Effects of intravenous diltiazem administration in patients with inducible tachycardia

The efficacy of diltiazem was studied with programmed electricalstimulation of the heart in 13 patients with inducible tachycardia(atrioventricular nodal tachycardia: 8 cases; orthodromic circusmovement tachycardia involving an accessory pathway: 4 cases;ventricular tachycardia: one case). Diltiazem was administeredintravenously at a dose of 0.25 mg kg^-l over 2 min. It lengthenedthe transnodal conduction time, and the effective and the functionalrefractory periods of the A V node. The shortest pacing cyclelength with I: I conduction through the node lengthened bothin the anterograde and retrograde directions. Diltiazem didnot alter anterograde or retrograde refractoriness of accessorypathways. Infused intravenously during episodes of tachycardia,diltiazem interrupted the arrhythmia in all patients. Tachycardiacould still be initiated in 2 patients after drug, but the arrhythmiawas not sustained in one case. One patient with preexcitationand atrialfibrillation exhibited an increase in ventricularrate after diltiazem. The shortest RR intervals before and afterdiltiazem were 240 ms and 180 ms, respectively. Thus, iv diltiazemis an effective antiarrhythmic drug for patients with reciprocalsupraventricular tachycardia and for selected patients withventricular tachycardia.     

Electrocardiographic subset analysis of diltiazem administration on long-term outcome after acute myocardial infarction. The Multicenter Diltiazem Post-Infarction Trial Research Group

The effect of diltiazem on long-term outcome after acute myocardial infarction (AMI) was assessed in 2,377 patients enrolled in the Multicenter Diltiazem Post-Infarction Trial and subsequently followed for 25 +/- 8 months. The study population included 855 patients (36%) with at least 1 prior AMI before the index infarction and 1,522 patients (64%) with a first AMI, of whom 409 (27%) had a first non-Q-wave AMI, 664 (44%) a first inferior Q-wave AMI, and 449 (30%) a first anterior Q-wave AMI. This post hoc analysis revealed that, among patients with first non-Q-wave and first inferior Q-wave AMI, there were fewer cardiac events during follow-up in the diltiazem than in the placebo group, and that the reverse was true for patients with first anterior Q-wave AMI or prior infarction. The diltiazem:placebo Cox hazard ratio (95% confidence limits) for the trial primary end point (cardiac death or nonfatal reinfarction, whichever occurred first) was: first non-Q-wave AMI-0.48 (0.26, 0.89); first inferior Q-wave AMI-0.66 (0.40, 1.09); first anterior Q-wave AMI-0.82 (0.51, 1.31); and prior AMI-1.11 (0.85, 1.44). Use of cardiac death alone as an end point gave an even more sharply focused treatment difference: first non-Q-wave AMI-0.46 (0.18, 1.21); first inferior Q-wave AMI-0.53 (0.27, 1.06); first anterior Q-wave AMI-1.28 (0.68, 2.40); prior infarction-1.26 (0.90, 1.77). Further analysis revealed that these differences in the effect of diltiazem in large part reflected the different status of the 4 electrocardiographically defined subsets in terms of left ventricular function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous diltiazem in acute myocardial infarction: hemodynamic evaluation

The acute hemodynamic effects of intravenous Diltiazem were studied in 20 pts. with acute myocardial infarction, admitted to Coronary Care Unit within 24 hours from onset of Symptoms--19 men, 1 woman, aged from 46 to 83 years, 14 with anterior myocardial infarction, 6 with inferior myocardial infarction. All, but one, where at the time of their admission to CCU in first Forrester's hemodynamic subset (CI greater than 2.2 L/min/m2, WP less than 18 mmHg); in the last patient WP was 21 mmHg, CI 2.6 L/min/m2. Hemodynamic measurements were performed before (no drugs with hemodynamic effects were allowed during 4-6 hours before the study protocol) and after the administration of Diltiazem, 0,3 mg/kg i.v. administered in 2 min. (bolus) in 12 patients, Group A. In 8 pts--Group B--the bolus was followed by continuous infusion of Diltiazem at the rate of 5 mcg/Kg/min for three hours. The hemodynamic measurements were repeated: in Group A 2-5-30-60-120 min. after the end of the bolus; in the Group B at the same time as Group A, at the end of infusion (180 min) and 60 min after the end of infusion. Diltiazem induced no significant changes of HR, CVP, WP, CI, LVSWI and Triple product, in both groups of pts., at any time. Systolic and diastolic blood pressure decreased significantly (P less than 0.01) only 2 min. after Diltiazem administration (Group A: SBP 125.0 +/- 15.8----114.0 +/- 16.0 mmHg, DBP 85.4 +/- 6.5----76.6 +/- 10.5 mmHg; Group B: SBP 123.0 +/- 20.0----113.0 +/- 11.0 mmHg, DBP 78.1 +/- 7.0----75.0 +/- 4.9 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacodynamic aspects of intravenous diltiazem administration

