A direct determination of thymidine triphosphate concentrations without dephosphorylation in peripheral blood mononuclear cells by LC/MS/MS.

A rapid, sensitive and specific analytical method with minimal sample preparation for the measurement of thymidine triphosphate (TTP) in peripheral blood mononuclear cells (PBMC) by LC/MS/MS has been developed. PBMC were separated from whole blood or buffy coat. The analyte and internal standard were extracted from PBMC with 70% methanol (pH 7.

An LC-MS-MS method for the determination of indinavir, an HIV-1 protease inhibitor, in human plasma.

A method for the determination of indinavir (IDV) (L-735 524) in human plasma by LC-MS-MS is discussed, and the validation data is presented. The analyte and internal standard are isolated from plasma by a simple acetonitrile precipitation of plasma proteins followed by centrifugation. LC-tandem mass spectrometry in positive ion, multiple reaction monitoring mode used pairs of ions at m/z of 614/421 for indinavir and 628/421 for internal standard, respectively.

Liquid chromatographic determination of urinary 6beta-hydroxycortisol to assess cytochrome p-450 3A activity in HIV positive pregnant women.

Assessing the activity of CYP3A4 is important for predicting the pharmacokinetic behavior of protease inhibitors in HIV positive patients, especially in pregnant women. The endogenous hormonal ratio of 6beta-hydroxycortisol (beta-OHF) to cortisol (F) in the urine is an index for metabolic enzyme activity of cytochrome p-450 (CYP) 3A4. Because the ratio is a unique way to assess the enzyme activity without using any exogenous probes for this isozyme, it is practical for use in pregnant women.

Removal of Foscarnet by hemodialysis using dialysate-side values.

Foscarnet is an antiviral agent widely used in the treatment of cytomegalovirus (CMV) infection. We describe a cardiac transplant patient, who while being maintained with hemodialysis because of tobramycin-induced acute renal failure, was given Foscarnet for disseminated CMV infection. Using dialysate-side clearance methodology, we found the dialyzer clearance of Foscarnet to be in the order of 89 ml/min.

High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes.

Ribavirin is an antiviral agent used in the treatment of chronic hepatitis C virus infection. One of the limitations associated with the use of ribavirin is a reversible anemia caused by its accumulation in erythrocytes. Therefore, it is of interest to determine ribavirin levels in erythrocytes, as well as in plasma, as these measurements may be predictive of hematotoxicity.

Antiviral therapy for HIV patients with renal insufficiency.

Patients with HIV infection and HIV-related opportunistic infections are treated extensively with a spectrum of drugs. Introduction of new antiretroviral drugs, such as protease inhibitors and nonnucleoside reverse transcriptase inhibitors in addition to nucleoside reverse transcriptase inhibitors, has created exciting dimensions in treatment strategies. Renal dysfunction is also common in HIV-infected patients.

Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease.

Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT.

Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4).

Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations.

Background: Foscarnet is an antiviral agent commonly used for managing patients with cytomegalovirus infection. Despite its clinical usefulness, foscarnet is associated with substantial adverse effects including nephrotoxicity. Moreover, foscarnet is primarily eliminated unchanged through the kidneys, thus requiring aggressive dose adjustment during kidney failure.

Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis.

Background: Cidofovir is an antiviral agent used for the treatment of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. Because cidofovir is primarily eliminated by the kidneys and because its main adverse effect is nephrotoxicity, an understanding of the pharmacokinetic disposition of cidofovir in patients with renal insufficiency is necessary.

Methods: Twenty-four subjects were enrolled into this study and were divided into 6 groups depending on their degree of renal dysfunction, including subjects receiving maintenance continuous ambulatory peritoneal dialysis and high-flux hemodialysis.

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals.

Intracellular phosphorylation of zidovudine (ZDV) and other nucleoside reverse transcriptase inhibitors (RTI) used for human immunodeficiency virus (HIV) infection.

Dramatic reductions of viral load and increased survival have been achieved in patients infected with the Human Immunodeficiency Virus (HIV) with the introduction of combination antiretroviral therapy. Currently 11 agents including nucleoside reverse transcriptase inhibitors (RTI), non-nucleoside RTI and protease inhibitors are available for the use for treatment of HIV infection. Recent studies have demonstrated that certain combinations of these drugs are advantageous over their individual use as monotherapy with an even more sustained viral suppression.

Simple high-performance liquid chromatographic determination of the protease inhibitor indinavir in human plasma.

Indinavir is a member of a class of protease inhibitors that actively prevent the acquired immunodeficiency syndrome virion from maturing. A high-performance liquid chromatographic (HPLC) assay was developed and validated for the determination of indinavir in human plasma. Indinavir and the internal standard were isolated from the plasma by ether extraction.

Phase I study of a human monoclonal antibody directed against the CD4-binding site of HIV type 1 glycoprotein 120.

A phase I dose escalation study was conducted with the human monoclonal anti-gp120 antibody F105, to evaluate the safety, pharmacokinetics, and functional activity of F105 in HIV-1-infected individuals. F105 is an IgG1(kappa) antibody reactive with a discontinuous epitope that overlaps the CD4-binding site of gp120. F105 neutralizes laboratory strains of HIV-1 and some primary isolates, and synergizes with other antibodies in neutralizing an expanded spectrum of isolates.

High-performance liquid chromatographic determination of pyrazoloacridine, a nitro-9-methoxyacridine anticancer agent, in human plasma.

Pyrazoloacridine (PZA) is a 9-methoxy substituted acridine with a reducible nitro group. PZA has shown selective solid tumor cytotoxicity with activity against hypoxic cells, non-cycling cells and cells expressing the multidrug resistant phenotype. A high-performance liquid chromatographic (HPLC) assay was developed and validated for the determination of PZA in human plasma to support phase II clinical trials.

Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism.

Objective: To compare relative bioavailability of Synthroid, Levoxine (Levoxine has been renamed Levoxyl), and 2 generic levothyroxine sodium preparations.

Design: Single-blind (primary investigators blinded), randomized, 4-way crossover trial.

Setting: Ambulatory care.

Effect of renal impairment on the pharmacokinetics of grepafloxacin.

Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.

Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor: the effects of zidovudine.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHu GM-CSF) enhances bone marrow production of and stimulates granulocytes, macrophages, and eosinophils. Granulocyte-macrophage colony-stimulating factor may be used concomitantly with zidovudine in human immunodeficiency virus (HIV)-positive patients to minimize zidovudine-associated neutropenia. This open-label, randomized, placebo-controlled study was performed to evaluate the pharmacokinetic disposition of rHu GM-CSF in HIV-positive, asymptomatic patients in the absence and presence of concomitant zidovudine administration.

Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients.

Objective: To determine some of the factors influencing the time to progression of cytomegalovirus (CMV) retinitis among HIV-infected patients being treated with foscarnet.

Design: A retrospective analysis of two open-label Phase I/II studies in multiple university hospitals. Patients were studied in both inpatient and outpatient settings.

Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus.

Background: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment.

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1.

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2.

Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection.

Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.

Protein binding of clindamycin in sera of patients with AIDS.

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.