Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of skeletal muscle tissue (cachexia) is one of the hallmarks of HIV infection. It has been found (1) that creatine kinase, i.e., an enzyme of pivotal importance in muscular mitochondrial energy metabolism, is inhibited by oxidative glutathiolation, and (2) that reduced glutathione (GSH) is decreased in skeletal muscle of SIV-infected rhesus monkeys. We, therefore, have studied the phosphocreatine (P-Cr) levels. Muscle tissue from SIV-infected macaques showed significantly decreased P-Cr but normal creatine (Cr), ATP, and ADP when compared with uninfected macaques. Individual P-Cr levels were significantly correlated with GSH. Our findings may explain the dysregulation of energy metabolism in cachexia.
 ...
PMID:Decrease in phosphocreatine level in skeletal muscle of SIV-infected rhesus macaques correlates with decrease in intracellular glutathione. 928 13

Human immunodeficiency virus (HIV-1) associated myopathy can be a debilitating disease in humans, leading to weakness, myalgia, and muscle wasting. Subclinical neuromuscular involvement is also common. A range of histologic lesions have been described in both forms that include both inflammatory and degenerative changes. The purpose of this study was to determine whether a myopathy was present in adult cats experimentally infected with feline immunodeficiency virus (FIV). Six specific pathogen-free, laboratory-housed cats were challenged intravenously with 1000 TCID50 of the Maryland isolate of FIV (FIV-MD) at 8 months of age. The highest serum creatine kinase values were seen at 18 months postinfection (mean 9838, SD 4805 U/L) compared to preinfection (mean 950, SD 374 U/L). Needle EMG studies revealed abnormal spontaneous activity in 2 cats. All FIV-MD infected cats exhibited at least one abnormality in muscle pathology. Of the 24 muscle samples, 15 (63%) had histopathologic lesions. The predominant histologic abnormalities consisted of perivascular and pericapillary lymphocytic infiltration, and myofiber necrosis, phagocytosis, and regeneration. Lymphocytic infiltration was graded 2+ or higher in 12 of 24 muscle samples (0 = negligible; 4+ = extensive). Immunohistochemical phenotypic lymphocyte labeling in all cats demonstrated only CD8+ lymphocyte staining. This report demonstrates the presence of a FIV associated inflammatory myopathy in the adult cat. Several similarities are apparent in comparison to HIV-1 associated polymyositis reported in humans. Future studies in the cat may thus prove useful in elucidating the pathogenesis of retrovirus related myopathy in humans.
 ...
PMID:Feline immunodeficiency virus associated myopathy in the adult cat. 984 69

Acute exercise is known to activate the immune system and thus could lead to increased human immunodeficiency virus (HIV) replication. We sought to determine whether a single acute bout of exercise, similar to what people experience when starting an intensive exercise program, has a detrimental effect on plasma HIV RNA levels. Twenty-five patients with HIV infection performed one 15-min bout of acute exercise. Absolute neutrophil counts, serum creatine phosphokinase, and 72-h urinary 3-methylhistidine (a marker of muscle protein breakdown) were measured before and after the exercise, along with plasma HIV RNA levels. There were increases in neutrophil counts (P < 0.06), serum creatine phosphokinase (P < 0. 01), and urinary 3-methylhistidine (P < 0.01) in response to exercise, indicating a mild acute-phase response with muscle proteolysis. However, mean HIV RNA, which was elevated at baseline in 22 of the 25 subjects (mean of 4 x 10(5) +/- 0.7 x 10(5) copies/ml), did not increase during the week after exercise (P = 0. 12). Small changes in RNA were seen in the three subjects with initially undetectable HIV RNA, but the significance of these changes is unclear. Acute exercise does not have a deleterious effect on HIV replication in adults with high viral loads. Because regular exercise training has not been shown to activate the acute-phase response, the lack of increased viral loads in response to an acute exercise intervention suggests that exercise training is safe in people with HIV infection.
 ...
PMID:Effect of a single bout of acute exercise on plasma human immunodeficiency virus RNA levels. 1019 3

