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British Journal of Clinical Pharmacology Mar 19941. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.
Topics: Administration, Oral; Adult; Diltiazem; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Female; Half-Life; Humans; Midazolam; Psychomotor Performance; Verapamil
PubMed: 8198928
DOI: 10.1111/j.1365-2125.1994.tb04266.x -
British Heart Journal Jul 1984The effects of the new calcium channel blocking agent diltiazem were evaluated in 11 patients with stable angina pectoris and confirmed obstructive coronary artery...
The effects of the new calcium channel blocking agent diltiazem were evaluated in 11 patients with stable angina pectoris and confirmed obstructive coronary artery disease at rest and during rapid atrial pacing. Symptomatic, metabolic, coronary, and systemic haemodynamic indices were monitored at rest and during pacing induced ischaemia. At rest, after the administration of intravenous diltiazem, potent vasodilator effects were observed with a significant fall in mean blood pressure and an increase in cardiac index. Importantly, however, the systemic vasodilator effect of diltiazem was associated with no significant increase in heart rate. During pacing there was similar decrease in mean blood pressure after diltiazem, and mean pacing time to angina increased significantly. Three patients did not develop angina on repeat pacing. Coupled with an improved pacing time to angina there was a significant improvement in myocardial lactate extraction during pacing, changing from lactate production to lactate extraction after diltiazem. This study confirms the antianginal effects of diltiazem and suggests that this agent may have advantages in the management of angina pectoris. The results suggest that diltiazem may exert its beneficial effect not only by reducing afterload reduction but also by a direct metabolic effect on the myocardium.
Topics: Angina Pectoris; Benzazepines; Coronary Disease; Diltiazem; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Pacemaker, Artificial; Time Factors
PubMed: 6743423
DOI: 10.1136/hrt.52.1.53 -
AAPS PharmSciTech 2008The objective was to investigate the suitable polymeric films for the development of diltiazem hydrochloride (diltiazem HCl) transdermal drug delivery systems....
The objective was to investigate the suitable polymeric films for the development of diltiazem hydrochloride (diltiazem HCl) transdermal drug delivery systems. Hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) were used as hydrophilic and hydrophobic film formers, respectively. Effects of HPMC/EC ratios and plasticizers on mechanical properties of free films were studied. Effects of HPMC/EC ratios on moisture uptake, in vitro release and permeation through pig ear skin of diltiazem HCl films were evaluated. Influence of enhancers including isopropyl myristate (IPM), isopropyl palmitate (IPP), N-methyl-2-pyrrolidone, oleic acid, polyethylene glycol 400, propylene glycol, and Tween80 on permeation was evaluated. It was found that addition of EC into HPMC film produced lower ultimate tensile strength, percent elongation at break and Young's modulus, however, addition of EC up to 60% resulted in too hard film. Plasticization with dibutyl phthalate (DBP) produced higher strength but lower elongation as compared to triethyl citrate. The moisture uptake and initial release rates (0-1 h) of diltiazem HCl films decreased with increasing the EC ratio. Diltiazem HCl films (10:0, 8:2 and 6:4 HPMC/EC) were studied for permeation because of the higher release rate. The 10:0 and 8:2 HPMC/EC films showed the comparable permeation-time profiles, and had higher flux values and shorter lag time as compared to 6:4 HPMC/EC film. Addition of IPM, IPP or Tween80 could enhance the fluxes for approx. three times while Tween80 also shorten the lag time. In conclusion, the film composed of 8:2 HPMC/EC, 30% DBP and 10% IPM, IPP or Tween80 loaded with 25% diltiazem HCl should be selected for manufacturing transdermal patch by using a suitable adhesive layer and backing membrane. Further in vitro permeation and in vivo performance studies are required.
