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British Journal of Clinical Pharmacology May 2001To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation...
AIMS
To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil.
METHODS
Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1-250 microM). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate.
RESULTS
When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 microM for all major metabolites. The IC50 values ranged from 4.8 to 5.6 microM on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from 110-127 microM and from 21-27 microM, respectively. Verapamil and diltiazem inhibited testosterone 6beta-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 +/- 0.04 min-1 (mean +/- s.d.) and 2.9 +/- 0.6 microM, respectively, for verapamil and 0.07 +/- 0.01 min-1 and 3.3 +/- 1.5 microM, respectively, for diltiazem.
CONCLUSIONS
The IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
Topics: Calcium Channel Blockers; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diltiazem; Dose-Response Relationship, Drug; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Microsomes, Liver; Simvastatin; Verapamil
PubMed: 11422004
DOI: 10.1046/j.1365-2125.2001.01386.x -
British Journal of Pharmacology Sep 1986In pentobarbitone-anaesthetized rats, intravenous administration of diltiazem at 5 micrograms kg-1 min-1 did not change blood pressure or renal blood flow but increased...
In pentobarbitone-anaesthetized rats, intravenous administration of diltiazem at 5 micrograms kg-1 min-1 did not change blood pressure or renal blood flow but increased glomerular filtration rate by approximately 16%, urine flow by 85%, calcium excretion by 151% and absolute and fractional sodium excretions by 100% and 69%, respectively. A similar pattern of responses was obtained in renally denervated animals, except that calcium excretion did not change statistically. Diltiazem given at 20 micrograms kg-1 min-1 into renally innervated and denervated groups of animals depressed blood pressure between 15-17 mmHg but had no effect on renal haemodynamic or tubular function. Nitrendipine administered at 0.5 microgram kg-1 min-1 to renally innervated and denervated animals significantly depressed blood pressure in intact animals by 6 mmHg and in both groups did not change renal haemodynamics but caused similar increases in urine flow of between 79-98%, calcium excretion of between 87 and 125%, absolute sodium excretion of between 108 and 140% and fractional sodium excretion of between 83 and 170%. Infusion of nitrendipine at 1.0 micrograms kg-1 min-1 into intact or renally denervated animals decreased blood pressure by 18-20 mmHg and increased urine flow by 84-111%, calcium excretion by 85%, absolute sodium excretion by 81-137% and fractional sodium excretion by 52-102%. Stimulation of the renal nerves at low frequencies (0.8 to 1.5 Hz) caused minimal changes in renal haemodynamics but decreased urine flow by 27%, calcium excretion by 35%, absolute and fractional sodium excretions 32% and 36%, respectively. In different groups of animals given either diltiazem at 20 pg kg- I min' or nitrendipine at 0.5 pg kg'- min' or 1.0 fg kg'- min', a similar degree of renal nerve stimulation caused an identical pattern of excretory responses of similar magnitude to those obtained in the absence of drug. 4 The calciuretic, diuretic and natriuretic activities of diltiazem and nitrendipine were not dependent on renal nerves and probably represented a direct action on the tubular reabsorptive processes of these ions. The renal nerve-induced increases in tubular calcium and sodium reabsorption indicate that these alpha-adrenoceptor-mediated responses are not dependent on the inward movement of calcium
Topics: Animals; Blood Pressure; Calcium; Diltiazem; Electric Stimulation; Kidney; Male; Nitrendipine; Rats; Rats, Inbred Strains; Renal Circulation; Sodium; Sympathetic Nervous System
PubMed: 3801781
DOI: 10.1111/j.1476-5381.1986.tb11125.x -
British Journal of Pharmacology Mar 19901. We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary...
