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

Tuberculosis (TB) is the leading infectious cause of death today and 3.81 million cases occurred in 1997 and 1998. Even today in spite of having four drugs like isoniazid, rifampicin, streptomycin/pyrazinamide and ethambutol for the intensive phase, the total duration of treatment remains six months. Because of the global health problems of TB, the increasing rate of multidrug resistant TB (MDR-TB) and the high rate of co-infection with HIV, the need for effective non-toxic antituberculous agents is essential. Fluoroquinolones have been classified as drugs having low bactericidal activity by the WHO. To date, they have been used for preventive therapy, empirical treatment of patients with TB and retreatment of patients with relapsing TB. In-vitro and in-vivo clinical studies have identified ofloxacin as a promising new agent in the treatment of MDR-TB. Ofloxacin has been advocated by the WHO in case of MDR-TB, when susceptibility to test results are not available before starting the new treatment, in the continuation period (18 months) and if resistance is proven to at least isoniazid and rifampicin.
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PMID:Ofloxacin in multidrug resistant tuberculosis. 1460 81

The appearance of viral strains that are resistant to protease inhibitors is one of the most serious problems in the chemotherapy of HIV-1/AIDS. The most pervasive drug-resistant mutants are those that affect all inhibitors in clinical use. In this paper, we have characterized a multiple-drug-resistant mutant of the HIV-1 protease that affects indinavir, nelfinavir, saquinavir, ritonavir, amprenavir, and lopinavir. This mutant (MDR-HM) contains six amino acid mutations (L10I/M46I/I54V/V82A/I84V/L90M) located within and outside the active site of the enzyme. Microcalorimetric and enzyme kinetic measurements indicate that this mutant lowers the affinity of all inhibitors by 2-3 orders of magnitude. By comparison, the multiiple-drug-resistant mutant only increased the K(m) of the substrate by a factor of 2, indicating that the substrate is able to adapt to the changes caused by the mutations and maintain its binding affinity. To understand the origin of resistance, three submutants containing mutations in specific regions were also studied, i.e., the active site (V82A/I84V), flap region (M46I/I54V), and dimerization region (L10I/L90M). None of these sets of mutations by themselves lowered the affinity of inhibitors by more than 1 order of magnitude, and additionally, the sum of the effects of each set of mutations did not add up to the overall effect, indicating the presence of cooperative effects. A mutant containing only the four active site mutations (V82A/I84V/M46I/I54V) only showed a small cooperative effect, suggesting that the mutations at the dimer interface (L10I/L90M) play a major role in eliciting a cooperative response. These studies demonstrate that cooperative interactions contribute an average of 1.2 +/- 0.7 kcal/mol to the overall resistance, most of the cooperative effect (0.8 +/- 0.7 kcal/mol) being mediated by the mutations at the dimerization interface. Not all inhibitors in clinical use are affected the same by long-range cooperative interactions between mutations. These interactions can amplify the effects of individual mutations by factors ranging between 2 and 40 depending on the inhibitor. Dissection of the energetics of drug resistance into enthalpic and entropic components provides a quantitative account of the inhibitor response and a set of thermodynamic guidelines for the design of inhibitors with a lower susceptibility to this type of mutations.
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PMID:Multidrug resistance to HIV-1 protease inhibition requires cooperative coupling between distal mutations. 1462 12

Our purpose was to summarize current knowledge on "multidrug resistance", or MDR, an intrinsic or acquired cross resistance to a variety of structurally and functionally unrelated drugs, still representing one of the major problems in the therapy of cancer and other diseases. MDR depends on various mechanisms, the best known being the activity of ABC transport proteins, mainly Pgp, MDR1 gene product,and MRPs; but also other transporters can cause resistance, for example TAP, a peptide transporter, CFTR, cystic fibrosis transmembrane regulator, ABCG2, or breast cancer resistance protein (BCRP) and LRP, lung resistance protein. MDR has been detected in nearly all types of cancer, because it affects many organs and can occur against a wide number of drugs; it is frequent even in other diseases, such as epilepsy and HIV. We focused on MDR phenomenon in HCC, one of the commonest tumors in the world, and one of the most resistant to pharmacological treatment. This characteristic might be partly determined by a link between MDR and angiogenic phenotypes. The relationship between MDR in hepatocellular carcinoma and the effectiveness of therapeutic treatments has been particularly examined. Finally, the importance to overcome the strong chemoresistance of hepatocellular carcinoma with methods alternative to drugs, namely gene therapy, which makes use of antisense oligonucleotides and anti-MDR1 ribozymes, has been pointed out.
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PMID:[MDR (multidrug resistance) in hepatocarcinoma clinical-therapeutic implications]. 1499 22

