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)

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), a potent inhibitor of human immunodeficiency virus reverse transcriptase (in its anabolized triphosphorylated form), mediates virologic and immunologic improvements in AIDS patients. Clinical studies using ddC have shown various ddC-related toxicities, the most pronounced being a dose-limiting peripheral neuropathy. The dose responsiveness and manifestation of the ddC-related neuropathy vary among species, with greatest sensitivity in human > monkey > rabbit whereas mice and rats are insensitive to ddC-related neuropathy. This study has examined nucleotide pool sizes of ddCTP and its constituents (ddC, ddCMP, ddCDP) in cultured fibroblasts (human, rabbit, mouse) and freshly isolated peripheral lymphocytes (monkey, rabbit, rat, and mouse). Cells were treated with 10 microM [3H]ddC and nucleotide pool sizes analyzed by HPLC. The formation of nucleotide pools increased during the 24-hr assay period. Fibroblast pool formation of phosphorylated metabolites was significantly greater in human > rabbit > mouse. Lymphocytes demonstrated a similar pattern with monkey > rabbit > mouse = rat. Total ddC anabolite pools were also found to be significantly smaller (p < 0.05) in rodent lymphocytes than in those of rabbit or monkey, and rodent fibroblasts were smaller than those of human or rabbit (p < 0.05). These findings indicate that nucleoside phosphorylation and intracellular levels of phosphorylated metabolites may play an important role in determining species sensitivity and manifestation of ddC-related toxicity.
...
PMID:Species differences in nucleotide pool levels of 2',3'-dideoxycytidine: a possible explanation for species-specific toxicity. 823 52

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, including the gene for the peripheral myelin protein 22 (PMP-22). Because of the proposal that a decreased dosage of the PMP-22 gene was the cause of HNPP, we evaluated sural nerves from eight patients with the 17p11.2 deletion and from five normal controls. The relative amount of PMP-22 mRNA was significantly lower in HNPP patients compared with normal controls (p < 0.02) using a semiquantitative reverse transcriptase-polymerase chain reaction. There was no significant decrease of Pzero mRNA. Sural nerves from HNPP patients showed normal immunostaining with monoclonal antibodies against PMP-22, Pzero, and myelin basic protein, and only rare myelinated fibers, classified as "tomacula," showed a patchy staining of the compact myelin with monoclonal antibody against PMP-22. The significant underexpression of PMP-22 mRNA in HNPP patients compared with normal controls demonstrates that a decreased dosage of the PMP-22 gene is the most likely pathogenetic mechanism in HNPP.
...
PMID:Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies. 904 Jul 36

Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy. We investigated whether peripheral nerve myelin protein-22 (PMP22), the gene for which is duplicated in hereditary motor sensory neuropathy type la, can also induce EAN. PMP22 cDNA produced by the reverse transcriptase-polymerase chain reaction from rat sciatic nerve was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST). Ten Lewis rats were immunized with purified PMP22 fusion protein (50-100 microg) and eight controls with the same amount of GST. Two additional animals were immunized with each of two peptides (250 microg) of the human PMP22 extracellular sequences. Animals were examined daily until 20 days following immunization, when they underwent neurophysiological examination. A serum sample was then taken, prior to perfusion with glutaraldehyde and removal of the sciatic nerves and cauda equina. PMP22-immunized animals developed antibodies to the fusion protein and five out of 10 developed limp tails. No changes were observed in controls immunized with GST or in animals immunized with peptide. The mean compound motor action potentials elicited in the foot muscles by stimulation of the sciatic nerve at the sciatic notch and of the tibial nerve at the ankle were significantly reduced in the PMP22-immunized group (P < 0.05). Spinal roots from the group of animals immunized with PMP22 showed sparse infiltration of mononuclear cells, oedema and demyelination. PMP22 now deserves consideration as an autoantigen in human acute inflammatory demyelinating polyradiculoneuropathy.
...
PMID:Induction of experimental autoimmune neuritis with peripheral myelin protein-22. 979 45

Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multi-factorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a sub-optimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetyl-L-carnitine) and nerve growth factors such as recombinant human nerve growth factor.
...
PMID:Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. 988 91