Topics: Administration, Cutaneous; Animals; Calcium Channel Blockers; Cellulose; Chemistry, Pharmaceutical; Citrates; Delayed-Action Preparations; Dibutyl Phthalate; Diffusion; Diffusion Chambers, Culture; Diltiazem; Dosage Forms; Drug Carriers; Drug Compounding; Hypromellose Derivatives; Kinetics; Methylcellulose; Models, Chemical; Myristates; Palmitates; Permeability; Plasticizers; Polysorbates; Skin; Skin Absorption; Solubility; Swine; Technology, Pharmaceutical; Tensile Strength; Water
PubMed: 18431661
DOI: 10.1208/s12249-008-9062-8 -
Journal of Pharmacy & Pharmaceutical... 2007We investigated a potential hepatoprotective role of d-cis diltiazem, l-cis diltiazem, thiamine and the combination d-cis diltiazem and thiamine against lipid...
PURPOSE
We investigated a potential hepatoprotective role of d-cis diltiazem, l-cis diltiazem, thiamine and the combination d-cis diltiazem and thiamine against lipid peroxidation in a piglet liver microsomal model. A modified in vitro dichlorofluorescein assay was developed to assess the extent of peroxidative damage induced by reactive oxygen species in the piglet liver microsomal fraction.
METHODS
Microsomal membrane fraction, obtained from 3 week old female piglets, was treated with either the biologically vasoactive d-cis diltiazem or the non-vasoactive stereoisomer l-cis diltiazem (5-1000 microM) for 1 hour at 37 degrees C followed by one hour incubation with the free radical generator AAPH (2,2'-azobis-(2-amidinopropane) dihydrochloride; 1 mM) to initiate lipid peroxidation. In a separate study, piglet liver microsomes were pre-treated with d-cis diltiazem (50 or 500 microM) and thiamine (10-100 microM) to assess the antioxidant activity of the combination.
RESULTS
A dose dependant inhibition of membrane lipid peroxidation was observed with d-cis diltiazem (p<0.05) but not with l-cis diltiazem, suggesting that diltiazem is stereospecific in protecting against microsomal lipid peroxidation. Combining diltiazem with thiamine further protected microsomes against lipid peroxidation compared to use of individual drugs.
CONCLUSION
We conclude that diltiazem and the combination of diltiazem and thiamine offers a hepatoprotective effect against free radicals.
Topics: Animals; Antioxidants; Calcium Channel Blockers; Diltiazem; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Fluoresceins; Lipid Peroxidation; Microsomes, Liver; Protective Agents; Reactive Oxygen Species; Stereoisomerism; Swine; Thiamine
PubMed: 17727801
DOI: No ID Found -
Heart (British Cardiac Society) Oct 1997To assess antianginal efficacy and possible adverse haemodynamic effects of combination treatment with trimetazidine and diltiazem in patients with stable angina. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To assess antianginal efficacy and possible adverse haemodynamic effects of combination treatment with trimetazidine and diltiazem in patients with stable angina.
DESIGN
Double blind, randomised, placebo controlled trial of four weeks duration.
SETTING
Outpatient department of two Indian hospitals.
SUBJECTS
64 male patients with stable angina, uncontrolled on diltiazem alone.
INTERVENTIONS
Diltiazem 180 mg and trimetazidine 60 mg, or diltiazem 180 mg and placebo daily.
MAIN OUTCOME MEASURE
Change in exercise time to 1 mm ST segment depression.
RESULTS
33 patients (55%) had no exercise induced angina at 3 mm ST segment depression at inclusion in the study (silent ischaemia). Intention to treat analysis showed that of 32 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was: for anginal attacks, 28 (87.5) v 15 (46.9), p < 0.001; for exercise time to 1 mm ST segment depression, 21 (65.6) v 9 (28.1), p < 0.003; for exercise time to angina, 12 (37.5) v 5 (15.6), p < 0.05; and for maximum work at peak exercise, 17 (53.1) v 8 (25), p < 0.02. Compared to placebo, there was net improvement with trimetazidine in mean anginal attacks of 4.8/ week (95% confidence interval (CI) 7.5 to 2.1; p < 0.002); in mean exercise times at 1 mm ST segment depression of 94.2 seconds (95% CI 182.8 to 5.6; p < 0.05), and at onset of angina of 113.1 seconds (95% CI 181.6 to 44.6; p < 0.02); and in mean maximum work at peak exercise of 1.4 metabolic equivalents (95% CI 2.4 to 0.3; p < 0.05).
