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Biomedical subjects

A M Stoysich

Publications and source records attributed to A M Stoysich.

7 recordsLinked to original sources
PubMed1996

Pharmacodynamics and pharmacokinetics of A-80556 using microdialysis in a Streptococcus pneumoniae meningitis model.

Using microdialysis in a rabbit model of Streptococcus pneumoniae meningitis, the pharmacokinetics and pharmacodynamics of a new fluoroquinolone, A-80556, were determined. A-80556 (10 mg/kg iv) was administered to four rabbits. Saline was given to four separate control animals. A microdialysis probe perfused the CSF (2 microL/min) and effluent was collected at 0-0.25, 0.25-1, 1-2, 2-4, and 4-6 h after injection of A-80556. Seven blood samples were collected and analyzed by HPLC. At 0, 2, 4 and 6 h 300 microL of CSF was withdrawn for pharmacodynamic measurements. Plasma A-80556 concentrations demonstrated AUC0-infinity 2.40 +/- 0.272 micrograms.h/mL; T1/2 beta 1.07 +/- 0.011 h; Vd 6.35 +/- 0.50 L/kg; and Cl1 4.23 +/- 0.48 L/h.kg. Penetration into the CSF was 18.21%. Pharmacodynamics using time-kill curves showed a 3-log reduction in bacterial counts in CSF at 2 h after administration continuing for the remaining four hours of the experiment. These results demonstrate that microdialysis can be used for determination of drug penetration and efficacy in experimental S. pneumoniae meningitis.

Animals↗
PubMed1996

Further elucidation of pharmacokinetic interaction between diltiazem and warfarin.

Diltiazem and warfarin are both highly protein-bound providing the opportunity for a protein-binding displacement interaction to occur. Additionally, diltiazem has demonstrated the ability to inhibit the metabolic clearance of hepatically cleared drugs (e.g. warfarin). We evaluated these pharmacokinetic mechanisms for a potential interaction. A single warfarin 25 mg oral dose was given with and without oral diltiazem 30 mg 3 times daily to 20 healthy male volunteers in a randomized crossover design with a washout period of at least 6 days. Serial blood samples for INRs and free and total warfarin concentrations were obtained over 144 hours after each warfarin dose. Free fraction was extracted by equilibrium dialysis and free and total warfarin concentrations were analyzed by HPLC. Anticoagulation was assessed using AUC0-6,INR (days). Diltiazem was found not to potentiate anticoagulation by warfarin. Furthermore, warfarin protein binding displacement did not occur. Diltiazem inhibited both free and total warfarin clearance, though not statistically significant. Although slightly inhibiting metabolism of warfarin, based on warfarin clearance, diltiazem did not increase warfarin's anticoagulant effect making it an acceptable addition to therapy if required.

Adult↗
PubMed1992

Impact of food on the bioavailability of encainide.

The bioavailability of drugs that undergo extensive presystemic hepatic metabolism may be increased by concomitant ingestion with food. The effect of food on the bioavailability of encainide, a class IC antiarrhythmic agent, was evaluated in 14 healthy subjects in this randomized crossover study. The subjects received encainide 35 mg every 8 hours for 7 days and were randomized to receive their test dose of encainide with food or after an overnight fast. Encainide area-under-the-concentration versus time curve (AUCs) were detectable in 3 of 14 subjects after fasting and in 7 of 14 after feeding. Although food increased the mean encainide AUC by more than threefold, this increase did not reach statistical significance because of the large number of subjects with indeterminate encainide AUCs. Food did significantly increase the AUC of O-demethyl-encainide (ODE), but not the AUC of methoxy-O-demethyl-encainide (MODE). Despite the increase in ODE AUC, no significant effect on the surface electrocardiogram 2 hours after dose administration could be detected. Food may increase the bioavailability of encainide and one of its active metabolites (ODE). The clinical relevance of this pharmacodynamic effect warrants further evaluation.

Adult↗
PubMed1992

Efficacy and safety of early versus late initiation of warfarin during heparin therapy in acute thromboembolism.

There is no universally accepted approach to the initiation of systemic anticoagulant therapy. In an open, randomized study, two anticoagulant regimens that differed only in the timing of warfarin therapy after the start of heparin were compared. We randomized 119 patients with acute thromboembolic events to receive warfarin either within 48 hours of the start of heparin (early group, n = 63) or 96 hours or later after the start of heparin (late group, n = 56). Heparin was given as a 5000 IU bolus as a constant infusion titrated to maintain the activated partial thromboplastin time at 1.5 to 2 times control values. Warfarin was started at 10 mg daily for 3 days and the dose was titrated to maintain the prothrombin time at 1.2 to 1.5 times control values. There were no significant differences between the early and late warfarin groups with regard to age, sex, indication for anticoagulation, heparin dose, mean activated partial thromboplastin time during heparin, warfarin dose at discharge, length of warfarin therapy before discharge, bleeding, recurrent thromboembolic events, or mortality rates. Time to the start of warfarin after heparin was 31 hours and 108 hours in the early and late groups, respectively. Length of hospitalization, hospital costs, and the incidence of heparin-induced infusion phlebitis and thrombocytopenia were significantly less in the early group compared with the late group. Early initiation of warfarin after heparin is safer, less expensive, and as effective as the late initiation of warfarin.

Aged↗
PubMed1991

Influence of mexiletine on the pharmacokinetics of theophylline in healthy volunteers.

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two-way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained-release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2 beta, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline-mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0-24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine therapy.

Adult↗
PubMedDate not supplied

Cost-minimization analysis of initial antihypertensive therapy in patients with mild-to-moderate essential diastolic hypertension.

In addition to efficacy and safety, the cost of therapy has become an increasingly important factor to consider when selecting drugs to treat patients with mild-to-moderate hypertension. However, acquisition prices alone do not determine the total cost of therapy. To better assess total costs, we conducted a systematic, retrospective, cost-minimization analysis of drugs used to treat 673 patients with newly diagnosed, mild-to-moderate (> 95 to < 110 mmHg) diastolic hypertension between the years 1985 and 1992. Patients included in the study had started antihypertensive monotherapy, and a minimum of one dose titration was required before adding another antihypertensive agent to the regimen. A patient had to have a diastolic blood pressure of < or = 90 mmHg while undergoing therapy to be included in the analysis. Drug classes included diuretics, beta-adrenergic blockers, centrally acting alpha 2-agonists, alpha 1-adrenergic blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Costs, adjusted to 1992 price levels, were analyzed for 32 individual agents for each of the following five cost variables: initial drug acquisition, supplemental drug acquisition, laboratory monitoring, clinic visits, and treatment of side effects. Mean total costs per patient for all five variables by drug class were $895 for beta-blockers, $1043 for diuretics, $1165 for centrally acting alpha 2-agonists, $1243 for ACE inhibitors, $1288 for alpha 1-blockers, and $1425 for calcium channel blockers. However, costs within each class varied considerably. Acquisition cost was often a poor predictor of the total cost of treatment. Therefore, acquisition cost must be considered in conjunction with a number of outcome variables to assess the true cost of antihypertensive therapy.

Adrenergic alpha-Agonists↗