Chemical structure of zalcitabine.
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Zalcitabine

Zalcitabine (2'-3'-dideoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse transcriptase inhibitor (NARTI) sold under the trade name HividĀ®. more...

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Zalcitabine is the least potent of all antiretroviral drugs, is inconvenient to take, and has serious side effects. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV).

History

Zalcitabine was developed in the National Cancer Institute (NCI) by Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan at the National Cancer Institute (NCI). Like didanosine, it was then licensed because the NCI may not market drugs. The National Institutes of Health (HIH) thus licensed it to Hoffman LaRoche Co.

Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV infection and AIDS. It was approved on Jun 19, 1992 as a monotherapy and again in 1996 for use in combination with Zidovudine (AZT). Using combinations of NRTIs was in practice prior to the second FDA approval and the triple drug combinations with dual NRTIs and a protease inhibitor (PI) were not far off by this time.

Mechanism of action

Zalcitabine is an analog of pyrimidine. It is a derivative of the naturally existing deoxycytidine, made by replacing the hydroxyl group in position 3' with a hydrogen.

It is phosphorylated in the T cell and other HIV target cells into its active triphosphate form, ddCTP. This active metabolite works as a substrate for HIV reverse transcriptase, and also by incorporation into the viral DNA, hence terminating the chain elongation due to the missing hydroxyl group. Since zalcitabine is a reverse transcriptase inhibitor it possess activity only against retroviruses. It is used for the treatment of HIV infection only in combination with zidovudine.

Zalcitabine has a very high oral absorption rate, of over 80%. The most common side effect in the beginning of the treatment is nausea and headache. The more serious side effects are peripheral neuropathy, oesophagitis and pancreatitis.

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ZALCITABINE - Hivid
From Research Initiative/Treatment Action!, 3/1/00

Zalcitabine is supplied in 0.750 mg tablets (shown) that are oval, gray, film-coated and imprinted with "HIVID 0.750" on one side and "Roche" on the other side. The drug is also supplied in 0.375 mg tablets that are oval, beige, film-coated and imprinted with "HIVID 0.375" on one side and "Roche" on the other side.

"There can be no more polite dialogue with your company. The community has begun to express its outrage...."

Letter from Treatment Action Group to Hoffmann-LaRoche

"These individuals proceeded to pour red paint, shout obscenities, turn over tables, chairs and generally trash the room. Quite frankly, the action had a chilling effect upon all Roche employees present...."

Letter from Hoffmann-LaRoche to Treatment Action Group

Also known as: ddC

Background and description. When zalcitabine (Hivid) received marketing clearance from the US Food and Drug Administration (FDA) in June 1992, it became the first antiretroviral drug licensed under the accelerated approval process. The drug is produced by Hoffmann-LaRoche. Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI). The drug is indicated in combination with other antiretrovirals for the treatment of HIV infection.

Guidelines classification. The Panel on Clinical Practices for the Treatment of HIV Infection classifies zalcitabine as an "alternative" NRTI. Of the 4 dual nucleoside combinations "not recommended" by the US Department of Health and Human Services, zalcitabine is included in 3 of them.

Dose. The recommended dose is one 0.750 mg tablet every 8 hours.

Food restrictions. Zalcitabine may be taken with or without food.

Storage. Tablets should be stored in a tightly closed container and kept at a temperature of 59 [degrees] to 86 [degrees] F.

Side effects and toxicity. Peripheral neuropathy is the toxicity most commonly produced by zalcitabine, occurring in approximately one third of those receiving the drug. The risk of neuropathy is higher in individuals with advanced disease, and the pain can be so severe as to require narcotic analgesics. Prompt discontinuation of the drug usually yields a slow resolution of neuropathy, but in some cases the condition is irreversible.

Fatal pancreatitis has occurred in approximately 1% of those receiving zalcitabine. Other toxicities reported in conjunction with zalcitabine use include lactic acidosis, hepatic failure, oral ulcers, esophageal ulcers and congestive heart failure. As a class, NRTIs have been implicated in damage to mitochondrial DNA and may therefore play a role in the development of metabolic and morphologic abnormalities. Unless faced with a pressing need for rescue therapy, HIV-infected individuals are probably best served by avoiding this drug.

Drug interactions. Zalcitabine should not be used with other agents that can cause peripheral neuropathy or pancreatitis, including didanosine (Videx), stavudine (Zerit) and lamivudine (Epivir). Since zalcitabine is eliminated through the kidneys, dose adjustment is required in individuals with impaired renal function. When administered concomitantly with probenecid (Benemid) or cimetidine (Tagamet), monitor for renal toxicity. Avoid co-administration of Maalox and zalcitabine.

Resistance and cross-resistance. Mutations at positions 65, 69, 74 and 151 are associated with resistance to zalcitabine; however, resistance is slow to emerge. The mutation at position 151 is associated with resistance to the entire NRTI class. The insertion at position 69 can also lead to broad NRTI resistance. In the Delta 1 study, no mutations were identified after 112 weeks among subjects receiving zalcitabine and zidovudine (Retrovir). Prior therapy with lamivudine may confer cross-resistance to zalcitabine.

Clinical data. Although zalcitabine has been studied in trials involving more than 21,000 participants, the data from those trials are largely meaningless in the present-day context of highly active antiretroviral therapy (HAART). Most of the 20 studies of zalcitabine examined combinations of dual nucleoside therapy--rarely prescribed today--and only a few of the trials provided any data on zalcitabine's antiviral activity as measured by reductions in viral load. These limitations reflect the clinical standards and lack of technology at the time zalcitabine was approved.

ACTG 175 found that a combination of zalcitabine plus zidovudine offered improved clinical outcome when compared to zidovudine alone in antiretroviral naive subjects. However, the combination of zalcitabine/ zidovudine was no better than didanosine alone. For study participants with a history of zidovudine use, the combination of zalcitabine/zidovudine offered no clinical benefit compared to continued zidovudine monotherapy. Two other trials, ACTG 229 and ACTG 193A, showed benefit in combining zalcitabine and a protease inhibitor.

Patient assistance. Hoffmann-LaRoche provides a patient assistance program. For more information, call 800.282.7780.

COPYRIGHT 2000 The Center for AIDS: Hope & Remembrance Project
COPYRIGHT 2000 Gale Group

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