Treatment of chronic anal fissure: a feasibility study on Levorag® Emulgel versus Diltiazem gel 2.

PURPOSE: To compare the standard treatment, diltiazem gel 2%, with Levorag® Emulgel for chronic anal fissures. METHODS: This was a single-blinded, randomised, controlled, clinical trial with a non-inferiority design. Patients with a chronic anal fissure were randomised to treatment with diltiazem or Levorag® Emulgel twice daily for 8 weeks. Primary endpoint was complete healing of the anal fissure after 12 weeks. Secondary endpoints included incidence of adverse events and efficacy on pain relief. RESULTS: In total, 55 patients were included. Inclusion was terminated prematurely due to a slow inclusion rate. Complete fissure healing at 12 weeks follow-up was overall achieved in 31 of 55 (56%) patients, 18 of 29 (62%) in the diltiazem group compared with 13 of 26 (50%) in the Levorag® Emulgel group (P = 0.424). Pain relief was significantly better at day seven in patients treated with diltiazem (P = 0.040) compared with Levorag® Emulgel, whereas there were no differences in early (3 days) or late (12 weeks) pain relief. Three patients (10.3%) developed severe perianal exanthema during diltiazem treatment, whereas no side effects were observed in the Levorag® Emulgel group. CONCLUSION: The study demonstrated statistical non-inferiority of Levorag® Emulgel compared with diltiazem in the treatment of chronic anal fissure. Diltiazem resulted in a more prompt pain relief and also in a substantial number of local allergic reactions. Levorag® Emulgel may therefore be an alternative in these patients. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT02158013.

[The choked heart]. / Das abgewürgte Herz.

A couple of days after increasing the dosage of betaadrenergic- and adding calcium channel blockers due to an increased heart rate in atrial fibrillation, a 77 year old female was found in cardiogenic shock. After exclusion of further causes a therapy with catecholamines, calcium, high dose insulin and phosphodiesterase inhibitors was initiated. Despite this combined therapy the shock persisted. Only after administration of levosimendan, a calcium sensitizer, a normalization of the heart function could be observed. We discuss the danger of combining drugs with negative inotropic properties for rate control in atrial fibrillation and review the therapy with focus on the effects on cardiac cells of all recommended drugs in the treatment of intoxication with betareceptor- and calcium channel blockers.

Paralytic ileus associated with use of diltiazem.

PURPOSE: A case of paralytic ileus in a patient receiving oral diltiazem therapy for atrial fibrillation is reported. SUMMARY: A 64-year-old man with a history of multiple serious comorbidities, poly-pharmacy, and a recent hospital stay for acute cardiac problems was readmitted to the hospital for gastrointestinal (GI) bleeding. On day 2 of the readmission, he suffered a myocardial infarction complicated by atrial fibrillation with a rapid ventricular response. After initial treatment with oral metoprolol for ventricular rate control was discontinued (due to ineffective rate control and patient complaints of respiratory symptoms), oral diltiazem hydrochloride therapy (30 mg every six hours) was initiated on day 7; the dose was adjusted to a maximum of 120 mg every six hours on day 10. On day 12, the patient complained of nausea, abdominal pain and tenderness, and infrequent bowel movements; imaging studies on day 13 indicated paralytic ileus. Pursuant to a surgical consultation, a nasogastric tube was inserted and nothing was given by mouth except medications. After initial improvement of the GI symptoms, the feeding tube was removed; however, the symptoms worsened over the next two to three days, requiring reinsertion of the tube on day 16. On day 18, after other potential causes of ileus were ruled out, diltiazem therapy was withdrawn. The man experienced rapid symptomatic improvement, with no further GI symptoms, and was discharged four days later. CONCLUSION: A 64-year-old man receiving high-dose diltiazem to treat atrial fibrillation developed paralytic ileus, which quickly resolved after the medication was discontinued.

Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction.