The diltiazem serum concentration and the magnitude and time course of systemic and coronary hemodynamic and ECG responses to intravenous diltiazem (250 micrograms/kg intravenous bolus plus 1.4 micrograms/kg/min infusion) were investigated in 14 patients with chronic stable angina pectoris. After 3, 8, and 15 minutes this dosing schedule produced serum concentrations of 570 +/- 259, 199 +/- 62, and 136 +/- 30 ng/ml, respectively (mean +/- SD). These drug levels were associated with a small, transient increase in heart rate (6 bpm, mean) at 3 minutes, which occurred during the nadir of the blood pressure response. But at 8 and 15 minutes, heart rate was unchanged compared to control rates, although blood pressure remained decreased (19%, p less than 0.01 at 15 minutes). Pressure-rate product was significantly reduced as left ventricular end-diastolic pressure and dP/dT remained unchanged. Systemic resistance decreased 17% (p less than 0.05) and stroke index increased 10% (p less than 0.01). Coronary flow was maintained as coronary resistance declined (14%, p less than 0.01). PR interval prolongation (14%, p less than 0.01) occurred at 15 minutes. Correlations between changes in systolic, diastolic, and mean pressures and drug concentration were significant (r = -0.59, -0.80, and -0.78, respectively, all p less than 0.05). The intercept for each regression line was approximately 96 ng/ml diltiazem concentration, suggesting that this represents the minimum effective diltiazem serum concentration. These results indicate that intravenous diltiazem is well tolerated and promptly reduces blood pressure and both systemic and coronary resistances without oxygen-wasting effects of an increase in heart rate.     

Effects of long-term administration of octreotide in portal vein-stenosed rats

The hemodynamic effects of long-term administration of octreotide in portal hypertension has not been established. In addition, whether long-term octreotide treatment prevents the development of portosystemic shunts has not yet been evaluated. Hence, the current study was undertaken to evaluate the effects of long-term administration of octreotide in rats with portal vein stenosis. Immediately after portal vein stenosis or sham operation, rats were given either a long-term octreotide administration of 100 micrograms/kg or a placebo every 12 hours by subcutaneous injection for 14 consecutive days. Systemic hemodynamics and regional blood flows, degree of mesenteric-systemic shunts, and plasma glucagon concentrations were measured after the final dose of octreotide or placebo. A fifth group of portal vein-stenosed rats received hemodynamic and plasma glucagon measurements after 1-day octreotide treatment given at 14 days after surgery. Long-term octreotide treatment modified the hyperdynamic circulation without affecting the degree of mesenteric-systemic shunts, and 1-day octreotide treatment decreased portal tributary blood flow without affecting the portal pressure, systemic hemodynamics, and degree of mesenteric-systemic shunts. Plasma glucagon levels were decreased in portal vein-stenosed rats receiving either long-term or 1-day octreodtide compared with rats receiving placebo. In contrast, chronic octreotide treatment did not affect any of the hemodynamic values or plasma glucagon levels in sham-operated rats. In conclusion, long-term administration of octreotide modified in part the development of portal hypertension and hyperdynamic circulation in portal vein-stenosed rats without affecting the degree of mesenteric-systemic shunts. (Hepatology 1996 Mar;23(3):537-43)     

Beneficial effects of long-term diltiazem treatment in dilated cardiomyopathy

There is increasing evidence that chronic enhanced exogenous or endogenous catecholamine stimulation in patients with dilated cardiomyopathy may worsen hemodynamic status and prognosis. The cause of this deterioration may lie in myocellular calcium accumulation and microcirculatory disorders. In a prospective study, the calcium channel antagonist diltiazem was given to 22 patients with dilated cardiomyopathy (60 to 90 mg three times daily) in addition to conventional therapy of digitalis, diuretics and vasodilators. Twenty-five patients received the conventional therapy and served as historical controls. Eight additional patients who were not originally included in this control group received adjunctive diltiazem treatment after initially receiving conventional therapy alone. The three patient groups were similar in all hemodynamic and anamnestic features. Only patients with reduced myofibrillar volume fraction on myocardial biopsy were included in the trial, because they could be expected to show hemodynamic deterioration. The mean survival time was 29 months in the control group, whereas no patient in the diltiazem group died over a mean follow-up period of 15.4 months (p less than 0.001). Mean left ventricular ejection fraction increased from 0.34 to 0.44 (p less than 0.001) and New York Heart Association functional class improved significantly in the diltiazem group and during the diltiazem period in the crossover patients, but deteriorated in the control group. The results suggest that adjunctive diltiazem treatment in dilated cardiomyopathy has beneficial effects on mortality, hemodynamics and symptoms.     

