Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy

Fischl, Margaret A.; Olson, Richard M.; Follansbee, Stephen; Lalezari, Jacob; Henry, David H.; Frame, Peter T.; Remick, Scot C.; Salgo, Miklos; Lin, Amy; Nauss-Karol, Cheryl; Lieberman, Judith P.; Soo, Whaijen

doi:10.7326/0003-4819-118-10-199305150-00002

Cited by 83 publications

(21 citation statements)

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“…However, before initiation of ddC therapy, all the studied patients denied any neuropathic symptoms, and no abnormal neurological signs were recorded by the primary care physician. In addition, in all four patients, the neuropathic symptoms began 6 to 10 weeks after ddC therapy, a pattern typically seen with ddC-related neuropathy (Berger et al, 1993;Blum et al, 1996;Dalakas, 2001;Dubinsky et al, 1989;Fischl et al, 1993;Lewis and Dalakas, 1995;Moyle and Sadler, 1998;Yarchoan et al, 1988). Other causes of neuropathy, such as diabetes, alcohol, drug abuse, nutritional factors, low B12 levels, or exposures to other neurotoxins, were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Z alcitabine (ddC) is a synthetic 2'3'-dideoxynucleoside analog commonly used for the treatment of patients infected with acquired immunodeficiency syndrome (AIDS) (Fischl et al, 1993;Mitsuya and Broder, 1986;Yarchoan et al, 1988). Since the time it was first introduced for the treatment of AIDS, ddC was causally connected with a dose-dependent, painful, sensorimotor axonal peripheral neuropathy (Berger et al, 1993;Blum et al, 1996;Dubinsky et al, 1989;Lewis and Dalakas, 1995;Moyle and Sadler, 1998).…”

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confidence: 99%

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Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Dalakas

Semino–Mora

Leon‐Monzon

2001

Laboratory Investigation

198

122

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SUMMARY:The 2'3'-dideoxycytidine (ddC), a nonazylated dideoxynucleoside analog used for the treatment of AIDS, causes a dose-dependent, painful, sensorimotor axonal peripheral neuropathy in up to 30% of the patients. To investigate the cause of the neuropathy, we performed morphological and molecular studies on nerve biopsy specimens from well-selected patients with ddC-neuropathy and from control subjects with disease, including patients with AIDS-related neuropathy never treated with ddC. Because ddC, in vitro, inhibits the replication of mitochondrial DNA (mtDNA), we counted the number of normal and abnormal mitochondria in a 0.04 mm 2 cross-sectional area of the nerves and quantified the copy numbers of mtDNA by competitive PCR in all specimens. A varying degree of axonal degeneration was present in all nerves. Abnormal mitochondria with enlarged size, excessive vacuolization, electron-dense concentric inclusions and degenerative myelin structures were prominent in the ddC-neuropathy and accounted for 55% Ϯ 2.5% of all counted mitochondria in the axon and Schwann cells, compared with 9% Ϯ 0.7% of the controls (p Ͻ 0.001). Significantly (p Ͻ 0.005) reduced copy numbers, with as high as 80% depletion, of the mtDNA was demonstrated in the nerves of the ddC-treated patients compared with the controls. We conclude that ddC induces a mitochondrial neuropathy with depletion of the nerve's mtDNA. The findings are consistent with the ability of ddC to selectively inhibit the ␥-DNA polymerase in neuronal cell lines. Toxicity to mitochondria of the peripheral nerve is a new cause of acquired neuropathy induced by exogenous toxins and may be the cause of neuropathy associated with the other neurotoxic antiretroviral drugs or toxic-metabolic conditions. (Lab Invest 2001, 81:1537-1544.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Dalakas

Semino–Mora

Leon‐Monzon

2001

Laboratory Investigation

198

122

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“…However, their associated toxicities are specific to each compound and do not overlap with one another. For AZT, inhibition of the growth of granulocyte-macrophage cells and early and late erythroid progenitors is a common effect (81), whereas peripheral neuropathy is a common side effect of ddC administration (12,38,108). Clinical trials were therefore conducted with AZT combined with ddC in the hope that the combination would have greater efficacy, as was suggested by in vitro studies, and that the combined toxicity would be less than the toxicity of either drug alone (32).…”

Section: Clinical Trials and Combination Regimens In Current Usementioning

confidence: 99%

Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection

Pirrone

Thakkar

Jacobson

et al. 2011

Antimicrob Agents Chemother

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The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4 ؉ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.

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“…These agents have now been li censed in most European countries for the treatment of infection with the human immunodeficiency virus (HIV), the causative agent of the acquired immuno deficiency syndrome (AIDS). Zidovudine delays pro gression of HIV infection and prolongs survival in patients with AIDS [1], Switching from zidovudine to didanosine [2 3] or to zalcitabine [4] therapy has been shown to be clinically beneficial after pro longed use of zidovudine, whereas combination ther apy with zidovudine and didanosine [5] or with zido vudine and zalcitabine [6] results in more prolonged increases in CD4+ T-lymphocyte counts than with these agents in monotherapy. Therefore, these three drugs will remain the mainstay of antiretroviral drug treatment for the near future and a thorough knowl edge of the clinical pharmacokinetics is needed to optimize their therapeutic use.…”

Section: Introductionmentioning

confidence: 99%

Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents

1995

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In this paper aspects of the clinical pharmacokinetics of the antiretroviral agents zidovudine, didanosine and zalcitabine are reviewed. Special attention is paid to possibly altered pharmacokinetics in special circumstances, such as hepatic and renal dysfunction, pregnancy, stage of disease, etc, The dideoxynucleoside antiretroviral agents have some clinical pharmacokinetic properties in common (rapid absorption and elimination), but substantial differences exist in their degree of absorption, metabolism and penetration into the cerebrospinal fluid. All agents display wide interpatient variability in pharmacokinetic parameters. The relevance of therapeutic drug monitoring of antiretroviral agents is also discussed.

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Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy

Abstract: The sample size for this study was smaller than planned, and no differences in survival and clinical end points were found. Slower rates of decline in CD4 lymphocyte counts and weight, however, were noted for the zalcitabine group.

Cited by 83 publications

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Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection

Concise overview of the clinical pharmacokinetics of dideoxynucleoside antiretroviral agents

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