INTRODUCTION: Fentanyl and diltiazem are frequently used medications. Diltiazem inhibits cytochrome P450 3A4 isoenzymes. This can suppress fentanyl metabolism. METHOD: We present a case of delirium after coadministration of fentanyl and diltiazem. DISCUSSION: Cautious use is warranted while concomitantly administering fentanyl and diltiazem as this can potentiate fentanyl toxicity. Other 3A4 inhibitors include ketoconazole, erythromycin, nefazodone, ritonavir, delavirdine, aprepitant and imatinib. Psychosomatic medicine psychiatrists, pain and palliative care physicians and cardiologists in particular should be aware of this interaction.

Clinical benefits versus shortcomings of diltiazem once-daily in the chronotherapy of cardiovascular diseases.

BACKGROUND: The introduction of chronotherapy (that is improving a drugs therapeutic efficacy by paralleling the drugs plasma levels to circadian rhythms) has recently become a focus of interest. OBJECTIVE: This article addresses the efficacy and potential shortcomings of chronotherapy, and focuses on one specific type of chronotherapy: a novel long-acting diltiazem formulation, DTZ-LA. METHODS: We reviewed the literature to assess the clinical benefits and shortcomings associated with DTZ-LA in the management of hypertension and angina. RESULTS/CONCLUSIONS: The clinical benefits of DTZ-LA outweigh its disadvantages when surrogate outcomes are evaluated, but it still remains to be determined whether chronotherapy benefits hard clinical outcomes. Nonetheless, chronotherapy has the potential to address the cardiovascular triggers that peak in the early morning hours when the preponderance of cardiovascular events occur, as well as providing better target organ protection compared with non-chronotherapeutic therapy.

La respuesta inicial al diltiazem tópico puede predecir la evolución de la fisura anal crónica / Initial response to topical diltiazem can predict outcome of chronic anal fissure

Introducción. Durante los últimos años, el tratamiento médico de la fisura anal crónica (esfinterotomía química) se ha ido implantando en la práctica como consecuencia de la morbilidad atribuida a la esfinterotomía quirúrgica. Sin embargo, el tratamiento médico presenta dos inconvenientes: la moderada eficacia, entre el 30 y el 80% y la necesidad de prolongarlo más de 8 semanas. Objetivo. Valorar la respuesta inicial a diltiazem al 2% tópico como factor de predicción de la curabilidad de la fisura anal crónica. Pacientes y método. Durante el período de febrero de 2004 a diciembre de 2005, todas las fisuras anales de más de 6 semanas de evolución fueron incluidas. Se excluyó a los pacientes con cirugía anal previa, embarazo, enfermedad inflamatoria intestinal, intolerancia al diltiazem y problemas de contacto para el seguimiento. Se empleó una fórmula magistral de gel de diltiazem al 2%, en 3 aplicaciones diarias durante 8 semanas. Se realizaron controles clínicos y medida del dolor mediante escala analógica visual (EAV) al final de la primera, la tercera, sexta y octava semanas. Se compararon los grupos con y sin respuesta al diltiazem mediante las pruebas de la χ2, exacta de Fisher y t de Student. Se realizó una curva ROC (Receiver Operating Characteristic) para valorar la eficacia diagnóstica de la respuesta inicial del dolor al diltiazem, así como la sensibilidad, la especificidad y los valores predictivos. Resultados. Se analizaron 100 pacientes (70 varones), con una media de edad de 43 (22-76) años. Localización posterior en el 87%, anterior en el 11% y lateral en el 2%. Todos tenían dolor; 65, sangrado y 13, prurito. Al final de las 8 semanas de tratamiento se curó el 62%, con una morbilidad del 5% (cefalea leve en el 2% y prurito en el 3%). No hubo diferencias significativas entre los grupos con y sin respuesta al diltiazem al 2% en relación con la edad, el sexo, la localización, el sangrado o el prurito. Hubo diferencias notables en la EAV del dolor al final de la primera, la tercera, la sexta y la octava semanas entre los grupos con y sin respuesta al tratamiento médico (p = 0,00). Con curvas ROC se estableció un punto de corte de 4 en la EAV al final de la primera semana, con un área bajo la curva de 0,925 (intervalo de confianza [IC] del 95%, 0,858-0,989). La capacidad predictora de curabilidad de la respuesta precoz al diltiazem mostró una sensibilidad del 85,5% (IC del 95%, 74,7-92,2%), una especificidad del 92,1% (IC del 95%, 79,2-97,3%), un valor predictivo positivo del 94,6% (IC del 95%, 85,4-98,2%) y un valor predictivo negativo del 79,5% (IC del 95%, 65,5-88,8%). Al final de la primera semana, tan sólo un 9% de los pacientes que no mejoraron con el diltiazem se curaron a las 8 semanas. Y por el contrario, de los que respondieron bien la primera semana, se curó el 94,6%. Conclusiones. La ausencia de respuesta al diltiazem al 2% tópico al final de la primera semana predice con buena fiabilidad el fracaso del tratamiento médico de la fisura anal crónica, y no es necesario prolongarlo hasta las 8 semanas (AU)

