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

---

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

Several new nucleoside analogues have been developed which can inhibit hepatitis B replication by at least two logs. Lamivudine is the most widely studied of these new agents. Extensive phase II and III studies in patients with chronic hepatitis B have been completed. The sustained HBeAg seroconversion rate in patients who have received 100 mg lamivudine increases from 17% after a year of treatment to 27% after 2 years of treatment. Histological improvement has been noted in 38%-52% of lamivudine-treated patients, exceeding the improvement seen in placebo recipients. Similar histological improvement has been noted in anti-HBe-positive, DNA- positive patients. Lamivudine can prevent recurrence of hepatitis B after liver transplantation. It is likely that in the absence of immune clearance to accelerate elimination of infected hepatocytes, inhibitors of virus replication such as lamivudine will need to be administered for a long period to reduce the burden of infected hepatocytes in the liver, and to prevent relapse. The drug is generally well tolerated with few direct adverse events. Genotypic mutations have been observed in 23% (range 13-32%). In a study in Asian patients treated for two years the incidence of these mutants increased to 38% (as detected by PCR). Loss of susceptibility to lamivudine has been found to be due to reverse transcriptase amino acid substitutions. Lamivudine is likely to be reserved for patients with replicative hepatitis B infection with active chronic hepatitis, and/or active cirrhosis. Copyright 1998 John Wiley & Sons, Ltd.
...
PMID:Lamivudine treatment of chronic hepatitis B. 1039 3

We report that simian immunodeficiency virus (SIV) infection in macaques is a valuable animal model for studying post-exposure chemoprophylaxis (PECP). PECP with the acyclic nucleoside reverse transcriptase inhibitors 9-(2-phosphonylmetho-xyethyl)adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) at early viral infection can provide long-term protection against subsequent heterologous SIV challenge. Eight macaques previously treated with PECP (called PECP macaques) and four naive controls were challenged intravenously with the most virulent form of SIV, SIV(PBj14). All controls showed signs of SIV(PBj14)-induced acute disease syndrome on days 6 and 7 post-inoculation (PI). One had a fatal viral infection and two surviving controls had persistent infection and decreased CD4+ cell count. Virologic studies of the three surviving controls revealed SIV in multiple lymphoid tissues and peripheral blood mononuclear cells (PBMCs) at necropsy. In contrast, the PECP macaques showed none to mild signs of acute disease syndrome at day 9 PI and exhibited only transient SIV infection in PBMCs between weeks 1 and 8 PI. In virologic studies of five PECP macaques necropsied, two macaques were SIV-negative and the other three were SIV-positive only in either lymph node or bone marrow. Three SIV(PBj14)-challenged PECP macaques, that were randomly reserved for a follow-up study for > 4.0 years PI showed extremely low to undetectable levels of PBMC-associated viremia and normal to increased levels of CD4 + and CD8 + cell counts throughout the study. Our results indicate that early PECP could activate immune responses to protect against subsequent infection with heterologous challenge virus.
...
PMID:Post-exposure chemoprophylaxis (PECP) against SIV infection of macaques as a model for protection from HIV infection. 1108 87

Since many new anti-HIV drugs are variations of currently available drugs, they may be more effective for people who are beginning treatment. One study shows favorable results when using efavirenz in triple combination therapy; however, it is recommended that this therapy be reserved for people who are treatment-naive and symptom-free. It is still unclear if all non-nucleoside RT inhibitors (NNRTIs) are as potent as efavirenz and whether the long-term potential for them is as promising as standard combinations. Researchers caution against pairing an NNRTI with a protease inhibitor in the event that resistance to the combination develops. That resistance may eliminate the option of using any other protease inhibitor or NNRTI in future therapies. Conversely, abacavir, an NARTI, has been effective in combination with many protease inhibitors. Amprenavir shows good antiviral activity; although studies show that it may not be successful as a salvage therapy with protease inhibitors. Nucleotide analogue reverse transcriptase inhibitors, such as adefovir and bis-poc PMPA, showed moderate anti-HIV potency. A study evaluating FTC alone showed a good reduction in viral load. FTC also fights hepatitis B and requires only one dose daily. Information is included about expanded access programs for abacavir, adefovir, and efavirenz.
...
PMID:New drugs on the horizon. 1136 12

