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British Heart Journal Jan 1985The antianginal effects of diltiazem 180 mg/day and propranolol 240 mg/day, alone and in combination, were investigated in 15 patients with effort related angina in a... (Clinical Trial)
Clinical Trial Comparative Study
The antianginal effects of diltiazem 180 mg/day and propranolol 240 mg/day, alone and in combination, were investigated in 15 patients with effort related angina in a double blind placebo controlled crossover trial, with each period of treatment lasting four weeks. Patients performed a symptom limited treadmill exercise test at the end of each period of treatment. Mean (SEM) time to onset of angina was increased from 293(32) s when receiving placebo to 347(38) s when receiving diltiazem alone, to 350(30) s when receiving propranolol alone, and further to 421(34) s when receiving diltiazem and propranolol combined. Similar changes occurred in the duration of exercise testing and time to 1 mm ST segment depression. The sum of ST segment depression at peak exercise was reduced by both diltiazem and propranolol alone compared with placebo, and combination treatment produced a further significant improvement. Rate pressure product was significantly reduced at rest and at peak exercise after propranolol alone and combination treatment. The study clearly showed the superior value of diltiazem and propranolol combined in effort related angina when compared with either drug used alone.
Topics: Aged; Angina Pectoris; Benzazepines; Clinical Trials as Topic; Diltiazem; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Humans; Male; Middle Aged; Propranolol
PubMed: 3881104
DOI: 10.1136/hrt.53.1.43 -
British Journal of Clinical Pharmacology Nov 1997To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients.
AIMS
To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients.
METHODS
Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day(-1). Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem.
RESULTS
Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day(-1)), the rate of increase slowed after 30-60 mg day(-1) but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0-12 h) and evening (12-24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ.
CONCLUSIONS
The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.
Topics: Adult; Area Under Curve; Calcium Channel Blockers; Cyclosporine; Diltiazem; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged
PubMed: 9384468
DOI: 10.1046/j.1365-2125.1997.t01-1-00616.x -
The Western Journal of Emergency... Mar 2018Atrial fibrillation (AF) is a common diagnosis of patients presenting to the emergency department (ED). Intravenous (IV) diltiazem bolus is often the initial drug of... (Observational Study)
Observational Study
INTRODUCTION
Atrial fibrillation (AF) is a common diagnosis of patients presenting to the emergency department (ED). Intravenous (IV) diltiazem bolus is often the initial drug of choice for acute management of AF with rapid ventricular response (RVR). The route of diltiazem after the initial IV loading dose may influence the disposition of the patient from the ED. However, no studies exist comparing oral (PO) immediate release and IV continuous infusion diltiazem in the emergency setting. The objective of this study was to compare the incidence of treatment failure, defined as a heart rate (HR) of >110 beats/min at four hours or conversion to another agent, between PO immediate release and IV continuous infusion diltiazem after an initial IV diltiazem loading dose in patients in AF with RVR.
METHODS
This was a single-center, observational, retrospective study conducted at a tertiary academic medical center. The study population included patients ≥18 years old who presented to the ED in AF with a HR > 110 beats/min and received an initial IV diltiazem loading dose. We used multivariate logistic regression to assess the association between routes of administration and treatment failure.
RESULTS
A total of 111 patients were included in this study. Twenty-seven percent (11/41) of the patients in the PO immediate-release group had treatment failure compared to 46% (32/70) in the IV continuous-infusion group. The unadjusted odds ratio (OR) of treatment failure with PO was less than IV at 0.4 (95% confidence interval [CI] [0.18, 0.99], p = 0.046). When we performed a multivariate analysis adjusted for race and initial HR, PO was still less likely to be associated with treatment failure than IV with an OR of 0.4 (95% CI [0.15, 0.94], p = 0.041). The median dose of PO diltiazem and IV continuous infusion diltiazem at four hours was 30 mg and 10 mg/h, respectively.
CONCLUSION
After a loading dose of IV diltiazem, PO immediate-release diltiazem was associated with a lower rate of treatment failure at four hours than IV continuous infusion in patients with AF with RVR.
Topics: Administration, Oral; Atrial Fibrillation; Diltiazem; Emergency Service, Hospital; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Retrospective Studies; Treatment Failure
PubMed: 29560075
DOI: 10.5811/westjem.2017.10.33832 -
Journal of Pharmaceutical and... Jan 2024A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor....
A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor. In this case, self-poisoning is the common method of suicide and cardiovascular drugs are among the major medications associated with fatal overdose, with calcium channel blockers being one of the most common agents. The present study describes two different fatal suicide cases involving four cardiovascular drugs: carvedilol, doxazosin and amlodipine (case 1) and diltiazem (case 2). The concentrations of the target cardiovascular drugs in the different biological specimens (central and femoral blood, urine, liver, brain) are presented, giving information about the potentially fatal data and the distribution of the drugs in the body. The study led to the implementation of a fast, sensitive and simple method for the detection and quantification of the four commonly prescribed cardiovascular drugs in post-mortem specimens including fluids and tissues for forensic purposes. The method was fully validated. The toxicological results of the studied cases are discussed, along with the autopsy results, histopathological evidence, and circumstances of death. The toxicological findings presented in the study provide new data regarding cardiovascular drugs in different post-mortem specimens, which will contribute to the currently limited knowledge about the toxicological profile of cardiovascular drugs and their distribution.
