zn(+2) uptake, whereas calcitriol, trans 1,2 cyclohexanediol, cis/trans 1,3 cyclohexanediol, and the L-type Ca(+2) channel agonist, Bay K8644, induced Zn(+2) uptake. These data were consistent with competition for a common transport mechanism on the brush border membrane, possibly a novel multimetal channel. Copyright 2001 Elsevier Science Inc.

  14. Summary of 32 Patients with Cardiac Syndrome X Treated by TCM Therapy of Regulating Qi Relieving Chest Stuffiness and Promoting Blood Circulation

    MAO Jing-yuan; ZHAO Gui-feng; WANG Zhan-wu; MA Xue-peng; ZHANG Zhen-peng; LI Ming; SHAO Lei; ZHAO Chun-yan; GE Yong-bin; WANG Heng-he; WANG Qiang; ZHANG Yun; YU Dong-ling; ZHANG Yu; HUANG Qi; ZHAO Zhi-qiang


    Objective:To evaluate the clinical effect of Liqi Kuanxiong Huoxue method(理气宽胸活血,LKH,traditional Chinese medicine,TCM therapeutic method for regulating qi,relieving chest stuffiness and promoting blood circulation) in treating patients with cardiac syndrome X (CSX).Methods:The prospective,non-randomized controlled study was conducted on 51 selected patients with CSX,who were non-randomly assigned to 2 groups,the treated group treated with LKH in addition to the conventional treatment(32 patients),and the control group treated with conventional treatment(19 patients)like nitrate,diltiazem hydrochloride,etc.The treatment course was 14 days.The changes of such symptoms as angina pectoris,TCM syndrome and indexes of treadmill exercise test before and after treatment were observed.Results:After treatment,such symptoms as chest pain and stuffy feeling and palpitation in the treated group were improved more than those in the control group(P<0.05);the total effective rate on angina pectoris and TCM syndrome in the treated group was better than that in the control group(P<0.05).The treadmill exercise test showed that the maximal metabolic equivalent(Max MET),the time of angina onset and ST segment depression by 0.1 mV were obviously improved after treatment in both groups,but the improvement in the treated group was better than that in the control group respectively (P<0.05).Conclusion:The LKH method could reduce the frequency of angina attacks and improve the clinical condition of patients with CSX.

  15. Heparin/heparan sulfates bind to and modulate neuronal L-type (Cav1.2) voltage-dependent Ca(2+) channels.

    Garau, Gianpiero; Magotti, Paola; Heine, Martin; Korotchenko, Svetlana; Lievens, Patricia Marie-Jeanne; Berezin, Vladimir; Dityatev, Alexander


    Our previous studies revealed that L-type voltage-dependent Ca(2+) channels (Cav1.2 L-VDCCs) are modulated by the neural extracellular matrix backbone, polyanionic glycan hyaluronic acid. Here we used isothermal titration calorimetry and screened a set of peptides derived from the extracellular domains of Cav1.2α1 to identify putative binding sites between the channel and hyaluronic acid or another class of polyanionic glycans, such as heparin/heparan sulfates. None of the tested peptides showed detectable interaction with hyaluronic acid, but two peptides derived from the first pore-forming domain of Cav1.2α1 subunit bound to heparin. At 25 °C the binding of the peptide P7 (MGKMHKTCYN) was at ~50 μM, and that of the peptide P8 (GHGRQCQNGTVCKPGWDGPKHG) was at ~21 μM. The Cav1.2α1 first pore forming segment that contained both peptides maintained a high affinity for heparin (~23 μM), integrating their enthalpic and entropic binding contributions. Interaction between heparin and recombinant as well as native full-length neuronal Cav1.2α1 channels was confirmed using the heparin-agarose pull down assay. Whole cell patch clamp recordings in HEK293 cells transfected with neuronal Cav1.2 channels revealed that enzymatic digestion of highly sulfated heparan sulfates with heparinase 1 affects neither voltage-dependence of channel activation nor the level of steady state inactivation, but did speed up channel inactivation. Treatment of hippocampal cultures with heparinase 1 reduced the firing rate and led to appearance of long-lasting bursts in the same manner as treatment with the inhibitor of L-VDCC diltiazem. Thus, heparan sulfate proteoglycans may bind to and regulate L-VDCC inactivation and network activity.

  16. Signaling mechanisms mediated by G-protein coupled receptors in human platelets

    Sheikh Arshad SAEED; Huma RASHEED; Faisal A Wahed FECTO; Mohammad Ilyas ACHAKZAI; Rahmat ALI; John Dennis CONNOR; Anwar-ul-Hassan GILANI


    AIM: The present study deals with the investigation of mechanisms involved in the synergistic interaction between epinephrine and arachidonic acid (AA). METHODS: Venous blood was taken from healthy human volunteers reported to be free of medications for one week. Platelet aggregation was monitored at 37 ℃ using Dual-channel Lumi-aggregometer. The resulting aggregation was recorded for 5 min by the measurement of light transmission as a function of time. RESULTS: The data show that a synergism in platelet aggregation mediated by subthreshold concentrations of epinephrine (1μmol/L) and AA (0.2μmol/L) was inhibited by the α2-receptor antagonist (yohimbine, IC50=0.6 μmol/L) and an inhibitor of AA-cyclooxygenase (COX), indomethacin (IC50=0.25 μmol/L).In examining receptor influence on intraplatelet signalling pathways, it was found that the synergistic effect was inhibited by calcium channel blockers, verapamil (IC50=0.4 μtmol/L) and diltiazem (IC50=2.5 μmol/L), as well as by low concentrations of inhibitors of phospholipase C (PLC) (U73122; IC50=0.2 μmol/L) and mitogens activated protein kinase (MAPK) (PD 98059; IC50=3.8 μmol/L). Herbimycin A, a specific inhibitor of tyrosine light chain kinase (TLCK), showed inhibition at IC50 value of 15 μmol/L, whereas chelerythrine, a protein kinase C (PKC)inhibitor, had no effect up to 20 μmol/L. CONCLUSION: These data suggest that synergism between epinephrine and AA in platelet aggregation is triggered through receptors coupled to G-protein, which in turn, activate PLC,COX, and MAP kinase-signaling pathways.

  17. Use of porous aluminosilicate pellets for drug delivery.

    Byrne, R S; Deasy, P B


    Three pelletized porous aluminosilicate ceramics were obtained commercially and their potential to act as extended release drug delivery systems was assessed. The pellets were drug loaded using a vacuum impregnation technique. Factors such as the concentration of the loading solution and the porosity and bulk density of the ceramic influenced the drug loading. The release of drug from the pellets was extended as the drug was entrapped within their porous interior. The rate of release was influenced by the porous microstructure of the pellets and the physicochemical properties of the drug. Extrusion-spheronization was used to prepare pellets similar to the porous ceramics. The pellet formulations contained an aluminosilicate clay mineral (kaolin or halloysite), ethylcellulose 100 cps, ethanol and varying quantities of sucrose. The latter two components acted as pore forming agents. Diltiazem HCl was loaded into the pellets and its release was extended. The release rate could be modified by changing the quantity of sucrose included in the initial formulation, as this influenced the porous microstructure of the pellets. In halloysite-based products the release was further extended due to entrapment of the drug within the halloysite microtubules. Porous kaolin-based pellets were also prepared by cryopelletization. This involved freezing droplets of an aqueous suspension containing kaolin, sodium silicate solution and sodium lauryl sulphate. The resulting pellets were freeze-dried, which removed ice from them to leave pores behind. The pellets gave extended drug release with the release rate being influenced by the porous microstructure of the pellets and their microclimate pH.

  18. Effects of Corocalm (Shuguan Capsule,疏冠胶囊) on Acute Myocardial Ischemia in Anesthetized Dogs


    Objective: To investigate the effects of Corocalm (Shuguan Capsule, 疏冠胶囊) on acute myocardial ischemia in anesthetized dogs and its possible therapeutic mechanism. Methods: The acute ischemia model was established by ligating the left anterior descending (LAD) artery. Twentyfive dogs were randomly divided into 5 groups (5 dogs in each group): the control group (treated with normal saline 3 mL/kg), the refined Guanxin Capsule group (精制冠心胶囊, GXC 200 mg/kg), high and Iow dose Corocalm groups (48.5 mg/kg for low dose group and 194.0 mg/kg for high dose group) and the Diltiazem group (5 mg/kg). The animals were treated via a single duodenal administration after the model was established. The experiments used epicardial electrocardiogram (EECG) to measure the scope and degree of myocardial ischemia. Simultaneously, the coronary blood flow (CBF) and serum activity levels of creatine phosphokinase (CK) and lactate dehydrogenase (LDH) were measured by electromagnetic flow meter and automatic biochemical analyzer respectively. The plasma endothelin (ET) content was quantified by radioimmunoassay. Results: Corocalm (48.5 mg/kg and 194.0 mg/kg) significantly decreased the degree and scope of myocardial ischemia, reduced the infarct area, markedly increased the CBF, and inhibited the increase of CK and LDH activities and ET levels induced by myocardial ischemia/infarction. Conclusion: Corocalm could improve the state of acute myocardial ischemia and infarction in dogs. The mechanism of action might be correlated to increasing CBF,inhibiting CK and LDH activities and preventing ET release.

  19. Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze.

    Biała, Grazyna; Kruk, Marta


    In this study, we investigated the effects of acute administration of nicotine on memory-related behavior in mice using the elevated plus maze test. In this test, the time necessary for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. Our results revealed that nicotine (0.035 and 0.175 mg/kg, base, sc) shortened the transfer latency relative to the saline-treated group. Moreover, we investigated the effects of bupropion (10, 20 and 40 mg/kg, ip) and L-type voltage-dependent calcium channel antagonists (nimodipine, flunarizine, verapamil, diltiazem - 5, 10 and 20 mg/kg, ip) on memory-related behavior. At all tested doses, bupropion, did not significantly affect transfer latency. However, flunarizine and verapamil (both at 10 mg/kg) resulted in a slight decrease in transfer latency, whereas nimodipine (10 mg/kg) increased transfer latency. Interestingly, both bupropion (20 mg/kg) and calcium channel blockers (5 mg/kg) attenuated the improvement of memory induced by nicotine. Our findings indicate that the cholinergic nicotinic system may play an important role in memory consolidation, and that neural calcium-dependent mechanisms can be involved in the modulation of memory-related responses induced by nicotine. The results of these studies have revealed neuronal mechanisms that are important for nicotinic modulation of cognition and will be useful for the treatments of human disorders in which cholinergic pathways have been implicated, such as psychiatric disorders and addiction.

  20. Zebularine regulates early stages of mESC differentiation: effect on cardiac commitment.

    Horrillo, A; Pezzolla, D; Fraga, M F; Aguilera, Y; Salguero-Aranda, C; Tejedo, J R; Martin, F; Bedoya, F J; Soria, B; Hmadcha, A


    Lineage commitment during embryonic stem cell (ESC) differentiation is controlled not only by a gamut of transcription factors but also by epigenetic events, mainly histone deacetylation and promoter DNA methylation. The DNA demethylation agent 5'-aza-2'-deoxycytidine (AzadC) has been widely described as an effective promoter of cardiomyogenic differentiation in various stem cell types. However, its toxicity and instability complicate its use. Therefore, the purpose of this study was to examine the effects of zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-1), a stable and non-toxic DNA cytosine methylation inhibitor, on mouse ESC (mESC) differentiation. Herein, we report that treating embryoid bodies, generated from mESCs, with 30 μM zebularine for 7 days led to greater cell differentiation and induced the expression of several cardiac-specific markers that were detected using reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, immunostaining and flow cytometry. Zebularine enhanced the expression of cardiac markers and the appearance of beating cells that responded to cardiac drugs, including ion channel blockers (diltiazem) and β-adrenergic stimulators (isoproterenol). Gene promoter methylation status was assessed using methylation-specific PCR (MSP) and validated by bisulfite sequencing analysis. Global gene expression profiling using microarrays showed that zebularine-differentiated cells are distinct from control ESCs. Pathway analysis revealed an enhancement of cellular processes such as embryonic development, cardiovascular system development and function. In addition, the whole-cell proteins exhibited different profiles as analyzed by two-dimensional differential-in-gel-electrophoresis. Our results indicate that zebularine regulates mesodermal differentiation of mESCs, controls promoter methylation of crucial cardiac genes and may help to improve cardiomyogenic differentiation.

  1. Zebularine regulates early stages of mESC differentiation: effect on cardiac commitment

    Horrillo, A; Pezzolla, D; Fraga, M F; Aguilera, Y; Salguero-Aranda, C; Tejedo, J R; Martin, F; Bedoya, F J; Soria, B; Hmadcha, A


    Lineage commitment during embryonic stem cell (ESC) differentiation is controlled not only by a gamut of transcription factors but also by epigenetic events, mainly histone deacetylation and promoter DNA methylation. The DNA demethylation agent 5′-aza-2′-deoxycytidine (AzadC) has been widely described as an effective promoter of cardiomyogenic differentiation in various stem cell types. However, its toxicity and instability complicate its use. Therefore, the purpose of this study was to examine the effects of zebularine (1-(β-𝒟-ribofuranosyl)-1,2-dihydropyrimidin-2-1), a stable and non-toxic DNA cytosine methylation inhibitor, on mouse ESC (mESC) differentiation. Herein, we report that treating embryoid bodies, generated from mESCs, with 30 μM zebularine for 7 days led to greater cell differentiation and induced the expression of several cardiac-specific markers that were detected using reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, immunostaining and flow cytometry. Zebularine enhanced the expression of cardiac markers and the appearance of beating cells that responded to cardiac drugs, including ion channel blockers (diltiazem) and β-adrenergic stimulators (isoproterenol). Gene promoter methylation status was assessed using methylation-specific PCR (MSP) and validated by bisulfite sequencing analysis. Global gene expression profiling using microarrays showed that zebularine-differentiated cells are distinct from control ESCs. Pathway analysis revealed an enhancement of cellular processes such as embryonic development, cardiovascular system development and function. In addition, the whole-cell proteins exhibited different profiles as analyzed by two-dimensional differential-in-gel-electrophoresis. Our results indicate that zebularine regulates mesodermal differentiation of mESCs, controls promoter methylation of crucial cardiac genes and may help to improve cardiomyogenic differentiation. PMID:23559004

  2. Modulation of oxidative stress and Ca(2+) mobilization through TRPM2 channels in rat dorsal root ganglion neuron by Hypericum perforatum.