1. We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin-1 (ET-1) in anaesthetized dogs. 2. ET-1, 1, 3 and 10 ng kg-1 i.c., produced dose-related increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET-1, 30, 100 and 300 ng kg-1 i.c., produced dose-related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose-related falls in cardiac output, mean arterial pressure, +dP/dt and -dP/dt and increases in left ventricular end-diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ng kg-1, ET-1 produced a 22% reduction in heart rate. 3. Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 +/- 2 min after 300 ng kg-1 ET-1. 4. The administration of diltiazem (15 micrograms kg-1 min-1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET-1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET-1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg-1 ET-1 by 60% but not the response to 30 or 300 ng kg-1 ET-1. Two out of five diltiazem-treated dogs died of ventricular fibrillation with a mean time to death of 20 min following treatment with ET-1 (300 kg- 1). 5. ET-1 is a very potent coronary vasodilator. At slightly higher doses ET-1 is also a coronary vasoconstrictor. ET-1 also appears to have direct cardiotoxicity independent of myocardial ischaemia. The vasoconstrictor activity and direct cardiotoxicity are only weakly inhibited by diltiazem.
Topics: Anesthesia; Animals; Blood Pressure; Cardiac Output; Coronary Circulation; Diltiazem; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Endothelins; Heart; Heart Rate; Injections; Male; Peptides
PubMed: 2184913
DOI: 10.1111/j.1476-5381.1990.tb12975.x -
British Journal of Pharmacology Oct 19901. Using front-surface fluorometry with fura-2-loaded porcine coronary arterial strips, we simultaneously measured effects of a Ca2+ antagonist, diltiazem, on cytosolic...
1. Using front-surface fluorometry with fura-2-loaded porcine coronary arterial strips, we simultaneously measured effects of a Ca2+ antagonist, diltiazem, on cytosolic Ca2+ concentrations [( Ca2+]i) and on tension development. 2. In the presence of extracellular Ca2+ (1.25 mM), histamine concentration-dependently induced abrupt (the first component) and then sustained (the second component) elevations of [Ca2+]i. In the absence of extracellular Ca2+, histamine induced transient elevations of [Ca2+]i, and the time course was similar to that of the first component observed in the presence of extracellular Ca2+. Histamine caused a greater contraction for a given change in [Ca2+]i than did potassium, at [Ca2+]i over 300 nM. 3. Diltiazem, 10(-8)M to 10(-5)M, concentration-dependently inhibited the second component of [Ca2+]i elevation and tension development induced by histamine (10(-5) M). Only at higher concentrations (over 10(-5) M) did diltiazem inhibit the first component of increases in [Ca2+]i and tension development induced by histamine, both in the presence and absence of extracellular Ca2+. 4. Diltiazem (10(-6) M) inhibited increases in [Ca2+]i and tension development induced by cumulative applications of extracellular Ca2+ during K(+)-depolarization. The curve of [Ca2+]i against tension of these Ca2(+)-induced contractions obtained in diltiazem-treated strips overlapped with that obtained in untreated strips. This suggests that diltiazem has no direct effects on contractile elements. 5. In contrast, the histamine-induced Ca2(+)-tension curve (second component) was shifted in parallel to the left by diltiazem. 6. We conclude that diltiazem, at therapeutic concentrations, specifically inhibits extracellular Ca2+- dependent increases in [Ca2 +]i, with no effects on the release of Ca2 + from intracellular store sites or on Ca2 +-sensitivity of the contractile elements involved in the contractions induced by elevations of [Ca2 +]i.
Topics: Animals; Calcium; Coronary Vessels; Cytosol; Diltiazem; Drug Interactions; Female; Fluorometry; Fura-2; Histamine; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Swine
PubMed: 2257435
DOI: 10.1111/j.1476-5381.1990.tb12700.x -
The Journal of Invasive Cardiology Mar 2012The aim of this study was to compare the efficacy of nitroglycerin and diltiazem versus nitroglycerin alone in preventing radial artery spasm (RAS) during transradial... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The aim of this study was to compare the efficacy of nitroglycerin and diltiazem versus nitroglycerin alone in preventing radial artery spasm (RAS) during transradial coronary procedures.
BACKGROUND
Spasm after transradial access decreases procedural success. Multiple spasmolytics are used to prevent spasm. Individual efficacy of these agents is not conclusively established.