Zalcitabine (ddC) is a nucleoside analogue reverse transcriptase inhibitor with demonstrated clinical benefit in combination use. More widespread use of zalcitabine has been limited by a number of factors including peripheral neuropathy and three times daily dosing. However, screening for the risk factors for peripheral neuropathy may enable a reduction in the incidence of neuropathy to below 10%. Additionally, new data on the use of zalcitabine twice daily suggest, based on the long intracellular half-life of the active triphosphate, that this is feasible. Additionally, while limited data exist for zalcitabine in true HAART combinations, data from small trials suggest a similar proportion of responders to standard HAART regimens.
...
PMID:Finding a role for zalcitabine in the HAART era. 1068 30

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
...
PMID:Peripheral neuropathy and antiretroviral drugs. 1129 2

Most of the information available on stavudine (d4T) comes from studies in patients with advanced human immunodeficiency virus (HIV) disease to whom stavudine was administered as monotherapy. Herein, we summarize the results of adding 40 mg stavudine twice daily to previous therapies in patients with mild to advanced immunological disease (mean CD4 T cell count 178 cells/mm3; range 6-480 cells/mm3). In an intention-to-treat, prospective, open trial, 64 patients (84.4% men; mean age 35.2 years) were analysed. Their average time on previous antiretroviral therapy was 19.8 months (range 6-52). Plasma HIV RNA load fell by a mean of 0.64 and 0.74 log at 1 and 3 months, respectively, after the start of stavudine therapy (P <0.001 Sign rank test). The CD4 cell count increased by a mean of 25.1 cells/mm3 in the third month (P = 0.002 Sign rank test). Antiviral activity was independent of the CD4 cell count at baseline, but more pronounced declines in viral load were seen in patients with shorter periods of previous antiretroviral therapy and in those in whom stavudine was combined with didanosine or lamivudine rather than zidovudine. Ten (15.6%) patients discontinued the drug during the first 6 months of treatment because of the development of toxicity (neuropathy in six cases, hepatitis in two, oedema in one and rash in another); all but one of them had CD4 counts < 200 cells/mm3. Another two patients stopped treatment voluntarily. The remaining 52 patients tolerated the drug well for the first 6 months and had a high level of compliance with treatment. In conclusion, stavudine is generally well tolerated and has significant antiretroviral activity when it is administered to patients with extensive previous treatment with multiple reverse transcriptase (RT) inhibitors. It should be expected that the short-term favourable effects of stavudine on laboratory markers will further translate into a reduced progression of disease and improved survival.
...
PMID:Short-term efficacy and safety of stavudine in pretreated HIV-infected patients. 1132 73

Charcot-Marie-Tooth 1A (CMT1A) neuropathy is caused by duplication of the peripheral myelin protein 22 (PMP22) gene, leading to protein overexpression. Although this protein has a role in regulating Schwann cell growth and peripheral myelin compaction, how altered concentrations of PMP22 impair myelination is unknown. We established dorsal root ganglia (DRG) cultures from a transgenic rat overexpressing PMP22 (PMP22tg) to study the behavior of PMP22tg Schwann cells in early stages of development and myelination. We used reverse transcriptase-polymerase chain reaction and light and electron microscopy to study PMP22 expression and myelin formation. Myelin ultrastructure was evaluated in sural nerves from CMT1A patients to compare experimental and human findings. PMP22tg DRG cultures contained a greater number of internodes devoid of myelin, in the absence of remyelination, and increased periodicity of myelin lamellae compared with normal cultures. Widening of myelin lamellae was also observed in CMT1A biopsy specimens. Our results suggest that both functions of PMP22, in regulating Schwann cell differentiation and contributing to peripheral myelin compaction, are affected by its overexpression. The presence of similar myelin abnormalities in PMP22tg cultures and human nerves emphasizes the importance of developing in vitro models of hereditary neuropathies to study their underlying pathomechanisms.
...
PMID:PMP22 transgenic dorsal root ganglia cultures show myelin abnormalities similar to those of human CMT1A. 1145 9

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.
...
PMID:The metabolic toxicities of antiretroviral therapy. 1151 63

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.
...
PMID:An introduction to nucleoside and nucleotide analogues. 1167 69


1 2 3 4 5 Next >>

---