    Nazıroğlu, M; Çiğ, B; Özgül, C


    A main component of St. John's Wort (Hypericum perforatum, HP) is hyperforin which has antioxidant properties in dorsal root ganglion (DRG) neurons, due to its ability to modulate NADPH oxidase and protein kinase C. Recent reports indicate that oxidative stress through NADPH oxidase activates TRPM2 channels. HP may be a useful treatment for Ca(2+) entry and oxidative stress through modulation of TRPM2 channels in the DRG. We aimed to investigate the protective role of HP on Ca(2+) entry and oxidative stress through TRPM2 channels in DRG neurons of rats. The native rat DRG neurons were used in whole-cell patch-clamp, Fura-2 and antioxidant experiments. Appropriate, nontoxic concentrations and incubation times for HP were determined in the DRG neurons by assessing cell viability. The H2O2-induced TRPM2 currents were inhibited by 2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA). TRPM2 current densities and cytosolic free Ca(2+) concentration in the neurons were also reduced by HP (2 and 24h). In Fura-2 experiments, cytosolic Ca(2+) mobilization was reduced by voltage-gated calcium channel blockers (verapamil+diltiazem, V+D) and HP. Glutathione peroxidase activity and GSH values in the DRG were high in HP, 2-APB and V+D groups although lipid peroxidation level was low in the groups. In conclusion, we observed a protective role for HP on Ca(2+) entry through a TRPM2 channel in the DRG neurons. Since over-production of oxidative stress and Ca(2+) entry are implicated in the pathophysiology of neuropathic pain and neuronal inflammation, our findings may be relevant to the etiology and treatment of neuropathology in DRG neurons.

  3. The cutting of cocaine and heroin: A critical review.

    Broséus, Julian; Gentile, Natacha; Esseiva, Pierre


    The illicit drug cutting represents a complex problem that requires the sharing of knowledge from addiction studies, toxicology, criminology and criminalistics. Therefore, cutting is not well known by the forensic community. Thus, this review aims at deciphering the different aspects of cutting, by gathering information mainly from criminology and criminalistics. It tackles essentially specificities of cocaine and heroin cutting. The article presents the detected cutting agents (adulterants and diluents), their evolution in time and space and the analytical methodology implemented by forensic laboratories. Furthermore, it discusses when, in the history of the illicit drug, cutting may take place. Moreover, researches studying how much cutting occurs in the country of destination are analysed. Lastly, the reasons for cutting are addressed. According to the literature, adulterants are added during production of the illicit drug or at a relatively high level of its distribution chain (e.g. before the product arrives in the country of destination or just after its importation in the latter). Their addition seems hardly justified by the only desire to increase profits or to harm consumers' health. Instead, adulteration would be performed to enhance or to mimic the illicit drug effects or to facilitate administration of the drug. Nowadays, caffeine, diltiazem, hydroxyzine, levamisole, lidocaïne and phenacetin are frequently detected in cocaine specimens, while paracetamol and caffeine are almost exclusively identified in heroin specimens. This may reveal differences in the respective structures of production and/or distribution of cocaine and heroin. As the relevant information about cutting is spread across different scientific fields, a close collaboration should be set up to collect essential and unified data to improve knowledge and provide information for monitoring, control and harm reduction purposes. More research, on several areas of investigation, should be

  4. Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries.

    Fransen, Paul; Van Hove, Cor E; Leloup, Arthur J A; Schrijvers, Dorien M; De Meyer, Guido R Y; De Keulenaer, Gilles W


    Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.

  5. Cytochrome P450 3A Conjugation to Ubiquitin in a Process Distinct from Classical Ubiquitination Pathway

    Zangar, Richard C.(BATTELLE (PACIFIC NW LAB)); Kimzey, Amy L.(ASSOC WESTERN UNIVERSITY); Okita, Janice R.(Washington State University); Wunschel, David S.(BATTELLE (PACIFIC NW LAB)); Edwards, Robert J.(Imperial College School of Medical, Hammersmith Campus); Kim, Hyesook (Wayne State University); Okita, Richard T.(Washington State University)


    We characterize a novel microsome system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not alter CYP4A or most other microsomal proteins. The formation of the HMM bands was observed in hepatic microsomes isolated from rats treated 1 week or more with high doses (50 mg/kg/day) of nicardipine, clotrimazole, or pregnenolone 16alpha-carbonitrile, but not microsomes from control, dexamethasone-, nifedipine-, or diltiazem-treated rats. Extensive washing of the microsomes to remove loosely attached proteins or cytosolic contaminants did not prevent the conjugation reaction. In contrast to prototypical ubiquitination pathways, this reaction did not require addition of ubiquitin, ATP, Mg(2+), or cytosol. Addition of cytosol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteasome inhibitors. Immunoprecipitated CYP3A contained HMM ubiquitin. Even so, mass spectrometric analysis of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a diffuse pool of ubiquitinated proteins already present in the microsomes. Addition of CYP3A substrates inhibited the formation of the HMM CYP3A and the cytosol-dependent degradation of HMM CYP3A. These results suggest that after extended periods of elevated CYP3A expression, microsomal factors are induced that catalyze the formation of HMM CYP3A conjugates that contain ubiquitin. This conjugation reaction, however, seems to be distinct from the classical ubiquitination pathway but may be related to the substrate-dependent stabilization of CYP3A observed in vivo.

  6. Extent of use of immediate-release formulations of calcium channel blockers as antihypertensive monotherapy by primary care physicians: multicentric study from Bahrain.

    Sequeira R


    Full Text Available BACKGROUND: The issue of cardiovascular safety of calcium channel blockers (CCBs has been widely debated in view of reflex increase in sympathetic activity induced by immediate release (IR / short acting formulations. It is generally agreed that such CCBs should not be used alone in the management of hypertension. AIMS: We have determined the extent to which primary care physicians prescribe CCBs as monotherapy, especially the immediate release formulations, in the management of uncomplicated hypertension and diabetic hypertension - with an emphasis upon the age of the patients. SETTING, DESIGN AND METHODS: A retrospective prescription-based study was carried out in seven out of 18 Health Centres in Bahrain. The study involved a registered population of 229,300 representing 46% of registered individuals, and 35 physicians representing 43% of all primary care physicians. The data was collected between November 1998 and January 1999 using chronic dispensing cards. RESULTS: In all categories CCBs were the third commonly prescribed antihypertensive as monotherapy, with a prescription rate of 11.1% in uncomplicated hypertension, 18% in diabetic hypertension and 20.1% in elderly patients above 65 years of age. Nifedipine formulations were the most extensively prescribed CCBs. Almost half of the CCB-treated patients were on IR-nifedipine, whereas IR-diltiazem and IR-verapamil, and amlodipine were infrequently prescribed. CONCLUSION: Prescription of IR-formulations of CCBs as monotherapy by primary care physicians does not conform with recommended guidelines. In view of concerns about the safety of such practice, measures to change the prescribing pattern are required.

  7. Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis.

    Yoshimoto, K; Saima, S; Nakamura, Y; Nakayama, M; Kubo, H; Kawaguchi, Y; Nishitani, H; Nakamura, Y; Yasui, A; Yokoyama, K; Kuriyama, S; Shirai, D; Kugiyama, A; Hayano, K; Fukui, H; Horigome, I; Amagasaki, Y; Tsubakihara, Y; Kamekawa, T; Ando, R; Tomura, S; Okamoto, R; Miwa, S; Koyama, T; Echizen, H


    We previously reported that manidipine, a new dihydropyridine type calcium channel blocker, produced chylous peritoneal dialysate being visually indistinguishable from infective peritonitis in 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [Yoshimoto et al. 1993]. To study whether such an adverse drug reaction would also be elicited by other commonly prescribed calcium channel blockers in CAPD patients, we have conducted postal inquiry to 15 collaborating hospitals and an institutional survey in International Medical Center of Japan as to the possible occurrence of calcium channel blocker-associated non-infective, turbid peritoneal dialysate in CAPD patients. Our diagnostic criteria for drug-induced turbidity of dialysate as a) it developed within 48 h after the administration of a newly introduced calcium channel blocker to the therapeutic regimen, b) absence of clinical symptoms of peritoneal inflammation (i.e., pyrexia, abdominal pain, nausea or vomiting), c) the fluid containing normal leukocyte counts and being negative for bacterial and fungal culture of the fluid, and d) it disappeared shortly after the withdrawal of the assumed causative agent. Results showed that 19 out of 251 CAPD patients given one of the calcium channel blockers developed non-infective turbid peritoneal dialysis that fulfilled all the above criteria. Four calcium channel blockers were suspected to be associated with the events: benidipine [2 out of 2 (100%) patients given the drug], manidipine [15 out of 36 (42%) patients], nisoldipine [1 out of 11 (9%) patients] and nifedipine [1 out of 159 (0.6%)] in descending order of frequency. None of the patients who received nicardipine, nilvadipine, nitrendipine, barnidipine and diltiazem (25, 7, 2, 1 and 8 patients, respectively) exhibited turbid dialysate. In conclusion, we consider that certain dihydropyridine type calcium channel blockers would cause turbid peritoneal dialysate being similar to that observed in

  8. The pharmacological properties of lipophilic calcium antagonists.

    van Zwieten, P A


    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  9. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.

    Harmsze, Ankie M; Robijns, Karen; van Werkum, Jochem W; Breet, Nicoline J; Hackeng, Christian M; Ten Berg, Jurrien M; Ruven, Hendrik J T; Klungel, Olaf H; de Boer, Anthonius; Deneer, Vera H M


    Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

  10. Warfarin and royal jelly interaction.

    Lee, Nancy J; Fermo, Joli D


    An 87-year-old African-American man came to the internal medicine clinic for a routine anticoagulation management visit. He had no complaints. His medical history was significant for stage IV-A follicular non-Hodgkin's lymphoma, atrial fibrillation, and hypertension. His long-term drug therapy consisted of warfarin, felodopine, lisinopril-hydrochlorothiazide, controlled-release diltiazem, potassium chloride, and oxycodone. He reported adherence with his prescribed drugs and denied taking any over-the-counter or herbal products. Overall, the patient's drug therapy had been consistent during the preceding 3 months, no significant changes had occurred in his clinical status, and no significant changes had been noted in his diet; his international normalized ratio (INR) had ranged from 1.9-2.4 (therapeutic range 2-3). He denied tobacco use, alcohol consumption, and recent travel. Four weeks later, the patient came to the emergency department with hematuria. He denied dysuria, taking more than the prescribed amount of warfarin, any changes in his diet, taking any over-the-counter or herbal products, and any other bleeding. On admission to the hospital, his INR was 6.88, which increased to 7.29 during his hospital stay. On further investigation, the patient admitted that he had started taking an herbal supplement, royal jelly, 1 week earlier. When asked specifically about the ingredients in the supplement, he stated that royal jelly was the only component. Relative to the patient's denial of any other changes in his condition or drug regimen, the most probable explanation for his elevated INR and subsequent bleeding is a possible interaction between royal jelly and warfarin. To our knowledge, no case reports concerning royal jelly and warfarin taken concomitantly have been reported. Clinicians should be proactive and repeatedly provide education regarding the potential dangers of dietary supplements taken with conventional drugs.

  11. Calcium-dependent synergistic interaction of platelet activating factor and epinephrine in human platelet aggregation%血小板活化因子和肾上腺素对人血小板凝集的钙依赖性协同作用

    Sheikh Arshad SAEED; Huma RASHEED


    AIM: To investigate the mechanism (s) involved in the synergistic interaction of platelet activating factor (PAF) and epinephrine. METHODS: Blood was obtained from healthy human subjects reported to be free of medications for at least two weeks before sampling. Aggregation was monitored at 37 ℃ using Dual-channel Lumi-aggregometer.The resulting aggregation was recorded for 5 min by the measurement of light transmission as a function of time.RESULTS: Platelet aggregation mediated by subthreshold concentrations of PAF (5-8 nmol/L) plus epinephrine (0.5-2 μmol/L) was inhibited by α2-receptor blocker, yohimbine, and PAF receptor antagonist WEB 2086. This synergism was inhibited by calcium channel blockers, verapamil and diltiazem. In addition, platelet aggregation by co-addition of PAF and epinephrine was also inhibited by very low concentrations of phospholipase C (PLC)inhibitor (U73122; IC50=0.2 μmol/L), the MAP kinase inhibitor, PD 98059 (IC50=3 μmol/L), and cyclooxygenase (COX-1) inhibitors including indomethacin (IC50=0.25 μmol/L), flurbiprofen (IC50=0.7 μmol/L), and piroxicam (IC50=7 μmol/L). However, COX-2 inhibitors, nimesulide (IC50=26 μmol/L), NS-398 (IC50=7 μmol/L), and etodolac (IC50=15 μmol/L) were also effective in inhibiting the aggregation. The inhibitors of protein kinase C (chelerythrine)and tyrosine kinase (genistien), and phosphatidylinositol 3-kinase inhibitor (wortmannin) had no significant effect on platelet aggregation induced by PAF and epinephrine. CONCLUSION: The synergistic effect of PAF and epinephrine on human platelet aggregation is receptor-mediated and involves the activation of PLC/Ca2+, COX and MAP kinase signalling pathways.

