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Effects of diltiazem on sympathetic activity in patients with aneurysmal subarachnoid hemorrhage.
Ogura, T, Takeda, R, Ooigawa, H, Nakajima, H, Kurita, H
Acta neurochirurgica. Supplement. 2015;:47-50
Abstract
This study evaluated the effect of diltiazem, a calcium antagonist, on sympathetic activity in patients with aneurysmal subarachnoid hemorrhage (SAH) during the hyperacute stage. Of patients with aneurysmal SAH who underwent aneurysm repair between August 2008 and June 2011, 119 consecutive patients were enrolled in this prospective study. On admission, patients were assigned to an antihypertensive treatment receiving continuous infusion of diltiazem (67 patients) or nicardipine (52 patients). Plasma levels of adrenaline (AD), noradrenaline (NA), and dopamine (DP) were repeatedly measured using high-performance liquid chromatography (HPLC). There were no significant differences in patient characteristics or aneurysm topography between the two groups. In all patients, acute surge of catecholamines was observed with mutual correlation. However, patients receiving diltiazem exhibited a significantly lower plasma concentration of DP than those receiving nicardipine, 3 and 6 h after admission. A similar trend was observed for NA, but the difference was not significant at 6 h. Conversely, the concentration of AD was similar between the two groups. Diltiazem may suppress sympathetic activity in the hyperacute stage of aneurysmal SAH. Further studies are needed to verify the beneficial effect of diltiazem in patients with SAH.
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A randomized, prospective, double-blind, placebo-controlled trial of the effect of a calcium channel blocker ointment on pain after hemorrhoidectomy.
Silverman, R, Bendick, PJ, Wasvary, HJ
Diseases of the colon and rectum. 2005;(10):1913-6
Abstract
PURPOSE Spasm of the internal sphincter plays a role in hemorrhoidal disease and may be a source of anal pain after hemorrhoid surgery. We have evaluated the effects of topical diltiazem, a calcium channel blocker, in reducing pain after hemorrhoidectomy. METHODS After hemorrhoidectomy, 18 patients were randomly assigned to receive 2 percent diltiazem ointment (n = 9) or a placebo ointment (n = 9). Ointments were applied to the perianal region three times daily for seven days. Patients were prescribed hydrocodone bitartrate (Vicodin) to take as needed. The type and number of prescribed or nonprescribed medications taken during the postoperative period were recorded. Patients maintained a log to measure postoperative pain daily and perceived benefit of the ointment, using a Visual Analog Scale ranging from 0 to 10. Any postoperative morbidity noted during the follow-up period was recorded. RESULTS Patients using the diltiazem ointment had significantly less pain and greater benefit than those in the placebo group throughout the first postoperative week. Postoperative pain scores in the placebo group averaged 8.8 +/- 1.2 early and diminished to 5.2 +/- 1.7 at the end of one week, compared to the diltiazem group of 5.2 +/- 2.4 early and 2.3 +/- 1.2 at the end of one week (P < 0.001, both time periods). Perceived benefit in the placebo group averaged 2.7 +/- 1.2 vs. 5.6 +/- 1.4 in the diltiazem group (P < 0.001). Total and daily narcotic use was higher in the placebo group, but this was not statistically significant (P = 0.13). No differences in the frequency of use of nonsteroidal anti-inflammatory drugs and acetaminophen were seen between the two groups, and there were no differences in morbidity between the two groups. CONCLUSIONS Perianal application of 2 percent diltiazem ointment after hemorrhoidectomy significantly reduces postoperative pain and is perceived as beneficial, with no increase in associated morbidity. Patients using a placebo ointment tend to take more prescription narcotics for pain relief postoperatively, with a similar usage of nonsteroidal anti-inflammatory drugs and acetaminophen, although differences were not significant.
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Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers.
Glesby, MJ, Aberg, JA, Kendall, MA, Fichtenbaum, CJ, Hafner, R, Hall, S, Grosskopf, N, Zolopa, AR, Gerber, JG, ,
Clinical pharmacology and therapeutics. 2005;(2):143-53
Abstract
BACKGROUND Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir. METHODS Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19. RESULTS Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed. CONCLUSIONS Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.
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Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein.
Pinto, AG, Horlander, J, Chalasani, N, Hamman, M, Asghar, A, Kolwankar, D, Hall, SD
British journal of clinical pharmacology. 2005;(4):440-6
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AIMS: To determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects. METHODS Intestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 microM) and NADPH for 5 min and the rate of formation of 1'-hydroxymidazolam was quantified. RESULTS All subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1'-hydroxymidazolam (446 pmol min(-1) mg(-1) 6 (control) vs. 170 (CI 112, 228) pmol min(-1) mg(-1) 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05). CONCLUSION Diltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.
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[Diltiazem and verapamil therapy in patients with angina pectoris associated with arterial hypotension].
