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 t 1/2s 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.

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 evidence 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.

Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.

OBJECTIVE: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. METHODS: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. RESULTS: A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml). CONCLUSIONS: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.

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 greater than or equal to 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 greater than or equal to 40% (p less than 0.001), we believe that platelets should be monitored frequently when patients are treated with heparin for ischemic cerebrovascular disease.

The use of the Computerized Neuropsychological Test Battery (CNTB) in an efficacy and safety trial of BMY 21,502 in Alzheimer's disease.

BMY 21,502 is a nootropic which protects memory and enhances long-term potentiation according to preclinical findings. Alzheimer's disease (AD) patients who were diagnosed by DSM-III-R and NINCDS-ADRDA criteria were enrolled in a 12-week double-blind investigation of BMY 21,502 vs. placebo at 300 mg tid. The study design included a 1-week placebo lead-in and a 4-week placebo washout in addition to the 12-week double-blind treatment period. Efficacy was assessed with the Alzheimer's Disease Assessment Scale (ADAS) and the Computerized Neuropsychological Test Battery (CNTB) at weeks 4, 8, 12, and 16. Clinical Global Impression (CGI) assessments were also performed biweekly. Sixty-nine patients (28M, 41F; mean age 72 years, range 54 to 92 years) were enrolled in the study. Baseline Mini-Mental Status Examination (MMSE) scores ranged from 16 to 26 (mean 23.5) in patients on active drug (n = 34), and from 15 to 26 (mean 22.5) in placebo patients (n = 35). Baseline efficacy scores were comparable for drug and placebo patients (p > 0.05). Twelve (35%) patients who received BMY 21,502 withdrew from the study, 8 (24%) due to adverse events. Three (9%) patients who received placebo withdrew from the study, all due to adverse events. Patients on active drug who were valid for analysis of efficacy (n = 22) showed a mean decrease in ADAS of -1.5 at week 12, vs. a mean change of -0.5 in patients who received placebo (n = 32), although there was no significant difference between the two (p > 0.05). Correlations between the CNTB summary scores and ADAS cognitive subscores were, nevertheless, highly significant at baseline (r = -0.83, p = 0.0001) and week 12 (r = -0.83, p = 0.0001). Correlations between the word list learning, spatial, and naming subtests of the ADAS and CNTB were also highly significant (p = 0.0001). Although modest, the findings for active drug vs. placebo response in this study suggest that BMY 21,502 should be further investigated, with a larger study population, in order to fully determine the compound's potential efficacy.

Effect of sucralfate on the absorption and pharmacokinetics of chlorpropamide.

This study compared the pharmacokinetics of chlorpropamide (C) when administered alone, or in combination with sucralfate (S) to evaluate whether a drug-drug interaction exists between these two agents in vivo. A two-way, randomized, cross-over study was performed in 12 healthy male volunteers who received 250 mg C alone or were pretreated with S qid for two days and then received a single 250-mg dose of C with S on day 3 and continued to take sucralfate throughout the day while serial blood samples were drawn. High-performance liquid chromatography determination of plasma concentrations found there to be no statistically significant differences in maximum concentration, time to maximum concentration, elimination rate constant, or area under the concentration-time curve from 0 to 96 hours. However, there was a statistically significant difference in the area under the curve from 0 to infinity data (P less than .05). The authors conclude that there appears to be no drug interaction between sucralfate and chlorpropamide when given concurrently; however, a trend towards less drug availability was seen that may warrant a future multiple-dose study to further evaluate the significance of this finding.

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.

The utility of salivary amylase as an evaluation of M3 muscarinic agonist activity in Alzheimer's disease.

1. In this double-blind, placebo-controlled phase I study of the safety/tolerance of two doses of xanomeline tartrate (100 mg and 115 mg tid) given to 12 AD patients, the authors measured serum amylase, fractionated into pancreatic and salivary isoenzymes, as a potential marker for M3 activity associated with maximally tolerated dose (MTD). 2. MTD of xanomeline was determined to be 100 mg tid based on intolerable adverse events at 115 mg tid. One patient at the 115 mg tid level presented with moderate hypersalivation and salivary amylase levels 400% of baseline. 3. Overall amylase results were not significant, however a trend in the results for salivary amylase in the 115 mg panel suggests that salivary amylase may be a useful marker for M3 activity.

Benzodiazepine utilization in a family medicine residency program.