CONCLUSIONS
Patients with stable angina uncontrolled with diltiazem had a clinically important improvement after combination treatment with trimetazidine, without adverse haemodynamic events or increased side effects.
Topics: Angina Pectoris; Calcium Channel Blockers; Diltiazem; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Exercise Test; Humans; Male; Middle Aged; Trimetazidine; Vasodilator Agents
PubMed: 9404250
DOI: 10.1136/hrt.78.4.353 -
British Journal of Pharmacology Nov 1984The frog spinal cord was used to determine the characteristics of the actions of caroverine and diltiazem, two organic Ca2+-antagonists, on synaptic responses and...
The frog spinal cord was used to determine the characteristics of the actions of caroverine and diltiazem, two organic Ca2+-antagonists, on synaptic responses and L-glutamate-induced depolarization. Caroverine and diltiazem (10(-4)M) depressed the dorsal root potential (DR-DRP) induced by electrical stimulation of an adjacent dorsal root. Diltiazem also depressed the ventral root potential (DR-VRP), whereas caroverine augmented both the polysynaptic component in the ventral root reflex and the size of the DR-VRP. The root potentials induced by high frequency stimulation (20 Hz, for 1 s) were markedly depressed by these Ca2+-antagonists at a concentration of 10(-4)M. When the preparation was perfused with normal medium, the compounds depressed L-glutamate-induced depolarizations in ventral and dorsal roots. In preparations treated with tetrodotoxin (TTX) (2 X 10(-7)M), the antagonizing actions of the drugs against L-glutamate-induced depolarizations in the ventral root were markedly reduced or abolished, while significant antagonizing actions on the depolarization in the dorsal root were still observed. The increase in extracellular K+ activity induced by L-glutamate in the TTX-treated preparation was significantly reduced by the compounds. Caroverine and diltiazem had no effect on the presynaptic nerve spike and on the focal synaptic potential induced by a single stimulation of a dorsal root; however, the focal synaptic potential induced by high frequency stimulation (20 Hz, 1 s) was attenuated. Motoneuronal action potentials were abolished by the drugs, while the excitatory postsynaptic potential remained unaffected. 9 The present results suggest that caroverine and diltiazem are not specific L-glutamate antagonists in the frog spinal cord, but that they block the initiation of an action potential without affecting presynaptic nerve conduction, transmitter release or transmitter-receptor interactions. The inhibitory effects of these compounds on L-glutamate-induced K+-efflux are discussed with reference to their Ca2+-antagonizing actions.
Topics: Animals; Benzazepines; Diltiazem; Evoked Potentials; Glutamates; Glutamic Acid; In Vitro Techniques; Microelectrodes; Motor Neurons; Neuromuscular Depolarizing Agents; Potassium; Quinoxalines; Rana catesbeiana; Spinal Nerve Roots; Synapses; Tetrodotoxin; Vasodilator Agents
PubMed: 6150743
DOI: 10.1111/j.1476-5381.1984.tb16237.x -
Acta Pharmacologica Sinica Jul 2015Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered...
AIM
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.
METHODS
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.
RESULTS
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.
CONCLUSION
MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Aged; Asian People; Calcineurin Inhibitors; Cyclosporine; Diltiazem; Drug Synergism; Drug Therapy, Combination; Female; Genotype; Humans; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Young Adult
PubMed: 25891084
DOI: 10.1038/aps.2015.6 -
British Journal of Pharmacology Dec 19781 The effects of diltiazem on electrical and mechanical properties of vascular smooth muscles of the rabbit were examined by various experimental procedures. 2 In the...