  12. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

    Graudins, Andis; Lee, Hwee Min; Druda, Dino


    Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

  13. 高血压治疗的现代观念%Modern concept of hypertension therapy



    过去7年,相继发表了9项重要高血压临床试验:高血压的合理治疗(hypertension optimal treatment,HOT)、卡托普利预防试验(captopril prevention project,CAPPP)、瑞典老人高血压试验-2(Swedish trial in old patients with hypertension 2,STOP-2)、抗高血压药和调血脂药预防心脏病发作试验(antihypertensive and lipid-lowering treatment to prevent heart attack trial,ALLHAT)、北欧地尔硫(艹卓)试验(Nordic diltiazem study,NORDIL)、高血压治疗目标(intervention as a goal in hypertension treatment,INSIGHT)、氯沙坦对高血压试验终点的干预(losartan intervention for endpoint reduction in hypertension study,LIFE)、缬沙坦长期使用评估(valsartan antihypertensive long-term use evaluation,VALUE)、英国人和斯堪的那维亚人心脏试验-降血压篇(Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm,ASCOT-BPLA),使高血压治疗观念和策略发生日新月异变化.可概括为早期、快速、平稳、联合、综合.

  14. Studies on applicability of press-coated tablets using hydroxypropylcellulose (HPC) in the outer shell for timed-release preparations.

    Fukui, E; Uemura, K; Kobayashi, M


    Press-coated tablets, containing diltiazem hydrochloride (DIL) in the core tablet and coated with hydroxypropylcellulose (HPC) as the outer shell, were examined for applicability as timed-release tablets with a predetermined lag time and subsequent rapid drug release phase. Various types of press-coated tablets were prepared using a rotary tabletting machine and their DIL dissolution behavior was evaluated by the JP paddle method. The results indicated that tablets with the timed-release function could be prepared, and that the lag times were prolonged as the viscosity of HPC and the amount of the outer shell were increased. The lag times could be controlled widely by the above method, however, the compression load had little effect. Two different kinds of timed-release press-coated tablets that showed lag times of 3 and 6 h in the in vitro test (denoted PCT(L3) and PCT(L6), respectively) were administered to beagle dogs. DIL was first detected in the plasma more than 3 h after administration, and both tablets showed timed-release. The lag times showed a good agreement between the in vivo and in vitro tests in PCT(L3). However, the in vivo lag times were about 4 h in PCT(L6) and were much shorter than the in vitro lag time. The dissolution test was performed at different paddle rotation speeds, and good agreement was obtained between the in vivo and in vitro lag times at 150 rpm. This suggested that the effects of gastrointestinal peristalsis and contraction should also be taken into consideration for the further development of drug delivery systems.

  15. The Effects of Diuretics on Intracellular Ca2+ Dynamics of Arteriole Smooth Muscles as Revealed by Laser Confocal Microscopy

    Tamagawa, Yasunori; Saino, Tomoyuki; Matsuura, Makoto; Satoh, Yoh-ichi


    The regulation of cytosolic Ca2+ homeostasis is essential for cells, including vascular smooth muscle cells. Arterial tone, which underlies the maintenance of peripheral resistance in the circulation, is a major contributor to the control of blood pressure. Diuretics may regulate intracellular Ca2+ concentration ([Ca2+]i) and have an effect on vascular tone. In order to investigate the influence of diuretics on peripheral resistance in circulation, we investigated the alteration of [Ca2+]i in testicular arterioles with respect to several categories of diuretics using real-time confocal laser scanning microscopy. In this study, hydrochlorothiazide (100 µM) and furosemide (100 µM) had no effect on the [Ca2+]i dynamics. However, when spironolactone (300 µM) was applied, the [Ca2+]i of smooth muscles increased. The response was considerably inhibited under either extracellular Ca2+-free conditions, the presence of Gd3+, or with a treatment of diltiazem. After the thapsigargin-induced depletion of internal Ca2+ store, the spironolactone-induced [Ca2+]i dynamics was slightly inhibited. Therefore, the spironolactone-induced dynamics of [Ca2+]i can be caused by either a Ca2+ influx from extracellular fluid or Ca2+ mobilization from internal Ca2+ store, with the former being dominant. As tetraethylammonium, an inhibitor of the K+ channel, slightly inhibited the spironolactone-induced [Ca2+]i dynamics, the K+ channel might play a minor role in those dynamics. Tetrodotoxin, a neurotoxic Na+ channel blocker, had no effect, therefore the spironolactone-induced dynamics is a direct effect to smooth muscles, rather than an indirect effect via vessel nerves. PMID:19759873

  16. Evaluation of Sterculia foetida gum as controlled release excipient.

    Chivate, Amit Ashok; Poddar, Sushilkumar Sharatchandra; Abdul, Shajahan; Savant, Gaurav


    The purpose of the research was to evaluate Sterculia foetida gum as a hydrophilic matrix polymer for controlled release preparation. For evaluation as a matrix polymer; characterization of Sterculia foetida gum was done. Viscosity, pH, scanning electronmicrographs were determined. Different formulation aspects considered were: gum concentration (10-40%), particle size (75-420 microm) and type of fillers and those for dissolution studies; pH, and stirring speed were considered. Tablets prepared with Sterculia foetida gum were compared with tablets prepared with Hydroxymethylcellulose K15M. The release rate profiles were evaluated through different kinetic equations: zero-order, first-order, Higuchi, Hixon-Crowell and Korsemeyer and Peppas models. The scanning electronmicrographs showed that the gum particles were somewhat triangular. The viscosity of 1% solution was found to be 950 centipoise and pH was in range of 4-5. Suitable matrix release profile could be obtained at 40% gum concentration. Higher sustained release profiles were obtained for Sterculia foetida gum particles in size range of 76-125 microm. Notable influences were obtained for type of fillers. Significant differences were also observed with rotational speed and dissolution media pH. The in vitro release profiles indicated that tablets prepared from Sterculia foetida gum had higher retarding capacity than tablets prepared with Hydroxymethylcellulose K15M prepared tablets. The differential scanning calorimetry results indicated that there are no interactions of Sterculia foetida gum with diltiazem hydrochloride. It was observed that release of the drug followed through surface erosion and anomalous diffusion. Thus, it could be concluded that Sterculia foetida gum could be used a controlled release matrix polymer.

  17. Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels

    Meighan, Peter C.; Peng, Changhong; Varnum, Michael D.


    Cyclic nucleotide gated (CNG) channels are a critical component of the visual transduction cascade in the vertebrate retina. Mutations in the genes encoding these channels have been associated with a spectrum of inherited retinal disorders. To gain insight into their pathophysiological mechanisms, we have investigated the functional consequences of several CNGB3 mutations, previously associated with macular degeneration (Y469D and L595F) or complete achromatopsia (S156F, P309L, and G558C), by expressing these subunits in combination with wild-type CNGA3 in Xenopus oocytes and characterizing them using patch-clamp recordings in the inside-out configuration. These mutations did not prevent the formation of functional heteromeric channels, as indicated by sensitivity to block by L-cis-diltiazem. With the exception of S156F, each of the mutant channels displayed electrophysiological properties reflecting enhanced channel activity at physiological concentrations of cGMP (i.e., a gain-of-function phenotype). The increased channel activity produced by these mutations resulted from either increased functional expression levels, or increased sensitivity to cyclic nucleotides. Furthermore, L595F increased the spontaneous open probability in the absence of activating ligand, signifying a ligand independent gain-of-function change. In addition to the CNGB3 disease-associate mutations, we characterized the effects of several common CNGB3 and CNGA3 single-nucleotide polymorphisms (SNPs) on heteromeric CNGA3+CNGB3 channel function. Two of the SNPs examined (A3-T153M, and B3-W234C) produced decreased ligand sensitivity for heteromeric CNG channels. These changes may contribute to background disease susceptibility when combined with other genetic or non-genetic factors. Together, these studies help to define the underlying molecular phenotype for mutations relating to CNG channel disease pathogenesis. PMID:26106334

  18. Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels.

    Peter eMeighan


    Full Text Available Cyclic nucleotide gated (CNG channels are a critical component of the visual transduction cascade in the vertebrate retina. Mutations in the genes encoding these channels have been associated with a spectrum of inherited retinal disorders. To gain insight into their pathophysiological mechanisms, we have investigated the functional consequences of several CNGB3 mutations, previously associated with macular degeneration (Y469D and L595F or complete achromatopsia (S156F, P309L, and G558C, by expressing these subunits in combination with wild-type CNGA3 in Xenopus oocytes and characterizing them using patch-clamp recordings in the inside-out configuration. These mutations did not prevent the formation of functional heteromeric channels, as indicated by sensitivity to block by L-cis-diltiazem. With the exception of S156F, each of the mutant channels displayed electrophysiological properties reflecting enhanced channel activity at physiological concentrations of cGMP (i.e., a gain-of-function phenotype. The increased channel activity produced by these mutations resulted from either increased functional expression levels, or increased sensitivity to cyclic nucleotides. Furthermore, L595F increased the spontaneous open probability in the absence of activating ligand, signifying a ligand independent gain-of-function change. In addition to the CNGB3 disease-associate mutations, we characterized the effects of several common CNGB3 and CNGA3 single-nucleotide polymorphisms (SNPs on heteromeric CNGA3+CNGB3 channel function. Two of the SNPs examined (A3-T153M, and B3-W234C produced decreased ligand sensitivity for heteromeric CNG channels. These changes may contribute to background disease susceptibility when combined with other genetic or nongenetic factors. Together, these studies help to define the underlying molecular phenotype for mutations relating to CNG channel disease pathogenesis.

  19. Effects of acute and chronic nicotine on elevated plus maze in mice: involvement of calcium channels.

    Biala, Grazyna; Budzynska, Barbara


    The current experiments examined the anxiety-related effects of acute and repeated nicotine administration using the elevated plus maze test in mice. Nicotine (0.1 mg/kg s.c., 5 and 30 min after injection; 0.5 mg/kg, s.c., 5 min after injection) had an anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open arm entries. Tolerance developed to this anxiogenic action after 6 days of daily nicotine administration (0.1 mg/kg, s.c.). Five minutes after the seventh injection, an anxiolytic effect was observed, i.e., specific increases in the percentage of time spent on the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5, 10, 20 mg/kg) and diltiazem (5, 10, 20 mg/kg, i.p.) were also injected prior to an acute low dose of nicotine or to each injection of chronic nicotine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of nicotine as well as the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and chronic nicotine injection that may ultimately lead to addiction and smoking relapse in human smokers.

  20. Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test.

    Biala, Grazyna; Kruk, Marta


    The purpose of the current experiments was to examine the anxiety-related effects of repeated amphetamine and nicotine administration using the mouse elevated plus maze (EPM). d-amphetamine was administered daily for 8 days (2 mg/kg, i.p.). On the 9th day, mice were challenged with amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.), and were tested 30 min after this last injection. Additionally, a distinct group of mice was pretreated with nicotine (0.1 mg/kg, s.c., 6 days). These mice were subjected to nicotine (0.1 mg/kg, s.c.) or amphetamine (2 mg/kg, i.p.) challenge on the seventh day to see if full crossover effects developed after the pretreatment of both psychostimulant drugs. Moreover, the L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5 and 10 mg/kg, i.p.) and diltiazem (5 and 10 mg/kg, i.p.) were injected prior to each injection of chronic d-amphetamine or nicotine. We observed cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine that was blunted by a pretreatment with calcium channel blockers. Overall our findings imply that similar neural calcium-dependent mechanisms are involved in the anxiety-related responses to chronic amphetamine and nicotine injections. As anxiety seems to be an important factor for the development of psychostimulant dependence, the L-type VDCC antagonists can offer an interesting approach for the pharmacotherapy of addiction, including amphetamine and/or nicotine dependence.

  1. Renoprotective effects of anti-TGF-β antibody and antihypertensive therapies in Dahl S rats

    Murphy, Sydney R.; Dahly-Vernon, Annette J.; Dunn, Kathryn M. J.; Chen, Chun Cheng Andy; Ledbetter, Steven R.; Williams, Jan M.


    This study examined the effects of anti-TGF-β antibody (1D11) therapy in Dahl S (S) rats fed a 4% NaCl diet. Baseline renal expression of TGF-β1 and the degree of injury were lower in female than male S rats maintained on a 0.4% NaCl diet. 4% NaCl diet increased mean arterial pressure (MAP), proteinuria, and renal injury to the same extent in both male and female S rats. Chronic treatment with 1D11 had renoprotective effects in both sexes. The ability of 1D11 to oppose the development of proteinuria when given alone or in combination with antihypertensive agents was further studied in 6-wk-old female S rats, since baseline renal injury was less than that seen in male rats. 1D11, diltiazem, and hydrochlorothiazide (HCT) attenuated the development of hypertension, proteinuria, and glomerular injury. 1D11 had no additional effect when given in combination with these antihypertensive agents. We also explored whether 1D11 could reverse renal injury in 9-wk-old male S rats with preexisting renal injury. MAP increased to 197 ± 4 mmHg and proteinuria rose to >300 mg/day after 3 wk on a 4% NaCl diet. Proteinuria was reduced by 30–40% in rats treated with 1D11, HCT, or captopril + 1D11, but the protective effect was lost in rats fed the 4% NaCl diet for 6 wk. Nevertheless, 1D11, HCT, and captopril + 1D11 still reduced renomedullary and cardiac fibrosis. These results indicate that anti-TGF-β antibody therapy reduces renal and cardiac fibrosis and affords additional renoprotection when given in combination with various antihypertensive agents in Dahl S rats. PMID:22538513

  2. Comparative Efficacy and Safety of Antihypertensive Agents for Adult Diabetic Patients with Microalbuminuric Kidney Disease: A Network Meta-Analysis.