Introduction. In the last few years, the medical treatment of chronic anal fissure (chemical sphincterotomy) has been introduced as a consequence of the morbidity attributed to surgical sphincterotomy. However, medical treatment has two disadvantages: moderate effectiveness (between 30% and 80%) and the need for treatment to be prolonged for more than 8 weeks. Objective. To evaluate initial response to topical diltiazem 2% topical gel as a predictive factor in the curability of chronic anal fissure. Patients and method. From February 2004 to December 200, all patients with a history of anal fissure of more than 6 weeks were included in this study. Pregnant patients and those with prior anal surgery, inflammatory bowel disease, diltiazem intolerance and problems for maintaining contact during follow-up were excluded. A magistral formula of diltiazem 2% gel was used in three applications daily for 8 weeks. Patients were followed-up clinically and pain was measured through a visual analog scale (VAS) at the end of weeks 1, 3, 6, and 8. Groups with and without response to diliazem were compared through the χ2 test, Fisher's exact test and Student's t-test. A Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic efficacy of initial pain response to diliazem, as well as sensitivity, specificity and predictive values. Results. One hundred patients (70 men), with a mean age of 43 years (22-76) were analyzed. Localization was posterior in 87%, anterior in 11% and lateral in 2%. All patients had pain, 65 had bleeding, and 13 had pruritus. At the end of the 8-week treatment, cure was achieved in 62%, with morbidity of 5% (mild headache in 2%, and pruritus in 3%). No significant differences were found between the groups with and without response to diltiazem 2% in terms of age, sex, localization, bleeding, or pruritus. Notable differences were found in the VAS for pain at the end of weeks 1, 3, 6, and 8 between the two groups (p = 0.00). ROC curves established a cut-off point of 4 in the VAS at the end of week 1, with an area below the curve of 0.925 (95% CI, 0.858-0.989). The capacity of early response to diliazem to predict curability showed a sensitivity of 85.5% (95% CI, 74.7%-92.2%), a specificity of 92.1% (95% CI, 79.2%-97.3%), a positive predictive value of 94.6% (95% CI, 85.4%-98.2%), and a negative predictive value of 79.5% (95% CI, 65.5%-88.8%). Among patients who showed no response to diltiazem by the end of week 1, cure was achieved in only 9% at 8 weeks. In contrast, among those with a favorable response in the first week, cure was achieved in 94.6%. Conclusions. Lack of response to topical diltiazem 2% gel at the end of the first week reliably predicts failure of medical treatment for chronic anal fissure, obviating the need to prolong treatment for 8 weeks (AU)

The influence of simvastatin at high dose and diltiazem on myocardium in rabbits, the biochemical study.

