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Combination antiretroviral therapy that includes zidovudine has proved much better in treating human immunodeficiency virus infection than monotherapy Diminished responses to zidovudine, especially when it was given alone, was likely due to factors including interpatient variability in pharmacokinetics, nonadherence, emergence of resistant mutants, and reduced cellular enzymatic processes to phosphorylate the drug. This study evaluated the intracellular metabolism of zidovudine up to 6 weeks using a hollow fiber cellular model system that simulated exposure of cells to steady-state concentrations achieved in humans. The CEM-T4 lymphocytes were exposed to simulated 200-, 600-, and 1200-mg daily doses of zidovudine. Samples were analyzed for monophosphate, diphosphate, and triphosphate metabolites of zidovudine by high-performance liquid chromatography separation and radiochemical detection. The monophosphate metabolite increased as simulated doses increased, but no corresponding increases in the active triphosphate metabolite occurred. In addition, intracellular metabolism of zidovudine did not change after exposure for 6 weeks. These results suggest that the active triphosphate metabolite of zidovudine does not change much when doses are increased or when exposed for at least 6 weeks. Hollow fiber models may be used effectively to investigate intracellular metabolism of antiviral agents and for some duration of time.

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Human immunodeficiency virus (HIV) protease inhibitors have revolutionized the treatment of individuals infected with this pathogen. The protease is an enzyme that is essential for viral replication because it cleaves both structural and functional proteins from precursor viral polyprotein strands. Inhibition of this process suppresses viral replication, which produces immature noninfectious virions. When combined with reverse transcriptase inhibitors, these agents are very potent in suppressing viral replication. Pharmacologic properties, toxic profile, drug interactions, and resistance patterns differ among protease inhibitors, and all must be considered when selecting the drugs for therapeutic use in humans. The best combination, sequence of use, durability of response, and magnitude of immune reconstitution and function are issues that have yet to be fully elucidated.

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Stavudine (d4T) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to response to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concentrations within 2 hours and increases linearly as doses increase. The absolute oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses < 2 mg/kg/day is most efficient at increasing CD4 + cell numbers. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.

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Zidovudine (ZDV) and clarithromycin (CLR) are often used simultaneously in the management of patients with AIDS. While pharmacokinetic studies show decreased absorption of ZDV when it is administered with CLR, it is unknown if CLR affects the intracellular metabolism of ZDV. We investigated the effects of CLR on the intracellular metabolism of ZDV in vitro. CEM-T4 cells were coincubated with a microM ZDV ([3 H] ZDV, 3 microCi/ml) either alone or with 1 or 10 microM CLR. Cells were also grown in the presence of CLR for 48 h prior to exposure to ZDV. Samples were analyzed for mono-, di-, and triphosphate metabolites of [3 H] ZDV by high-performance liquid chromatography separation and radiochemical detection. There were no significant differences in levels of intracellular metabolites of ZDV following exposure to ZDV, either alone or with 1 or 10 microM CLR and under both coincubated and preincubated conditions. These results show that treatment with CLR does not alter the formation of phosphorylated metabolites of ZDV in this cell line.

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OBJECTIVE: To report two cases of hypertension related to amphotericin B infusion. CASE SUMMARY: A 63-year-old woman with Candida albicans bacteremia and an 84-year-old man with Aspergillus fumigatus pneumonia developed hypertension within minutes of amphotericin B administration. Both patients' blood pressure returned to baseline soon after the infusion of amphotericin B was stopped. Neither patient was rechallenged. DISCUSSION: A causal relationship may exist between the administration of amphotericin B and these hypertensive episodes. Blood pressure in both patients normalized without treatment on discontinuation of the infusion. The mechanism of amphotericin B-associated hypertension is unclear but could include vasoconstricting properties of the drug or the administration of intravenous NaCl 0.9% prior to amphotericin B infusion. We recommend that intravenous NaCl 0.9% be administered following amphotericin B infusion and that the infusion be stopped if hypertensive episodes arise. CONCLUSIONS: Both acute hypertension and hypotension can occur in patients receiving amphotericin B for systemic fungal infections.

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