    Huang, Rongzhong; Feng, Yuxing; Wang, Ying; Qin, Xiaoxia; Melgiri, Narayan Dhruvaraj; Sun, Yang; Li, Xingsheng


    Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed. A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria. Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for

  3. Synergism interaction between arachidonic acid by 5-hydroxytryptamine in human platelet aggregation is mediated through multiple signalling pathways%多种信号途径介导花生四烯酸与5-羟色胺在促人类血小板凝集中的协同作用

    Sheikh Arshad SAEED; Huma RASHEED; Anwar-ul-Hassan GILANI


    AIM: To examine the signalling mechanisms involved in the synergistic interaction of 5-hydroxytryptamine (5-HT)and arachidonic acid (AA) in human platelet aggregation. METHODS: Blood was obtained from healthy human subjects, mixed with 3.8 % sodium citrate (9:1), and centrifuged to prepare platelet rich plasma (PRP). Aggregation was monitored using a Dual-channel Lumi-aggregometer. The agonist-induced influx of Ca2+ was measured using Fura-2 AM. TXA2 formation was studied using radiochemical method. RESULTS: Subthreshold concentration of 5-HT (2 μmol/L) potentiated the effect of low dose of AA (0.2 mmol/L) in human platelets. This synergistic effect was blocked by 5-HT2 receptor antagonist (methysergide IC50=5.2 nmol/L; cyproheptadine IC50=0.6 nmol/L), and thromboxane A2 receptor antagonist (SQ 29 548; IC50=30 nmol/L), showing that the effect is receptor-mediated.To examine the down-stream signalling pathways, we found that such an interaction was inhibited by calcium channel blockers (diltiazem; IC50=3 μmol/L and verapamil; IC50=5 μmol/L), phospholipase C (PLC) inhibitor (U73122;IC50=4 μmol/L), cyclooxygenase inhibitor, (indomethacin; IC50=0.2 μmol/L) and mitogen-activated protein (MAP)kinase inhibitor (PD98059; IC50=3 μmol/L). The effect was also inhibited by a specific tyrosine light chain kinase (TLCK) inhibitor, herbimycin A with IC50 value of 5 μmol/L. Pretreatment of platelet with 5-HT and AA induced rise in intracellular calcium and this effect was blocked by verapamil. CONCLUSION: The synergism between 5-HT and AA in platelet aggregation involves activation of PLC/Ca2+, COX, and MAP kinase pathways.

  4. IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4.

    Burt, Howard J; Galetin, Aleksandra; Houston, J Brian


    The predictive utility of two in vitro methods (empirical IC(50)-based and mechanistic k(inact)/K(I)) for the assessment of time-dependent cytochrome P450 3A4 (CYP3A4) inhibition has been compared. IC(50) values were determined at multiple pre-incubation time points over 30 min for five CYP3A4 time-dependent inhibitors (verapamil, diltiazem, erythromycin, clarithromycin, and azithromycin). The ability of IC(50) data obtained following pre-incubation to predict k(inact)/K(I) parameters was investigated and its utility was assessed relative to the conventional k(inact)/K(I) model using 50 reported clinical drug-drug interactions (DDIs). Models with either hepatic or hepatic with intestinal components were explored. For low/medium potency time-dependent inhibitors, 81% of the predicted k(inact)/K(I(unbound)) from IC(50) data were within an order of magnitude of the actual values, in contrast to 50% of potent inhibitors. An underprediction trend and > 50% of false-negatives were observed when IC(50) data were used in the DDI hepatic prediction model; incorporation of the intestine improved the prediction accuracy. On the contrary, 86% of the DDI studies were predicted within twofold using k(inact)/K(I) mechanistic approach and the combined hepatic and intestinal model. Use of the empirical IC(50) approach as an alternative to the mechanistic k(inact)/K(I) model for in vivo DDI prediction is limited and is best restricted to preliminary investigations.

  5. Validation of cytochrome P450 time-dependent inhibition assays: a two-time point IC50 shift approach facilitates kinact assay design.

    Perloff, E S; Mason, A K; Dehal, S S; Blanchard, A P; Morgan, L; Ho, T; Dandeneau, A; Crocker, R M; Chandler, C M; Boily, N; Crespi, C L; Stresser, D M


    1. Recent guidance from the US Food and Drug Administration (USFDA) has advocated testing of time-dependent inhibition of cytochrome P450 (CYP), which can be addressed by performing IC(50) shift as well as K(I)/k(inact) determinations. 2. Direct (IC(50), K(i)) and time-dependent inhibition (IC(50) shift, K(I)/k(inact)) assays were validated in human liver microsomes with liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis for the following enzyme/substrate/inhibitor combinations: CYP1A2/phenacetin/alpha-naphthoflavone/furafylline, CYP2C8/amodiaquine/montelukast/gemfibrozil-1-O-beta-glucuronide, CYP2C9/diclofenac/sulfaphenazole/tienilic acid, CYP2C19/S-mephenytoin/S-benzylnirvanol/S-fluoxetine, CYP2D6/dextromethorphan/quinidine/paroxetine, and CYP3A4/midazolam/testosterone/ketoconazole/azamulin/verapamil/diltiazem. IC(50) shift assays were performed with two pre-incubation time points (10 and 30 min) to facilitate k(inact) assay design. 3. Data obtained show good agreement with literature values. For rapid acting inhibitors, such as azamulin/CYP3A4 and tienilic acid/CYP2C9, the IC(50) shifts were similar at both time points suggesting a short maximum pre-incubation time with closely spaced time points for the K(I)/k(inact) assay. Slow acting inhibitors (such as verapamil/CYP3A4 or S-fluoxetine/CYP2C19) showed an increase in IC(50) shift between 10 and 30 min suggesting a longer maximum pre-incubation time with wider spacing of time points for K(I)/k(inact). 4. The two-time point IC(50) shift experiment proved to be an excellent method for the selection of appropriate K(I)/k(inact) assay parameters and is suitable for the routine analysis of P450 inhibition by drug candidates.

  6. Occurrence of pharmaceuticals and personal care products in fish: results of a national pilot study in the United States.

    Ramirez, Alejandro J; Brain, Richard A; Usenko, Sascha; Mottaleb, Mohammad A; O'Donnell, John G; Stahl, Leanne L; Wathen, John B; Snyder, Blaine D; Pitt, Jennifer L; Perez-Hurtado, Pilar; Dobbins, Laura L; Brooks, Bryan W; Chambliss, C Kevin


    Pharmaceuticals and personal care products are being increasingly reported in a variety of biological matrices, including fish tissue; however, screening studies have presently not encompassed broad geographical areas. A national pilot study was initiated in the United States to assess the accumulation of pharmaceuticals and personal care products in fish sampled from five effluent-dominated rivers that receive direct discharge from wastewater treatment facilities in Chicago, Illinois; Dallas, Texas; Orlando, Florida; Phoenix, Arizona; and West Chester, Pennsylvania, USA. Fish were also collected from the Gila River, New Mexico, USA, as a reference condition expected to be minimally impacted by anthropogenic influence. High performance liquid chromatography-tandem mass spectrometry analysis of pharmaceuticals revealed the presence of norfluoxetine, sertraline, diphenhydramine, diltiazem, and carbamazepine at nanogram-per-gram concentrations in fillet composites from effluent-dominated sampling locations; the additional presence of fluoxetine and gemfibrozil was confirmed in liver tissue. Sertraline was detected at concentrations as high as 19 and 545 ng/g in fillet and liver tissue, respectively. Gas chromatography-tandem mass spectrometry analysis of personal care products in fillet composites revealed the presence of galaxolide and tonalide at maximum concentrations of 2,100 and 290 ng/g, respectively, and trace levels of triclosan. In general, more pharmaceuticals were detected at higher concentrations and with greater frequency in liver than in fillet tissues. Higher lipid content in liver tissue could not account for this discrepancy as no significant positive correlations were found between accumulated pharmaceutical concentrations and lipid content for either tissue type from any sampling site. In contrast, accumulation of the personal care products galaxolide and tonalide was significantly related to lipid content. Results suggest that the detection of

  7. The influence of calcium antagonists on the adenine nucleotide metabolism in the guinea-pig working heart during ischaemia and reperfusion.

    Hugtenburg, J G; Mathy, M J; de Haan, N; Beckeringh, J J; van Zwieten, P A


    With the aim of gaining more insight into the metabolism of adenine nucleotides in working normoxic guinea-pigs and in hearts subjected to 45 min of global ischaemia and subsequent reperfusion for 25 min, we evaluated the effect of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and dipyridamole on the adenine nucleotide catabolite levels in these hearts. The drugs were applied at the concentrations that reduced the aortic dP/dt of normoxic working hearts by 10% (EC10) and 30% (EC30). In globally ischaemic hearts there was a large accumulation of adenine nucleotide catabolites. Inosine proved to be the major catabolite. The drugs, with the exception of bepridil, CERM 11956 and dipyridamole (3 mumol/l), decreased the accumulation of catabolites. In hearts treated with mioflazine and dipyridamole the amount of adenosine increased. A deficit in the balance between adenine nucleotides and catabolites indicated that in globally ischaemic hearts there was a large accumulation of inosine monophosphate. Indeed, a substantial amount of inosine monophosphate was determined in untreated hearts, and hearts treated with nifedipine (EC30) and mioflazine (EC10). During the first 5 min of reperfusion a large quantity of catabolites, mainly inosine, was washed out. During 20 min of subsequent reperfusion in untreated hearts and in nifedipine and mioflazine-treated hearts the efflux of catabolites returned to normoxic values. Similar to the effect in ischaemic hearts, in early perfusate from lidoflazine, mioflazine and dipyridamole-treated hearts the adenosine/inosine ratio was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Protective effect of bepridil against veratrine-induced contracture in rat atria.

    Leboeuf, J; Baissat, J; Massingham, R


    In isolated stimulated rat atria, superfusion with veratrine caused a marked contracture (VIC) which was absent in calcium-free medium and which was inhibited by tetrodotoxin (IC50VIC of 1.38 microM). Lowering the extracellular calcium concentration from 2.5 to 0.5 or 0.1 mM reduced the veratrine-induced contracture and delayed its onset. Superfusion of bepridil (1-10 microM) for 60 min before and during veratrine exposure markedly slowed the onset of contracture, reduced the maximum response (IC50VIC = 2.11 microM) and facilitated recovery upon washout of the alkaloid. The direct negative inotropic effect (NIE) of bepridil (IC50NIE = 10.96 microM) resulted in an VIC/NIE ratio of 5.19 for this drug. The protective effects of bepridil were rate-independent and were not modified by the presence of atropine (1.4 microM) and propranolol (0.3 microM) in the medium. Diltiazem, verapamil and nifedipine only reduced veratrine-induced contracture at concentrations much higher than those producing a negative inotropic effect, giving them negative NIE/VIC ratios of 0.31, 0.08 and 0.08 respectively. Like bepridil, flunarizine had a positive NIE/VIC ratio (15.87, IC50VIC = 3.71 microM). The lack of effect of the quaternary derivative of bepridil CERM 11888 indicated that intracellular sites of action may be involved in the activity of bepridil on veratrine-induced contracture. Given that veratrine-induced changes may mimic some of the pathological changes occurring in ischaemia, the results suggest that bepridil and flunarizine may be more effective than L-type, slow calcium ion-channel blockers in protecting against calcium overload during ischaemia and reperfusion injury.

  9. Comparative Efficacy and Safety of Antihypertensive Agents for Adult Diabetic Patients with Microalbuminuric Kidney Disease: A Network Meta-Analysis

    Huang, Rongzhong; Feng, Yuxing; Wang, Ying; Qin, Xiaoxia; Melgiri, Narayan Dhruvaraj; Sun, Yang; Li, Xingsheng


    Background Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease. Methods MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed. Results A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria. Conclusions Trandolapril+candesartan appears to be the most efficacious intervention

  10. Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models.

    Patai, Zoltán; Guttman, András; Mikus, Endre G


    Drotaverine is considered an inhibitor of cyclic-3',5'-nucleotide-phophodiesterase (PDE) enzymes; however, published receptor binding data also support the potential L-type voltage- operated calcium channel (L-VOCC) blocking effect of drotaverine. Hence, in this work, we focus on the potential L-VOCC blocking effect of drotaverine by using L-VOCC-associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. Drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca(2+)- induced contraction in a concentration- dependent fashion. The PDE inhibitor theophylline had no effect on the KCl-evoked contractions, indicating its lack of inhibition on inward Ca(2+) flow. Drotaverine was also tested on the L-VOCC-mediated resting Ca(2+) refill model. In this model, the extracellular Ca(2+) enters the cells to replenish the emptied intracellular Ca(2+) stores. Drotaverine and L-VOCC blocker reference molecules inhibited Ca(2+) replenishment of Ca(2+)-depleted preparations detected by agonist-induced contractions in post-Ca(2+) replenishment Ca(2+)-free medium. Theophylline did not modify the Ca(2+) store replenishment after contraction. It seems that drotaverine, but not theophylline, inhibits inward Ca(2+) flux. The addition of CaCl2 to Ca(2+)-free medium containing the agonist induced inward Ca(2+) flow and subsequent contraction of Ca(2+)-depleted tracheal preparations. Drotaverine, similar to the L-VOCC blockers, inhibited inward Ca(2+) flow and blunted the slope of CaCl2-induced contraction in agonist containing Ca(2+)-free medium with Ca(2+)-depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but, unlike PDE inhibitors using L-VOCC associated in vitro experimental models.

