Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse transcriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations. In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in 1 study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity. Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest.
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PMID:Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. 137 14

Great strides have been made in the therapy of human immunodeficiency virus (HIV) infection. Currently approved drugs include zidovudine and didanosine. A third drug, dideoxycytidine (zalcitibine), has recently been filed for approval with the Food and Drug Administration. All these drugs work through inhibition of the reverse transcriptase enzyme. Zidovudine is the only drug that has shown clinical efficacy against HIV. Treatment of patients with advanced HIV disease (i.e., acquired immune deficiency syndrome [AIDS] or symptomatic infection with < 200 CD4+ lymphocytes per mm3), results in a prolongation and improved quality of life. Zidovudine is the only antiretroviral agent approved for the treatment of asymptomatic patients. Early intervention with zidovudine has been shown to delay progression to AIDS when patients' CD4+ lymphocyte counts decline to less than 500/mm3, irrespective of clinical signs or symptoms of HIV infection. Didanosine is currently indicated for the treatment of patients with advanced HIV disease who are intolerant to or failing zidovudine therapy. The major toxicity of zidovudine is bone marrow suppression with anemia and granulocytopenia (which occurs in from 1% to 45% of patients, depending on the clinical stage of disease and the dose of the drug). Didanosine and zalcitibine have both been associated with a severe peripheral neuropathy, which is generally reversible on cessation of the drug. In addition, didanosine has been implicated as a cause of pancreatitis that has been fatal in a small percentage of cases. The toxicities of didanosine and zalcitibine range from 1% to 10%, depending on dose, duration of therapy, and the presence of underlying HIV-related peripheral neuropathy or a previous history of pancreatitis. The clinical hallmark of HIV infection is the development of opportunistic infections and malignancies, which are a consequence of the profound immunodeficiency. The risk of an opportunistic infection increases significantly as the T-helper lymphocyte count declines to less than 20%, or 200 to 250/mm3. The spectrum of opportunistic infections ranges from viruses to protozoa. Patients with advanced HIV disease are also at increased risk of infection with nonopportunistic, community-acquired pathogens. Primary and secondary prophylaxis against the most common AIDS-defining opportunistic infection, Pneumocystis carinii pneumonia, is now recommended. Studies are currently underway to determine the efficacy of prophylaxis against other opportunistic pathogens. Treatment of opportunistic infections associated with AIDS has improved significantly over the past 5 years as new drugs and combination regimens of antimicrobials have been developed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:AIDS: Part II. 139 36

Therapy of AIDS comprises two aspects: (1) causative therapy, directed against HIV, and (2) symptomatic therapy of opportunistic infections and malignancies. The best results regarding antiretroviral therapy - both in vitro and in vivo - have been obtained, so far, with inhibitors of reverse transcriptase. We discuss the mechanism of action, the efficacy, and the side effects of AZT, a nucleoside analogue, and comment on combined therapies with acyclovir and immunomodulators. We report on the therapy of the most frequent opportunistic infection - i.e. Pneumocystis carinii pneumonia - with sulfamethoxazole/trimethoprim and pentamidine as well as the chemoprophylaxis of this disease. During the last few years, important progress has been made in the field of antiviral chemotherapy (HSV, CMV, VZV) and the therapy of gastrointestinal infections. Moreover, the therapy of Kaposi's sarcoma associated with AIDS and that of non-Hodgkin's lymphoma has been established by now.
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PMID:[AIDS therapy]. 220 64

Zidovudine (Retrovir) is the only drug found to be useful for managing human immunodeficiency virus (HIV) infection in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The drug is virostatic, ie, it prevents replication of HIV by inhibiting the enzyme reverse transcriptase. Zidovudine is well tolerated and provides short-term benefits by improving the quality of life and extending survival time. It is expensive and can be toxic, however, so its use requires close supervision. Zidovudine at present is approved only for patients with documented Pneumocystis carinii pneumonia or with a CD4 count below 200/mm3. Other probable indications include HIV wasting syndrome, HIV dementia complex, oral candidiasis, Kaposi's sarcoma, the presence of early markers of HIV infection, and HIV-related symptomatic thrombocytopenia. A stepwise approach to initiating zidovudine therapy should include detailed counseling and close surveillance.
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PMID:Zidovudine for treating AIDS. What physicians need to know. 266 55

3'-azido-3'-deoxythymidine is a thymidine analogue with an in vitro as well as in vivo efficacy towards HIV-mediated infection. Zidovudine exerts its action, following an intracellular three-step phosphorylation, through viral reverse transcriptase inhibition. Its half-life is approximately one hour. Oral biodisponibility is 65%, and passage through blood-brain barrier results in therapeutic levels is CSF. Clinical evaluation has enabled demonstration of a beneficial effect on survival of stage IV AIDS patients, when treated after a PCP episode. In this setting, aggregate survival ratios reach 73% after one year of follow-up, and 41% after 2 years. In addition, zidovudine activity has been demonstrated in treatment of HIV-induced thrombopenias as well as HIV-related central nervous system disorders. Presently, zidovudine therapeutic evaluation proceeds through the following main axes: dosage tuning (either by lowering of standard dose, and/or dose interval modification); combination with other antiviral therapies; lastly, patient treatment et an early stage of disease.
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PMID:[Zidovudine. The current status of its evaluation]. 269 36