3-Hydroxy-3-methyl-glytaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") have been proved to be extremely useful in the management of hypercholesterolemia, as well as in prevention of primary and secondary coronary heart disease. However, they may produce rare but severe muscle-related symptoms such as myopathy and rhabdomyolysis. Recent findings in vitro have shown that statins can reduce cardiomyocyte viability. The exact mechanism of statin myotoxicity still remains unclear. Diltiazem as CYP3A4 inhibitor, is a well recognized risk factor of skeletal muscles myopathy, if co-administered with simvastatin. It is not known whether such interaction affects myocardial efficiency causing biochemical changes. The experiments were performed on thirty six New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC (control group): diltiazem (5 mg/kg); simvastatin (50 mg/kg) or diltiazem + simvastatin, daily for 14 days (po). The following biochemical parameters were estimated: creatine kinase (CK), serum transaminases (ALT and AST), as well as myocardial injury markers: troponin I (Tnl) and creatine kinase MB (CK-MB). Simultaneous administration of simvastatin and diltiazem caused 23-fold increase (p < 0.01), in rabbit serum CK levels and 20-fold increase (p = 0.056) in TnI levels, as compared to the initial values. Also in these rabbits significant increase in CK (12411,60 vs 839.87 IU/L) and TnI (0,26 vs 0,014 ng/mL), as compared to control group were observed. Significant increase in CK (12411,60 vs 1100,92 IU/L) and TnI (0,26 vs 0,012 ng/mL), as compared to diltiazem alone were noted, too. This may suggest another mechanism of drug-drug interaction than the one based on CYP3A4 inhibition if the impact on cardiac or skeletal muscle is considered.

Effects of graded-release diltiazem versus ramipril, dosed at bedtime, on early morning blood pressure, heart rate, and the rate-pressure product.

BACKGROUND: Therapeutic agents for the treatment of hypertension may differ in their efficacy during the early morning period, a time when both morbid and mortal cardiovascular events are increased compared to other times of the day. METHODS: We studied the effects of a graded-release delivery system of diltiazem (diltiazem HCL extended release tablets) versus ramipril, both dosed at bedtime, on blood pressure (BP), heart rate, and the heart rate-systolic BP product during the first 4 hours after awakening in a double-blind, titration-to-effect trial. There were 261 men and women enrolled in the trial with an untreated sitting diastolic BP of 90 to 109 mm Hg and ambulatory daytime diastolic BP of 85 to 109 mm Hg. Patients were randomized to either diltiazem extended release (ER) tablets each evening (240 mg titrated to 360 mg and to 540 mg) or ramipril each evening (5 mg titrated to 10 mg and to 20 mg). Early morning assessments of BP, heart rate, and the heart rate-systolic BP product were performed using 24-hour ambulatory recordings after 10 weeks of therapy. RESULTS: In each therapeutic group, 76% of patients were titrated to the highest possible dose. After 10 weeks of treatment, reductions in early morning BP by diltiazem ER tablets were significantly greater (-18/-15 mm Hg) than reductions by ramipril (-13/-8 mmHg, P <.005 for systolic BP and P <.001 for diastolic BP). Diltiazem ER tablets also led to greater reductions in morning heart rate and the heart rate-pressure product compared to ramipril. Reductions in mean 24-hour diastolic BP, heart rate, and the rate-pressure product were greater in patients treated with diltiazem ER tablets compared to ramipril, while reductions in 24-hour systolic BP were similar in each group. The observed adverse effects were not serious and incidences were similar for the 2 treatment groups. CONCLUSIONS: These data demonstrate that bedtime administration of diltiazem ER, an agent designed to parallel the circadian rhythm of BP and heart rate, led to significantly greater early morning hemodynamic effects compared to the angiotensin-converting enzyme inhibitor ramipril, also dosed in the evening.

Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium.

A 51 year old man took a mixed overdose including 1.8-3.6 g of diltiazem, paracetamol, aspirin, isosorbide nitrate, and alcohol. He initially presented to hospital after six hours with mild hypotension and was treated with activated charcoal and intravenous fluids. Eighteen hours after the overdose he had two generalised tonic-clonic seizures. The patient remained unresponsive with junctional bradycardia, unrecordable blood pressure, and then became asystolic. He was resuscitated with high dose (13.5 g) intravenous calcium and adrenaline (epinephrine). He required inotropic support and temporary pacing over the next 48 hours. This case suggests there is a role for aggressive high dose intravenous calcium therapy in severe diltiazem overdose, particularly with the onset of asystole. It should be considered early in cases of cardiac arrest after diltiazem overdose. The case also highlights the problems with delayed toxicity when whole bowel irrigation is not administered.

Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN).

The combination of calcium channel blockers and beta blockers is more effective for the treatment of exercise-induced angina pectoris than beta blocker monotherapy. Since ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 and 10 mg, diltiazem XR 200 and 300 mg, and mibefradil 50 and 100 mg treatment added to baseline beta blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. Although none of the calcium channel blockers improved duration of exercise or amount of workload, all of them significantly delayed onset of 1 mm ST segment depression on ETT (p<0.001 for any treatment versus baseline). In addition, mibefradil, both low- and high-dose treatment, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, p<0.003 and <0.001, respectively; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, p<0.001 and <0.001, respectively). These effects were linearly correlated to the amount of rate pressure product (RPP) reduction. Serious symptoms of dizziness likewise occurred significantly more frequently with mibefradil (p<0.05) and led 19 patients taking mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with negative chronotropic property provide better delay of ischemia in patients with exercise-induced angina but that the concomitant risk of intolerable dizziness largely reduces this benefit.

Combination of calcium channel blockers and beta-adrenoceptor blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. Netherlands Working Group on Cardiovascular Research (WCN).

AIMS: The combination of calcium channel blockers and beta-adrenoceptor blockers is more effective for the treatment of exercise-induced angina pectoris than beta-adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds. METHODS: A 335 patient double-blind parallel-group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. RESULTS: Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST-segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial. CONCLUSIONS: Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.

Diltiazem for maintenance tocolysis of preterm labor: comparison to nifedipine in a randomized trial.

The objective of this study was to compare the safety and efficacy of maintenance tocolysis with oral diltiazem to oral nifedipine in achieving 37 weeks gestation. After successful intravenous tocolysis with magnesium sulfate, 69 women with preterm labor at <35 weeks gestation were randomly assigned to nifedipine (20 mg orally every 4-6 hr), or diltiazem (30-60 mg orally every 4-6 hr). The primary outcome was the percentage of patients achieving 37 weeks gestation. Maternal cardiovascular alterations and neonatal outcomes were also assessed. Sixty-nine patients were available for final analysis. Less patients on diltiazem as compared to nifedipine achieved 37 weeks (15.1% vs. 41.7%, P = 0.019). Gestational age at delivery was also less for patients receiving diltiazem (35.5 +/- 3.5 weeks vs. 33.4 +/- 3.9 weeks, P = 0.022). There were fewer days gained in utero from randomization to delivery with diltiazem as compared to nifedipine; however, this difference was not statistically significant (22.4 +/- 16.3 days vs. 31.2 +/- 24.4 days, P = 0.084). Maternal blood pressure and pulse during tocolysis did not differ significantly between groups. Despite the theoretical advantages of diltiazem tocolysis, maintenance tocolysis with diltiazem offered no benefit over nifedipine in achieving 37 weeks gestation. The cardiovascular alterations with either drug in normotensive, pregnant patients appear minimal.

Diltiazem-associated thrombocytopenia.

Nine days after starting diltiazem therapy for new-onset atrial fibrillation, a patient's platelet count had diminished to 61 x 10(3)/mm3, and 2 weeks later the nadir was reached at 23 x 10(3)/mm3. No hypersensitivity reaction otherwise was noted, and other hematologic values were unaffected. The patient's platelet counts were not affected by platelet transfusions. Bone marrow examination showed normal to increased numbers of megakaryocytes, suggesting peripheral destruction. After discontinuing diltiazem and administering high-dose immunoglobulin infusions, the platelet count returned to normal. This case suggests an immune-mediated cause for thrombocytopenia after exposure to diltiazem.

Mibefradil in the treatment of systemic hypertension: comparative studies with other calcium antagonists.