  11. Novel tacrine derivatives that block neuronal calcium channels.

    de los Ríos, Cristóbal; Marco, José L; Carreiras, María D C; Chinchón, P M; García, Antonio G; Villarroya, Mercedes


    A new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) derivatives were synthesized and their effects on 45Ca(2+) entry into bovine adrenal chromaffin cells stimulated with dimethylphenylpiperazinium (DMPP) or K(+), studied. At 3 microM, compound 1 did not affect (45)Ca(2+) uptake evoked by DMPP. Compounds 14, 15 and 17 inhibited the effects of DMPP by 30%. Compounds 3, 9 and tacrine blocked the DMPP signal by about 50%. Compounds 5 and 12 were the most potent blockers of DMPP-stimulated 45Ca(2+) entry (90%); the rest of the compounds inhibited the effects of DMPP by 70-80%. Compounds 1, 3, 4, 8, 10, 11, 13, 16, 17 and tacrine inhibited 45Ca(2+) uptake induced by K(+) about 20%. Compounds 6, 14 and 15 inhibited the K(+) effects by 10% or less. Compounds 7, 9, 12 and 18 blocked the K(+) signal by 30% and, finally, compounds 2 and 5 inhibited the K(+)-induced 45Ca(2+) entry by 50%. None of the new compounds was as effective as diltiazem (IC(50)=0.03 microM) in causing relaxation of the rat aorta precontracted with 35 mM K(+); the most potent was compound 7 (IC(50)=0.3 microM). Compounds 5, 6, 8, 9, 10 and 13 had IC(50)s around 10 microM and compounds 3, 4, 11 and 12 around 20 microM. Blockade of Ca(2+) entry through neuronal voltage-dependent Ca(2+) channels, without concomitant blockade of vascular Ca(2+) channels, suggests that some of these compounds might exhibit neuroprotectant effects but not undesirable hemodynamic effects.

  12. Calcium Channel Genes Associated with Bipolar Disorder Modulate Lithium's Amplification of Circadian Rhythms

    McCarthy, Michael J.; LeRoux, Melissa; Wei, Heather; Beesley, Stephen; Kelsoe, John R.; Welsh, David K.


    Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca2+ changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2∷luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 hr in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca2+ less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. controls. We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms. PMID:26476274

  13. Homer proteins mediate the interaction between STIM1 and Cav1.2 channels.

    Dionisio, Natalia; Smani, Tarik; Woodard, Geoffrey E; Castellano, Antonio; Salido, Gines M; Rosado, Juan A


    STIM1 is a ubiquitous Ca2+ sensor of the intracellular, agonist-sensitive, Ca2+ stores that communicates the filling state of the Ca2+ compartments to plasma membrane store-operated Ca2+ (SOC) channels. STIM1 has been presented as a point of convergence between store-operated and voltage-operated Ca2+ influx, both inducing activation of SOC channels while suppressing Cav1.2 channels. Here we report that Homer proteins play a relevant role in the communication between STIM1 and Cav1.2 channels. HEK-293 cells transiently expressing Cav1.2 channel subunits α1, β2 and α2δ-1 exhibited a significant Ca2+ entry upon treatment with a high concentration of KCl. In Cav1.2-expressing cells, treatment with thapsigargin (TG), to induce passive discharge of the intracellular Ca2+ stores, resulted in Ca2+ influx that was significantly greater than in cells not expressing Cav1.2 channels, a difference that was abolished by nifedipine and diltiazem. Treatment with TG induces co-immunoprecipitation of Homer1 with STIM1 and the Cav1.2 α1 subunit. Impairment of Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, or using siRNA Homer1, reduced the association of STIM1 and the Cav1.2 α1 subunit. These findings indicate that Homer is important for the association between both proteins. Finally, treatment with siRNA Homer1 or the PPKKFR peptide enhanced the nifedipine-sensitive component of TG response in Cav1.2-expressing cells. Altogether, these findings provide evidence for a new role of Homer1 supporting the regulation of Cav1.2 channels by STIM1. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists.

    King, G N; Fullinfaw, R; Higgins, T J; Walker, R G; Francis, D M; Wiesenfeld, D


    Although it is established that the immunosuppressant cyclosporin-A (CsA) and calcium antagonists [Nifedipine (Nif) and Diltiazem (Dz)] can independently induce gingival enlargement, little has been documented on the significance of the salivary CsA levels and the combined effect of CsA and a calcium antagonist upon gingival tissues. In the present cross-sectional investigation, clinical periodontal parameters and the pharmacologic profiles of CsA, Nif, and Dz were determined for 66 renal transplant recipients. Subjects were divided into the following groups: Group (Gp) 1: CsA [n = 18]; Gp 2: CsA + Nif [n = 15]; Gp 3: CsA + Dz [n = 12] and a negative Control Gp 4: azathioprine [n = 21]. A gingival enlargement score was assessed for each patient from study models using a hyperplastic index (HI). Pharmacologic profiles included CsA whole blood and whole saliva levels as measured by fluorescence polarization immunoassay. The HI scores between Gp 1, 2 and 3 were not significantly different. However, when compared with controls (Gp 4), there was a significant difference in HI and all individual groups (Gp 1, 2, 3) (p < 0.05). Gingival hyperplasia was only weakly related to plaque and calculus but was unrelated to CsA dose (mg/kg/day), duration of CsA therapy (months), CsA blood or saliva levels (ng/ml), or the concurrent administration of a Nif or Dz. Gingival enlargement was found to occur in 49% of subjects who were either on CsA or CsA and a calcium antagonist. It is concluded that CsA alone or in combination with a calcium antagonist caused a significant increase in gingival enlargement compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Exposure-response relationships and drug interactions of sirolimus.

    Zimmerman, James J


    Sirolimus (rapamycin, RAPAMUNE, RAPA) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactions of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs or =4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(-)verapamil.

  16. Relationship between gingival hyperplasia and class II histocompatibility antigens in renal transplant recipients.

    Türkmen, A; Ak, G; Furuncuoglu, Y; Akar, U; Seyhun, Y; Türk, S; Carin, M; Sever, M S


    Gingival hyperplasia, a well-known side effect of ciclosporin A (CS-A), is much more prominent when CS-A is used in combination with calcium channel blockers, especially dihydropyridines. On the other hand, it is interesting to note that this complication is not observed in all patients using this drug combination. This study was conducted in order to investigate the relationship (if any) between major histocompatibility complex antigens and gingival hyperplasia. Seventy-six renal transplantation patients were evaluated by an experienced dentist for gingival hyperplasia. The patients were then divided into two groups according to the presence (group 1, n = 18) or absence (group 2, n = 58) of gingival hyperplasia. There was no significant difference between the two groups regarding age, sex, transplant age, donor type, antihypertensive and immunosuppressive therapy protocols, and CS-A levels. HLA-DR2 antigen was present in 63% of the patients with gingival hyperplasia and in 34% of the patients without gingival hyperplasia. However, the HLA-DR1 antigen frequencies were found to be 11 and 22% in group 1 and group 2, respectively. In patients receiving nifedipine as an antihypertensive therapy, gingival hyperplasia developed more often than in patients receiving verapamil or diltiazem. As a result, in renal allograft recipients with HLA-DR1 antigen, gingival hyperplasia was seen less frequently than in HLA-DR2-positive patients. It is believed that the presence of these antigens regulates the response of the patients to either CS-A and/or calcium channel blockers.

  17. Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling.

    Jarvis, Gavin E; Barbosa, Roseli; Thompson, Andrew J


    Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5-HT-evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use-dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5-HT3 receptors (IC50 = 45 µg ml(-1)) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml(-1)) and guinea pig ileum (IC50 = 20 µg ml(-1)), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators.

  18. 应用美托洛尔与地尔硫卓治疗心肌反复梗塞的临床研究录



    目的:探讨在治疗心肌梗死患者中出现反复梗塞情况时应用美托洛尔与地尔硫卓的临床疗效。方法对我院2012年2月至2013年1月收治的心肌反复梗塞患者临床治疗病例进行抽样,将40例心肌反复梗塞患者病例按照抽签法随机分为对照组与治疗组,每组20例。治疗组采用美托洛尔治疗,对照组采用地尔硫卓治疗。观察两组患者疗效。结果两组心肌反复梗塞患者经过治疗之后,治疗组治疗结束后24h内缓解11例(55.00%),1个月内疼痛复发4例(20.00%),1个月内出现心衰5例(25.00%),1个月内死亡数11例(55.00%);对照组治疗结束后24h内缓解4例(20.00%),1个月内疼痛复发12例(60.00%),1个月内出现心衰18例(90.00%),1个月内死亡数16例(80.00%)。两组心肌反复梗塞患者临床治疗效果具有显著差异性,具备统计学意义(P<0.05)。结论心肌反复梗塞患者采用美托洛尔治疗的临床疗效明显优于地尔硫卓治疗的临床疗效,能够避免患者心肌梗塞的面积扩大,降低心肌的耗氧量,缓解患者的疼痛感,值得进行临床推广应用。%Objective To investigate the clinical efficacy of metoprolol and diltiazem application appears repeatedly infarction in patients with acute myocardial in-farction.Methods Myocardial in our hospital from 2012 February to 2013 January were repeated clinical treatment in patients with infarction of sampling ,40 cases of my-ocardial infarction in patients with recurrent cases according to randomly divided into control group and treatment group ,20 patients in each group.Treatment group were treated with metoprolol treatment,the control group using diltiazem treatment.Observation of the efficacy of the two groups.Results The of two groups of patients with my-ocardial infarction repeatedly after treatment, the treatment group after treatment24 h remission

  19. Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint.

    Neugebauer, V; Vanegas, H; Nebe, J; Rümenapp, P; Schaible, H G


    1. The present study addresses the involvement of voltage-dependent calcium channels of the N and L type in the spinal processing of innocuous and noxious input from the knee joint, both under normal conditions and under inflammatory conditions in which spinal cord neurons become hyperexcitable. In 30 anesthetized rats, extracellular recordings were performed from single dorsal horn neurons in segments 1-4 of the lumbar spinal cord. All neurons had receptive fields in the ipsilateral knee joint. In 22 rats, an inflammation was induced in the ipsilateral knee joint by kaolin and carrageenan 4-16 h before the recordings. The antagonist at N-type calcium channels, omega-conotoxin GVIA (omega-CTx GVIA), was administered topically in solution to the dorsal surface of the spinal cord at the appropriate spinal segments in 6 rats with normal joints and in 12 rats with inflamed knee joints. The antagonist at L-type channels, nimodipine, was administered topically in 5 rats with normal joints and in 11 rats with inflamed knee joints. In another five rats with inflamed joints, antagonists at L-type calcium channels (diltiazem and nimodipine) and omega-CTx GVIA were administered ionophoretically with multibarrel electrodes close to the neurons recorded. 2. The topical administration of omega-CTx GVIA to the spinal cord reduced the responses to both innocuous and noxious pressure applied to the knee joint in a sample of 11 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed joint (hyperexcitable neurons). The responses were decreased to approximately 65% of the predrug values within administration times of 30 min. A similar reduction of the responses to innocuous and noxious pressure was observed when omega-CTx GVIA was administered ionophoretically to nine hyperexcitable neurons. In neurons with input from the normal or the inflamed knee joint, the administration of omega-CTx GVIA led also to a reduction of the responses to

  20. Cardiovascular effects of ethanol extract of Rubus chingii Hu (Rosaceae) in rats: an in vivo and in vitro approach.

    Su, X H; Duan, R; Sun, Y Y; Wen, J F; Kang, D G; Lee, H S; Cho, K W; Jin, S N


    Rubus chingii Hu (Rosaceae) is an important traditional Chinese medicine that has been used to improve function of the kidney and treat excessive polyuria. However, the effects of Rubus chingii on the cardiovascular system and its pharmacological mechanisms of action have not been studied. The aim of the present study was to evaluate the cardiovascular effects of ethanol extract of Rubus chingii (ERC) in rats. The changes in systolic blood pressure and heart rate of rats and vascular tone of aortic rings in in vitro were measured using pressure transducer and force transducer, respectively, connected to a multichannel recording system. ERC decreased systolic blood pressure and heart rate in a concentration-dependent manner. ERC induced vasorelaxation in a concentration-dependent manner. The ERC-induced vasorelaxation was not observed in the absence of the endothelium. The vasorelaxant effect of ERC was significantly attenuated by inhibition of endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), or Ca(2+) entry from extracellular sources with L-NAME, ODQ, diltiazem, or extracellular Ca(2+) depletion, respectively. Similarly, an inhibition of Akt with wortmannin attenuated the ERC-induced vasorelaxation. Modulators of the store-operated Ca(2+) entry, thapsigargin, Gd(3+), and 2-aminoethyl diphenylborinate markedly attenuated the ERC-induced vasorelaxation. Furthermore, 4-aminopyridine an inhibitor of voltage-dependent K(+) (KV) channel, significantly attenuated the ERC-induced vasorelaxation. However, tetraethylammonium and glibenclamide, had no significant effect on the ERC-induced vasorelaxation. Indomethacin, atropine, and propranolol had no effects on the ERC-induced vasorelaxation. The present study demonstrates that ERC induces vasorelaxation via endothelium-dependent two-step signaling: an activation of the Ca(2+)-eNOS-NO signaling in the endothelial cells and then subsequent stimulation of the NO-sGC-cGMP-KV channel signaling in the vascular