The phosphoramidate triester prodrugs of anti-human HIV 2', 3'-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5'-monophosphate (ddNMP), resulting in an improved formation of ddN 5'-triphosphate and, hence, higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of 2',3'-didehydro-2', 3'-dideoxythymidine (d4T) in both wild-type and thymidine kinase-deficient CEM cells, the concept is far less successful for the 3'-azido-2',3'-dideoxythymidine (AZT) triesters. We now investigated the metabolism of triester prodrugs of d4T and AZT using pure enzymes or different biological media. The efficiency of the first activation step, mediated by carboxylesterases, consists of the formation of the amino acyl ddNMP metabolite. The efficiency of this step was shown to be dependent on the amino acid, alkyl ester, and ddN moiety. Triesters that showed no conversion to the amino acyl ddNMP accumulated as the phenyl-containing intermediate and had poor, if any, anti-HIV activity. In contrast to the relative stability of the triesters in human serum, carboxylesterase-mediated cleavage of the prodrugs was found to be remarkably high in mouse serum. The subsequent conversion of the amino acyl ddNMP metabolite to ddNMP or ddN was highest in rat liver cytosolic enzyme preparations. Although L-alaninyl-d4TMP was efficiently converted to d4TMP, the main metabolite formed from L-alaninyl-AZTMP was the free nucleoside (AZT), thus explaining why d4T prodrugs, but not AZT prodrugs, retain anti-HIV activity in HIV-infected thymidine kinase-deficient cell cultures. The rat liver phosphoramidase responsible for the formation of ddNMP was shown to be distinct from creatine kinase, alkaline phosphatase, and phosphodiesterase.
 ...
PMID:Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. 1049 51

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.
 ...
PMID:Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. 1155 62

Studies of ischemia/reperfusion (I/R) injury and preconditioning have shown that ion homeostasis, particularly calcium homeostasis, is critical to limiting tissue damage. However, the relationship between ion homeostasis and specific cell death pathways has not been investigated in the context of I/R. Previously we reported that calpain cleaved Bid in the absence of detectable caspase activation (1). In this study, we have shown that an inhibitor of the sodium/hydrogen exchanger prevented calpain activation after I/R. Calpain inhibitors prevented cleavage of Bid as well as the downstream indices of cell death, including DNA strand breaks, creatine kinase (CK) release, and infarction measured by triphenyl tetrazolium chloride (TTC) staining. In contrast, the broad spectrum caspase inhibitor IDN6734 was not protective in this model. To ascertain whether mitochondrial dysfunction downstream of these events was a required step, we utilized a peptide corresponding to residues 4-23 of Bcl-x(L) conjugated to the protein transduction domain of HIV TAT (TAT-BH4), which has been shown to protect mitochondria against Ca2+-induced deltaPsi(m) loss (2). TAT-BH4 attenuated CK release and loss of TTC staining, demonstrating the role of mitochondria and a pro-apoptotic Bcl-2 family member in the process leading to cell death. We propose the following pathway. (i) Reperfusion results in sodium influx followed by calcium accumulation. (ii) This leads to calpain activation, which in turn leads to Bid cleavage. (iii) Bid targets the mitochondria, causing dysfunction and release of pro-apoptotic factors, resulting in DNA fragmentation and death of the cell. Ischemia/reperfusion initiates a cell death pathway that is independent of caspases but requires calpain and mitochondrial dysfunction.
 ...
PMID:Calpain and mitochondria in ischemia/reperfusion injury. 1204 24

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.
 ...
PMID:Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. 1221 67