Our interest in the male accessory glands (MAGs) of Leptinotarsa decemlineata was raised recently by our finding that certain cells produce a secretory substance that is recognized by one of our monoclonal antibodies (MAC-18), developed for the immunohistochemical demonstration of peptidergic neurons in the brain. We undertook to isolate this substance, presumably a peptide, to find out more about its role in the post-mating physiology of the recipient of this peptide, the mated female. This paper describes the purification and chemical characterization of the immunoreactive peptide from 100 pairs of male accessory glands. The peptide was purified by two subsequent reversed-phase-HPLC runs, and fractions were analyzed on Western blots that were immunostained by MAC-18. This indicated the presence of an 8 kDa peptide in the MAG. Partial analysis of the N-terminal amino acids by automated Edman degradation revealed a sequence of 40 amino acid residues. To obtain the full amino acid sequence of this peptide, the technique of reverse transcriptase PCR (3'RACE) was used. A PCR product of 350 bp was obtained, which encoded the 3'-end of the mRNA. After cloning and sequencing, this product contained most of the genetic information of the MAG peptide. The PCR product was also used as a probe for screening a cDNA library constructed from mRNA extracted from MAGs. The nucleotide sequence coding for the signal peptide was elucidated by 5'RACE. The cDNA and 5'RACE clones were analyzed and sequenced. The sequence of the cDNA clone contained an insert of 411 bp, which agreed well with the mRNA size measured by Northern blotting. Translation of the DNA sequences confirmed the data from partial amino acid sequence analyses and also predicted the remainder of the amino acid sequence. The entire peptide, designated Led-MAGP, consists of 74 residues; its mass was calculated and confirmed by mass spectrometry at 7971 Da. The peptide contains seven imperfect hexa-repeats, and this hexa-repeat sequence shows remarkable similarity to the hexa-repeat section of the chicken prion protein. The physiological function of the peptide has yet to be determined, but the hexa-repeat motif has recently been identified as the signal that induces internalization of the prion protein by coated-pit mediated endocytosis. Possible implications for the control of reproductive activities in L. decemlineata are discussed. Copyright 1997 Elsevier Science Ltd. All rights reserved
...
PMID:A Peptide from the Male Accessory Gland in Leptinotarsa decemlineata: Purification, Characterization and Molecular Cloning. 1276 97

Immunotherapy in the form of donor lymphocyte infusions in early-phase relapse might be advantageous as it induces a higher response, but this may be offset by increased toxicity, especially during the early period after transplantation. Among 45 consecutive patients receiving an allograft for CML, 13 patients were diagnosed to have molecular relapse (MRel), as defined by real-time quantitative reverse transcriptase-polymerase chain reaction, and another four patients were diagnosed to have cytogenetic relapse (CRel) within 6 months. Patients with MRel were randomly assigned to either a 'no therapy' group (group A, n=6), in which immunotherapy was reserved until CRel, or an 'immunotherapy' group (group B, n=7). In group A, all MRel progressed to CRel, and molecular remission (MR) was achieved in four (67%) after immunotherapy. The remaining two patients died of extensive GVHD and fungal pneumonia. In group B, only two MRel progressed to CRel and the remaining five (71%) achieved MR. Two patients died in the absence or loss of response. In patients relapsing directly into CRel (n=4), immunotherapy induced MR in two patients (50%). Earlier intervention played a role in preventing disease progression but this effect was not translated into better survival, which could have been overcome by imatinib mesylate, which induced MR and cytogenetic remission in nonresponders without toxicity.
...
PMID:Preemptive treatment of minimal residual disease post transplant in CML using real-time quantitative RT-PCR: a prospective, randomized trial. 1471 40