  1. Thyrotoxic and pheochromocytoma multisystem crisis: a case report.

    Suzuki, Kodai; Miyake, Takahito; Okada, Hideshi; Yamaji, Fuminori; Kitagawa, Yuichiro; Fukuta, Tetsuya; Yasuda, Ryu; Tanaka, Yoshihito; Okamoto, Haruka; Nachi, Sho; Doi, Tomoaki; Yoshida, Takahiro; Kumada, Keisuke; Yoshida, Shozo; Ushikoshi, Hiroaki; Toyoda, Izumi; Ogura, Shinji


    Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 μIU/mL. Thyroid echography demonstrated no thyroid swelling (23 × 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 × 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave's hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor

  2. 光敏性药疹68例临床分析%Clinical analysis of 68 patients with photosensitization drug eruption

    朱敏刚; 魏盛; 王音; 胡晓波; 刘卫


    目的::明确光敏性药疹的临床特征及相关药物。方法:对我院门诊诊断为光敏性药疹患者的临床资料进行回顾性分析。结果:68例患者中,噻嗪类药物所致37例,喹诺酮类19例,多西环素3例,维胺酯、辛伐他丁及秋水仙碱各2例,氯丙嗪、地尔硫卓及乙胺碘呋酮各1例。皮损仅局限于曝光部位的62例,主要表现为水肿性红斑;皮损同时累及非曝光部位的有6例,表现为湿疹样皮损等多形性损害。患者停用可疑药物及避光,口服抗组胺药、烟酰胺或中小剂量糖皮质激素,外用炉甘石洗剂或糖皮质激素乳膏。65例患者皮损于4周内基本消退。结论:噻嗪类利尿剂及喹诺酮类是引起光敏性药疹最常见的药物。%Objective:To determine the types of drugs which caused photosensitization drug eruption and the clinical features of the patients. Methods: The data of patients with photosensitization drug eruption was analyzed retrospectively. Results: Out of 68 patients, 37 patients were caused by thiazine diuretics, 19 by quinolones, 3 by doxycycline, 2 by viaminate, 2 by Simvastatin, 2 by colchicine, 1 by chlorpromazine, 1 by diltiazem and 1 by amiodarone. The lesions were located on exposed area only and mainly manifested as edem-atous erythema in 62 patients. The lesions were located on both exposed and unexposed areas and manifested as various lesions in 6 patients. All patients stopped the suspicious drugs, kept away from the sun exposure and were given oral antihistamines, nicotinamide, low-medium doses of glucocorticoid and topical calamine lotion and corticosteroids cream. Six five patients were cured after the treatment of 4 weeks. Conclusion:Thia-zine diuretics and quinolones are the most common drugs inducing the photosensitization drug eruption in our patients.

  3. Pharmacological approaches in the treatment of atrial fibrillation.

    Tamargo, Juan; Caballero, Ricardo; Delpón, Eva


    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with substantial cardiovascular morbidity and mortality. The arrhythmia can be initiated and/or maintained by rapidly firing foci, single- and multiple-circuit reentry. Once initiated, AF alters atrial electrical and structural properties (atrial remodeling) in a way that promotes its own maintenance and recurrence and may alter the response to antiarrhythmic drugs. Thus, initial episodes of paroxysmal (self-terminating) AF lengthens to the point where the arrhythmia becomes persistent (requires cardioversion to restore sinus rhythm) and permanent. AF usually requires a trigger for initiation and a favorable electrophysiological and/or anatomical substrate for maintenance. The substrate includes both cardiovascular (coronary artery disease, valvular heart disease, heart failure, hypertension, dilated cardiomyopathy) and non cardiovascular diseases (thyrotoxicosis, pulmonary diseases). Accordingly, the initial step in patients with AF requires a careful assessment of symptoms and identification of underlying reversible triggers and potentially modifiable underlying structural substrate and treat them aggressively. In contrast to other cardiac arrhythmias, antiarrhythmic drugs (ADs) are the mainstay of therapy. Long-term treatment of AF is directed to restore and maintain the sinus rhythm with class I and III ADs (rhythm-control) or to allow AF to persist and ensure that the ventricular rate is controlled (rate-control) with atrioventricular nodal blocking drugs (digoxin, beta-blockers, verapamil, diltiazem) and prevent thromboembolic complications with anticoagulants. However, the long-term efficacy of ADs for preventing AF recurrence is far from ideal, because of limited efficacy (AF recurs in at least one-half of the patients) and potential side effects, particularly proarrhythmia. Thus, the choice of the appropriate AD will depend on the temporal pattern of the arrhythmia

  4. Differentialtherapie mit Kalziumantagonisten

    Dörffel Y


    Full Text Available Der antihypertensive Effekt der Kalziumantagonisten ist bei allen Altersgruppen und Rassen seit längerem erwiesen. Darüber hinaus sind verschiedene andere positive Wirkungen dokumentiert, wie z. B. die Verbesserung der Endothelfunktion, Reduktion der Atheroskleroseprogression in der A. carotis, Reduktion der linksventrikulären und der arteriolären Hypertrophie sowie eine Verbesserung der arteriellen Compliance. Kalziumantagonisten verschlechtern nicht den Lipid- oder Glukosestoffwechsel. Für den Einsatz in der Praxis ist die Kenntnis der Heterogenität der Substanzklasse mit sich daraus ableitenden Vor- und Nachteilen sowie unterschiedlichen Indikationen von großer Relevanz. Den Prototypen der Non-Dihydropyridine Verapamil (chem. Phenylalkylamin und Diltiazem (chem. Benzothiazepine steht die umfangreiche Substanzklasse der Dihydropyridine (DHP gegenüber. Zu den DHPs zählen neben dem Prototyp Nifedipin die neueren Substanzen wie Nitrendipin, Nisoldipin, Amlodipin, Felodipin, Lacidipin und Lercanidipin. DHPs sind in erster Linie Vasodilatatoren, die durch eine Reduktion des peripheren vaskulären Widerstandes den arteriellen Blutdruck senken. Insbesondere bei älteren Präparaten mit schnellem Wirkungseintritt, wie z. B. beim unretardierten Nifedipin, einem DHP der ersten Generation, kann eine autonome Gegenregulation ausgelöst werden. Bei den modernen DHPs mit längerer Wirkungsdauer und bei den Non-DHPs ist dieser Effekt bedeutend abgeschwächt oder gar nicht mehr nachweisbar. In mehreren prospektiven, randomisierten und placebokontrollierten Studien konnte bei Patienten mit isolierter systolischer Hypertonie eine Reduktion der Schlaganfallrate dokumentiert werden (Syst-Eur, Syst-China, signifikante Unterschiede bezüglich Mortalität und Morbidität ergaben sich im Vergleich mit anderen Antihypertensiva (Diuretika, Betablocker, ACE-Hemmer nicht (STOP-2, INSIGHT, NORDIL, ALLHAT, INVEST. In der meist erforderlichen antihypertensiven

  5. Solid state crystallisation of oligosaccharide ester derivatives

    Wright, Elaine Ann


    An investigation of the solid state properties of oligosaccharide ester derivatives (OEDs) with potential applications in drug delivery has been carried out. The amorphous form of two OEDs, trehalose octa-acetate (TOAC) and 6:6'-di-({beta}-tetraacetyl glucuronyl)-hexaacetyl trehalose (TR153), was investigated as a matrix for the sustained release of active ingredients. The matrices showed a tendency to crystallise and so polymorph screens were performed to provide crystalline samples for structural analysis. The crystal structures of TOAC methanolate and TR153 acetonitrile solvate have been determined by single-crystal laboratory X-ray diffraction. TOAC methanolate crystallises in the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1} with a = 15.429(18) A, b = 17.934(19) A and c = 13.518(4) A at 123 K. The structure is isomorphous with the previously reported structure of TOAC monohydrate form II. TR153 acetonitrile solvate crystallises in the monoclinic spacegroup C2 with a = 30:160(6) A, b = 11.878(3) A, c 20.6645(5) A and {beta} = 115.027 (10) deg at 123 K. The crystal structures of both TOAC methanolate and TR153 acetonitrile solvate are stabilised by complex networks of intermolecular C--H...O contacts. Two model compounds were selected for dissolution studies: diltiazem hydrochloride, as a water- soluble organic salt, and ketoprofen as a poorly water-soluble organic compound. Dissolution of both compounds from amorphous TOAC and TR153 matrices was investigated. The release of both drugs was more rapid and complete from TOAC matrices than from TR153 matrices, with both matrices showing a tendency to crystallise (devitrify) during the course of the dissolution experiments. This tendency was greater for the TOAC matrix, which transformed to the extent of ca. 100% within 48 hours. The available evidence suggests that devitrification of the matrix in contact with water produces a polycrystalline, non-monolithic structure rich in microscopic cracks and pores

  6. Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn.

    Chaudhary Mueen


    Full Text Available Abstract Background The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn., whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. Methods The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in-vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37°C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. Results In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 μM. When tested on K+ (80 mM-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM and carbachol (CCh, 1 μM-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 μM, caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0-5.0 mg/ml. The cardio-stimulant effect was abolished in the presence of propranolol, similar to

  7. Renal Dysfunction after Off-Pump Coronary Artery Bypass Surgery- Risk Factors and Preventive Strategies

    Gaurab Maitra


    preoperative risk factors and therefore the high risk groups by developing clinical scoring systems. Preoperative treatment of congestive cardiac failure and volume depletion is mandatory. Avoidance of nephrotoxic drugs and prevention of significant hemodynamic events that may insult the kidney are essential. Perioperative hydration, aggressive control of serum glucose, haemodynamic monitoring and optimization of ventricular function are important strategies. Several drugs have been evaluated with inconsistent results. Dopamine and diuretics once thought to be renoprotective has not been shown to prevent renal failure. Mannitol is probably effective if given before the insult takes place. Some of the newer drugs like fenoldopam, atrial natriuretic peptide, N-acetylcysteine, clonidine and diltiazem have shown some promise in preventing renal dysfunction but more studies are needed to establish their role of renoprotection in cardiac surgery.

  8. Amiodarone -- waxed and waned and waxed again.

    Doggrell, S A


    undertaken to ascertain which patients are most likely to benefit from ICDs, as these are more expensive than treatment with amiodarone. Patients with severely depressed ejection fractions should be the first to be considered for ICDs. A new indication for amiodarone is atrial fibrillation or flutter. Amiodarone is effective in chronic and recent onset atrial fibrillation and orally or iv. for atrial fibrillation after heart surgery. In atrial fibrillation amiodarone is more than or equi-effective with flecainide, quinidine, racemic sotalol, propafenone and diltiazem and therefore should be considered for first line therapy. Amiodarone is also safe and effective in controlling refractory tachyarrhythmias in infants and is safe after cardiac surgery.

  9. Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats.

    Ghazizadeh, Vahid; Nazıroğlu, Mustafa


    Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

  10. Aging Reduces L-Type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers

    Albarwani, Sulayma A.; Mansour, Fathi; Khan, Abdul Aleem; Al-Lawati, Intisar; Al-Kaabi, Abdulla; Al-Busaidi, Al-Manar; Al-Hadhrami, Safa; Al-Husseini, Isehaq; Al-Siyabi, Sultan; Tanira, Musbah O.


    Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5–3 months (young) and 22–26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1 nM–1 μM), verapamil (0.1 nM–10 μM), or diltiazem (0.1 nM–10 μM). Relaxation-concentration response curves produced by cumulative concentrations of three different CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pIC50 ± s.e.m: (8.37 ± 0.06 vs. 8.04 ± 0.05, 7.40 ± 0.07 vs. 6.81 ± 0.04, and 6.58 ± 0.07 vs. 6.34 ± 0.06) in young vs. old. It was observed that the maximal contractions induced by phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 (1 μM) increased resting tension by 23 ± 4.8% in young arteries and 4.7 ± 1.6% in old arteries. LTCC current density were also significantly lower in old arteries (−2.77 ± 0.45 pA/pF) compared to young arteries (−4.5 ± 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced

  11. Aging Reduces L-type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers

    Sulayma A Albarwani


    Full Text Available Calcium channel blockers are widely used to treat cardiovascular disease (CVD including hypertension. As aging is an independent risk factor for CVD, the use of calcium channel blockers increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5 - 3 months (young and 22 - 26 months (old were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1nM - 10 µM, verapamil (0.1nM-10 µM or diltiazem (0.1nM - 10µM. Relaxation-concentration response curves produced by cumulative concentrations of three different calcium channel blockers (CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pEC50 ± s.e.m: (8.37 ± 0.06 vs 8.04 ± 0.05 , 7.40 ± 0.07 vs 6.81 ± 0.04 and 6.58 ± 0.07 vs 6.34 ± 0.06 in young vs old. It was observed that the maximal contractions induced by 100 mM KCl, phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 increased resting tension by 23±4.8% in young arteries and 4.7±1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 ± 0.45 pA/pF compared to young arteries (-4.5 ± 0.40 pA/pF; with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may

  12. Elastic and Muscular Arteries Differ in Structure, Basal NO Production and Voltage-Gated Ca(2+)-Channels.

    Leloup, Arthur J A; Van Hove, Cor E; Heykers, Annick; Schrijvers, Dorien M; De Meyer, Guido R Y; Fransen, Paul