METHODS
One hundred and fifty patients undergoing coronary procedures through radial artery were enrolled and divided into two groups of 75 patients each. Patients in Group A received 200 μg nitroglycerin plus 2.5 mg diltiazem intra-arterially, and group B patients received 200 μg nitroglycerin plus placebo (saline). Blood pressure (BP) and heart rate (HR) were recorded at baseline and for 5 minutes after cocktail was given. Clinical signs of RAS, such as pain and resistance during catheter maneuver, were recorded in both groups during the procedure.
RESULTS
Systolic and diastolic BP decreased significantly in Group A compared to Group B after cocktail was given (P<.001 and P<.022, respectively). There were no significant changes of HR in either group. There was no significant difference in the incidence of clinical RAS between Group A (diltiazem plus nitroglycerin) versus Group B (nitroglycerin alone) (5% vs 7%; P=1.000). Furthermore, we found higher incidence of local burning pain in the forearm in patients that receive intra-arterial diltiazem plus nitroglycerin compared to nitroglycerin alone (21% vs 9%; P=.041).
CONCLUSION
Diltiazem plus nitroglycerin showed no advantage compared to nitroglycerin alone in prevention of RAS in transradial approach.
Topics: Aged; Angioplasty, Balloon, Coronary; Blood Pressure; Cardiovascular Diseases; Diltiazem; Drug Therapy, Combination; Female; Heart Rate; Humans; Male; Middle Aged; Nitroglycerin; Prospective Studies; Radial Artery; Spasm; Vascular Diseases; Vasoconstriction; Vasodilator Agents
PubMed: 22388304
DOI: No ID Found -
Drug Delivery Nov 2017Diltiazem hydrochloride (DTZ) is a calcium channel antagonist depicted by extensive first pass metabolism and low oral bioavailability. The aim of this work was to...
Diltiazem hydrochloride (DTZ) is a calcium channel antagonist depicted by extensive first pass metabolism and low oral bioavailability. The aim of this work was to develop niosomes for potential nasal delivery of DTZ. Niosomes protect hydrophilic drugs inside their core while nasal route offers both rapid onset and evasion of first-pass metabolism. Niosomes were prepared using a combination of Span 60 or Brij-52 with cholesterol (CHOL) in different molar ratios followed by determination of entrapment efficiency, particle size and in vitro drug release. A parallel design was adopted to evaluate the pharmacokinetic performance of DTZ-loaded niosomes in male Wistar rats. Non-compartmental analysis was performed where C, T, t, MRT, area under the release curve (AUC) and K were assessed. The prepared niosomes were spherical with mean particle size 0.82-1.59 μm. Span 60-cholesterol niosomes (1:1 molar ratio) showed the highest entrapment and release efficiencies. In vivo study revealed an increase in MRT, t and AUC with a decrease in K. In conclusion, nasal niosomal formulation of DTZ expressed suitable pharmacokinetic parameters and bioavailability through prolonged duration of action inside the body as well as low rate of elimination depicting a promising alternate to the conventional oral route.
Topics: Administration, Intranasal; Animals; Biological Availability; Delayed-Action Preparations; Diltiazem; Liposomes; Male; Rats; Rats, Wistar
PubMed: 28165822
DOI: 10.1080/10717544.2016.1259371 -
British Journal of Pharmacology May 1987The effect of chronic feeding of New Zealand White rabbits with nicardipine (60 mg kg-1 daily for 5 weeks) on the endothelium-dependent relaxation (EDR) to acetylcholine...