Effects of long-term rifampicin administration in primary biliary cirrhosis.

The effects of rifampicin treatment (10 mg.kg-1.day-1) on pruritus and cholestasis were evaluated in 16 patients with primary biliary cirrhosis and pruritus followed up for 2-24 months. Assessment of pruritus severity, liver tests, aminopyrine breath test, and bile acids was done at 2 weeks and every 3 months after the beginning of the study. Two patients (12.5%) were withdrawn after 2 months of treatment because they had hepatitis caused by rifampicin. Four patients were withdrawn after 4 months because of liver transplantation (3 cases) and the development of leg edema associated with administration of rifampicin. The remaining 10 patients received therapy for 14.4 +/- 0.7 months and did not experience side effects. Pruritus improved in all patients and disappeared in 11 patients (79%) after 3 months of treatment. Moreover, all patients followed up for more than 1 year were free of pruritus. The alkaline phosphatase level decreased significantly, and the aminopyrine breath test results increased significantly after 2 weeks of treatment (P less than 0.001) and did not change thereafter. In the 9 patients treated for 15 months, alkaline phosphatase levels decreased to 63% of the basal levels and aminopyrine breath test results increased to 153% of baseline values. Transaminases, gamma-glutamyltransferase, and total bile salt levels decreased significantly after 2 weeks of treatment but returned to baseline after 3 months. No changes in bilirubin and cholesterol levels were observed. It is concluded that long-term rifampicin treatment is effective for relieving pruritus in primary biliary cirrhosis, but liver enzymes should be monitored to detect drug-induced hepatitis.     

Effects of methylprednisolone administration in acute myocardial infarction

Methylprednisolone sodium succinate, 50 mg/kg body weight, was given as an intravenous bolus injection to 15 dogs with acute myocardial infarction and the results were compared with data in control animals. Methylprednisolone was thought to improve the critical oxygen balance of the infarcted heart by two mechanisms: (1) by diminishing heart rate, afterload and preload in the initial 15 minutes after its administration and thereby decreasing the oxygen need of the heart, and (2) by increasing coronary arterial blood flow. Both mechanisms were believed to contribute to the increase in cardiac output, efficiency and ventricular performance. This improvement in performance was presumably not due to a positive inotropic effect, since studies in isolated heart muscle showed no effect of methylprednisolone on contractility. Regional circulations other than the coronary circulation seemed to be little affected by administration of methylprednisolone except for blood pressure-related increases in superior mesenteric and femoral arterial blood flow.     

Effects of diltiazem on conduction of premature impulses during acute myocardial ischemia and reperfusion

The effect of diltiazem on conduction of cardiac impulses was studied using premature impulses. Conduction times were measured in the epicardium and endocardium in both anterograde and retrograde directions during ischemia and reperfusion of the left ventricular anterior wall. In 16 dogs (8 control and 8 treated with diltiazem), the left anterior descending artery was occluded initially below the second diagonal branch and 30 minutes later below the first diagonal branch. Infusion of diltiazem (0.02 mg/kg per min) was begun at the time of the first ligation in the treated dogs. Conduction delay in normal, ischemic and reperfused myocardium and at the border of ischemia or reperfusion was compared in the two groups. In addition, treated and nontreated ischemic zones were analyzed in the diltiazem-treated group. Results showed significantly less ischemia-induced conduction delay in the diltiazem-treated group in both ischemic myocardium and at the border of ischemia. This beneficial effect was seen in the ischemic segment in the treated dogs whether or not the medication was given before or after coronary ligation. Further, the effect of the drug on epicardial and endocardial conduction did not differ significantly. These data suggest that diltiazem may have potential value in the treatment of ventricular reentrant arrhythmias associated with acute ischemia over and above the well recognized hemodynamic and metabolic effects of calcium channel blocking agents.     