A study was conducted to determine the benzodiazepine-prescribing habits of residents in a family medicine training program. Data were collected from medication profiles of all patients seen at the Family Practice Center from July 1975 to February 1981. Additional demographic data (ie, age, sex) were collected on patients prescribed benzodiazepines, and prescribing behavior was validated according to the Psychopharmacological Screening Criteria Development Project. Of 7,802 patients only 110 (1.4 percent) had been prescribed a benzodiazepine. Female patients (61 percent) received benzodiazepines more frequently than did male patients (39 percent). Diazepam, with 94 prescriptions, was the most frequently utilized benzodiazepine, and flurazepam was next with 18 prescriptions. Eighty-four percent of the benzodiazepines were prescribed for valid indications. Minimal or no documentation could be determined for the remaining 16 percent. Significantly higher dosages of diazepam were prescribed for skeletal muscle injury or spasm than for anxiety neuroses. Seventy-one percent of the patients prescribed diazepam and 78 percent of the patients prescribed flurazepam received therapy for less than one month's duration. Data indicate that benzodiazepines were prescribed relatively infrequently at the Family Practice Center.

Management of fibromyalgia, a distinct rheumatologic syndrome.

The pathophysiology and management of fibromyalgia, a unique nonarticular rheumatologic syndrome characterized by diffuse musculoskeletal aches and pains, stiffness, discrete tender points at typical soft-tissue sites, and a characteristic sleep disturbance, are reviewed. The prevalence and incidence of fibromyalgia are not known, but it is one of the most common conditions seen by rheumatologists (after degenerative joint disease and rheumatoid arthritis). It was previously thought to involve inflammation of fibrous intermuscular septa and is sometimes referred to in the literature as fibrositis. It is not primarily psychogenic, but psychological factors may contribute. The tender points are the key to diagnosis. Fibromyalgia may be classed as primary (when no underlying disease is present) or secondary (when an associated condition exists). The pathophysiology of fibromyalgia is unknown but appears to involve complex interactions of central neurotransmitters with a relationship to pain perception, mood, and sleep. Treatment is empiric; nondrug treatment involving education, relaxation, and increased physical activity is essential. Few controlled trials of drug therapy have been conducted. Analgesics, anti-inflammatory drugs, phenothiazines, tricyclic antidepressants, and the tricyclic muscle relaxant cyclobenzaprine have been used; low doses of amitriptyline or cyclobenzaprine provide increased control of pain and mood.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Comparison of quantitative methodologies to define chronic pressure ulcer measurements.

The objective of this study was to evaluate and compare various methodologies of measuring the characteristics of pressure ulcers. This prospective, four-week, follow-up study consisted of 20 patients, of whom 17 completed the study. Each patient had at least one full-thickness pressure ulcer (surface area between 1.2 and 61.6 cm2) that had been present for at least four weeks. The ulcers were assessed weekly for four weeks using the following techniques: direct measurement (length, width, and depth), tracing of the ulcer outline onto transparent material, standard photography, and volume measurement. Computer-assisted planimetry from the tracings and photographs, and calculations from the direct measurements determined ulcer areas. Each technique estimating ulcer area gave similar results; however, the areas obtained from the direct measurements slightly over-estimated the areas when compared with the areas obtained by computer-assisted planimetry (mean difference of about 1.5 cm2). Areas obtained from the photographs were more variable than the other measurement techniques. Volumes calculated from bedside measurements were consistently larger than those calculated by jeltrate impression (mean difference of 4.0 cm3). While all the measurement methodologies gave similar and reproducible results, the areas obtained from the photographs were more variable than the areas obtained from the other measurement techniques. The photographic measurements could be improved either by tracing the ulcer outline at the bedside onto the photograph shortly after being taken, or by drawing an outline of the ulcer margin directly on the patient's skin just before taking the photograph.

Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients.

The pharmacokinetics of single and co-administered didanosine and stavudine were evaluated in 10 HIV-seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1 and 2. Beginning on day 3, subjects received the same doses of both drugs simultaneously every 12 h for nine doses. Serial blood and urine samples were obtained on single dose days 1 and 2, first simultaneous dose day 3, and last simultaneous dose day 7. The average maximum plasma concentrations of didanosine and stavudine before and after simultaneous administration were 422 +/- 184 (s.d.) ng ml-1 and 603 +/- 160 (s.d.) ng ml-1, and 419 +/- 153 (s.d.) ng ml-1 and 726 +/- 188 (s.d.) ng ml-1, respectively. Didanosine and stavudine AUC values before and after simultaneous administration were 615 +/- 170 (s.d.) ng ml-1 h and 1246 +/- 230 (s.d.) ng ml-1 h, 637 +/- 155 (s.d.) ng ml-1 h and 1326 +/- 267 (s.d.) ng ml-1 h, respectively. No significant changes in maximum plasma concentration, AUC elimination half-life, or renal clearance of didanosine and stavudine were observed when the drugs were administered simultaneously. Co-administration of didanosine 100 mg and stavudine 40 mg is well tolerated and the drugs do not interact pharmacokinetically.