1 The effects of diltiazem on electrical and mechanical properties of vascular smooth muscles of the rabbit were examined by various experimental procedures. 2 In the pulmonary artery, diltiazem (0.1 to 10 microgram/ml) did not modify the membrane potential (-56 mV), length constant of the tissue (1.47 mm) or rectifying properties of the membrane. Diltiazem (0.1 to 10 microgram/ml) did not modify the membrane potential of the mesenteric artery (-62.5 mV). 3 Diltiazem (1 to 10 microgram/ml) suppressed mechanical responses of pulmonary and mesenteric arteries induced either by direct stimulation of the muscle (1.0 s pulse) or by neural activation (0.5 ms pulse, 30 Hz and 10 s total duration). Diltiazem suppressed the contraction induced by nerve stimulation to a greater extent than that induced by direct muscle stimulation. 4 When the depolarization-contraction relationship of the smooth muscle of the pulmonary artery was observed by voltage clamp technique, diltiazem (1 to 10 microgram/ml) raised the critical membrane potential to evoke contraction from 5 mV to 12 mV, and reduced the amplitude of contraction obtained at any given depolarization level. 5 In the pulmonary artery, diltiazem (10 microgram/ml) suppressed K-induced contraction and raised the mechanical threshold, while K-induced depolarization was not suppressed. Diltiazem (1 to 10 microgram/ml) also suppressed noradrenaline-induced contraction, raised the mechanical threshold and suppressed noradrenaline-induced depolarization. 6 The vasodilator actions of diltiazem on the vascular smooth muscle were compared to vasodilator actions observed with other Ca-antagonists.
Topics: Animals; Benzazepines; Blood Vessels; Diltiazem; Female; In Vitro Techniques; Male; Membrane Potentials; Muscle Contraction; Muscle, Smooth; Rabbits
PubMed: 728679
DOI: 10.1111/j.1476-5381.1978.tb17311.x -
Japanese Journal of Pharmacology Jul 2000We determined the effect of 1-cis diltiazem, the enantiomer of diltiazem (d-cis isoform), on the energy metabolism of isolated guinea pig hearts during...
We determined the effect of 1-cis diltiazem, the enantiomer of diltiazem (d-cis isoform), on the energy metabolism of isolated guinea pig hearts during ischemia-reperfusion. We used 31P-NMR to measure the high-energy phosphate content and intracellular pH (pHi) during global ischemia for 30 min followed by reperfusion for 30 min. Before ischemia, the left ventricular developed pressure (LVDP) was reduced less by 10 microM l-cis diltiazem than by 3 microM diltiazem or 500 nM nifedipine. However, 10 microM l-cis diltiazem preserved the intracellular ATP content during ischemia and reperfusion, reduced the end-diastolic pressure increase during ischemia and reperfusion, and restored LVDP after reperfusion. Nifedipine at 50 nM, which reduced the LVDP more than 10 microM l-cis diltiazem, showed no cardioprotective effect. Ten micromolar l-cis diltiazem and 3 microM diltiazem, but neither 50 nor 500 nM nifedipine, reduced the pHi decrease that occurred 25 or 30 min after the onset of ischemia. Therefore, l-cis diltiazem has a cardioprotective effect on ischemic and reperfused myocardium and is less cardiodepressive than diltiazem and nifedipine. The effect of l-cis diltiazem during ischemia and reperfusion involves energy preservation, which is probably independent of its Ca2+-channel blocking action.
Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Diltiazem; Guinea Pigs; Heart; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Nifedipine; Phosphocreatine; Phosphorus Isotopes
PubMed: 10952071
DOI: 10.1254/jjp.83.225 -
Journal of Veterinary Internal Medicine 2007Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. (Clinical Trial)
Clinical Trial
BACKGROUND
Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied.
HYPOTHESES
Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment.
ANIMALS
Fourteen healthy horses.
METHODS
Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect).
RESULTS
Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg.
CONCLUSIONS AND CLINICAL IMPORTANCE
Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation.
Topics: Animals; Atrial Function; Atrioventricular Node; Cardiovascular Agents; Diltiazem; Dose-Response Relationship, Drug; Electrophysiologic Techniques, Cardiac; Female; Heart Atria; Horses; Male; Quinidine; Sinoatrial Node
PubMed: 17338165
DOI: 10.1892/0891-6640(2007)21[166:asnaan]2.0.co;2