This paper summarizes the results of 4 double-blind studies of antihypertensive therapy in which mibefradil was compared with other commonly used calcium antagonists (diltiazem CD, amlodipine, nifedipine SR, and nifedipine GITS) at the recommended dose range. A total of 640 patients were included, with 361 randomized to mibefradil, 98 to diltiazem CD, 119 to amlodipine, 71 to nifedipine SR, and 36 to nifedipine GITS. Trials included an active treatment phase of 6 or 12 weeks in duration. Compared with diltiazem CD or nifedipine SR, mibefradil demonstrated statistically significant greater efficacy. Decreases in sitting diastolic blood pressure (SDBP) after treatment with mibefradil 100 mg once daily were 14.0 +/- 7.8 mm Hg compared with 9.5 +/- 7.5 mm Hg with diltiazem CD 360 mg once daily (p = 0.001), and 12.8 +/- 8.4 mm Hg compared with 8.1 +/- 19.2 mm Hg with nifedipine SR 40 mg twice daily (p = 0.014). Patients on mibefradil also had higher normalization (SDBP reduced to < or = 90 mm Hg) and response (SDBP reduction > or = 10 mm Hg or normalization) rates than did those on diltiazem CD or nifedipine SR. The overall incidence of adverse events was similar among these 3 compounds, but the number of premature withdrawals due to adverse events was greater with both comparators than with mibefradil. Treatment with 100 mg mibefradil or 10 mg amlodipine once daily resulted in statistically significant decreases from baseline in SDBP of 11.5 +/- 8.2 mm Hg and 13.2 +/- 7.9 mm Hg, respectively, which were statistically equivalent. However, patients treated with amlodipine had a considerably greater incidence of leg edema than did those treated with mibefradil (33.6% vs 4.2%, respectively). Similarly, 100 mg mibefradil was equivalent in efficacy to 60 mg nifedipine GITS once daily, but patients on mibefradil experienced fewer vasodilatory related adverse events. In summary, mibefradil demonstrated superior efficacy to diltiazem CD and nifedipine SR and equivalent efficacy to amlodipine and nifedipine GITS in the treatment of hypertension.

The modulatory effect of diltiazem on human in vitro alloreactivity when used alone or in combination with cyclosporin A and/or methylprednisolone.

The calcium channel blocker diltiazem is often included in post-transplant regimens in combination with other immunosuppressive drugs such as cyclosporin A (CyA). It is primarily used because of its antinephrotoxic and antihypertensive effects, so that undesirable side effects induced by the immunosuppressive therapy can be reduced. Its alleged ability to induce direct immunosuppression may explain the encouraging results from its clinical use and would appear to encourage a much wider use of this drug. The present study shows the effect of diltiazem on the human in vitro alloresponse when used alone or in combination with cyclosporin A (CyA) and methylprednisolone (MP). The results show that, when administered alone, diltiazem exerts a suppressive effect, but only at high, non-therapeutic doses. Interestingly, in combination with CyA or MP, diltiazem enhances the suppressive effect of these two drugs on in vitro alloresponses at lower doses. This additional effect of diltiazem may contribute to better graft survival in clinical transplantation.

Evaluation of gingival and periodontal conditions following causal periodontal treatment in patients treated with nifedipine and diltiazem.

It is established that phenytoin, cyclosporin and some calcium antagonists produce gingival overgrowth, but it is not known how this condition may respond to causal periodontal treatment. In order to find out, a longitudinal study was carried out, over a year, comparing a group of patients who were given nifedipine (NG, n = 18) and another group who were given diltiazem (DG, n = 13) with 2 others: one comprised cardiopathic patients who took no calcium antagonists (CG, n = 12) and the other contained patients who were medically healthy, with moderate periodontitis (HG, n = 12). On their basal visit, they were examined and instructed in oral hygiene, and then given causal periodontal treatment, being seen again at 4 and 8 months, when hygiene instructions were reinforced. They were seen for the last time at 12 months, when they were again examined. Groups NG and DG, on their basal visit, showed larger gum size than groups HG and CG, which was statistically significant; on their final visit, these differences remained only at the interproximal level. The number of patients with gingival overgrowth-taking the average of group HG as a minimal value-was much higher in groups CG (92%), DG (100%) and NG (89%) on the basal visit; on the final visit, the differences remained only in groups DG (85%) and NG (83%). The probing pocket depth reduction was much greater in groups HG and CG than in DG and NG, basically due to a greater gaining on clinical attachment level. The % of sites in which the pocket depth improved by more than 2 mm was 39.8% in HG, 54.5% in CG, 23.7% in DG and 28.7% in NG. The % of sites where the attachment gain by more than 2 mm was 46.2% in HG, 55.5% in CG, 22.8% in DG and 21.4% in NG. The amount of plaque and bleeding on probing, which was similar in all groups on the basal visit, decreased throughout the study, especially between the basal and 2nd visit in groups HG and CG. We have demonstrated that patients that take nifedipine and diltiazem show a larger gum size and their response to causal periodontal treatment is poorer than in the healthy and the cardiac groups.