    In the last decades, the search for mechanisms underlying progressive arterial stiffening and for interventions to avoid or reverse this process has gained much attention. In general, arterial stiffening displays regional variation and is, for example, during aging more prominent in elastic than in muscular arteries. We hypothesize that besides passive also active regulators of arterial compliance [i.e., endothelial and vascular smooth muscle cell (VSMC) function] differ between these arteries. Hence, it is conceivable that these vessel types will display different time frames of stiffening. To investigate this hypothesis segments of muscular arteries such as femoral and mesenteric arteries and elastic arteries such as the aorta and carotid artery were isolated from female C57Bl6 mice (5-6 months of age, n = 8). Both microscopy and passive stretching of the segments in a myograph confirmed that passive mechanical properties (elastin, collagen) of elastic and muscular arteries were significantly different. Endothelial function, more specifically basal nitric oxide (NO) efficacy, and VSMC function, more specifically L-type voltage-gated Ca(2+) channel (VGCC)-mediated contractions, were determined by α1-adrenoceptor stimulation with phenylephrine (PE) and by gradual depolarization with elevated extracellular K(+) in the absence and presence of eNOS inhibition with L-NAME. PE-mediated isometric contractions significantly increased after inhibition of NO release with L-NAME in elastic, but not in muscular vessel segments. This high basal eNOS activity in elastic vessels was also responsible for shifts of K(+) concentration-contraction curves to higher external K(+). VGCC-mediated contractions were similarly affected by depolarization with elevated K(+) in muscular artery segments or in elastic artery segments in the absence of basal NO. However, K(+)-induced contractions were inhibited by the VGCC blocker diltiazem with significantly higher sensitivity in the muscular

  13. Elastic and muscular arteries differ in structure, basal NO production and voltage-gated Ca2+-channels

    Arthur J.A. Leloup


    Full Text Available In the last decades, the search for mechanisms underlying progressive arterial stiffening and for interventions to avoid or reverse this process has gained much attention. In general, arterial stiffening displays regional variation and is, for example, during aging more prominent in elastic than in muscular arteries. We hypothesize that besides passive also active regulators of arterial compliance (i.e. endothelial and vascular smooth muscle cell (VSMC function differ between these arteries. Hence, it is conceivable that these vessel types will display different time frames of stiffening. To investigate this hypothesis segments of muscular arteries such as femoral and mesenteric arteries and elastic arteries such as the aorta and carotid artery were isolated from female C57Bl6 mice (5-6 months of age, n=8. Both microscopy and passive stretching of the segments in a myograph confirmed that passive mechanical properties (elastin, collagen of elastic and muscular arteries were significantly different. Endothelial function, more specifically basal nitric oxide (NO efficacy, and VSMC function, more specifically L-type voltage-gated Ca2+ channel (VGCC-mediated contractions, were determined by α1-adrenoceptor stimulation with phenylephrine (PE and by gradual depolarization with elevated extracellular K+ in the absence and presence of eNOS inhibition with L-NAME. PE-mediated isometric contractions significantly increased after inhibition of NO release with L-NAME in elastic, but not in muscular vessel segments. This high basal eNOS activity in elastic vessels was also responsible for shifts of K+ concentration-contraction curves to higher external K+. VGCC-mediated contractions were similarly affected by depolarization with elevated K+ in muscular artery segments or in elastic artery segments in the absence of basal NO. However, K+-induced contractions were inhibited by the VGCC blocker diltiazem with significantly higher sensitivity in the muscular

  14. Using saliva nitrite and nitrate levels as a biomarker for drug induced gingival overgrowth

    Erkan eSukuroglu


    Full Text Available Aim: Drug-induced gingival overgrowth has a multifactorial nature and the pathogenesis is still uncertain. It has been suggested that Nitric Oxide (NO might play a role in the pathogenesis of drug-induced gingival overgrowth due to the contribution of NO to immune response and matrix degradation. NO levels in biological fluids have been used as a diagnostic biomarker in many diseases. The aim of this study is to determine whether NO levels in plasma, saliva and gingival crevicular fluid (GCF can serve as a potential biomarker for the evaluation of drug-induced gingival overgrowth risk. Material and Methods: A total of 104 patients, receiving cyclosporine A (n=35, phenytoin (n=25, nifedipine (n=26 or diltiazem (n=18 participated in the study. The amount of gingival overgrowth was evaluated with two indices and was given as percentage. Periodontal clinical parameters including plaque index (PI, gingival index (GI, gingival bleeding time index (GBTI and probing depth (PD were also assessed. Saliva, GCF and plasma samples were obtained from each participants. Nitrite and nitrate levels in saliva, GCF and plasma were analyzed by Griess reagent. Results: Salivary nitrite and nitrate levels in responders were significantly higher than those in non-responders in only phenytoin group (p˂0.05. Nitrite and nitrate levels of gingival crevicular fluid and plasma did not significantly differ between responders and non-responders in all study groups (p˃0.05. Salivary nitrite levels exhibited a significant correlation with PD, GBTI, severity of gingival overgrowth (%GO and GCF volume (p˂0.05. Additionally, a strong positive correlation was detected between saliva and plasma nitrate levels (p˂0.005. However, both nitrite and nitrate levels in GCF and plasma demonstrated no significant correlation with clinical parameters, GO severity and GCF volume (p˃0.05.Conclusion: Salivary nitrite and nitrate levels could be used as periodontal disease biomarkers in

  15. Protective effects of phenolic alkaloids of Menispermum Dauricum on ischemia and ischemia - reperfusion injury%蝙蝠葛酚性碱对心肌缺血及缺血再灌注损伤的保护作用

    黎培员; 李英茜; 杨晓燕; 龚培力


    Objective To investigate the effects of phenolic alkaloids of Menispermum Dauricum (PAMD) on myocardial ischemia and ischemia - repurfusion in rats. Methods Myocardial ischemia in SD rats were induced by isoprenaline injection (isoprenaline, 85 mg · kg-1). Saline, PAMD(7.5,15 or 30 mg · kg-1) , diltiazem 10 mg · kg-1or Diaoxinxue-kang (DAXXK) 150 mg · kg-1 were administrated intragastriclly at 30 min before isoprenaline injectioa The level of lactate dehydrogenase (LDH) , creatine kinase(CK) , super oxide dismutase(SOD) , and ma-londialdehyde (MDA) were measured and myocardial pathological grade were evaluated. The langendorff perfused rat hearts were subjected to 30 min of global ischemia following by 40 rain reperfusion. PAMD( 1,10 or 100 mg · L-1 )or DAXXK 100 mg · L-1 were added into the modified KH solution. The changes of left ventricular systolic pressure (LVSP), left ventricular end dilated pressure (LVEDP) , maximum rising and failing rate of left ventricular pressure ( ± dp/dtmax ) , the flow of coronary artery, SOD and MDA were measured. Results In myocardial ischemia rats, PAMD obviously decreased the level of LDH, CK and MDA in serum , increased the activity of SOD and improved the pathological grade of myocardial lesion. After subjected to ischemia — reperfusion, PAMD improved the recovery of the index of contraction and stretch, such as LVSP, LVEDP and + dp/dtmax It also increased the flow of coronary artery and the activity of SOD, as well as decreased the content of MDA in myocardium. Conclusion PAMD can attenuate ischemia and ischemia - reperfusion injury in rat hearts.%目的 研究蝙蝠葛酚性碱(PAMD)对心肌缺血及缺血再灌注损伤的作用.方法 用大鼠皮下注射异丙肾上腺素85 mg·kg-1造成心肌缺血模型,于造模前30 min灌胃给予生理盐水、PAMD(7.5,15或30 mg·kg-1)、地尔硫(革)10 mg·kg-1或地奥心血康150 mg·kg-1,测定心肌缺血后乳酸脱氢酶(LDH)、肌酸激酶(CK)、超氧化物

  16. [Historical sketch of modern pharmaceutical science and technology (Part 4). Post World War II 50 years].

    Yamakawa, K


    ethical drugs and re-evaluation of drugs. Many facilities were built for the purpose of ensuring efficacy and safety, as shwon in Table 1. 6. Problems of Intellectual Property and followed the revisionist line of research and development for new ethical drugs. In 1976, Japanese pharmaceutical companies ceased to be an imitation industry, and increased research for the development of new drugs. 7. Pharmaceutical science and technology innovation (After 1985). Many of the pharmaceutical innovations during this period were as follows: 7.1) Technology innovation for evaluation of drug efficacy; 7.2) 1st to 3rd medical diagnostic technology innovations; 7.3) medical analytical methods and spectrometry technologies; 7.4) Computer-aided drug-design technology and drug information technology innovation; and 7.5) Drug delivery system and treatment drugs. 8. Recent research and development of new ethical drugs in Japan (1970 to 1995). Cephalosporine type beta-lactams (cefazolin, cefametazole, furomoxef, cefdinir), new quinolones (norfloxcin, ofloxacin, tosfloxcin), H1-Blockers (famotidine), Ca-antagonists (diltiazem, nicardipine), and other new drugs (pravastatine, taclolimus, leuprine) etc. came onto the market. 9. International Harmonization Age and Review toward 21 century. The rapid development and globalization of the pharmaceutical market has promoted international harmonization and rationalization of pharmaceutical regulatory affairs. In 1990, the Japan Pharmaceutical Manufacturers Association published a report toward 21 century, which described practical plans.

  17. Recombinant soluble expression,immobilization and characterization of lipase from Serratia marcescens H30%Serratia marcescens H30脂肪酶的重组可溶表达、固定化及其酶学性质

    徐晶晶; 苏二正; 吴向萍; 马昱澍; 魏东芝


    为了提高Serratia marcescens H30脂肪酶的可溶表达水平,分别将目的基因与 pGEX 4T 1、pET28a和pET32a构建重组表达载体,转入大肠杆菌BL21( DE3),通过优化诱导过程,发现可溶性酶的最高活性可达25000 U/L。再经Ni2+亲和柱纯化、LH EP 固定化后,固定化酶的比酶活为214 U/g(以1 g湿质量计),酶活回收率为51%。固定化后重组脂肪酶的最适温度由30℃提高到35℃,最适pH从7�0偏移至8�0左右,并且稳定性也有所增加。该固定化重组脂肪酶同样能够拆分消旋体反式4甲氧苯基缩水甘油酸甲酯,光学选择性没有改变。反应14 h,转化率为48�5%,底物的e�e.值为99�2%,表明该固定化脂肪酶能有效拆分消旋体反式4甲氧苯基缩水甘油酸甲酯,为工业生物催化制备地尔硫卓提供了可能。%To enhance the recombinant soluble expression of lipase from Serratia marcescens H30 in E�coli, different expression vectors such as pGEX⁃4T⁃1, pET28a and pET32a were studied�After optimization of inducing conditions, the maximum lipase activity reached to 25 000 U/L in shake flasks�The recombinant lipase was purified by Ni⁃NTA superflow column�Two carriers were used to immobilize the recombinant lipase, and LH⁃EP was the best one�Optimal temperature and pH of the immobilized lipase were 35 ℃ and 8�0, respectively�The thermal and pH stability of the lipase was improved after being immobilized onto LH⁃EP�The kinetic resolution of ( ± )⁃MPGM by immobilized lipase was studied, and a conversion of 48�5% was achieved along with an e�e. value of 98�2%�Our study reveals the good potential of immobilized Serratia marcescens H30 lipase for application in industrial production of diltiazem.

  18. Efeito da nifedipina gel 0,2% nas pressões de canal anal e na dor pós-operatória: estudo após hemorroidectomia pela técnica aberta Effect of 0.2% nifedipine gel on anal canal pressures and postoperative pain: study following hemorrhoidectomy by open technique

    Maria Auxiliadora Prolungatti Cesar


    Full Text Available INTRODUÇÃO: As hemorróidas são muito freqüentes e após o seu tratamento cirúrgico tem se observado que a dor causa muito sofrimento. Várias alternativas tem sido estudadas para melhorar a dor pós-operatória dentre elas a esfincterotomia cirúrgica que pode em alguns casos causar algum grau de incontinência fecal. Por esse motivo vários estudos tem utilizado a esfincterotomia química com nifedipina, diltiazen, trinitrato de glicerina e toxina botulínica. O objetivo dessa pesquisa foi avaliar o efeito da nifedipina tópica nas diminuições das pressões do canal anal e consequente influência na melhora da dor pós-operatória. MATERIAL E MÉTODO: Utilização da nifedipina tópica gel 0,2% (Grupo 1 e lidocaina 2% (Grupo 2 no pós operatório de hemorroidectomia aferindo as pressões no pré, primeiro, quarto e sétimo dias de pós operatório, associado de medida de dor todos os dias do pós-operatório através de tabela analógica. RESULTADOS: Os autores não encontraram diferenças em relação às pressões de canal anal mas em relação à dor referida estas foram em menor intensidade no grupo que recebeu a nifedipina. CONCLUSÕES: a nifedipina gel foi eficiente na analgesia pós-operatória, no entanto não alterou as pressões do canal anal.INTRODUCTION: Hemorrhoids are very common and pain following their surgical treatment causes great suffering. Various alternatives have been studied for reducing postoperative pain. Among these is surgical sphincterotomy, which may in some cases cause some degree of fecal incontinence. For this reason, several studies have used chemical sphincterotomy, with nifedipine, diltiazem, glycerin trinitrate or botulinum toxin. The objective of the present study was to investigate the effects of topical nifedipine for reducing anal canal pressures and consequently reducing postoperative pain. MATERIAL AND METHOD: Topical gels of 0.2% nifedipine plus 2% lidocaine (Group 1 and 2% lidocaine alone