Topics: Humans; Amlodipine; Diltiazem; Carvedilol; Doxazosin; Cardiovascular Agents; Suicide
PubMed: 37980865
DOI: 10.1016/j.jpba.2023.115831 -
PloS One 2018Arterial graft spasm is a severe complication after coronary artery bypass graft (CABG). Among numerous potential antispasmodic agents, systemic application of diltiazem... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Arterial graft spasm is a severe complication after coronary artery bypass graft (CABG). Among numerous potential antispasmodic agents, systemic application of diltiazem and nitroglycerin had been investigated most frequently over the past three decades. However, it remains inconclusive if either or both agents could improve patient outcomes by preventing graft spasm when applied perioperatively, and, if so, which one would be a better choice. The current systematic review and network meta-analysis aims to summarize the data from all available randomized clinical trials of perioperative continuous intravenous infusion of diltiazem and/or nitroglycerin in patients undergoing on-pump CABG in order to define and compare their roles in graft spasm prevention and their impacts on perioperative outcomes.
METHODS
We searched Ovid Medline, PubMed, CINAHL, Google Scholar and Cochrane Center for randomized controlled trials that reported outcome effects of perioperative continuous intravenous infusion of diltiazem and/or nitroglycerin in patients undergoing elective on-pump CABG. Conventional meta-analyses were conducted to evaluate the pairwise comparisons (diltiazem vs. placebo; nitroglycerin vs. placebo; diltiazem vs. nitroglycerin) on perioperative outcomes. Network meta-analyses were implemented to compare the three regimens through direct and indirect comparison.
RESULTS
Twenty-seven studies involving 1,660 patients were included. Pairwise and network meta-analyses found no significant difference in mortality among the groups. There are four studies that reported blood flow measurements of internal mammary artery grafts intraoperatively after dissecting or immediately after distal anastomosis while patients were on continuous intravenous infusion of diltiazem and nitroglycerin. Although insufficient for data synthesis, the measured results from all four studies suggest that both diltiazem and nitroglycerin significantly increased blood flow of arterial grafts compared to placebo. For other perioperative outcomes, compared to diltiazem, patients that received nitroglycerin had higher odds of postoperative atrial fibrillation (OR = 2.67, 95% CI: 1.15 to 6.24) and higher peak serum cardiac enzymes. Patients that received placebo had higher odds of atrial fibrillation (OR = 3.00, 95% CI: 1.18 to 7.63) and lower odds of requiring inotrope support (OR = 0.19, 95% CI: 0.04 to 0.73) compared to diltiazem. Data from the network meta-analysis indicated that diltiazem had significantly lower odds of postoperative atrial fibrillation compared to nitroglycerin (OR = 0.39, 95% CI: 0.18 to 0.85). In fact, the rank from highest to lowest rates of postoperative atrial fibrillation was placebo>nitroglycerin>diltiazem. The rank from highest to lowest odds of requiring inotropic support is nitroglycerin> diltiazem>placebo. However, placebo had significantly higher odds of postoperative myocardial infarction than diltiazem (OR = 4.51, 95% CI: 1.34 to 15.25). The rank from highest to lowest odds of postoperative myocardial infarction, transient cardiac ischemic event and atrial fibrillation is placebo>nitroglycerin>diltiazem.
CONCLUSION
Compared to nitroglycerin and placebo, perioperative continuous intravenous infusion of diltiazem had stronger protective effects against postoperative ischemic cardiac injuries and atrial fibrillation although patients may need more inotropic support. The increased blood flow from diltiazem use in arterial grafts may potentially contribute to the drug's outcome benefits.
Topics: Administration, Intravenous; Cardiotonic Agents; Coronary Artery Bypass; Diltiazem; Humans; Nitroglycerin; Perioperative Care; Postoperative Complications; Randomized Controlled Trials as Topic
PubMed: 30161246
DOI: 10.1371/journal.pone.0203315 -
Gut Nov 1999Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects.
AIMS
To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure.
METHODS
Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure.
RESULTS
A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours.
CONCLUSIONS
Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.
Topics: Administration, Oral; Administration, Topical; Adult; Anal Canal; Bethanechol; Calcium Channel Blockers; Diltiazem; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Gels; Humans; Male; Middle Aged; Muscarinic Agonists
PubMed: 10517908
DOI: 10.1136/gut.45.5.719 -
Acta Pharmacologica Sinica Apr 2011To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of...
AIM
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 fKv1.4, a potassium channel that generates the cardiac transient outward potassium current.
METHODS
The cRNA for fKv1.4ΔN, an N-terminal deleted mutant of the ferret Kv1.4 potassium channel, was injected into Xenopus oocytes to express the fKv1.4ΔN channel in these cells. Currents were recorded using a two electrode voltage clamp technique.
