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)

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

Zidovudine, the first widely used antiretroviral agent, prevents replication of the human immunodeficiency virus (HIV) by inhibiting reverse transcriptase. Its use in patients with acquired immunodeficiency syndrome slows progression of the disease and prolongs survival. Zidovudine also significantly reduces the rate of progression to AIDS in adults with asymptomatic HIV infection and CD4 T-lymphocyte counts below 500 per mm3. The major toxicity of the drug is bone marrow suppression resulting in anemia or granulocytopenia, or both. Recently, lower doses have been shown to be effective and are associated with less toxicity.
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PMID:Zidovudine for the treatment of HIV infection. 204 38

A number of cytokines have been shown to have stimulatory activity on multipotent haematopoietic precursors. These include kit ligand (KL), interleukins (IL) 1, 3 and 6 and granulocyte macrophage-colony stimulating factor (GM-CSF). Using reverse transcriptase/polymerase chain reaction method (RT/PCR) we have examined the expression of these cytokines, the c-kit and IL-6 receptors, in long-term bone marrow culture (LTC) adherent layer cells in human bone marrow hypoplasia syndromes. Disorders studied include Fanconi's anaemia (FA, n = 16), idiopathic aplastic anaemia (AA, n = 11), Seckel's syndrome (n = 2), dyskeratosis congenita (n = 2), Shwachman-Diamond syndrome (n = 1), thrombocytopenia with absent radii syndrome (n = 1), acquired amegakaryocytosis (n = 1), paroxysmal nocturnal haemoglobinuria (n = 1) and acquired agranulocytosis (n = 1). IL-6 and GM-CSF expression appeared reduced in most patients with FA, suggesting that impaired production of these cytokines may contribute to the bone marrow failure seen in most patients with FA. In contrast, abundant IL-6 and GM-CSF expression were seen in most patients with AA when compared with the FA group and controls; these may be mediators of a stromal response in this disorder. No obvious differences were seen between the different patients' groups and controls in expression of the other cytokines or cytokine receptors studied.
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PMID:The expression of cytokine and cytokine receptor genes in long-term bone marrow culture in congenital and acquired bone marrow hypoplasias. 751 72

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.
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PMID:Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates. 908 99

Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus disease. To establish its safety profile, we conducted a review of data from prospective US and international clinical trials involving a total of 906 adult patients and 468 pediatric patients treated with NVP. Drug-related adverse events were similar in adults and children, with rash and nausea most frequently reported in adults and rash and granulocytopenia most frequently reported in children. A separate analysis of rash based on data from adult patients in controlled trials demonstrated a 16% rate of NVP-attributable rash in these patients. Of patients with NVP-associated rash, 65% developed rash within the first 6 weeks of therapy, and it has been shown that a lower lead-in dose (200 mg/d vs the standard 400 mg/d) for the first 2 weeks of NVP treatment reduces the frequency of drug-associated rash. Serious rash (Stevens-Johnson syndrome [SJS] or SJS/toxic epidermal necrolysis transition syndrome) occurred with an incidence of 0.3% and clinical hepatitis with an incidence of 1.0% among NVP-treated patients in clinical trials. Adverse event data from long-term clinical trials demonstrated a lower incidence of NVP-related adverse events than in short-term trials of NVP therapy. An analysis of abnormal laboratory findings using thresholds similar to those found in the prescribing information for other commonly used antiretroviral agents and data from controlled trials in adults showed that the most frequently observed laboratory abnormalities were elevations in liver function test results. Approximately 50,000 patients in the United States had been treated with marketed NVP at the time of writing, and postmarketing surveillance has supported the overall safety profile observed in clinical trials. NVP has been shown to be well tolerated in both adult and pediatric patients.
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PMID:Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection. 991 3