Effects of long-term administration of methionine on vascular endothelium in rabbits

BACKGROUND AND AIM: We studied the effects of long-term methionine administration on the vascular endothelium of Japanese white rabbits. METHODS AND RESULTS: Eleven rabbits were divided into a control group (n = 6) and a methionine-fed group (n = 5), and reared for 22 weeks. Blood samples were collected at baseline and after 22 weeks for the measurement of serum homocysteine and cysteine, serum lipids and serum superoxide dismutase activity. At the end of experiments, the animals were sacrificed, and the thoracic aorta was removed for the measurement of isometric tension and histopathological examination. The blood samples taken from the methionine group in the 22nd week showed slight but significant increases in serum homocysteine and cysteine levels (Hcy: 13.7 +/- 1.4 vs 21.0 +/- 4.9, p < 0.01; Cys: 241.6 +/- 37.8 vs 342.6 +/- 35.0, p < 0.01). In the isometric tension experiments, the methionine group had a significantly decreased (p < 0.01) vasodilatation reaction induced by acetylcholine, an endothelium-dependent vasodilator. The histopathological examination (immunostaining in response to eNOS and tissue factor) showed significant increases in endothelium expression in the methionine group before atherosclerotic changes appeared. CONCLUSIONS: The above results suggest that vascular endothelial dysfunction played an important role in the atherosclerosis occurring after excess methionine feeding.     

Effects of long-term oral administration of DDT on nonhuman primates

Because of reports on tumorigenic activity in different animal species exposed to DDT a decision was made in 1969 to evaluate the long-term effects of DDT on 24 cynomolgus and rhesus monkeys. DDT (20 mg/kg) was given in the diet for 130 months, followed by an observation period that ended in 1994. The two cases of malignant tumor detected in the DDT group included a metastatic hepatocellular carcinoma in a 233-month-old male and a well-differentiated adenocarcinoma of the prostate in a 212-month-old monkey. Benign tumors detected in the DDT group included three cases of leiomyoma, two of which were uterine and one, esophageal. No tumor was detected in the control group of 17 monkeys. Fatty changes in the liver were observed in 52.9% of the DDT group and 29.4% of the control group. More specific signs of hepatotoxicity were documented microscopically in seven DDT monkeys. Severe tremors and histological evidence of CNS and spinal cord abnormalities were observed in six DDT monkeys. The present findings show clear evidence of hepatic and CNS toxicity following long-term DDT administration to cynomolgus and rhesus monkeys. However, the two cases involving malignant tumors of different types are inconclusive with respect to a carcinogenic effect of DDT in nonhuman primates. Received: 17 November 1998 / Accepted: 27 January 1999     

硫氮(卓)酮治疗阵发性心房颤动的长期临床观察

目的 :探讨硫氮酮对阵发性心房颤动 (房颤 )的治疗效果。方法 :选择 6 2例阵发性房颤患者 ,随机分为硫氮酮组 (31例 )和对照组 (31例 ) ,随访 3年 ,观察房颤年发作次数、持续时间和转变为持续性房颤的情况。结果 :①硫氮酮明显减少房颤年发作次数、持续时间 (P <0 .0 1) ,但用药后 1～ 2年间差异无显著性意义(P >0 .0 5 ) ;②对照组房颤年发作次数、持续时间逐年增加 ,年与年之间差异有非常显著性意义 (P <0 .0 1) ;③随访期间 ,对照组有 6例而硫氮酮组无一例转变为持续性房颤 ,两组间差异有显著性意义 (P <0 .0 5 )。结论 :硫氮酮可明显减少阵发性房颤发作次数和持续时间 ,在阻止其转变为持续性房颤也有一定的作用 ,推测与硫氮酮阻止房颤电重构的发生有关     

Effects of diltiazem in supraventricular paroxysmal tachyarrhythmias

Diltiazem (0.3 mg/kg body weight intravenous in 2 minutes) was administered to 40 patients (24 males, 16 females, mean age 51.55 years) with paroxysmal supraventricular tachyarrhythmias: 7 patients with atrial fibrillation, 6 patients with atrial flutter, 25 patients with paroxysmal supraventricular tachycardia, 2 patients with uncommon atrioventricular reciprocating tachycardia. In patients with atrial fibrillation intravenous diltiazem produced a significant decrease of ventricular response (from 160 +/- 11 to 113.57 +/- 10.34--p less than 0.01). In patients with atrial flutter intravenous diltiazem produced variable effects: an increase in atrio-ventricular block (from 2:1 to 3:1 atrio-ventricular conduction (2 patients); conversion to sinus rhythm (1 patient); change to atrial fibrillation (1 patient); no appreciable change of the basic rhythm (2 patients). In paroxysmal supraventricular tachycardia patients conversion to sinus rhythm occurred in 20/22 patients (91%) treated with intravenous diltiazem (mean conversion time 4.69 minutes). In the 2 patients with uncommon atrioventricular nodal reciprocating tachycardia diltiazem increased P'-R and R-P' intervals without appreciable change of the basic rhythm. No serious side effects from drug administration were noted. Intravenous diltiazem appears to be as a highly effective medication in conversion or control of paroxysmal supraventricular tachyarrhythmias.     

