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During a recent clinical trial of ciprofloxacin in the therapy of acute diarrhea, two subjects infected with Campylobacter jejuni who received ciprofloxacin failed microbiologically and one also failed clinically. Although both pretreatment isolates were susceptible to ciprofloxacin, the posttreatment isolates were resistant to ciprofloxacin (MIC = 32 micrograms/ml) and to other quinolones. The posttreatment isolates remained susceptible to nonquinolone antimicrobials. DNA gyrase holoenzyme was isolated from one of the resistant posttreatment isolates and was 8- to 16-fold less sensitive to inhibition by ciprofloxacin than was the gyrase from the paired pretreatment susceptible isolate. Ciprofloxacin accumulation was diminished in the two resistant posttreatment isolates. These results show that mutation in C. jejuni can occur in vivo and is associated with clinically significant resistance to the newer quinolones.

In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.

Cyclosporine has been shown to exert antiadrenergic actions in previous studies from this laboratory. Interactions of CsA with the alpha-one and alpha-two receptor were studied in rabbits. Blood pressure studies revealed that CsA exerts a competitive, reversible antagonism against norepinephrine, epinephrine, and phenylephrine. Further studies of heart rate depression by clonidine also demonstrated that CsA antagonizes this action. In conclusion, cyclosporine appears to act as a nonspecific alpha antagonist.

From June 1985 to September 1987, 202 adults were enrolled in a randomized, double-blinded study comparing ciprofloxacin (500 mg) with sulfamethoxazole and trimethoprim (160 mg/800 mg) or placebo for adults with acute diarrhea. All patients were treated on the day of presentation and received medication on a twice-daily schedule (every 12 hours) for 5 days. Bacterial isolates from these patients included 35 Campylobacter, 18 Shigella, and 15 Salmonella. Treatment at the time of presentation with ciprofloxacin compared with placebo shortened the duration of diarrhea (2.4 vs 3.4 days), and increased the percentage of patients cured or improved by treatment days 1, 3, 4, and 5. Similar significant differences for sulfamethoxazole and trimethoprim compared with placebo were not seen.

In vitro studies on primaquine have been carried out to examine its ability to stimulate the oxidative pathway of glucose metabolism in human erythrocytes and in vivo studies were carried out after ingestion of the drug to determine plasma levels and to investigate the formation of metabolites and the effects of the drug on human erythrocytes. These investigations showed that:1) Two mechanisms are involved in the stimulation of the oxidative pathway. This was demonstrated by comparing the effects of methylene blue, ascorbic acid, primaquine, and other drugs on normal, glutathione-reductase-deficient, and G6PD-deficient erythrocytes. A start was made towards classifying drugs according to the mechanism by which they stimulate CO(2) production.2) Following oral ingestion of primaquine, three as yet unidentified metabolites were present, two in the plasma and one in the urine. The rapid disappearance of primaquine from the plasma (within 24 hours) was confirmed.3) Two factors that stimulate glucose oxidation in human erythrocytes were found in plasma; one occurred only in fresh plasma, when EDTA was present, and the other occurred in all plasma and serum samples studied.4) The erythrocytes of blood drawn 24 hours after the ingestion of primaquine (after primaquine had disappeared from the plasma) showed increased ability to oxidize glucose.It is not yet known whether serum or plasma prepared from blood drawn 24 hours after ingestion of primaquine has the ability to increase the oxidation of glucose.

Although the antimalarial activity, hemolytic and methemoglobinemic side effects, and detoxification of primaquine are all thought to depend on various biotransformation products of the drug, their site and mechanism of formation and degradation are unknown and their specific biologic effects remain very poorly understood, particularly in humans. We have therefore explored the feasibility of studying primaquine metabolism in cultured human cells. We found that the biotransformation of primaquine can be investigated in vitro in serum-supplemented liquid cultures of partially synchronized and exponentially growing human erythroleukemic K562 cells. Further, these cells can be replaced by cells present in normal bone marrow. Primaquine is rapidly and predominantly converted in vitro into carboxyprimaquine (CPQ) in a quantitative manner and without further modification. In addition to CPQ, a compound Xc that is not 6-methoxy-8-aminoquinoline, and is not derived from CPQ, appears in minor amounts in a delayed fashion. With the K562 as well as with the bone marrow cells the formation of CPQ from primaquine can be totally blocked by large concentrations of the nitrosourea, 1,3-bis-(2-chloroethyl)-nitrosourea (BCNU). With bone marrow, increasing blockade of CPQ formation by BCNU leads invariably to a progressive and striking accumulation of Xc. The availability of reproducible, quantitative, and practical new tools for the study of primaquine metabolism in vitro raises a number of challenging questions and may improve understanding of the mode of action, toxicology, and pharmacogenetics of 8-aminoquinolines.