The structures, and mechanisms of activation, of plasma membrane intracellular-messenger-activated, non-selective cation channels in animal cells are not well understood. The PC12 adrenal chromaffin cell line is a well-characterized example of a nerve cell. In PC12 cells, 1-oleolyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, initiated the inflow of Ca(2+), Mn(2+) and Sr(2+). Acetylcholine and thapsigargin initiated the inflow of Ca(2+) and Mn(2+), but not of Sr(2+). The activation of bivalent cation inflow by OAG: (i) was mimicked by another membrane-permeant diacylglycerol analogue, 1,2-dioctanoyl-sn-glycerol, but not by the membrane-impermeant analogue 1-stearoyl-2-arachidonyl-sn-glycerol; (ii) was not blocked by staurosporin or chelerythrine, inhibitors of protein kinase C; (iii) was enhanced by RHC80267 and R50922, inhibitors of diacylglycerol lipase and diacylglycerol kinase respectively; and (iv) was inhibited by extracellular Ca(2+). When OAG was added after acetylcholine, the effect of OAG on Ca(2+) inflow was over-and-above that induced by acetylcholine. 2-Aminoethyl diphenylborate (2-APB) inhibited Ca(2+) inflow initiated by either acetylcholine or thapsigargin, but not that initiated by OAG. Flufenamic acid inhibited OAG-initiated, but not acetylcholine-initiated, Ca(2+) and Mn(2+) inflow. OAG-initiated Ca(2+) inflow was less sensitive to inhibition by SK&F96365 than acetylcholine-initiated Ca(2+) inflow. In polyadenylated RNA prepared from PC12 cells, mRNA encoding TRP (transient receptor potential) proteins 1-6 was detected by reverse transcriptase (RT)-PCR, and in lysates of PC12 cells the endogenous TRP-6 protein was detected by Western blot analysis. It is concluded that PC12 cells express a diacylglycerol-activated, non-selective cation channel. Expression of this channel function correlates with expression of the TRP-3 and TRP-6 proteins, which have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann, and Schultz (1999) Nature (London) 397, 259-263].
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PMID:A diacylglycerol-activated Ca2+ channel in PC12 cells (an adrenal chromaffin cell line) correlates with expression of the TRP-6 (transient receptor potential) protein. 1153 32

In Jurkat and human peripheral blood T-lymphocytes, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, activated the influx of Ca(2+), Ba(2+) and Sr(2+). OAG also caused plasma-membrane depolarization in Ca(2+)-free media that was recovered by the addition of bivalent cation, indicating the activation of Na(+) influx. OAG-induced cation influx was (i) mimicked by the natural dacylglycerol 1-stearoyl-2-arachidonyl-sn-glycerol, (ii) not blocked by inhibiting protein kinase C or in the absence of phospholipase C activity and (iii) blocked by La(3+) and Gd(3+). Differently from OAG, both thapsigargin and phytohaemagglutinin activated a potent influx of Ca(2+), but little influx of Ba(2+) and Sr(2+). Moreover, the influx of Ca(2+) activated by thapsigargin and that activated by OAG were additive. Furthermore, several drugs (i.e. econazole, SKF96365, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, 2-aminoethoxy diphenylborate and calyculin-A), while inhibiting the influx of Ca(2+) induced by both thapsigargin and phytohaemagglutinin, did not affect OAG-stimulated cation influx. Transient receptor potential (TRP) 3 and TRP6 proteins have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann and Schultz (1999) Nature (London) 397, 259-263]. In both Jurkat and peripheral blood T-lymphocytes, mRNA encoding TRP proteins 1, 3, 4 and 6 was detected by reverse transcriptase PCR, and the TRP6 protein was detected by Western blotting in a purified plasma-membrane fraction. We conclude that T-cells express a diacylglycerol-activated cation channel, unrelated to the channel involved in capacitative Ca(2+) entry, and associated with the expression of TRP6 protein.
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PMID:Diacylglycerol activates the influx of extracellular cations in T-lymphocytes independently of intracellular calcium-store depletion and possibly involving endogenous TRP6 gene products. 1198 98

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.
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PMID:NQO2 gene is associated with clozapine-induced agranulocytosis. 1461 31

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