Randall D. Seifert

Heparin kinetics: Variables related to disposition and dosage

A method to determine heparin kinetics and dosage requirements was examined in 20 patients with active thromboembolic disease. Pretreatment heparin sensitivities were determined to establish the relationship between heparin concentration and activated partial thromboplastin times (APTTs). After an initial bolus dose, serial APTTs were measured, heparin concentrations were estimated, and kinetic determinations followed. Heparin elimination rate, distribution volume, and clearance were used to calculate dosage requirements. There was a 500% range in pretreatment heparin sensitivities. Smokers had more rapid heparin elimination rates and t½s than nonsmokers did. Men had more rapid drug clearances than women did. Body weight was related to heparin dosage requirements. Patients treated early after onset of symptoms required higher doses than patients in whom treatment was delayed. A multiple regression model was developed for heparin dosage requirements from body weight, sex, delay between onset of symptoms and treatment, and smoking. This statistical model explained 78% of the variance in heparin requirements.

Heparin‐induced thrombocytopenia in patients with cerebrovascular ischemic disease

We studied 137 patients who were treated with heparin for cerebral infarction (73), partially reversible ischemic neurologic deficit (22), or transient ischemic attack (42). Platelet counts were performed before therapy, twice weekly, and at cessation of therapy. Platelets decreased in 118 patients (86%). In 21 (15.3%), platelets dropped ≥40%; 9 of 14 new ischemic events and three of six deaths occurred in this group of patients. Because there was a significant association between poor outcome and platelet drop ≥40% (p < 0.001), we believe that platelets should be monitored frequently when patients are treated with heparin for ischemic cerebrovascular disease.

Effect of cardiopulmonary bypass on cefazolin disposition

Cefazolin kinetics was studied in 8 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass (CPB) surgery. PREOP (48.6 ml/min) and POSTOP (46.6 ml/min) total body clearances were of the same order and both were greater than the SURG (27.4 ml/min) total body clearance. Since cefazolin is almost entirely eliminated by the kidney, the lower SURG clearance is a result of reduced renal elimination, as confirmed by measuring cefazolin SURG (28.7 ml/min) and POSTOP (52.9 ml/min) renal clearance. The reduction in cefazolin renal elimination was the same throughout the surgical procedure, including the period of extracorporeal circulation. Cefazolin distribution was altered by the operative procedure as evidenced by a higher SURG steady‐state volume of distribution. This increase in apparent cefazolin distribution volume brought about by surgery was not seen with cephalothin, which was investigated by us in a similar group of patients. The different effect of CPB surgery on cefazolin and cephalothin distribution may be due to differences in plasma protein binding.

Hospital acquired gram-negative pneumonias: response rate and dosage requirements with individualized tobramycin therapy.

Individualized tobramycin therapy was systemically evaluated in 26 patients with gram-negative pneumonias involving Pseudomonas aeruginosa and other multiple antibiotic-resistant pathogens. Patient prognoses were classified by underlying diseases, and response was determined according to previously established criteria. Twenty-three patients (88%), including all 11 cases involving multiple antibiotic-resistant pathogens and 12 of 15 cases involving Pseudomonas aeruginosa, successfully responded to individualized tobramycin therapy. Tobramycin daily dosages and pharmacokinetic parameters demonstrated a wide interpatient variability. Measured peak and trough serum concentrations resulting from individualized dosage regimens closely matched desired peak and trough concentrations. Clinical ototoxicity or nephrotoxicity were not observed. Individualizing dosage regimens was an important factor in obtaining therapeutic serum concentrations that may influence treatment response to tobramycin therapy.

Systematically Individualizing Tobramycin Dosage Regimens

Tobramycin dosage regimens were individually calculated from serum concentration-time data in 64 patients. Tobramycin pharmacokinetic parameters and dosage requirements demonstrated wide interpatient variation. The tobramycin half-life varied from 0.5 to 8.6 hours in patients with normal serum creatinines. The mean (+/- S.D.) distribution volume was 0.22 (+/- 0.09) liter/kg for all patients. Dosage requirements were higher for the younger patients, however, considerable variability existed within age groups. In patients with normal serum creatinines, an 8-hour dosing interval was optimal in only 17 of the 46 patients. A multiple regression model using age, weight, and creatinine clearance could explain only 44.2% of the variance in tobramycin clearance. Measured steady-state peak and trough concentrations compared favorably with desired peak and trough concentrations. The mean (+/- S.D.) desired peak was 7.2 (+/- 1.8) microgram/ml, and the mean (+/- S.D.) measured peak was 7.1 (+/- 2.0) microgram/ml. The mean (+/- S.D.) desired trough was 1.1 (+/- 0.9) microgram/ml, and the mean (+/- S.D.) measured trough was 1.3 (+/- 0.8) microgram/ml. Many patients required dosage regimens exceeding those commonly recommended; however, no cases of ototoxicity or nephrotoxicity were encountered. This model proved successful in calculating dosage regimens of tobramycin to obtain optimal serum concentrations.

Acetylcholinesterase inhibition by zifrosilone: Pharmacokinetics and pharmacodynamics

To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers.

Clinical Experience with MDL 73,745; Pharmacokinetics, Pharmacodynamics, and Clinical Tolerance in Normal Volunteers

Alzheimer’s disease (AD) represents one of the major debilitating illnesses facing our elderly population today (Jellinger et al., 1990). The magnitude of the financial and social costs associated with this progressive disorder is expected to increase dramatically as the numbers of people reaching their seventies, eighties and nineties continue to grow (Evans et al., 1989). There is clearly a pressing need for new therapies; those which can bring about symptomatic relief, those which can slow down the disease process, and those that can prevent onset of the disease itself. One clinical strategy being explored to relieve symptoms of dementia is to increase levels of the neurotransmitter, acetylcholine (ACh). The scientific rationale is based on the known cholinergic deficit found on post mortem examination (Perry et al., 1978) and clinical observations of improvement using acetylcholinesterase (AChE) inhibitors in the setting of cholinergic deficit (Thal et al., 1989; Davis et al., 1992).