A high-performance liquid chromatographic method was developed for the simultaneous determination of primaquine and its metabolites from plasma and urine samples obtained after oral administration of primaquine diphosphate. Following partial deproteinization with acetonitrile, samples were chromatographed by direct injection onto a cyano column with UV detection at 254 nm. Levels as low as 100 ng/mL per 20-microL injection were quantitated. Preliminary pharmacokinetic analysis is reported for two human volunteers after oral doses of 60 mg and 90 mg. Two apparent plasma metabolites and two possible urinary metabolites of primaquine are also reported.

Thirty-one patients with Gram-negative bacteremia with organisms susceptible to cefotaxime (CTX) (MIC of 1 microgram/ml or less) were randomized to receive 2 g of CTX every 6, 8, or 12 hr. Five-hour susceptibility studies were performed on a bacterial pellet obtained from the patient's positive blood culture vial. Thus, patients were enrolled within hours after Gram-negative organisms were demonstrated in their blood cultures. All bacteremias were cleared although two patients had unsatisfactory responses to therapy. Trough serum bactericidal levels were 1:2 or greater in all patients. This study supports that CTX can be used at an 8- or 12-hr intervals in selected patients with Gram-negative bacteremia.

Almitrine bismesylate was administered to young, healthy, non-smoking male subjects as single oral doses, multiple oral doses and multiple oral doses with food. A variety of physiological parameters and blood parameters were tested at specified times in relationship to drug ingestion, and multiple blood samples for plasma almitrine bismesylate levels were obtained. Evaluation of the data revealed almitrine bismesylate to be safe at all doses tested, up to 400 mg per day, with symptoms of mild nausea and headache occurring most frequently when the drug was administered in the fasting state. A striking complaint of shortness of breath on exertion was reported by subjects, with increased frequency and severity related to total amount of drug ingested and level of physical activity. Increased oxygen uptake and tidal volume were found after multiple oral dosing. Plasma almitrine bismesylate levels were highly variable, and marked individual differences in peak levels and terminal phase rate constants and half lives were found. Multiple oral dosing, either fasting or with food, significantly prolonged the terminal phase half life when compared to single oral dosing.

The cardiovascular effects of i.v. infusion of cyclosporine were studied in pentobarbital-anesthetized rabbits. In doses ranging from 0.5 to 120 mg/kg/hr, CsA induced significant, sustained, dose-dependent hypotension. At the 60 mg/kg/hr dose the average drop in diastolic blood pressure was 27 mmHg (n = 9). Possible mechanisms were investigated by comparison of heart rate and blood pressure responses to physiologic manipulation, metabolic inhibition, or receptor antagonism before and after infusion of CsA. CsA did not modify responses to vagal stimulation, decreases in heart rate and blood pressure, P less than 0.001 and P less than 0.002, respectively. However, the cardiovascular reflex response during recovery was significantly attenuated after CsA infusion, P less than 0.05, n = 7. Response to bilateral carotid occlusion after CsA was decreased by 17 mmHg (n = 8, P less than 0.01). There were no significant differences between CsA alone and CsA plus glycopyrrolate or CsA plus aspirin. In this cyclosporine-induced hypotensive rabbit model, the hypotensive response appears to be related to a decrease in the endogenous sympathetic adrenergic activity, not to alterations in cholinergic tone, ganglionic transmission, or vasodilatory prostaglandin metabolism.

Three hexosaminidase (EC 3.2. 1.52) isoenzymes other than isoenzymes A and B in body fluids have been separated by chromatography on diethylaminoethyl cellulose. By inserting a microcolumn into a continuous-flow system for automated, fluorometric hexosaminidase analysis [Clin. Chem. 20, 538 (1974)], samples eluted with buffered-NaCl gradients can be continuously monitored. Isoenzyme patterns were obtained for fluids from normal individuals, pregnant women, Tay-Sachs disease carriers, pregnant carriers, and patients with the disease. These chromatograms revealed a hitherto undetected isoenzyme (I-3) in serum. An increase in serum hexosaminidase isoenzyme I-2 (or P) during pregnancy is characteristic of a carrier pattern. Our data show that serum and urinary hexosaminidase isoenzyme patterns may be used in addition to leukocyte analysis, to distinguish a pregnant carrier from a normal pregnant woman. All fluids tested demonstrated no isoenzyme A activity and above-normal activity of isoenzymes B and (or) I-2 in homozygotes. Urine is preferred fluid for postnatal and amniotic fluid for the prenatal diagnosis of the disease. Quantitative data on isoenzyme A obtained with the procedure described here agree well with those obtained by heat-and pH-inactivation methods.