Nerve agents: a review.

Nerve agents produce neuromuscular blockade and convulsions in exposed humans. Military personnel in areas of potential exposure take prophylactic pyridostigmine. They are instructed to self-administer atropine and pralidoxime at the first sign of nerve agent toxicity. The key to treatment of nerve agent poisoning is the administration of atropine in doses larger than is customary in most other disorders, repeated as often as needed. Mechanical ventilation may be required. Convulsions are treated with diazepam, but only after atropine has been administered.

Capreomycin kinetics in renal impairment and clearance by hemodialysis.

The single-dose kinetics of capreomycin are described for 12 renal patients and seven healthy control subjects. Creatinine clearances (CrCl) ranged from zero to 121 ml/min. After single-dose intravenous infusions, mean +/- SD capreomycin clearance values (L/kg/h x 10(-2)) were 0.558 +/- 0.160 for the dialysis group (n = 4, CrCl = 1.4 +/- 1.9), 1.77 +/- 0.45 for the moderate renal group (n = 3, CrCl = 25 +/- 5), 2.82 +/- 1.52 for the mild renal group (n = 4, CrCl = 46 +/- 5), and 5.73 +/- 1.54 for the normal renal group (n = 7, CrCl = 109 +/- 11); p less than 0.01, using analysis of variance. The correlation between capreomycin clearance and CrCl was r = 0.90. Hemodialysis cleared clinically significant amounts of capreomycin. These data imply that capreomycin maintenance doses need to be reduced for renal patients.

Comparison of sustained-release quinidines given twice daily to patients with ventricular ectopy.

To compare the steady-state kinetic profiles and ectopy-suppression rates of two sustained-release forms of quinidine with those of a conventional quinidine preparation, 18 patients with ventricular ectopy were studied in randomized crossover fashion. The drugs were conventional quinidine sulfate 300 mg q6h, sustained-release quinidine sulfate 600 mg q12h, and sustained-release quinidine gluconate 648 mg q12h. Following baseline electrocardiographic ambulatory monitoring, each drug was given for three days, with repeat ambulatory monitoring and serial plasma drug level determinations performed on the third day. There were no washout periods between treatments. Plasma quinidine levels were assayed by both enzyme multiplied immunoassay technique (EMIT) and quinidine-specific high-performance liquid chromatography (HPLC) methods. Using actual steady-state HPLC values, there were no differences in the area under the plasma concentration-time curve (AUC) among the three treatments; the dose-corrected AUC was greater for quinidine gluconate than for the other two preparations. Using EMIT values, mean plasma quinidine levels from the conventional quinidine sulfate regimen were greater during the last five hours of the 12-hour study interval. A consistently strong inverse relationship between EMIT plasma quinidine levels and hourly ectopy rates was present in only one of eight (13%) responders. Diurnal variation of quinidine kinetics was observed after two days of each treatment; trough values at midnight were slightly lower than trough values at noon. Among patients demonstrating at least 70% suppression of premature ventricular contractions (PVCs), there were no differences in ectopy rates or ectopy-suppression rates among treatments. Dosing sustained-release quinidine sulfate 600 mg or quinidine gluconate 648 mg q12h was clinically acceptable in the small number of responders studied.

Quinidine assays: enzyme immunoassay versus high performance liquid chromatography.

Plasma quinidine results determined by enzyme multiplied immunoassay (EMIT) (Syva) were compared with results from a quinidine-specific high performance liquid chromatographic (HPLC) assay. During a clinical study, 16 patients with stable ventricular arrhythmias were treated with three oral quinidine preparations given during three consecutive 3-day periods. Seventeen plasma samples were drawn from each patient at steady-state during each period. Each specimen was divided into two portions, one for assay by EMIT and the other for assay by HPLC. EMIT assays were done on a Syva Autolab 6000 System using Syva quinidine kits and bilevel Ortho Diagnostics controls. The overall mean (+/- SD) quinidine concentrations by EMIT and HPLC were 2.16 +/- 0.58 and 1.81 +/- 0.60, respectively, n = 816, with a mean overall EMIT/HPLC ratio of 1.23 +/- 0.18. Mean ratios in individual patients ranged from 1.01 to 1.56; the average of mean individual ratios was 1.23 +/- 0.13. The EMIT assay, which also reports dihydroquinidine and small amounts of quinidine metabolites as quinidine, reported quinidine values that averaged 1.2-fold greater than results from a quinidine-specific HPLC method.

Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis.

Metoclopramide kinetics were examined in 24 adult patients with diminished renal function and in eight healthy subjects with normal renal function. Creatinine clearance correlated with metoclopramide plasma clearance, renal clearance, nonrenal clearance, and elimination t1/2. Regardless of renal function, renal clearance accounted for less than or equal to 21% of total plasma clearance. Nonrenal clearance was reduced in patients and accounted for most of the reduction in plasma clearance. The comparatively small plasma clearances in patients imply that maintenance doses should be reduced accordingly to avoid drug cumulation. Metoclopramide clearance by hemodialysis was also assessed in four patients. Metoclopramide losses from hemodialysis were relatively small compared to estimates of total body metoclopramide stores. Compensatory dosage increases are probably unnecessary for most patients. These data also suggest that hemodialysis is not likely to be effective in metoclopramide overdose.

Very high dose loxapine in refractory schizophrenic patients.

The authors report on three chronic, treatment-refractory schizophrenic patients who dramatically improved when placed on very high doses of loxapine (300-500 mg/day). Numbness transiently appeared in two patients at very high doses of loxapine; it may be a frequently occurring but unreported side effect. The relative lack of serious side effects to very high dose loxapine suggests that this may be a useful intervention in carefully selected refractory patients. The authors recommend that controlled studies be done to elucidate the benefit to risk ratio.

Effect of refrigeration on bactericidal activity of four preserved multiple-dose injectable drug products.

The influence of refrigeration on the bactericidal capability of preservative systems in multiple-dose injectable drug products was studied. Commercially available multiple-dose injectable drug products containing preservatives--atropine/phenol, lidocaine/methylparaben, cyanocobalamin/benzyl alcohol and diphenhydramine/benzethonium chloride--were divided into two groups, one to be maintained under refrigeration (5C) and the other to be maintained at room temperature (25C). In separate tests the multiple-dose vials (MDVs) were individually inoculated with the following organisms: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Serratia marcescens, and cultured to establish bacterial concentrations at 0, 1, 2, 4, 8 and 24 hours. Bacteria in the preservative systems tested remained viable significantly longer under refrigeration. (Data for diphenhydramine/benzethonium were not obtainable with the methodology used.) It is recommended that sterile medications maintained in preserved MDVs be stored at romm temperature after initial use (i.e., after exposure to possible contamination) unless drug stability considerations dictate otherwise.