The effect of chronic feeding of New Zealand White rabbits with nicardipine (60 mg kg-1 daily for 5 weeks) on the endothelium-dependent relaxation (EDR) to acetylcholine (ACh) was examined in vitro. The effect of acute exposure to nicardipine and diltiazem (10 mumol l-1) in the tissue bath was also examined. A bioassay system for endothelium-dependent relaxation factor (EDRF) in which a rabbit aortic ring with endothelium removed was used as recipient and a segment of rabbit aorta with endothelium as donor (producing EDRF in response to ACh) was developed. This system enabled the effect of nicardipine on the synthesis/release and on the relaxation to EDRF to be studied separately. The maximum relaxations to ACh in control and nicardipine-fed animals were 43.6 +/- 5.5 and 53.8 +/- 6.7% (mean +/- s.e. mean) of the contractile response to noradrenaline (NA, 1 mumol l-1) (n = 6, P greater than 0.05). Similarly the EDR to ACh was not significantly altered by acute exposure (30 min) to nicardipine or diltiazem. The maximum relaxations without and with nicardipine were 32.4 +/- 4.2% and 28.0 +/- 3.1% of the contraction to NA (1 mumol l-1) (n = 11, P greater than 0.05). The corresponding data for diltiazem were 42.1 +/- 5.7 and 36.4 +/- 7.3% respectively (n = 11, P greater than 0.05). Both calcium antagonists inhibited the contraction induced by potassium (100 mmol l-1). Nicardipine and diltiazem in concentrations of 100 mumol l-1 reduced the potassium-induced contraction to 33.0 +/- 9.0% and 53.8 +/- 6.7% of control respectively (n = 6, P less than 0.05). In the bioassay experiments the infusion of nicardipine on (a) the recipient tissue only and (b) the donor and the recipient tissue had no significant effect on the relaxant response observed in the recipient tissue when superfused with Krebs-bicarbonate buffer containing ACh via the donor tissue (n = 6, P greater than 0.05). These results indicate that nicardipine and diltiazem had no significant effect on synthesis/release and the relaxant response to EDRF in the rabbit aorta. Thus the translocation of Ca2+ accompanying the EDR to ACh in the rabbit aorta is likely to utilize Ca2+ channels not blocked by these calcium antagonists.
Topics: Acetylcholine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Diltiazem; Endothelium; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nicardipine; Nitric Oxide; Rabbits; Vasodilator Agents
PubMed: 3496138
DOI: 10.1111/j.1476-5381.1987.tb08994.x -
Journal of the American College of... Dec 1988A double-blind crossover trial comparing diltiazem (360 mg/day) and nifedipine (120 mg/day) for treatment of stable angina was conducted in 21 of 27 patients with proven... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A double-blind crossover trial comparing diltiazem (360 mg/day) and nifedipine (120 mg/day) for treatment of stable angina was conducted in 21 of 27 patients with proven coronary artery disease who completed the trial. All patients started with a 2 week placebo period followed by a random assignment to either drug treatment for 3 weeks and subsequent crossover to the other treatment. The two drug treatment periods were separated by a 1 week placebo washout phase and the study was completed with a 1 week placebo phase. There were no significant differences between patients' responses to diltiazem and nifedipine in relation to time to onset of angina, ST depression responses to exercise, heart rate or systolic or diastolic blood pressure. A total of 37 adverse effects were reported with nifedipine compared with 9 with diltiazem in the 22 patients in whom drug safety was analyzed. Additionally, two patients treated with nifedipine were withdrawn from study participation before crossover. There was a significant (p less than 0.05) difference with respect to incidence of edema (7 of 22 patients taking nifedipine, 1 of 22 taking diltiazem) and dizziness (7 of 22 patients taking nifedipine, 0 of 22 taking diltiazem). The most frequent adverse effect reported with diltiazem was rash (3 of 22 patients). Severe adverse effects were reported in four patients: in one with diltiazem (rash) and in three with nifedipine (palpitation in two and headache in one). A reduction in prescribed dosage was required in 37% of nifedipine-treated compared with 6% of diltiazem-treated patients. Efficacy measures were significantly improved above placebo levels by both diltiazem and nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Angina Pectoris; Clinical Trials as Topic; Diltiazem; Double-Blind Method; Exercise Test; Heart Rate; Humans; Middle Aged; Nifedipine; Prospective Studies; Random Allocation