Idrisova, EM, Stepacheva, TA, Borovkova, NV, Chernov, VI, Karpov, RS, Vorob'eva, EV, Poponina, IuS
Klinicheskaia meditsina. 2004;(2):42-6
Abstract
A randomized blind cross-over study with placebo lead-in compared efficacy of calcium antagonists diltiazem and verapamil in 71 patients with stable angina concurrent with arterial hypotension (group 1) and 38 normotensive patients with ischemic heart disease (group 2). By acute bicycle exercise test evidence, verapamil was effective in 80% and 82% patients of group 1 and 2, respectively, dilitiazem--in 67 and 77%, respectively. Cumulation of the effect (p < 0.01) to the third month of verapamil course was comparable in both groups. Tolerance to an antianginal effect of dilitazem developed in 53% patients of group 1 (against 30% in group 2, p < 001) in 2-4 weeks of therapy (against 4-12 weeks in group 2, p < 0.05). By stress 199-T1 scintigraphy of the myocardium, administration of effective doses of diltiazem reduced the number of hypoperfused segments by at least 30%.
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Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
Chaitman, BR, Pepine, CJ, Parker, JO, Skopal, J, Chumakova, G, Kuch, J, Wang, W, Skettino, SL, Wolff, AA, ,
JAMA. 2004;(3):309-16
Abstract
CONTEXT Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications. In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance; however, its long-term efficacy and safety have not been studied in combination with beta-blockers or calcium antagonists in a large patient population with severe chronic angina. OBJECTIVES To determine whether, at trough levels, ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking standard doses of atenolol, amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia, effect on angina attacks and nitroglycerin use, and effect on long-term survival in an open-label observational study extension. DESIGN, SETTING, AND PATIENTS A randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the 118 participating ambulatory outpatient settings in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial from July 1999 to August 2001 and followed up through October 31, 2002. INTERVENTION Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine. Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment. MAIN OUTCOME MEASURES Change in exercise duration, time to onset of angina, time to onset of ischemia, nitroglycerin use, and number of angina attacks. RESULTS Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P =.01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year. CONCLUSION Twice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking standard doses of atenolol, amlodipine, or diltiazem, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.
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Calcium chloride before i.v. diltiazem in the management of atrial fibrillation.
Kolkebeck, T, Abbrescia, K, Pfaff, J, Glynn, T, Ward, JA
The Journal of emergency medicine. 2004;(4):395-400
Abstract
Diltiazem is commonly used to treat atrial fibrillation or flutter (AFF) with rapid ventricular response (RVR). Although it is very effective for rate control, up to an 18% prevalence of reported diltiazem-induced hypotension [defined by systolic blood pressure (SBP) < 90 mm Hg], and a mean of 9.7% hypotension have been reported from several studies totaling over 450 patients. This hypotension may complicate therapy. Our objective was to determine if calcium chloride (CaCl(2)) pre-treatment would blunt a SBP drop after i.v. diltiazem, while allowing diltiazem to maintain its efficacy. A prospective, randomized, double-blind, placebo-controlled study was conducted. Seventy-eight patients with AFF and a ventricular rate of ≥ 120 beats per minute were enrolled. Half received i.v. CaCl(2) pre-treatment; the other half received placebo. All patients then received i.v. diltiazem in a standard, weight-based dose. A second dose of CaCl(2) pre-treatment or placebo and diltiazem was given if clinically indicated for additional rate control. Both CaCl(2) and placebo pre-treatment groups had equal lowering of heart rate (p < 0.001). There were no adverse events in the calcium pre-treatment study arm. One patient in the placebo group became paradoxically more tachycardic and apneic after the diltiazem infusion. Although i.v. CaCl(2) seems to be equally safe compared to placebo as a pre-treatment in the management of AFF with RVR, we were unable to find a statistically significant blunting of SBP drop with CaCl(2) i.v. pre-treatment. Until further research determines a benefit exists, we cannot recommend i.v. CaCl(2) pre-treatment before diltiazem in the treatment of AFF with RVR.
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Effects of diltiazem on platelet activation and cytosolic calcium during percutaneous transluminal coronary angioplasty.