Effects of long-term Hydergine administration on lipofuscin accumulation in senescent rat brain

The effects of ageing and of 6 months of Hydergine treatment on lipofuscin deposition within the cytoplasma of pyramidal neurons of rat prefrontal cortex, hippocampus (fields CA1 and CA3) and of Purkinje neurons were assessed microfluorimetrically. No lipofuscin autofluorescence was detected in the nerve cell populations of 3-month-old rats, but lipopigment had accumulated in nerve cell bodies of 16-month-old animals and increased significantly thereafter in rats of 22 months of age. In 22-month-old rats, Hydergine administration (0.6 and 1 mg/kg p.o.) started at 16 months caused a significant dose-related decrease in lipofuscin accumulation within the cytoplasm of the various kinds of nerve cells examined.     

Effects of diltiazem on long-term outcome after acute myocardial infarction in patients with and without a history of systemic hypertension. The Multicenter Diltiazem Postinfarction Trial Research Group

The effect of diltiazem on long-term outcome in patients with acute myocardial infarction with and without a history of systemic hypertension was investigated in 2,466 patients using the Multicenter Diltiazem Postinfarction Trial data-base. The baseline variables were comparable in the diltiazem and placebo-treated patients within the groups with and without hypertension. The initial 60-mg dose of diltiazem was associated with a significant (p less than 0.001) but modest (3%) reduction in blood pressure and heart rate in both groups with and without hypertension. Univariate and multivariate analyses revealed a meaningful overall reduction in first recurrent cardiac events (cardiac death or nonfatal reinfarction, whichever occurred first) and cardiac death in patients with hypertension treated with diltiazem compared with results in those treated with placebo. Similar effects were not observed in patients without a history of hypertension. When first recurrent cardiac events were used as the end point, the diltiazem:placebo hazard ratio (95% confidence limits) was 0.77 (0.58, 1.01) for the total hypertension group, and 0.67 (0.47, 0.96) and 1.32 (0.83, 2.10) for patients with hypertension with and without pulmonary congestion during the acute infarction, respectively. Similar results were observed using cardiac death as the end point. Beta blockers had a negligible effect on the hypertension-diltiazem relation. These findings suggest that diltiazem may exert a long-term beneficial effect in most patients with hypertension who do not have pulmonary congestion during an acute infarction, and a detrimental effect in the minority who have pulmonary congestion.     

Effects of long-term glibenclamide administration on gastrointestinal and pancreatic hormones in normal fasting rats

We previously reported that sulfonylurea treatment reduces insulin (IRI), glucagon (IRG) and somatostatin (SRIF) release following metabolic stimuli from the isolated perfused pancreas of normal rats and that a reduction in IRI, IRG and SRIF pancreatic content was also observed. The present work was undertaken to investigate the effects of long-term glibenclamide treatment on the gastrointestinal content of gut hormones in normal rats. Moreover, the effects of sulfonylurea treatment on IRI, IRG, and SRIF pancreatic content were also analyzed and compared to the peripheral hormone plasma levels. Two groups of male Sprague-Dawley rats received glibenclamide (1 mg/kg/day per os; n = 14) or placebo (distilled water; n = 10) for 5 months, respectively. Tissue contents of IRI, IRG and SRIF in acid-ethanol extracts of pancreas and of gastric inhibitory peptide (GIP), vasoactive intestinal polypeptide (VIP), entero-glucagon (gut-GLI) and SRIF in acid-ethanol extracts of intestine were determined. Blood glucose and plasma pancreatic hormone levels were also measured. Glibenclamide treatment lowered the levels of IRI, IRG and SRIF in the pancreatic tissue; in the same way gut-GLI, SRIF and VIP intestinal concentrations were significantly reduced, whereas no significant inhibition was detected in intestinal GIP content. Blood glucose levels and IRI and SRIF plasma concentrations were similar in the two groups. IRG plasma levels were reduced in the sulfonylurea group. These findings might suggest that sulfonylurea suppresses hormone biosynthesis in a non-specific manner.     

Effects of long-term administration of vitamin D3 analogs to mice

This study explores the effects of chronic administration of vitamin D(3) compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D(3) analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D(3) analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)(2)D(3) had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D(3) analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D(3) administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.