Low-dose zalcitabine-related toxic neuropathy

Blum, André; Pan, Gongbu; Feinberg, Judith; Raines, Charles; Mayjo, K.; Cornblath, David R.; McArthur, Justin C.

doi:10.1212/wnl.46.4.999

Cited by 76 publications

(37 citation statements)

References 6 publications

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confidence: 99%

“…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). The neuropathy occurs in 34% of patients receiving ddC, and it is a limiting factor in the use of this drug in the treatment of AIDS (Dalakas, 2001;Dubinsky et al, 1989;Berger et al, 1993;Lewis and Dalakas, 1995;Blum et al, 1996;Moyle and Sadler, 1998). It is manifested approximately 6 to 8 weeks after the initiation of therapy and usually improves 3 to 4 weeks after discontinuation of the drug (Berger et al, 1993;Blum et al, 1996;Dalakas, 2001;Dubinsky et al, 1989;Lewis and Dalakas, 1995;Moyle and Sadler, 1998).…”

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confidence: 99%

“…The neuropathy occurs in 34% of patients receiving ddC, and it is a limiting factor in the use of this drug in the treatment of AIDS (Dalakas, 2001;Dubinsky et al, 1989;Berger et al, 1993;Lewis and Dalakas, 1995;Blum et al, 1996;Moyle and Sadler, 1998). It is manifested approximately 6 to 8 weeks after the initiation of therapy and usually improves 3 to 4 weeks after discontinuation of the drug (Berger et al, 1993;Blum et al, 1996;Dalakas, 2001;Dubinsky et al, 1989;Lewis and Dalakas, 1995;Moyle and Sadler, 1998). In conjunction with other neurotoxic risk factors or antiretroviral agents, the incidence of ddCassociated neurotoxicity appears increased (Benbrik et al, 1997;Dalakas, 2001;Moyle and Sadler, 1998).…”

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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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confidence: 99%

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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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“…19 In the HAART era, particular antiviral therapies, collectively known as ''d-drugs,'' were found to cause a toxic-DSP, occurring in up to 34% of patients. [8][9][10][11] Classically, symptoms are usually temporally related to the start of therapy occurring in the first 6 weeks of exposure. Although symptomatic improvement can occur with very early drug cessation, there is usually incomplete resolution of symptoms and signs.…”

Section: Nakamoto Et Almentioning

confidence: 99%

“…5 In the early HAART era, three dideoxynucleoside reverse transcriptase inhibitors (d-NRTI)-zalcitabine (Hivid, 2 0 ,3 0 -dideoxycytidine or ddC), stavudine (Zerit, 2 0 ,3 0 -didehydro-3 0 -deoxythymidine or d4T), didanosine (Videx, dideoxyinosine or ddI)-known collectively as ''d-drugs'' caused toxic DSP, which was clinically difficult to differentiate from HIV-associated DSP. [8][9][10][11] The risk of developing a toxic DSP from a d-drug usually peaks in the first 3 months of initiating therapy. 12 One study 13 suggested that if DSP did not develop within the first year of using a d-drug, it was less likely to occur in subsequent years.…”

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Incident Neuropathy in HIV-Infected Patients on HAART

Nakamoto

McMurtray

Davis

et al. 2010

AIDS Research and Human Retroviruses

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We determined the incidence of and risk factors for distal sensory polyneuropathy (DSP) in individuals on HAART. Sixty-one HIV-positive subjects on HAART for at least 6 months and neuropathy free were retrospectively selected. The study included subjects who had previously tolerated d-drugs without developing DSP. Neuropathy incidence over 4 years was calculated. Cox proportional hazards models were used to determine risk factors associated with incident DSP. Nineteen subjects developed DSP over a mean follow-up of 2.4 years. Subjects never treated with a d-drug developed DSP at a rate of 21 cases per 100 person-years (95% CI, 8.9-33.7). Subjects with a history of d-drug treatment but not on a d-drug at enrollment developed DSP at a rate of 17 cases per 100 person-years (95% CI, 2.1-31.8). Those on d-drug treatment developed DSP at a rate of 25 cases per 100 person-years (95% CI, 8.7-41.6). Multivariable analysis identified age [hazard ratio (HR) ¼ 1.09; p < 0.01] and low CD4 þ nadir [hazard ratio (HR) ¼ 0.79; p ¼ 0.03] as significant risk factors. Current or prior history of treatment with d-drug was not a significant risk factor for incident DSP in subjects who had previously tolerated d-drug treatment without developing a toxic DSP. Age and low CD4 þ are risk factors for incident DSP. However, current or prior history of d-drug treatment is not a significant risk factor for incident DSP in subjects who had previously tolerated d-drug treatment without developing a toxic DSP.

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