(1) There is still no cure for HIV infection. The short-term treatment aims are to drive viral load below the current detection limit and to increase the CD4+ T cell count, in order to reduce morbidity and prolong survival. (2) Early initiation of treatment has both advantages and disadvantages. If the patient is symptomatic or if the CD4+ T cell count is below 200 per mm3, antiretroviral treatment should be started immediately. If the patient is asymptomatic, the CD4+ T cell count is above 350 per mm3, and viral load is below 50 000 copies/ml, antiretroviral treatment can often be deferred. Other situations should be considered case by case. (3) The benefits of treating symptomatic primary infection have not been adequately documented, and current recommendations diverge. (4) The advent of new antiretroviral drugs has increased the choice, but cross-resistance often limits treatment options. The new antiretroviral family to have emerged since 1999 is the fusion inhibitor; the only representative of this class, enfuvirtide, is reserved for patients with multiple treatment failure. (5) There is broad agreement on the principles of first-line antiretroviral treatment. It should combine at least two nucleoside (or nucleotide) inhibitors of HIV reverse transcriptase and one non nucleoside inhibitor, or at least one HIV protease inhibitor. Comparative studies have now identified the most effective combinations in terms of virological efficacy and tolerability. The combination should be chosen according to its established efficacy, adverse effects, risks of interactions, and convenience. There is no reference combination suitable for all patients. Among the combinations containing a non nucleoside inhibitor, those based on efavirenz are the most effective after 48 weeks of follow-up. There is less agreement on the optimal treatment of pregnant women. (6) Among the HIV protease inhibitor-based combinations, those containing nelfinavir or the lopinavir + ritonavir combination must be taken during meals. The lopinavir + ritonavir combination showed better virological efficacy than nelfinavir in a comparative trial. Experience and safety evaluation are in favour of nelfinavir, but recent American guidelines issued in November 2003 recommend the lopinavir + ritonavir combination. (7) There is no major difference in virological efficacy between non nucleoside inhibitors and protease inhibitors as first line therapy. (8) In combination with protease inhibitors or non nucleoside inhibitors, the best-assessed nucleoside inhibitors (effective for several years) are lamivudine + zidovudine and lamivudine + stavudine. For first-line treatment, combinations consisting of only three nucleoside (or nucleotide) inhibitors are less effective than combinations containing HIV protease inhibitors or non nucleoside inhibitors. (9) Efficacy is monitored on the basis of changes in viral load and the CD4+ T cell count, one month after the beginning of treatment, then about every three months. Attention must be paid to adverse effects, which may necessitate the replacement of the causative antiviral drug, treatment of the adverse effect, treatment modification or, in extreme cases, treatment withdrawal. (10) Treatment failures must be carefully investigated: the cause(s) may include poor adherence, drug interactions, and inadequate plasma drug concentrations. Ongoing antiretroviral regimens do not always have to be modified if treatment failure occurs. (11) Resistance tests can help to determine the most effective alternative in case of virological failure due to drug resistance. The choice of back-up treatments is complex, and is limited by cross-resistance. Multiple lines of treatment fail in about 3% to 4% of patients.
...
PMID:Antiretroviral treatment. HIV infection in adults: better-defined first-line treatment. 1553 40

