Dideoxycytidine: current clinical experience and future prospects: a summary

Article Abstract:

Researchers have discovered that HIV, the virus which causes AIDS, can be suppressed by agents that inhibit the viral enzyme known as reverse transcriptase; this enzyme is essential for the replication of HIV in the body. The dideoxynucleosides, zidovudine (AZT) and 2',3'-dideoxycytidine (ddC), inhibit the enzyme reverse transcriptase, and are therefore effective against HIV-1 infection. However, AZT treatment is associated with development of myelosuppression (inhibition of bone marrow function) which leads to blood disorders. Its use has also stimulated the development of AZT-resistant strains of HIV. Treatment with ddC has been associated with the occurrence of severe peripheral neuropathy, or nerve disease, which worsens with increasing doses of ddC. Using low doses of ddC reduces the incidence of adverse drug effects, but these doses remain effective at decreasing the levels of p24 antigen, a marker for HIV disease. Reduced ddC doses also remain effective at increasing the numbers of CD4+ lymphocytes, which are immune cells that are particularly vulnerable to destruction by HIV. Simultaneous treatment with both ddC and AZT allows the use of lower doses of each drug, resulting in a reduced incidence of toxic side effects. Drug regimens which alternate the use of AZT with ddC provide rest periods from each drug without interrupting anti-HIV treatment. Because AZT and ddC cause different toxicities, simultaneous and alternating regimens of ddC combined with AZT may be effective against HIV disease without causing adverse drug reactions. Clinical trials with human subjects are currently underway to test the effectiveness and safety of combined treatment with AZT and ddC in a simultaneous or alternating regimen. However, ddC is still an experimental drug and should not be used without clinical supervision. (Consumer Summary produced by Reliance Medical Information, Inc.)

Dosage and administration, Zidovudine

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Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus

Article Abstract:

The incidence of acquired immunodeficiency syndrome (AIDS) and infection by the human immunodeficiency virus (HIV), which causes AIDS, is increasing. HIV can be suppressed by agents that inhibit the viral enzyme called reverse transcriptase, which is essential for the replication, or production, of the virus. One of the first reverse transcriptase inhibitors was zidovudine (AZT), which has been shown to suppress HIV infection and prolong the life of patients with AIDS or AIDS-related complex (ARC). However, AZT causes myelosuppression, the inhibition of bone marrow function, and its widespread use has resulted in the development of HIV strains that are resistant to its effects. A more recently developed antiviral agent, 2',3'-dideoxycytidine (ddC), was shown to be a powerful inhibitor of reverse transcriptase. Doses of ddC as low as 0.5 micromoles per liter (uM/L) protect T cells, a type of immune cell that is particularly vulnerable to destruction by HIV. The activation of ddC depends on its phosphorylation, or the addition of a phosphate group, resulting in the formation of its 5'-triphosphate form. Current research is focusing on changing the ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate within the cell. The time taken to eliminate half of the administered dose of ddC is 1.2 hours. After oral ingestion, the bioavailability, or percentage of drug left for therapeutic action, is 87 percent, and 75 percent of ddC is eliminated unchanged in the urine. This new antiviral agent, ddC, was shown to be effective against HIV infection and to improve immune deficiencies, but causes as a side effect painful peripheral nerve disease. The use of lower doses of ddC with or without AZT may decrease toxicities associated with these antiviral agents, and is currently under investigation. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Dideoxycytidine (ddC): a potent antiretroviral agent for human immunodeficiency virus infection: an introduction

Article Abstract:

The effectiveness and safety of 2',3'-dideoxycytidine (ddC) in treating acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) has been assessed in clinical trials with human volunteers for the past three years. The results of some of these studies were presented at a symposium on ddC held in February 1990 in San Francisco, California. The human immunodeficiency virus (HIV), which causes AIDS, can be suppressed by agents that inhibit the viral enzyme reverse transcriptase, which is essential for the replication, or production, of the virus. One of the first reverse transcriptase inhibitors was zidovudine (AZT), which has been shown to suppress HIV infection and increase the duration of survival of patients with AIDS or ARC. However, AZT causes myelosuppression, or inhibition of bone marrow function, and its widespread use has also resulted in the development of AZT-resistant viral strains. The more recently developed reverse transcriptase inhibitor, ddC, has been tested with and without AZT for its ability to inhibit HIV replication. Treatment with ddC was shown to be associated with severe peripheral neuropathy, or disease of the peripheral nervous system, which was related to the dose and schedule, or timing, of ddC administration. The safety and effectiveness of ddC treatment can only be established by long-term clinical trials. The combined use of AZT and ddC may permit lower doses of each antiviral agent to be used and thereby may decrease the incidence of serious toxic effects. This might also prevent the development of drug-resistant strains of HIV. (Consumer Summary produced by Reliance Medical Information, Inc.)

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