Effect of chronic potassium depletion on digitalis-induced inotropy and arrhythmias

The arrhythmogenic and inotropic effects of digoxin were studied in normokalemic controls, chronically hypokalaemic, and potassium-repleted dogs instrumented to maintain heart rate, mean aortic pressure, mean left atrial pressure and autonomic tone constant. The duration of digoxin infusion needed to produce ventricular tachycardia (VT) was 56.7 +/- 3.6 min in depleted dogs, 69.0 +/- 2.7 min in controls (P less than 0.005 compared with depleted dogs), and 60.5 +/- 3.0 min in repleted dogs. Baseline left ventricular dP/dt (LV dP/dt) was similar in all groups. After digoxin, LV dP/dt increased more in controls and repleted dogs than in chronically hypokalaemic dogs; eg, after 45 min of digoxin infusion LV dP/dt increased 12.7 +/- 4.4% in hypokalaemic dogs; eg, after 45 min of digoxin infusion LV dP/dt increased 12.7 +/- 4.4% in hypokalaemic dogs, 43.8 +/- 3.3% in controls (P less than 0.025) and 39.3 +/- 8.5% in repleted dogs (P less than 0.025). The inotropic response to isoprenaline was also attenuated in the chronically hypokalaemic dogs. Plasma digoxin was similar in all groups. LV digoxin was also similar in control and depleted dogs. Although inhibition of Na+, K+-ATPase and the initial velocity of 3[H]-ouabain specific binding was less in depleted dogs at VT than in controls (P less than 0.05), the magnitude of this difference was not sufficient to explain the attenuated inotropic response. No histological abnormalities were seen on light or electron microscopy in any of the groups. Therefore chronic hypokalaemia has two deleterous effects. It increases sensitivity to the arrhythmogenic effects of digoxin and impairs the inotropic response to digoxin, and isoprenaline.     

Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with amprenavir. DESIGN: Prospective, open-label, within-subject pharmacokinetic study. SETTING: University research center. SUBJECTS: Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled. INTERVENTION: On study day 1, subjects received their usual once-daily dose of methadone alone. On study days 2-11, they received the same once-daily methadone dose plus amprenavir 1200 mg twice/day. Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R- and S-methadone, and over 12 hours on day 11 for serum amprenavir concentrations. MEASUREMENTS AND MAIN RESULTS: Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with amprenavir). Subjects served as their own control for methadone comparisons, and amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid-effect measures were assessed throughout the study. Coadministration of amprenavir with methadone resulted in a 3-4-hour delay in plasma R- and S-methadone enantiomer peak concentrations at steady state (Cmax-ss). The active R-methadone enantiomer area under the plasma concentration-time curve during a dosing interval (AUCt-ss, Cmax-ss, and the minimum plasma concentration at steady state (Cmin-ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and amprenavir. The inactive S-enantiomer AUCt-ss, Cmax-ss, and Cmin-ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject. CONCLUSION: No a priori adjustment in methadone dosage is required during coadministration with amprenavir as there is only a small effect on R-methadone exposure and no evidence of opioid withdrawal.     

Acute effects of short-term subcutaneous terbutaline on theophylline disposition

Summary Theophylline and subcutaneous terbutaline are frequently used concurrently in the management of acute asthma. Recent evidence demonstrating a reduction in theophylline serum concentrations during concomitant oral terbutaline therapy prompted our evaluation of subcutaneous terbutaline's effect on theophylline pharmacokinetics. Using a randomized, placebo controlled, crossover design, the disposition of a single oral theophylline dose (7 mg/kg) was studied in eight healthy, adult males before and after repeated subcutaneous administration of terbutaline (0.25 mg). Two-way analysis of variance revealed no significant difference in elimination rate constant (ke), area under the concentration-time curve (AUC), or apparent oral clearance (CL/F) of theophylline following terbutaline administration. These results indicate that subcutaneous administration of terbutaline does not alter the pharmacokinetics of single, oral doses of theophylline in adults.     

Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release

We evaluated the acute hemodynamic effects of doxorubicin in the open-chest dog. Doxorubicin at doses of 1-4 mg/kg administered over 2 min produced profound hemodynamic changes that were similar to those produced by histamine. These changes persisted despite administering the drug as a slow infusion. Histamine release in peripheral tissues was documented by a marked increase in venous histamine levels following doxorubicin administration. The heart extracted histamine during a period when arterial levels were increased, as indicated by consistently low coronary sinus/aortic ratios. Secondary catecholamine release occurred in response to histamine and histamine-mediated hemodynamic effects. Immunoreactive prostaglandins E and F were increased in coronary sinus blood beginning 30 min after the initiation of a continuous infusion of doxorubicin, and increased slowly thereafter. H1- and H2-receptor blockade with diphenhydramine and cimetidine prevented the early (2-30 min postinfusion) effects of doxorubicin, and combined histaminergic and adrenergic blockade prevented the late effects. A dose of doxorubicin (1 mg/kg) that released histamine and catecholamines produced primary cardiac effects acutely and a cardiomyopathy when administered chronically. The release of vasoactive substances could be part of the pathogenetic mechanism of anthracycline cardiomyopathy.     

Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.