The 10-23 RNA-cleaving DNAzymes require divalent metal ions, preferentially Mg(2+), for catalytic activity. For intracellular applications, it is important that a DNAzyme can perform maximal cleavage at physiological concentration of Mg(2+) (0.2-2mM). We designed DNAzymes targeting the mRNA of human telomere reverse transcriptase, two of them turned out to have large difference in Mg(2+) concentration requirement (1mM vs. 20mM) for maximal activity in vitro. When the two DNAzymes were transfected into HeLa cells, only the one requiring low Mg(2+) concentration showed inhibitory activity indicating that the in vitro property regarding Mg(2+) requirement was reserved in vivo. The cleavage of target RNA mainly involves two processes, that is hybridization of DNAzyme with substrate and cleavage of substrate in the DNAzyme-substrate duplex. To explore how the optimal Mg(2+) concentration was determined, we studied the effect of Mg(2+) on the two processes. For both DNAzymes, Mg(2+) enhanced hybridization over a range of concentration far beyond 1mM. Once the DNAzymes hybridized with their 19-mer substrates without flanking sequences, the cleavages showed little difference in Mg(2+) concentration-dependence. These facts suggest that the flanking sequences played a key role in determining the Mg(2+) concentration for maximal DNAzyme activity possibly via the formation of higher order structure in the DNAzyme-substrate duplex.
...
PMID:Two DNAzymes targeting the telomerase mRNA with large difference in Mg2+ concentration for maximal catalytic activity. 1749 43

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for "advanced salvage" drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for "lowest income" countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.
...
PMID:A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations. 1857 Dec 46

First-line treatment for HIV infection consists of a combination of antiretroviral drugs, specifically including a non-nucleoside reverse transcriptase inhibitor or an HIV protease inhibitor, usually boosted with ritonavir. Raltegravir, the only commercially available HIV integrase inhibitor, marketed since 2007 in the European Union, was initially reserved for patients with multiple treatment failure. It is now authorised for first-line use. Clinical evaluation of first-line raltegravir therapy is based on a comparative double-blind "non-inferiority" trial comparing raltegravir + tenofovir + emtricitabine versus efavirenz + tenofovir + emtricitabine in 566 patients. After 48 weeks, about 84% of the patients in the two arms had undetectable viral load. There are no trials versus other first-line combinations. The adverse effect profile of raltegravir is poorly documented. In the trial comparing raltegravir + tenofovir + emtricitabine with efavirenz + tenofovir+ emtricitabine, adverse effects of the two regimens were generally comparable. In practice, given the lack of firm evidence that raltegravir is a therapeutic improvement over existing first-line regimens, it is better to continue to reserve its use for patients with multiple treatment failure. Many satisfactory first-line combinations have been in use for several years.
...
PMID:First-line raltegravir. No evidence of comparative effectiveness. 2128 54

First-line treatment for HIV infection currently comprises a combination of antiretroviral drugs, including a non-nucleoside reverse transcriptase inhibitor such as efavirenz, or one or two protease inhibitors.The choice is based on the results of initial clinical trials of antiretroviral drugs with morbidity and mortality endpoints, and, since the 1990s, on trials with surrogate markers (viral load and the CD4+ T lymphocyte count). Maraviroc is the only CCR5 antagonist currently on the market. Drugs belonging to this class are designed to prevent HIV entry into CD4 T lymphocytes. Maraviroc is reserved for patients with multiple treatment failure, but has also been proposed for first-line treatment. Clinical evaluation of maraviroc in first-line treatment is limited to a single comparative trial designed to show the virological and immunological "non-inferiority" of the maraviroc + zidovudine + lamivudine combination versus efavirenz + zidovudine + lamivudine, after 96 weeks of treatment, in 721 patients with CCR5-tropic HIV strains. A more sensitive version of the test used to determine CCR5 tropism became available during the trial, leading to the exclusion of 107 patients who were infected by strains capable of using other coreceptors. This trial fails to answer important questions regarding the adverse effects of maraviroc, such as hepatotoxicity, infections, cancer, and cardiovascular disorders. Tests used to identify exclusively CCR5-tropic HIV strains are difficult to implement and their results are unreliable. This means that some patients in whom maraviroc will not be effective may receive this drug, and will thus be at risk of developing viral resistance to other drugs in their antiretroviral regimen. In practice, first-line use of maraviroc is imprudent, as it depends on a test of uncertain reliability. Furthermore, there is no evidence to suggest that maraviroc combination therapy has a better risk-benefit balance than regimens with well-documented and long established efficacy.
...
PMID:Maraviroc first-line therapy for HIV infection. Too risky. 2128 57


1 2 Next >>

---