PubMed: 3057036
DOI: 10.1016/s0735-1097(88)80026-3 -
The Canadian Veterinary Journal = La... May 2006Twenty-one cats with hypertrophic cardiomyopathy were enrolled in this study to determine if the administration of benazepril (0.5 mg/kg body weight [BW], PO, q24h) to... (Randomized Controlled Trial)
Randomized Controlled Trial
Twenty-one cats with hypertrophic cardiomyopathy were enrolled in this study to determine if the administration of benazepril (0.5 mg/kg body weight [BW], PO, q24h) to cats with subclinical hypertrophic cardiomyopathy improves cardiac diastolic function and reverses left ventricular hypertrophy when compared with diltiazem controlled delivery (CD) (10 mg/kg BW, PO, q24h). Cats were evaluated at day 0 and after 3 and 6 months of therapy. In the benazepril group (n = 11), the diastolic transmitral flow of the E and A waves ratio (E/A ratio) increased significantly between 0 and 6 months (P = 0.009) and the thickness of the left ventricular free wall in systole (LVFWs) decreased significantly between 0 and 3 months (P = 0.04). In the diltiazem CD group (n = 5), none of the parameters varied significantly throughout the study. There was no difference between the benazepril and the diltiazem CD group throughout the study. Therefore, the variations observed for the E/A ratio and the LVFWs may have been incidental. Further studies will be needed to establish the role of benazepril in subclinical hypertrophic cardiomyopathy in cat.
Topics: Animals; Antihypertensive Agents; Benzazepines; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Diltiazem; Double-Blind Method; Echocardiography; Female; Male; Prospective Studies; Treatment Outcome
PubMed: 16734369
DOI: No ID Found -
The Journal of Thoracic and... Feb 2003We aimed to measure the vasodilating effects of vitamin C on the radial arteries of healthy subjects and to assess whether vitamin C is superior in this regard to... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
OBJECTIVES
We aimed to measure the vasodilating effects of vitamin C on the radial arteries of healthy subjects and to assess whether vitamin C is superior in this regard to diltiazem, a commonly used vasodilator in coronary artery bypass using radial conduits.
METHODS
In a case-control study (study 1) oral single-dose vitamin C (2 g) was given to 15 healthy nonsmokers and 15 matched otherwise healthy smokers. In a randomized double-blind study (study 2) oral single-dose vitamin C (2 g, n = 15) and diltiazem (180 mg, n = 15) were compared in preoperative patients with coronary artery disease. We examined the dilation of the radial artery with high-resolution ultrasonography and measurement of the lumen surface and color Doppler images of the nondominant radial artery just before and 2 hours after drug administration.
RESULTS
In study 1 both smokers and nonsmokers showed a significant increase in the lumen surface at 2 hours compared with at baseline (P <.001 and P =.013, respectively). The increase was larger in smokers (median, 37.5% vs 14.3%; P =.004). In study 2 both groups showed statistically significant increases in the lumen surface at 2 hours compared with at baseline (P <.001 and P =.008 for vitamin C and diltiazem, respectively). Vitamin C achieved a larger increase than diltiazem (median, 33.3% vs 18.2%; P =.016). In multivariate modeling the increase in lumen surface was independently predicted by use of vitamin C over diltiazem (+21.2%, P =.007), diabetes mellitus (+14.5%, P =.085), increased cholesterol (+26.2%, P =.001), and smoking history (+20.8%, P =.017).
CONCLUSIONS
Vitamin C is a potent acute vasodilator in both smokers and nonsmokers and is superior to diltiazem in preoperative coronary patients who need protection from vasospasm of the radial conduit.
Topics: Adult; Aged; Ascorbic Acid; Case-Control Studies; Coronary Artery Bypass; Coronary Disease; Diabetes Complications; Diltiazem; Double-Blind Method; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Multivariate Analysis; Pilot Projects; Predictive Value of Tests; Radial Artery; Smoking; Ultrasonography, Doppler, Color; Vasodilation; Vasodilator Agents
PubMed: 12579102
DOI: 10.1067/mtc.2003.3