Nitric oxide (NO) which is produced by activation of Ca2+/calmodulin-dependent NO synthase is known to induce neuronal damage. We examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT, a reverse transcriptase inhibitor), pentamidine (a therapeutic drug for Pneumocystis carinii pneumonia) and calmodulin antagonists such as trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on NO synthase activation. Although AZT had no effect on the activity of constitutive neuronal NO synthase, pentamidine inhibited the activation of neuronal NO synthase as did trifluoperazine and W-7. The inhibition by pentamidine was prevented by the addition of purified calmodulin. In addition, pentamidine inhibited calmodulin-dependent activation of neuronal NO synthase purified from rat cerebellum. From these results, it is suggested that pentamidine inhibits the neuronal NO synthase activation by probably acting as a calmodulin antagonist.
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PMID:Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist. 754 7

Effects of pentamidine, a therapeutic drug for Pneumocystis carinii pneumonia (PCP) in acquired immunodeficiency syndrome (AIDS), on specific bindings of [3H](+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,11-imine maleate (MK-801) and [3H]nitrendipine were investigated in crude synaptic membranes (CSM) of rat brain. Pentamidine inhibited [3H]MK-801 binding but did not change [3H]nitrendipine binding, although neither binding was inhibited by 3'-azido-2',3'-dideoxythymidine or 2',3'-dideoxycytidine (inhibitors for reverse transcriptase of HIV-1), or FK-506 or cyclosporin A (immunosuppressants). In Triton X-100-treated CSM (post-synaptic density-rich fractions), the inhibitory effect of pentamidine on [3H]MK-801 binding was partially prevented by addition of spermine and NMDA plus glycine (Gly). Electrophysiological experiments showed that pentamidine also inhibited Ca(2+)-current evoked by NMDA plus Gly in Xenopus oocytes injected with rat brain mRNA. These results suggest that pentamidine is a potent inhibitor for NMDA receptor/channels.
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PMID:Inhibitory effects of pentamidine on N-methyl-D-aspartate (NMDA) receptor/channels in the rat brain. 774 90

Providing care to human immunodeficiency virus (HIV)-infected children requires a comprehensive, multidisciplinary approach. This review will address the current status of supportive care, treatment of HIV-associated complications and specific antiretroviral therapy. HIV affects multiple locations in the body resulting in a myriad of possible complications. These include opportunistic infections and malignancies secondary to immunodeficiency and central nervous system or other specific organ-related disease secondary to direct HIV involvement. Recent scientific advances have markedly enhanced the quantity and quality of life of HIV-infected children. Prophylaxis of Pneumocystis carinii pneumonia is the single most important therapeutic advance for the HIV-infected patient. Other advances for the treatment and prevention of HIV-related infections should similarly improve survival and reduce hospital stays. Antiretroviral therapy is relatively new. The currently available nucleoside reverse transcriptase inhibitors have proven efficacy. The role of single agents or combinations is being established. However, this group of antivirals has limitations that make alternate approaches essential. Augmentation of the patient's immune response will likely be a key to any future successful treatment regimen.
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PMID:Treatment of human immunodeficiency virus infection and its associated complications in children. 813 47

A majority of reported human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors are polyhydroxylated aromatic compounds containing two phenyl rings separated by aliphatic or aromatic linkers. Most inhibitors possessing a catechol moiety exhibit considerable toxicity in cellular assays. In an effort to identify nonhydroxylated analogs, a series of aromatic sulfones were tested for their ability to inhibit the 3' processing and strand transfer steps that are necessary for HIV replication. Several aromatic sulfones have previously been shown to have moderate activity against HIV-1 reverse transcriptase in cellular assays; however, their inhibitory potencies against IN have not been explored. In the present study, the inhibitory effect of a series of sulfones and sulfonamides against IN was determined. Among 52 diaryl sulfones tested, 4 were determined to be highly potent (50% inhibitory concentration [IC50], 0.8 to 10 micrograms/ml), 5 had good potencies (IC50, 11 to 50 micrograms/ml), 10 showed moderate potencies (IC50, 51 to 100 micrograms/ml), and 33 were inactive (IC50, > 100 micrograms/ml) against IN. All of the active compounds exhibited similar potencies against HIV-2 IN. Sulfa drugs, used extensively in treating Pneumocystis carinii pneumonia, a leading cause of morbidity and mortality in AIDs patients, were also examined. Among 19 sulfonamides tested, sulfasalazine (IC50, 50 micrograms/ml) was the most potent. We conclude that potent inhibitors of IN can be designed based on the results presented in this study.
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PMID:Diarylsulfones, a novel class of human immunodeficiency virus type 1 integrase inhibitors. 902 Nov 96

Recent advances in the chemotherapeutic agents against HIV enabled us to conduct combination therapies using two nucleoside reverse transcriptase inhibitors and a protease inhibitor. The three-drug combination chemotherapies have been shown to be very potent in inhibiting HIV replication; they markedly suppress plasma HIV-RNA levels, elevate CD4 counts, reduce opportunistic infections and prolong survival of the patients. Early and hard treatment is now recommended. Among opportunistic infections in patients with HIV infection/AIDS, most frequent are respiratory tract infections including Pneumocystis carinii pneumonia, bacterial pneumonia, pulmonary tuberculosis, CMV pneumonia and fungus infections. Sensitivity and specificity of PCR method to detect Pneumocystis carinii are much better than the conventional Grocott stain of sputa. Early diagnosis of tuberculosis and atypical mycobacteriosis became possible using PCR and other molecular technology. Multi-drug resistant tuberculosis is fortunately rare among Japanese HIV-positive patients. Early and correct diagnosis of opportunistic infections markedly improves the prognosis of the patients.
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PMID:[HIV Infection/AIDS and respiratory tract infections in Japan]. 979 9


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