  19. The ether lipid ET-18-OCH3 increases cytosolic Ca2+ concentrations in Madin Darby canine kidney cells.

    Jan, C R; Wu, S N; Tseng, C J


    The effect of the ether lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH3) on the intracellular free Ca2+ concentration ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells was studied using fura-2 as the Ca2+ probe. In Ca2+ medium, ET-18-OCH3 induced a significant rise in [Ca2+]i at concentrations between 10-100 microM with a concentration-dependent delay of 45-175 s. The [Ca2+]i signal was composed of a gradual rise and a sustained plateau. In Ca2+-free medium, ET-18-OCH3 (10-100 microM) induced a Ca2+ release from internal Ca2+ stores with a concentration-dependent delay of 45-175 s. This discharge of internal Ca2+ triggered capacitative Ca2+ entry in a concentration-dependent manner. This capacitative Ca2+ entry was not inhibited by econazole (25 microM), 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF96365; 50 microM), nifedipine (10 microM), verapamil (10 microM), diltiazem (10 microM) and cadmium (0.5 microM). Methyl 2-(phenylthio)ethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-dicarboxylat e (PCA-4248), a platelet-activating factor (PAF) receptor antagonist, inhibited 25 microM ET-18-OCH3-induced [Ca2+]i rise in a concentration-dependent manner between 1-20 microM, with 20 microM exerting a complete block. The [Ca2+]i rise induced by ET-18-OCH3 (25 microM) was not altered when the production of inositol 1,4,5-trisphosphate (IP3) was suppressed by the phospholipase C inhibitor U73122 (2 microM), but was partly inhibited by the phospholipase D inhibitor propranolol (0.1 mM) or the phospholipase A2 inhibitor aristolochic acid (20-40 microM). In Ca2+-free medium, pretreatment with 25 microM ET-18-OCH3 completely depleted the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin-sensitive Ca2+ store. In contrast, pretreatment with thapsigargin abolished 0.1 mM ATP-induced [Ca2+]i rise without altering the ET-18-OCH3-induced [Ca2+]i rise. This suggests that ET-18-OCH3 depleted thapsigargin

  20. Utility of C-2 (Cyclosporine) monitoring in postrenal transplant patients: A study in the Indian population.

    Thakur, V; Kumar, R; Gupta, P N


    The study was planned and conducted to assess the benefit of C-2 levels (blood cyclosporine levels two hours postdosing) monitoring over trough (C0) levels (predosing) in postrenal transplant patients. The patient population included 34 postrenal transplant individuals (28 males and six females, mean age of 39.9 +/- 12.3 years). The patients were first-transplant patients and were receiving a microemulsion form of cyclosporine A (CsA) as an immunosuppressant along with azathioprine and prednisolone. In addition, they were not on any enzyme inducer/inhibitor drugs, except for diltiazem. Timed collection of C0 and C-2 samples was done and the samples were immediately processed using the cedia cyclosporine plus assay kit. Estimation was done on a Beckman synchron CX5CE fully automated chemistry analyzer. Serum urea nitrogen and creatinine levels were checked. Poor graft survival was found in this population with 29.3% patients showing graft rejection. The graft rejection patients were assigned to two groups: group I with chronic graft rejection patients (17.6%) and group II with acute graft rejection patients (11.7%). Group III consisted of graft survival patients (70.7%). Mean +/- SD was calculated for C0 and C2 levels. Individual values for C0 and C-2 were plotted on a scatter chart. C0 and C-2 levels were normalized by calculating them as the percentage of their targets (data not shown) and compared using the Kruskal Wallis one-way analysis of variance. C0 levels in all the three groups were within the recommended therapeutic range (150-300 ng/mL) (P < 0.182). Blood C-2 concentrations did not achieve the recommended target levels in these patients. One-way analysis of variance for C-2 values when expressed as the percentage of the target values did not show any significant difference between these groups (P < 0.84). No significant difference was found in C0 levels between groups I, II, and group III patients when expressed as the percentage of the target values (P

  1. Effect of release of hydroxypropylmethyl cellulose on single and bilayer sustained-release matrix tablets%羟丙基甲基纤维素对单层及双层缓释骨架制剂体外释放的影响

    杨亚鹏; 汪梦圆; 常俊标; 郭旻彤


    Objective:To study the influence of HPMC as hydrophilic matrix materials and controlled-layer components on the drug release of sustained-release matrix tablets and bilayer tablets. Methods: Diltiazem hydrochloride was chosen as the water-soluble model drug to prepare different kinds of matrix tablets and double layer tablets with different formulations, and evaluate how the levels and grades of HPMC affect the drug release in sustained-release tablets and bilayer tablets. Results: HPMC with high viscosity and the amount of 20% -40% could delay the drug release to certain degree, but it was difficult to further slow down the drug release up to 24 h, especially for a water soluble drug. Combining HPMC with 5% -20% of CMC-Na was proven to be an effective way to achieve the 24 h release profile with the water soluble drug. HPMC was also investigated as a component in the double layer tablet as base layer. Drug release was complicated compared with EC as the base layer in the double layer tablet due to the great swelling ability of HPMC. HPMC' s larger swilling let it form a big cap to retard the drug release, which could significantly affect the drug release with a large ratio of the base layer to the drug layer; furthermore increasing the quality of 10% -40% of the base layer and the proportion of HPMC could reduce the initial burst release. Conclusion: The grade/level of HPMC and combinations with other matrix materials had a big impact on the drug release. HPMC could be used in the base layer of the double tablet to alternate the drug release profile, and reduce the initial burst release of the double-layer matrix tablet, and potentially change the drug mechanism.%目的:考察羟丙基甲基纤维素(hydroxypropylmethyl cellulose,HPMC)作为亲水凝胶材料和调控层材料对骨架型缓释制剂体外释放的影响.方法:以盐酸地尔硫卓为水溶性模型药物,HPMC为亲水凝胶材料,分别制备盐酸地尔硫卓缓释片和具

  2. 辛伐他汀和阿托伐他汀与CYP3A4酶抑制剂/诱导剂在心内科患者中联用情况调查%Investigation of the co-administration of simvastatin or atorvastatin with cytochrome P4503A4 inhibitors or inducers in cardiology ward

    钟雪; 张亚同; 纪立伟; 胡欣; 程刚


    patients were prescribed simvastatin or atorvastatin with CYP3A4 inhibitors, among which the patients used simvastatin accounted for 30%and atorvastatin accounted for 36%. The average duration of concomitant medication use were (7.04 ± 0.29) days. The CYP3A4 inhibitors that usually combined with simvastatin or atorvastatin were amlodipine, diltiazem, ranitidine, amiodarone, and ginkgo;while the CYP3A4 inducers were carbamazepine, prednisolone acetate tablets. The combination of simvastatin or atorvastatin with CYP3A4 inhibitors was more frequently than that with CYP3A4 inducers. There was no significant difference (P>0.05) when comparing the biochemical indicators of patients who used statins combined with inhibitors or not. Conclusion:The co-prescription of simvastatin or atorvastatin with CYP3A4 inhibitors is common in the hospital. Strategies should be taken to avoid co-administration of simvastatin or atorvastatin with CYP3A4 inhibitors or inducers. If it must be used, drug dosage should be limited according to the direction of drug. We should pay attention to the drug interactions with potential adverse effects, and follow-up patients' condition at regular intervals.

  3. Revascularização do miocárdio com a artéria radial Radial artery for coronary artery bypass grafting

    Luís Alberto Dallan


    éria submetida a endarterectomia. A artéria radial parece constituir uma alternativa de grande importância na revascularização do miocárdio, especialmente após o advento dos bloqueadores dos canais de cálcio. Entretanto, é necessário maior número de estudos e o seguimento a longo prazo dos pacientes, para conclusões definitivas.The radial artery (RA was used as a conduit for coronary artery bypass many years ago. Some years later, the graft was abandoned due to of a high incidence of narrowing or occlusion. The advent of new antispastic drugs led us to reinvestigate the use of the RA for coronary artery bypass grafting. Since May 1994,30 patients underwent myocardial revascularization using 31 RA grafts (1 patient received 2 grafts at our Service. The left internal thoracic artery (LITA was concomitantly used in all (100% patients, the right internal thoracic artery (RITA in 9 (30% patients and a saphenous vein graft in 24 (80% cases. A mean of 3.5 graft per patient was performed. The RA was anastomosed to the diagonal (n=10/33,3%, circunflex (n=8/26.6%, right coronary (n=8/26.6%, diagonalis (n=4/13.3% and anterior interventricular artery (n=1/3.3%. Two (6.6% patients presented for redo coronary surgery and 14 (46% had prior myocardial infarction. Two patients underwent associated ventricular aneurismectomy and 3 coronary endarterectomy. The left RA was used in 28 (93.4% patients, and the right RA in the 2 (6.6% remaining. The RA was used as a free graft. The proximal end of the RA was directly anastomosed to the ascending aorta using a 7-0 Polypropylene suture. After complete, the aortic clamp was removed and the blood flow throught the RA was tested. The distal anastomosis was then performed using a running 7-0 Polypropylene suture. All patientes received diltiazem started intraoperatively and continued at the follow-up period, when the AAS was associated. There was no mortality in this series. Angiographic controls were obtained in 7 (23.3% patients before the

  4. 经桡动脉路径介入治疗时应用经皮冠状动脉介入治疗导丝和球囊辅助指引导管成功跨越痉挛段33例分析%Feasibility study of guiding catheter passing through spasmodic vess els during percutaneous coronary intervention via radial artery access by the aid of PCI guiding wire and balloon

    倪祝华; 迟永辉; 张大鹏; 邓俊萍; 王益民; 刘广军; 张小良; 赵建红; 张继强; 刘佳胜; 祁树莹; 王乐丰; 杨新春; 王红石; 徐立; 李惟铭; 夏昆; 刘宇; 何冀芳


    ) patients undergoing PCI via radial artery access with radial artery or (and) brachial artery spasm ( group A ) were retrospectively analyzed .Among all these patients , guiding catheters were delivered through the spasmodic vessels successfully by the aid of PCI guiding wires and balloons .The clinical data of other 38 CAD patients having PCI during the same period performed by other operators via radial artery or ( and ) brachial artery approach and experienced vessel spasm were anlysed as the control ( group B ) .All patients in group B received conventional anti-spasm management during PCI .All vessel spasm was identified by angiography.For patients in group A , a diameter of 0.014 inch guiding wire was chosen to pass through the spasmodic vessel segment carefully and gently .The diameter of balloon should be chosen according to the diameter of guiding catheter .A balloon diameter of 2.0 mm and 2.5 mm was corresponded to 6F and 7F guiding catheter respectively .The balloon was advanced to the tip of guiding catheter , keeping a half in catheter and a half in vessel followed by inflating the balloon with a pressure of 8 atm.The balloon was kept inflated the guiding catheter was pushed in vitro carefully and slowly until the catheter passed through the spasmodic vessel segment .Then the balloon was deflated and pulled out together with PCI guiding wire . Exchanged a diameter of 0.035 inch wire and completed the positioning of guiding catheter .After finishing the PCI, radial or ( and) brachial angiography was performed again to observe if spasm disappeared and to determine if there any contrast medium exudation .For patients in group B , routine approach was applied including administration of nitroglycerine , diltiazem or nitroprusside etc . to relieve vessel spasm. Results The location of vessel spasm was similar in group A and group B ( P=0.150 ) , and the incidence rate of spasm in brachial artery was higher than that in radial artery in both groups .The chance of

  5. Status of β-blocker use and heart rate control in Chinese patients with stable coronary artery disease%中国稳定性冠心病患者心率控制与β受体阻滞剂使用状况分析

    孙艺红; 余金明; 胡大一


    .6 ±10.3 ) years old with 75.6% ( 1 983 ) male patients, 55.0%(1 443) patients had HR≥70 bpm.Mean HR measure by electrocardiogram(ECG) was (69.4 ±10.2)bpm, 50.9%(1 334 cases) patients had myocardial infarction (MI) history.A total of 21.9%(575 cases) patients had anginal symptoms; coronary angiography was performed in 88.8%(2 327 cases) of the patients.76.2%(1 997 cases) patients were treated with BB (any molecule and any dose ), 2.7%(70 cases) with digoxin or derivatives, 3.9%(103 cases) with verapamil or diltiazem, and 1.8%(47 cases) with amiodarone or dronedarone and 0.1%(2 cases) received ivabradine.BB use was similar among 3 HR groups(P>0.05).The independent risk factors associated with HR≥70 bpm were diabetes (OR=1.31), current smoker(OR=1.57), chronic heart failure(CHF) with NYHAⅢ(OR=2.13) and increased diastolic blood pressure ( OR=1.30 ).Conversely , high physical activity ( OR=0.61 ) , former smoker (OR=0.76) and history of percutaneous coronary intervention (PCI, OR=0.80) were associated with lower risk of HR≥70 bpm ( all P<0.05).The independent risk factors associated with non-BB use were older age (OR=1.11, 95%CI 1.01-1.47, P=0.005), lower diastolic blood pressure (OR=1.47, 95%CI 1.32-1.68, P=0.012), no history of MI (OR=1.86,95%CI 1.43-2.44, P<0.001) or PCI (OR=1.94, 95%CI 1.55 -3.73, P <0.001), asthma/chronic obstructive pulmonary disease (OR =1.32, 95%CI 1.15-1.99, P<0.001).Conclusions A total of 76.2%Chinese SCAD patients received BB medication but more than half of them did not reach the optimal HR.Clinical characteristics including diabetes , current smoker , CHF, increased diastolic blood pressure and no PCI were associated with poorly controlled HR(≥70 bpm).More efforts including adjusting the type and dose of heart rate lowering drugs are needed to achieve optimal HR control in Chinese SCAD patients.Clinical Trail Registry International Standard Randomized Controlled Trial ,ISRCTN43070564.