Muscular fatigue may result from HIV infection, and may be associated with antiretroviral drug treatment. Clinical features linked to muscle biopsy findings may assist in determining etiology, and guide treatment decisions. This case series examined HIV patients in an ambulatory HIV clinic who received antiretroviral therapy, and complained of unexplained muscular fatigue. Clinical features with measurement of acid-base status, levels of lactate, aminotransferases, triglycerides and creatine kinase were correlated to light and electron microscopic results of muscle biopsy. Three patients with acquired mitochondrial changes on biopsy shared common features of lactatemia, elevated aminotransferases and triglycerides, and ultrasonographic hepatic steatosis. A fourth patient with normal mitochondria had myositis with fibrosis, but no systemic symptoms. Biochemical parameters were unremarkable, except for a high creatine kinase. Acquired mitochondrial disease may manifest as systemic illness and muscular fatigue. Unique metabolic changes and other organ dysfunction may precede overt physical signs of HIV myopathy.
 ...
PMID:Clinical correlates to muscle biopsy findings in HIV patients experiencing fatigue: a case series. 1294 81

THREE GROUPS OF PRIMARY INFLAMMATORY MUSCLE DISEASES: The primary inflammatory muscle diseases comprise three main subsets: polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). PM and DM are characterized by a proximal weakness that develops along weeks to months and by elevated creatine phosphokinase levels. Cutaneous involvement including both erythema and edema and infantile or adult onset are DM specific. PM and IBM only concern adults. Several PM/DM manifestations must be searched for because of their severity: swallowing disorders, various mechanisms of respiratory dysfunction (swallowing pneumopathies, interstitial lung disease, respiratory muscle deficiency) and cardiac involvement. DIAGNOSTIC ELEMENTS FOR PM AND DM: Two investigations, beside biopsy, are particularly useful: muscle MRI imaging showing inflammatory pattern and specific detection of antisynthetase autoantibodies (PM/DM with interstitial lung disease) and anti-Mi-1 and 2 in DM. PHYSIOPATHOLOGICAL DATA: PM and DM differ in their histological and physiopathological characteristics: perivascular B and CD4 lymphocyte infiltrates and complement deposits at the origin of humoral induced vascular disease in DM and perimysial CD8 lymphocytes inducing a cellular mediated cytotoxic injury in PM. Class I HLA antigen expression on the muscle fibers and production of cytokines play a crucial role in the pathogenesis of these two diseases. PM and DM may be associated with cancers, connective-tissue disease (overlap syndrome). Some PM are secondary to HIV, HTLV1 virus and toxoplasmosis infection. CHARACTERISTICS OF INCLUSION BODY MYOSITIS: IBM, the most frequent acquired myopathy after 50 years of age, is characterized by particular features: not only clinical (late onset, selective weakness, early distal involvement, slow course, unresponsiveness to corticosteroid and immunosuppressant agents); but also histological (rimmed vacuoles, filamentous inclusions) and pathogenic (cytotoxic and degenerative inflammatory process, similar to Alzheimer's disease, with beta-amyloid protein accumulation).
 ...
PMID:[Polymyositis, dermatomyositis and inclusion body myositis, nosological aspects]. 1463 Dec 70

HIV affects many organs of the body, including the nervous system. As a result, a series of neurologic complications have created challenges for scientists and clinicians alike. Among these, HIV-associated neuropathy and myopathy may occur at all stages of the disease process. Of the neuropathies, distal symmetrical polyneuropathy is the most common form. The pathogenesis of primary HIV neuropathy is unknown. Other types of neuropathy seen in HIV-infected subjects include toxic neuropathy, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, and mononeuritis multiplex. In this review, we present the clinical manifestations, pathogenesis, diagnosis, and management of different types of neuropathy in HIV infection. Myopathy, another complication of HIV, is not associated with any particular stage of immunosuppression. Symptoms include symmetrical weakness of the proximal muscles in the extremities. Serum creatine kinase levels are often moderately elevated. Electromyography and muscle biopsy are helpful tests for diagnosis. Treatment of HIV myopathy includes corticosteroids, nonsteroidal anti-inflammatory agents, and intravenous immunoglobulin.
 ...
PMID:Neuromuscular complications in HIV. 1468 31


<< Previous 1 2 3 4 5 Next >>