Future Therapies in the Management of Critically Ill, AIDS Patients

Torres, Ramón A.; Franke-Ruta, Garance; Barr, Michael R.

doi:10.1016/s0749-0704(18)30214-8

Cited by 4 publications

(2 citation statements)

References 107 publications

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“…Peripheral neuropathy is the dose-limiting toxicity associated with clinical administration of d4T, ddC, and ddI (48,72,76). Because mitochondrial DNA polymerase -y is the cellular polymerase most sensitive to inhibition by the triphosphates generated from these nucleosides (references 53a and 69 and Table 9), and because mitochondrial defects have been associated with peripheral neuropathy (51), it has been suggested that inhibition of mitochondrial DNA synthesis is the mechanism by which these compounds exert their toxic effects on cells (12).…”

Section: Resultsmentioning

confidence: 99%

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Daluge

Purifoy

Savina

et al. 1994

Antimicrob Agents Chemother

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5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a selective anti-human immunodeficiency virus (H1V) agent. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 (HIV-1) obtained from patients naive to AZT (3'-azido-3'-deoxythymidine [zidovudine]), 935U83 inhibited virus growth with an average 50%v inhibitory concentration (IC50) of 1.8 ,uM; corresponding IC,Os were 0.10 ,uM for FLT (3'-deoxy-3'-fluorothymidine) and 0.23, 0.49, and 0.03 ,uM for the approved agents AZT, ddI (2',3'-dideoxyinosine), and ddC (2',3'-dideoxycytosine), respectively. Importantly, 935U83 retained activity against HIV strains that were resistant to AZT, ddl, or ddC. Of additional interest, we were unable to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was similar to that of AZT, and 93SU83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60%Yo in monkeys) and less extensive metabolism to the glucuronide relative to AZT. 935U83 showed low toxicity. In an in vitro assay for toxicity to a human erythrocyte progenitor, erythroid burst-forming unit (BFU-E), the IC50 for 935U83 (>400 ,uM) was more than 1,000-fold those of FLT (0.07 ,uM) and AZT (0.30 ,uM). Mild reversible reductions in erythrocytes and associated parameters were seen in mice dosed orally with 2,000 mg of 935U83 per kg per day for 1 and 6 months. In monkeys dosed orally with up to 700 mg/kg/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg/kg/day. At the highest doses in mice and monkeys, maximal concentrations in plasma were more than 100-fold the anti-H1V IC50s against clinical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date and has led us to begin evaluation of 935U83 in patients with HIV infection.

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Section: Resultsmentioning

confidence: 99%

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Daluge

Purifoy

Savina

et al. 1994

Antimicrob Agents Chemother

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show abstract

“…Evidence suggests that dose reduction or discontinuation of by guest on http://cid.oxfordjournals.org/ Downloaded from myelosuppressive therapies such as ganciclovir, trimethoprimsulfamethoxazole, and pyrimethamine, as may be necessitated by neutropenia, are associated with disease progression and death [57][58][59][60]. Filgrastim treatment has been shown to support neutrophil counts during administration of myelosuppressive agents and to allow tolerance of greater dosages of these drugs [7,9,12,61].…”

Section: G-csf In Hiv Infectionmentioning

confidence: 99%

Neutropenia, Neutrophil Dysfunction, and Bacterial Infection in Patients with Human Immunodeficiency Virus Disease: The Role of Granulocyte Colony-Stimulating Factor

Kuritzkes

2000

Clinical Infectious Diseases

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Neutropenia frequently complicates infection due to human immunodeficiency virus (HIV). The etiology of neutropenia in this setting includes bone marrow infection or infiltration, myelosuppressive therapies, the presence of antibodies to HIV, and accelerated apoptosis. Protection against microbial invaders by neutrophils is further compromised by impaired chemotaxis and phagocytosis, production of toxic oxygen species, and expression of cellular adhesion molecules. Neutropenia is a significant risk factor for bacterial infection in HIV-infected patients. Endogenous cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor, regulate neutrophil count and function. Treatment with recombinant human methionyl G-CSF (filgrastim) has lessened neutropenia in patients with HIV infection. Clinical trials have shown that the incidence of bacterial infections and the number of consequent days of hospitalization for HIV-infected patients receiving filgrastim therapy are lower. Filgrastim treatment also allows administration of larger doses of myelosuppressive agents.

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Changing testicular histology in AIDS: its implication for sexual transmission of HIV

Shevchuk

Pigato

Khalife

et al. 1999

Urology

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Future Therapies in the Management of Critically Ill, AIDS Patients

Cited by 4 publications

References 107 publications

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile

Neutropenia, Neutrophil Dysfunction, and Bacterial Infection in Patients with Human Immunodeficiency Virus Disease: The Role of Granulocyte Colony-Stimulating Factor

Changing testicular histology in AIDS: its implication for sexual transmission of HIV

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