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)

Irreversible congenital heart block (CHB) and the transient rash of neonatal lupus are strongly associated with maternal antibodies to SSA/Ro and SSB/La proteins; however, the precise mechanism by which these antibodies mediate organ-specific injury is not yet defined. Culturing of keratinocytes has provided critical insights. Accordingly, successful culturing of human fetal cardiac myocytes at high yield would constitute a powerful tool to directly examine conditions that promote expression of the target autoantigens. To accomplish this aim, fetal cardiac myocytes from 18- to 22-wk abortuses were established in culture using a novel technique in which cells were isolated after perfusion of the aorta with collagenase in a Langendorff apparatus. After preplating to decrease fibroblast contamination, cardiocytes were grown in flasks and slide chambers. Staining with monoclonal anti-sarcomeric alpha-actinin revealed the expected striations typical of cardiac myocytes in 70-90% of the cells after 4 d in culture. Furthermore, the cells were observed to beat at rates varying between 25-75 beats per minute (bpm) after the addition of 1.8 mM CaCl2. An average yield of 45-60 x 10(6) cells was obtained from a 3- to 5-g heart. Cellular localization of SSA/Ro and SSB/La by indirect immunofluorescence and demonstration of mRNA expression by reverse transcriptase polymerase chain reaction supports the feasibility of cultured cardiac myocytes for the study of congenital heart block. In contrast to the increased expression of SSA/Ro reported for keratinocytes, incubation of cultured human cardiac myocytes with either 17beta-estradiol or progesterone did not alter mRNA expression or cellular localization of 48 kD SSB/La, 52 kD SSA/Ro, or 60 kD SSA/Ro. In summary, we describe a novel method to successfully culture human fetal cardiac myocytes that should provide a valuable resource for investigation of the molecular mechanism(s) contributing to the development of congenital heart block. Differential constitutive and estradiol-induced expression of 52 and 60 kD SSA/Ro in human cardiac myocytes compared with keratinocytes may be a factor contributing to the marked discordance of clinically detectable injury in these two target tissues.
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PMID:mRNA and protein expression of SSA/Ro and SSB/La in human fetal cardiac myocytes cultured using a novel application of the Langendorff procedure. 1002

HIV-1 subtype C predominates in Zimbabwe. To identify factors which contribute to the HIV/AIDS epidemic in Zimbabwe, clinical and virologic characteristics of recently acquired HIV-1 subtype C infection among 21 men and 1 woman were determined. Among 12 of the 19 men who provided clinical histories, a sexually transmitted infection preceded serologic evidence of HIV-1, while 14 of 19 men complained of rash or fever before seroconversion. Quantitative p24 antigen levels, reverse transcriptase activity, and HIV RNA levels of 22 viral isolates correlated with in vitro infectivity in peripheral blood mononuclear cells. Biologic phenotype assessed in MT-2 cells found that 3 of 22 (14%) isolates were syncytia-inducing (SI), while the remaining 19 were non-syncytium-inducing (NSI). The early growth of HIV in culture was associated with increased plasma HIV RNA levels, decreased CD4 cell levels, and SI virus. These cases of recent HIV-1 subtype C infection through heterosexual transmission in Zimbabwe manifested clinical and virologic features consistent with reports of seroconversion to subtype B viruses.
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PMID:Primary subtype C HIV-1 infection in Harare, Zimbabwe. 1004 1

Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog reverse transcriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase I study was conducted to evaluate the pharmacokinetics and safety of abacavir following the administration of two single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected children ages 3 months to 13 years. Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was rapidly absorbed, with the time to the peak concentration in plasma occurring within 1.5 h postdosing. Pharmacokinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (Cmax) and the mean area under the curve from time zero to infinity (AUC0-infinity) increased by 16 and 45% more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (Cmax increased from 1.69 to 3.94 micrograms/ml, and AUC0-infinity increased from 2.82 to 8.09 micrograms.h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. The mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the dose increased. Neither body surface area nor creatinine clearance were correlated with pharmacokinetic estimates at either dose. The extent of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight. In conclusion, this study showed that abacavir is safe and well tolerated in children when it is administered as a single oral dose of 4 or 8 mg/kg.
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PMID:Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. 1004 75

Nevirapine is the first member of a new therapeutic class (NNRTI: non nucleoside inhibitors of the reverse transcriptase) in the treatment against human immunodeficiency virus (HIV). In association with two other antiretroviral products, it reduces significantly the viral load and increases the CD4-cells-count, especially in naive patients. Results at six months show that a tritherapy including nevirapine and 2 nucleoside inhibitors of the reverse transcriptase (NRTIs) has a similar efficacy than an association including 1 anti-protease and two NRTIs. Nevirapine is easy to take (1 tablet 2x/day, irrespective of the meals). Its tolerance profile is favourable. The principal side effect is a rash, which can be severe in rare cases.
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PMID:[Nevirapine (Viramune): a new HIV inhibitor]. 1033 4

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key
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PMID:Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. 1042 6

