The authors have shown previously that intracellular glutathione (GSH) plays an important role in the regulation of human immunodeficiency virus (HIV) transcription and replication in vitro, through modulation of signal transduction by inflammatory cytokines. Moreover, intracellular GSH levels are known to regulate T-lymphocyte function. In multiparameter FACS studies presented here, we show that relative GSH levels in CD4+ and CD8+ T cells from HIV+ individuals are significantly lower than in corresponding subsets from uninfected controls. These studies define the relative intracellular glutathione (GSH) levels in CD4+ T cells, CD8+ T cells, B cells, and monocytes from 134 HIV-infected individuals and 31 uninfected controls. The greatest decreases in intracellular GSH occur in subsets of T cells in individuals in the later stages of the HIV infection. In AIDS patients, GSH levels are 63% of normal in CD4+ T cells (p less than 0.0001) and are 62% of normal in CD8+ T cells (p less than 0.0001). Similarly, in AIDS-related complex (ARC) patients, GSH levels are 66% of normal in CD4+ T cells (p less than 0.003) and are 69% of normal in CD8+ T cells (p less than 0.003). These findings suggest that low intracellular GSH levels may be an important factor in HIV infection and in the resulting immunodeficiency.

The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 0.06 liter/h/kg in healthy volunteers and 0.21 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 + 0.13 and 0.66 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 + 0.14 versus 0.75 + 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 2.5 versus 5.3 1.0 mg/liter, P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particulariy for orally administered drugs.Toxoplasmic encephalitis (TE) is considered the most common cause of intracerebral mass lesions in patients with AIDS, occurring in 3 to 40% of AIDS patients (16). Standard therapy for TE includes the synergistic combination of pyrimethamine and sulfadiazine, which provides a sequential blockade of folic acid metabolism. However, many patients with AIDS are unable to complete a course of therapy because of adverse reactions (18).Clindamycin has been used either alone or more frequently in combination with pyrimethamine to treat TE in patients with AIDS who develop untoward side effects to the sulfonamide component of the standard pyrimethaminesulfadiazine therapy (4,10,15,21,23,24). Recently, the results of an international prospective study comparing the combinations pyrimethamine-sulfadiazine and pyrimethamine-clindamycin suggest that the relative efficacies of the two combination treatments are approximately equal (3).The activity of clindamycin against Toxoplasma gondii is controversial: clindamycin was effective in a murine model of TE (11) but was ineffective in a model based on Taxoplasma-infected rat monocytes (9). Clindamycin does not penetrate adequately into cerebrospinal fluid, even in the presence of bacterial meningitis (7); however, it has been suggested that damage of the blood-brain barrier in AIDS patients, involving marked tissue de...

The 4 generic and brand-name levothyroxine preparations studied are different but are bioequivalent by current Food and Drug Administration criteria and are interchangeable in the majority of patients receiving thyroxine replacement therapy. Further investigation is required to determine whether our results are equally applicable to all existing levothyroxine preparations.

Objective The study sought to develop a criteria-based scoring tool for assessing drug-disease knowledge base content and creation of a subset and to implement the subset across multiple Kaiser Permanente (KP) regions. Materials and Methods In Phase I, the scoring tool was developed, used to create a drug-disease alert subset, and validated by surveying physicians and pharmacists from KP Northern California. In Phase II, KP enabled the alert subset in July 2015 in silent mode to collect alert firing rates and confirmed that alert burden was adequately reduced. The alert subset was subsequently rolled out to users in KP Northern California. Alert data was collected September 2015 to August 2016 to monitor relevancy and override rates. Results Drug-disease alert scoring identified 1211 of 4111 contraindicated drug-disease pairs for inclusion in the subset. The survey results showed clinician agreement with subset examples 92.3%-98.5% of the time. Postsurvey adjustments to the subset resulted in KP implementation of 1189 drug-disease alerts. The subset resulted in a decrease in monthly alerts from 32 045 to 1168. Postimplementation monthly physician alert acceptance rates ranged from 20.2% to 29.8%. Discussion Our study shows that drug-disease alert scoring resulted in an alert subset that generated acceptable interruptive alerts while decreasing overall potential alert burden. Following the initial testing and implementation in its Northern California region, KP successfully implemented the disease interaction subset in 4 regions with additional regions planned. Conclusions Our approach could prevent undue alert burden when new alert categories are implemented, circumventing the need for trial live activations of full alert category knowledge bases.

Patients with AIDS have altered pharmacokinetics of clindamycin compared with those of healthy control subjects. In an attempt to better understand these differences, we undertook a study of protein binding of clindamycin in sera of patients with AIDS. Fifteen patients with AIDS and 15 healthy volunteers were given a single 600-mg dose of clindamycin orally and intravenously, and serum samples were collected at three time points corresponding to high, midpoint, and low clindamycin concentrations. Protein binding was determined by ultrafiltration, and total and unbound clindamycin concentrations were measured with a gas chromatography assay. AIDS patients had alpha 1-acid glycoprotein values approximately twice those of healthy volunteers (mean +/- standard deviation, 103 +/- 27 versus 61 +/- 11 mg/dl; P = 0.001). Overall, serum protein binding levels were higher in AIDS patients (mean +/- standard deviation, 83 +/- 7 versus 78% +/- 8%; P = 0.0001), which is likely the result of increased alpha 1-acid glycoprotein levels in these patients. Total concentrations of clindamycin in plasma were significantly higher in AIDS patients at most time points studied, while unbound serum clindamycin concentrations did not differ among the groups at each sampling time after both oral and intravenous dosing. Increased protein binding may partly explain the altered pharmacokinetic disposition of clindamycin in AIDS patients; however, other factors cannot be excluded.