Combined drug therapy with diltiazem, dextran, and hydrocortisone (DDH therapy) for late cerebral vasospasm after aneurysmal subarachnoid hemorrhage: assessment of efficacy and safety in an open clinical study.

Late cerebral vasospasm after subarachnoid hemorrhage (SAH) is a disastrous phenomenon for the patients and a definite treatment has not been established. We studied 48 consecutive patients receiving high-dose diltiazem (5 micrograms/kg/min) injection combined with dextran and hydrocortisone to late cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). All but 2 patients underwent surgery within 72 hours after SAH. Diltiazem was continuously given via a central venous line for up to 2 weeks in conjunction with simple cisternal drainage. 5% of dextran solution (500 ml/day) was infused for 7-10 days. Hydrocortisone was given 1,600 mg on the first day, then the dose was gradually decreased over 14 days. Symptomatic vasospasm (SVS) occurred in 5 patients (10.4%), 4 patients recovered, but 1 had severe neurological deficit. A low density area on CT-scan was observed in 2 patients. Thirty patients (62.5%) had good recovery, 10 patients (20.8%) had moderate disability, 3 (6.3%) had severe disability and 3 (6.3%) had vegetative survival. Two patients died of the initial brain damage. There were no severely hypotensive side effects. However, 3 patients showed atrioventricular blockage on electrocardiogram. These side effects subsided after the dose of the drug was decreased or administration was stopped altogether. These findings show that high-dose calcium antagonist diltiazem therapy combined with dextran and hydrocortisone injection is safe and effective for prevention of late cerebral symptomatic vasospasm after SAH.

Safety and compatibility of betaxolol hydrochloride combined with diltiazem or nifedipine therapy in stable angina pectoris.

Compared with placebo, adding betaxolol 20 mg every day to nifedipine (up to 60 mg/day in divided doses) or diltiazem (up to 360 mg/day in divided doses) for a 3-week treatment period in 135 patients with stable angina pectoris significantly (p < 0.05) lengthened the time to onset of moderate angina during exercise tolerance tests at all treatment time points. The median increases in the time to onset of moderate angina at the final exercise tolerance test (end point) compared with baseline were 1.08 and 0.53 minutes for betaxolol and placebo groups, respectively (p = 0.002, betaxolol and placebo groups, respectively (p = 0.002, betaxolol vs placebo). The time to onset of 1 mm ST-segment depression increased significantly (p < 0.05) with betaxolol compared with placebo at all but 1 treatment time point (median increase [p = 0.001] 1.77 and 0.37 minutes, respectively, at end point). Duration of exercise also was increased significantly (p < 0.05) after the third week of treatment and at end point (median 0.62 and 0.50 minutes, respectively; p = 0.03). Generally comparable results were found within the diltiazem (n = 128) and nifedipine (n = 25) subgroups, although the nifedipine group was too small to detect statistically significant differences between betaxolol and placebo treatment. Resting systolic blood pressure, heart rate and the rate-pressure product, measured both when angina occurred and at the end of exercise, also were influenced significantly (p < 0.05) by the betaxolol addition. The only serious adverse effect associated with betaxolol treatment was syncope, seen in 2 patients.