RESULTS
Diltiazem (10 to 1000 μmol/L) inhibited the fKv1.4ΔN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC(50) was 241.04±23.06 μmol/L for the fKv1.4ΔN channel (at +50 mV), and propafenone (10 to 500 μmol/L) showed a similar effect (IC(50)=103.68±10.13 μmol/L). After application of diltiazem and propafenone, fKv1.4ΔN 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 fKv1.4ΔN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery.
CONCLUSION
Diltiazem and propafenone accelerate the inactivation of the Kv1.4ΔN channel by binding to the open state of the channel. Unlike propafenone, diltiazem slows the recovery of the Kv1.4ΔN channel.
Topics: Animals; Cardiovascular Agents; Diltiazem; Female; Inhibitory Concentration 50; Kinetics; Kv1.4 Potassium Channel; Propafenone; Recombinant Proteins; Xenopus
PubMed: 21468083
DOI: 10.1038/aps.2010.234 -
British Journal of Pharmacology Mar 2011Diltiazem inhibits Ca(V)1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments...
BACKGROUND AND PURPOSE
Diltiazem inhibits Ca(V)1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments IIIS6, IVS6 and the selectivity filter of the pore forming α₁ subunit of Ca(V)1.2. The aim of the present study was to clarify the location of the diltiazem binding site making use of its membrane-impermeable quaternary derivative d-cis-diltiazem (qDil) and mutant α₁ subunits.
EXPERIMENTAL APPROACH
Ca(V)1.2 composed of α1, α2-δ and β2a subunits were expressed in tsA-201 cells and barium currents through Ca(V)1.2 channels were recorded using the patch clamp method in the whole cell configuration. qDil was synthesized and applied to the intracellular side (via the patch pipette) or to the extracellular side of the membrane (by bath perfusion).
KEY RESULTS
Quaternary derivative d-cis-diltiazem inhibited Ca(V)1.2 when applied to the intracellular side of the membrane in a use-dependent manner (59 ± 4% at 300 µM) and induced only a low level of tonic (non-use-dependent) block (16 ± 2% at 300 µM) when applied to the extracellular side of the membrane. Mutations in IIIS6 and IVS6 that have previously been shown to reduce the sensitivity of Ca(V)1.2 to tertiary diltiazem also had reduced sensitivity to intracellularly applied qDil.
CONCLUSION AND IMPLICATIONS
The data show that use-dependent block of in Ca(V)1.2 by diltiazem occurs by interaction with a binding site accessible via a hydrophilic route from the intracellular side of the membrane.
Topics: Amino Acid Sequence; Binding Sites; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Line; Cell Membrane; Cell Membrane Permeability; Diltiazem; Humans; Hydrophobic and Hydrophilic Interactions; Ion Channel Gating; Kinetics; Molecular Sequence Data; Mutant Proteins; Patch-Clamp Techniques; Protein Subunits; Recombinant Proteins
PubMed: 20973779
DOI: 10.1111/j.1476-5381.2010.01091.x -
Brazilian Journal of Cardiovascular... Oct 2020To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside.
OBJECTIVE
To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside.
METHODS
Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis.
RESULTS
Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups.
CONCLUSION
The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.
Topics: Diltiazem; Humans; Mammary Arteries; Nitroprusside; Papaverine; Vasodilator Agents
PubMed: 33118726
DOI: 10.21470/1678-9741-2019-0251 -
Interactive Cardiovascular and Thoracic... Jul 2012Perioperative vasospasm during cardiovascular surgery is a challenging problem. Several vasodilator agents are frequently utilized for its prevention in surgical... (Comparative Study)
Comparative Study
Perioperative vasospasm during cardiovascular surgery is a challenging problem. Several vasodilator agents are frequently utilized for its prevention in surgical practice. Magnesium and diltiazem both have known potential vasorelaxant effects. We planned to compare the efficacy of diltiazem and magnesium in relieving phenylephrine-precontracted rat aortic rings. Ten young adult female Wistar albino rats weighing 230-260 g were used in this study. The aortic rings in the organ bath equilibrated and reached their baseline tension. Precontraction was induced by 0.001 mmol/l phenylephrine and cumulative concentration-relaxation curves were obtained by consecutively increasing the addition of either diltiazem (10(-6)-0.1 mmol/l) or magnesium (0.1-10 mmol/l). The mean maximal relaxation responses observed by diltiazem and magnesium on separate aortic rings were 90 ± 3 and 53 ± 2%, respectively. The calculated EC50 of diltiazem was 0.01035 mmol/l, whereas the EC50 of magnesium was 4.064 mmol/l (P < 0.05). Both magnesium and diltiazem produced vasorelaxation on phenylephrine-precontracted rat aortic rings in this study, but the potency of diltiazem regarding the EC50 value was significantly higher than that of magnesium. Magnesium could be a candidate together with diltiazem to inhibit vasospasm on arterial grafts during coronary bypass surgery.
Topics: Animals; Aorta, Thoracic; Diltiazem; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Magnesium Sulfate; Phenylephrine; Rats; Rats, Wistar; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents
PubMed: 22523136
DOI: 10.1093/icvts/ivs051