A 31-year-old man with the acquired immunodeficiency syndrome who developed toxic epidermal necrolysis (TEN) was successfully treated with intravenous immunoglobulin. He presented with a widespread, blistering skin rash, extensive mucosal ulceration, high-grade fever and pancytopaenia. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, was suspected as the culprit drug, although the patient had been taking this medication for 6 months. The patient also demonstrated an increased number of gamma/delta (gamma delta) T cells that decreased concomitantly with his clinical improvement. This correlation has not been described in TEN previously and may be of pathophysiological significance.
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PMID:Toxic epidermal necrolysis in acquired immunodeficiency syndrome treated with intravenous gammaglobulin. 1043 28

Measles remains a major cause of childhood mortality, with questions about virus virulence and pathogenesis still requiring answers. Rhesus macaques were infected with 5 different culture-adapted strains of measles virus, including 2 from patients with progressive vaccine-induced disease, and a sixth nonculture-adapted strain, Bilthoven. All caused infection detectable by reverse transcriptase-polymerase chain reaction and induction of antibody. Chicago-1 and Bilthoven induced viremias detectable by leukocyte cocultivation. Bilthoven induced Koplik's spots, conjunctivitis, and rash. Lymphopenia and depressed interleukin (IL)-2 production were followed by monocytosis and eosinophilia. All monkeys, including 41 involved in a primate facility outbreak, showed suppressed responses to phytohemagglutinin. As the rash resolved production of IL-2, IL-1beta, tumor necrosis factor-alpha, IL-6, and IL-5 mRNA increased. Monkeys are useful for studies of measles immunopathogenesis, but virus strains must be carefully chosen. Increased virulence of vaccine strains isolated from immunocompromised infants with fatal infections was not evident.
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PMID:Measles virus infection in rhesus macaques: altered immune responses and comparison of the virulence of six different virus strains. 1047 17

Nevirapine (NVP) is a potent noncompetitive inhibitor of the reverse transcriptase enzyme, which is necessary for HIV replication. NVP selectively inhibits HIV-1 but not HIV-2 and any of the human DNA polymerases. NVP is active against ZDV-resistant HIV-1 and synergistic with nonnucleoside reverse transcriptase inhibitors. NVP has a favorable pharmacokinetic profile, becomes widely distributed throughout body tissues including the central nervous system, and is active in the adult at an oral dose of 200 mg administered twice daily after a 2 week lead-in dose of 200 mg/day due to its long elimination half life. Although the currently used protease inhibitors (PIs) may undergo more rapid rates of metabolism because NVP induces CYP3A, No dosage adjustments are required when NVP is taken in combination with PIs so far. When administered in triple combinations with antiretroviral agents, the antiviral effect of NVP has been profound and sustained in HIV-infected patients, particularly in naive patients to antiretroviral therapy. Resistance to NVP is rapid when given as monotherapy, but this is altered and made less clinically relevant when NVP is administered as a triple combination. NVP has a safety profile that does not overlap with other antiretroviral therapies, the most common treatment-limiting reaction being rash. It seems that NVP would be a very useful option in combination with antiretroviral agents.
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PMID:[Antiretroviral agent nevirapine: its pharmacological action and potential for clinical use]. 1058 33

Non nucleoside reverse transcriptase inhibitors (NNRTI) are a new arm in the treatment of the HIV infection. They inhibit the replication by direct non competitive binding to the enzyme, and do not require phosphorylation. The fast emergence of resistance in monotherapy obliges to use them in a triple association. The 103 mutation confers a cross-resistance. The most common adverse event is rash. Association with nucleoside analogues is additive or even synergistic. They are metabolized by the cytochrome P450. Within a combined therapy, their efficiency is comparable to protease inhibitors, notably in patients with low viral load.
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PMID:[Pharma-clinics. How I treat ... HIV infection. III. Non-nucleoside reverse transcriptase inhibitors]. 1068 94

Measles continues to be a major childhood disease in terms of global morbidity and mortality. In the main areas of its endemicity the only available means of diagnosis are based on clinical criteria: the presence of a maculopapular rash and fever accompanied by cough, coryza, and/or conjunctivitis. We have studied 38 clinically diagnosed cases of measles in Khartoum, Sudan, by means of serology, reverse transcriptase PCR (RT-PCR) on throat swabs and virus isolation from lymphocytes. On the basis of serology, 28 patients were diagnosed as having an acute measles virus (MV) infection, while in 10 cases the clinical symptoms proved to have other causes. It was shown that in cases with low serum immunoglobulin M (IgM) levels, an additional measurement of IgG or virus-neutralizing antibodies was necessary to discriminate between patients with an acute MV infection sampled during an early stage of the disease and patients who had experienced an MV infection in the more distant past. The serological laboratory diagnosis was validated by an MV-specific RT-PCR: for all confirmed measles cases tested a fragment of the correct size which hybridized with a third MV-specific primer could be amplified, while all serologically negative cases were also RT-PCR negative. MV could be isolated from 17 out of 23 of the serologically confirmed cases, demonstrating that virus isolation is less reliable as a diagnostic tool than serology or RT-PCR. This study stresses the urgent need for a rapid diagnostic field test for measles.
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PMID:Serological and virological characterization of clinically diagnosed cases of measles in suburban Khartoum. 1069 84


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