Steven A. Myre

Hepatitis B vaccination

Alcoholics are at risk to develop hepatitis B infections, chronic active hepatitis, and even hepatoma. Hence, immunization with hepatitis B vaccine is recommended. However, immune abnormalities may coexist which alter their responsiveness to vaccination. This study compares the immune response to this vaccine in controls (group I), alcoholics without overt liver disease (group II), and alcoholics with clinical liver disease (group III). By the seventh month after the initial vaccination, 89% in group I, 70% in group II, and 18% in group III had a response >36 RIA units. The magnitude of the response was significantly different in groups I, II, and III (19,456 vs 8,326 vs 153 RIA units, respectively; P <0.05, group I vs III). In those who did not respond, a significant (P < 0.02) lower helper/inducer (T4)class of lymphocytes was observed as compared to patients who exhibited an adequate response. These observations suggest: (1) that the response to hepatitis B vaccine is a T-cell-dependent event and (2) that in this population, using the existing vaccine, postvaccination evaluations of antibody concentrations are needed before protection against hepatitis B infection can be assumed.

Ancrod Causes Rapid Thrombolysis in Patients with Acute Stroke

Clot lysis is desirable in patients with thrombi in arteries and arterioles by a safe rapidly-acting thrombolytic agent. Ancrod cleaves fibrinogen; the resulting circulating ancrod-fibrin stimulates fibrinolysis. Ancrod action and effect were studied in 20 patients with acute developing stroke in a double-blind, placebo-controlled study. Patients were randomly assigned to one of two treatment groups, and received either normal saline or ancrod 0.5 mu/kg in normal saline administered as a constant-rate intravenous infusion over 6 hours. Subsequent doses of ancrod (or saline placebo) were determined daily thereafter for a total treatment period of 7 days. Neither bleeding nor re-thrombosis occurred within the 90 day follow-up period. That ancrod acted rapidly was shown by a significant decrease in functional plasminogen activator inhibitor (PA-I) within 60 minutes, and by significant elevations of fibrin(ogen) degradation products (FDP) and D-dimer within 3 and 4 hours. The biological effect of fibrinolysis in ancrod infused patients was demonstrated by a greater improvement in stroke score when compared to those infused with saline.

Pharmacokinetic Interactions with Calcium Channel Antagonists (Part II)

SummaryCalcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs.

Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p greater than 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p greater than 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p less than 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p greater than 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

Effect of Co-trimoxazole and Sulfamethoxazole on Serum Creatinine in Normal Subjects

Summary: Significant elevation of serum creatinine concentration and reduction in creatinine clearance have been reported following cotrimoxazole therapy in patients with normal and impaired renal function. Both components of co-trimoxazole, trimethoprim and sulfamethoxazole, have been proposed as the causative agent. Ten healthy male volunteers were treated for seven days with either sulfamethoxazole (5 subjects) or co-trimoxazole (5 subjects) in the usual recommended doses. After a one-week recovery period, the subjects were allocated to the alternate treatment regimen for another seven days. Cotrimoxazole caused a mean elevation in the serum creatinine concentration of 0.12 mg/dl over the base-line value (p < 0.05). Sulfamethoxazole produced an insignificant fall in the serum creatinine level. The increase in the serum creatinine concentration induced by co-trimoxazole was reversed seven days after discontinuation of the drug. From this study, it can be concluded that either trimethoprim alone or an interaction between trimethoprim and sulfamethoxazole is responsible for the increase in serum creatinine observed following co-trimoxazole therapy and that sulfamethoxazole alone is not the causative agent.

Uptake of trimethoprim by renal cortex.

The purpose of this study was to examine the mechanisms involved in the uptake of the urinary antibacterial drug trimethoprim by incubated slices of rat renal cortex. Concentration-dependent studies of the uptake process demonstrated that a saturable component was involved. The results of inhibitor studies as well as the time-course pattern support the conclusion that at least two processes are involved in the uptake of trimethoprim. These include active transport via the organic cation system, accounting for about 40% of the total uptake, and a second component that continues to operate under conditions of inhibited cellular metabolism. Chromatographic examination of post-incubation bathing medium and slice extracts failed to demonstrate renal cortex metabolism of trimethoprim.

Intravenous Ampicillin Pharmacokinetics in the Third Trimester of Pregnancy

The pharmacokinetics of a single dose of intravenous ampicillin were studied in nine patients during their third trimester of pregnancy. Each volunteer was given either 500 mg (5.7-8.8 mg/kg) or 1 g (15.4-21.4 mg/kg) of sodium ampicillin by rapid infusion. Postinfusion plasma concentration-time curves followed biexponential decay in all subjects. Calculated parameters included a mean plasma distribution volume of 177.1 +/- 97.5 ml/kg, tissue or peripheral distribution volume of 246.2 +/- 143.9 ml/kg, elimination half-life of 1.60 +/- 0.51 h, and total body clearance of 4.59 +/- 1.48 ml/min/kg. Dose-dependent disposition was not observed. Gestation-specific drug therapy research during pregnancy is discussed.

Theophylline: constant-rate infusion predictions.

Summary This study was undertaken to evaluate a method of prospectively estimating appropriate aminophylline infusion rates in acutely ill, hospitalized patients with bronchospasm. Steady-state serum theophylline concentrations (Css), clearances (Cl), and half-lives (t1/2) were estimated by the Chiou method using serum concentrations obtained 1 and 6 h after the start of a constant-rate intravenous aminophylline infusion in 10 male patients averaging 57 years of age. Using an enzyme-multiplied immunoassay (EMITR system for theophylline analysis, pharmacokinetic estimations were excellent for Css (r = 0.9103, p < 0.01) and Cl (r = 0.9750, p < 0.01). The mean estimation errors were 9.4% (range 0.8–21.5) for Css and 12.3% (range 1.3–28.0) for Cl. There was no correlation between patient age and Cl. This method is useful for rapidly individualizing aminophylline therapy in patients with acute bronchospasm.

Effects of Controlled Liver Injury and Ethanol Pretreatment on Monoethylglycine Xylidide Formation in the Rat

Measuring the monoethylglycine xylidide (MEGX) serum level 15-30 min after intravenous administration of lidocaine has been shown to be an accurate predictor of early success in liver transplants. This study evaluates the changes in the MEGX formation test associated with changes in liver mass and ethanol pretreatment in a rat model. Mean MEGX levels were significantly higher for the sham-operated group versus each of the partially hepatectomized groups at 15, 30, and 45 min after injection. No differences between mean MEGX levels for either of the surgically treated groups could be distinguished. Ethanol pretreatment and body weight had no effect on MEGX levels at any of the time points tested in this model.