Dai, H, Chen, J, Tao, Q, Zhu, J, Zhang, F, Zheng, L, Qiu, Y
Postgraduate medical journal. 2003;(935):522-6
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AIMS: To evaluate effects of diltiazem on platelet hyper-reactivity in situations associated with endothelial injury and their possible relationship to cytosolic calcium concentration. METHODS Blood samples were collected at seven time points from 35 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) who received combined diltiazem and aspirin/ticlopidine therapy or aspirin/ticlopidine therapy alone. Platelet expression of glycoprotein IIb/IIIa and P-selectin, production of thromboxane B(2), and cytosolic calcium concentration were measured, respectively, by whole blood flow cytometry, radioimmunoassay, and fluorospectrophotometry. The effects of diltiazem of different concentrations on expression of glycoprotein IIb/IIIa and P-selectin were also studied in vitro in blood samples from patients with chronic stable angina. RESULTS Of the two treatments, aspirin/ticlopidine therapy did not prevent an acute increase of expression of glycoprotein IIb/IIIa and P-selectin and plasma thromboxane B(2) five minutes and 10 minutes after first inflation and 10 minutes after PTCA, whereas combined diltiazem and aspirin/ticlopidine therapy had a significant inhibitory effect. In the group receiving aspirin/ticlopidine therapy, there was a short term increase of platelet [Ca(2+)](i) immediately after PTCA which was significantly reduced by diltiazem treatment. Expression of glycoprotein IIb/IIIa and P-selectin was significantly inhibited in vitro by diltiazem in the concentration of 200 ng/ml or higher, but not 50 ng/ml. CONCLUSIONS Combined diltiazem and aspirin/ticlopidine therapy significantly inhibited platelet activation that continued in the presence of conventional aspirin/ticlopidine treatment. Antiplatelet effects of diltiazem were probably a consequence of reduction of platelet [Ca(2+)](i) and may only be achieved in higher than therapeutic concentrations.
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Does diltiazem inhibit the inflammatory response in cardiopulmonary bypass?
Fansa, I, Gol, M, Nisanoglu, V, Yavas, S, Iscan, Z, Tasdemir, O
Medical science monitor : international medical journal of experimental and clinical research. 2003;(4):PI30-6
Abstract
BACKGROUND The objective of our study was to investigate the anti-inflammatory effect and inhibiting action of diltiazem, a calcium channel blocking agent, on the systemic inflammatory response seen after cardiopulmonary bypass (CPB) in humans, in a controlled prospective study. MATERIAL/METHODS Two groups of 15 candidates for coronary artery bypass graft were enrolled in the study. In the study group, 1 g/kg/min of diltiazem was infused during cardiopulmonary bypass, while the control group received saline. Interleukin-6 and 10 (IL-6, IL-10) levels were measured from systemic arterial blood at five time points. RESULTS The levels of IL-6, a marker of the severity of systemic inflammation, were significantly higher in the control group at the end of CPB and 3 hours later. At the end of CPB, the mean IL-6 level in the control group was significantly higher than in the diltiazem group (p=0.015), and at 3 hours after CPB the difference was even greater (p=0.002). The levels of IL-10, an anti-inflammatory cytokine that limits the effects of pro-inflammatory cytokines, were higher in the control group, but not statistically significant at any time point. CONCLUSIONS Diltiazem inhibits the release of the pro-inflammatory cytokine IL-6, which is strong evidence for its anti-inflammatory effect. It is clinically important to inhibit the inflammation that takes place during CPB and the inflammation of myocardium encountered after ischemia-reperfusion, since these effect the clinical status of the patient after CPB, as well as myocardial functions.
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Sustained-release diltiazem reduces myocardial ischemic episodes in end-stage renal disease: a double-blind, randomized, crossover, placebo-controlled trial.
Cice, G, Di Benedetto, A, D'Andrea, A, D'Isa, S, Ferrara, L, Russo, PE, Iacono, A, CalabrĂ², R
Journal of the American Society of Nephrology : JASN. 2003;(4):1006-11
Abstract
End-stage renal disease (ESRD) patients receiving maintenance hemodialysis and suffering from coronary artery disease (CAD) often receive doses of calcium channel antagonists that are too low. This may be the result of physician's desire to avoid adverse side effects during hemodialysis. The aim of this study was the assessment of the safety and efficacy of incremental doses of diltiazem for the treatment of myocardial ischemia in ERSD patients with CAD to identify the optimal dose of the drug. A total of 196 chronic hemodialysis patients were enrolled with CAD showing more than 5 min of transient myocardial ischemia during a 48-h Holter ECG monitoring. A double-blind, randomized, crossover, placebo-controlled trial design was used. Incremental doses of diltiazem (120 to 240 mg/d) were administered in 4 mo. With a dose of 120 and 180 mg/d, a significant reduction in the number and duration of total and symptomatic ischemic episodes was observed (P < 0.001), but the number and the duration of silent ischemic episodes were not reduced. Conversely, the efficacy on silent myocardial ischemia was obtained with a dosage of diltiazem of 240 mg/d (P < 0.001). In addition, with a sustained-release formulation (120 mg twice daily), the efficacy was similar to that obtained with four 60-mg tablets, but the safety was improved, especially during hemodialytic session. The circadian variations analysis of transient ischemic episodes showed a significant reduction in both ischemic peaks observed at baseline only with 240 mg/d of diltiazem. The findings emphasize that sustained-release diltiazem (120 mg twice daily) can be largely useful in uremic patients with CAD on maintenance dialysis. Diltiazem reduces the number and the duration of silent ischemic episodes, has a good tolerability, and positively modifies the circadian pattern of ischemic episodes.