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WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.

WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a tmax of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3-week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed-effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two-compartment open model with first-order absorption, a lag time, and first-order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory E max model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition >10% at the time of the trough.

Study Design. This study is a prospective, controlled study of the effect of intraoperative and postoperative blood loss during spinal surgery on serum cefazolin level. Objectives. To determine what effect, if any, intraoperative blood loss has on serum antibiotic levels, and to determine if adjustment of the dose or dose interval is appropriate in operative cases of significant blood loss. Summary of Background Data. The problem of infection at the operative site after posterior spinal fusion with internal fixation is significant. It commonly has been accepted that blood loss results in a more rapid clearance of antibiotic. Methods. Nineteen patients scheduled for elective spinal fusion with internal fixation were enrolled in this study. Each patient served as his or her own control. Baseline cefazolin clearance was determined the week before surgery. Cefazolin clearance again was determined intraoperatively. Blood loss was recorded throughout the procedure. Results. The mean blood loss was 650 mL. There was no significant difference between preoperative and intraoperative cefazolin clearance, and there was no correlation between blood loss and cefazolin level. Conclusions. It is not necessary to give cefazolin at a dosing interval of less than 4 hours with blood losses of up to 1200 mL. This will maintain the antibiotic concentration well above the minimum inhibitory concentration.

Methemoglobin (MHb) formation can be a clinically significant and dose-limiting side effect of 8-aminoquinoline antimalarials. MHb may also protect against cyanide poisoning. A two-compartment pharmacokinetic model, linked to a sigmoid Emax pharmacodynamic model, was developed to predict the MHb levels after administration of 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[(3- trifluoromethyl)phenoxy] quinoline succinate (WR 238605 succinate), a primaquine analogue. Six healthy male beagle dogs received four daily doses of 6.0 mg/kg (base) orally. Forty plasma drug concentrations and 19 MHb levels (effect) were determined over 7 weeks on each dog. Compartmental and noncompartmental pharmacokinetic and parametric and nonparametric pharmacodynamic analyses were performed. Model parameters (mean +/- SD) included a Vss/f of 18.5 +/- 2.8 L/kg, CL/f of 83 +/- 24 ml/hr/kg, terminal elimination t1/2 of 169.7 +/- 52.0 hr, t1/2keo of 123.0 +/- 22.4 hr, an Emax of 31.3 +/- 15.9% MHb, an EC50 of 596 +/- 128 ng/ml, and a sigmoidicity coefficient (n) of 1.94 +/- 0.47. The model was then validated in three additional dogs given three different dosing regimens. It predicted the peak plasma concentrations and MHb levels and the times of their occurrence well. This model could be useful for dose and sampling time selection in further animal studies and initial human phase I clinical testing.

The effect of intraoperative blood loss on serum levels of cefazolin in patients being managed with total hip arthroplasty was studied. Eighteen patients, thirteen men and five women, with a mean age of sixty-five years (range, forty to eighty-five years) were enrolled in the study. Fifteen had a primary total hip arthroplasty and three, a revision. Each patient served as his or her own control. Baseline clearance of cefazolin was determined at a minimum of forty-eight hours before the operation. Each patient received one gram of cefazolin intravenously. Serial serum concentrations were determined from specimens drawn at zero, five, ten, twenty, thirty, sixty, 120, 240, and 300 minutes after administration. Fifteen minutes before the skin incision was made, each patient again received one gram of cefazolin intravenously. Serum samples were collected at the same time-intervals, and the serum levels of cefazolin were determined with use of capillary electrophoresis. Data regarding intraoperative blood loss as well as replacement of fluid and blood were recorded. The administration of the antibiotic, retrieval of the serum samples, and estimation of the blood loss were performed by the same person in the same manner for all patients. The preoperative and intraoperative creatinine clearances (mean and standard deviation), estimated with use of the formula of Cockcroft and Gault, were 62.06 +/- 21.28 and 74.02 +/- 24.75 milliliters per minute, respectively. The amount of intraoperative blood loss averaged 1137 +/- 436 milliliters (range, 675 to 2437 milliliters). The preoperative and intraoperative cefazolin clearances averaged 0.49 +/- 0.21 and 0.52 +/- 0.30 milliliter per minute per kilogram, respectively. During joint replacement, the commonly accepted interval between doses of cefazolin is four hours. In the present study, the serum level of cefazolin at four hours was forty-five micrograms per milliliter. This corresponds to an osseous concentration that well exceeds the minimum inhibitory concentration for Staphylococcus aureus, which is 0.5 microgram per milliliter. This study suggests that, with blood losses of less [corrected] than 2000 milliliters, it is not necessary to administer cefazolin at intraoperative intervals of less than four hours in order to maintain a concentration of antibiotics that is higher than the minimum inhibitory concentration for the most common infecting organisms.

The prophylactic efficacy of WR 238605, a primaquine analog, was studied with a human Plasmodium falciparum challenge model. A single oral dose of 600 mg, administered 1 day prior to challenge, successfully protected three of four subjects. The fourth subject developed mild, oligosymptomatic malaria on day 31, with drug concentrations one-half of those in the protected individuals. WR 238605 appears to be a promising prophylactic drug for P. falciparum malaria.

Right ventricular hypertrophy (RVH) is the most frequent abnormality in children with heart disease. We have developed a computer electrocardiogram (ECG) diagnosis program to evaluate new scaler electrocardiographic criteria for the diagnosis of this condition in children. The overall performance of our program was comparable to that of a pediatric cardiologist. Computer program diagnosis was correct in 93% of 60 individuals using standard criteria and in 97% using our newly developed area criteria. The cardiologist's ECG diagnosis in the same individuals was correct in 99%. The sensitivities of our two new criteria, the R S area ratio in lead V1 and the R wave area in lead V1, were greater than currently used criteria for the diagnosis of RVH. Computer-derived electrocardiographic measurements, such as areas, can improve the accuracy of the ECG diagnosis of RVH.