Multidrug resistance-1 (MDR-1) is characterized by overfunction of P-glycoprotein (P-gp), a pump molecule that decreases intracellular drug concentration by effluxing them from the intracellular space. Broad ranges of structurally unrelated compounds are transported by P-gp, including antineoplastic agents, HIV protease inhibitors, prednisone, gold salts, methotrexate, colchicine as well as several antibiotics. In contrast, many other compounds such as calcium channel blockers (verapamil) and immunosupressors (cyclosporine-A) are able to inhibit P-gp function. The P-gp role in therapeutic failures has been extensively studied in cancer; however, there is little information regarding MDR-1 phenotype in autoimmune disorders. It has been reported that an increased number of lymphocytes are able to extrude P-gp substrates in rheumatoid arthritis, immune thrombocytopenic purpura and systemic lupus erythematosus, the patients with poor response to treatment being the ones that exhibit the highest values. This may be due, at least in part, to a simultaneous long-term usage of several drugs that induce P-gp function. Since abnormally activated cell compartments characterize autoimmune diseases, it is possible that those cells are the ones that exhibit drug resistance. The study of drug resistance mechanisms in autoimmunity may be helpful for the optimization of the current therapeutic schemes through their combination with low doses of P-gp inhibitors.
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PMID:P-glycoprotein in autoimmune diseases. 1511 Feb 30

Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme (NNRTI) of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the NNRTI binding pocket, the R stereoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding S stereoisomers, as reflected by their 10(4)-fold lower K1 values. The R stereoisomers of several PETT derivatives inhibited recombinant RT in vitro with lower IC(50) values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All the R isomers once again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) at nanomolar concentrations whereas their enantiomers were substantially less potent. The lead compounds in the respective groups were further tested against the NNRTI-resistant HIV strains, A17 (Y181C mutant), and A17Var (Y181C+K103N mutant) and RT MDR (V106N). The results showed that the lead compounds were several logs more potent than the standard NNRTI nevirapine. Structure-activity relationship studies also revealed a preference for the pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of regiochemistry. Our data provides experimental evidence that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity.
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PMID:Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds. 1524 4

We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K(d) of approximately 3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.
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PMID:Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. 1528 Apr 74

The case is 47-year-old, homeless man. He was diagnosed as cavitary, sputum smear positive pan-sensitive lung tuberculosis, and admitted to TB ward of our hospital. At the age of 4-year-old he had tuberculous hilar lymphadenopathy and took medicine. He had no other associated disease, and HIV test was negative. He started standard chemotherapy and 2 months later his sputum culture was converted to negative. His adherence to medicine was thought to be good. But about 2 weeks after the sputum conversion, his sputum culture was re-converted to positive for Mycobacterium tuberculosis. Thereafter, during and after the completion of standard chemotherapy, his sputum culture had been intermittently positive. The drug sensitivity tests of the strain after re-conversion showed multi-drug resistance. RFLP analysis revealed that the strain before conversion was totally different strain from the strain after re-conversion to positive. The case was considered to be caused by the double infection of MDR strain of Mycobacterium tuberculosis during the course of treatment for tuberculosis due to a sensitive strain of Mycobacterium tuberculosis.
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PMID:[Multi-drug resistant lung tuberculosis due to double infection of MDR strain]. 1529 52

Drug-resistant tuberculosis (TB) was reported soon after the introduction of streptomycin, although it did not receive major attention until recently. It was not considered a major issue in the industrialized world until outbreaks of multidrug-resistant TB (MDR-TB) were reported among HIV infected people. Administration of standard short-course chemotherapy (SSCC) with first-line drugs under directly observed therapy (DOT) is the cornerstone of modern TB control. Unfortunately, data available on the treatment outcome of MDR-TB cases under routine programmatic conditions suggest that patients with MDR-TB respond poorly to SSCC with first-line drugs. Since 1994, the World Health Organization and the International Union Against Tuberculosis and Lung Disease (IU-ATLD) have conducted anti-TB drug resistance surveys through a network of subregional laboratories and researchers. Drug resistance was present in almost all settings surveyed, and prevalence varied widely across regions. High prevalence of MDR-TB is widespread in the Russian Federation and areas of the former Soviet Union (Estonia, Kazakhstan, Latvia, and Lithuania) as well as Israel, Liaoning and Henan Provinces in China, and Ecuador. The Global Project has surveyed areas representing over one third of notified TB cases. However, enormous gaps still exist in the most crucial areas. The most effective strategy to prevent the emergence of drug resistance is through implementation of the directly observed treatment short (DOTS) strategy. Effective implementation of the DOTS strategy saves lives through decreased TB transmission, decreased risk of emergence of drug-resistance, and decreased risk for individual TB patients of treatment failure, TB relapse, and death. The World Bank recognizes the DOTS strategy as one of the most cost-effective health interventions, and recommends that effective TB treatment be a part of the essential clinical services package available in primary health care settings. Governments are responsible for ensuring the provision of effective TB control through the DOTS strategy. WHO and its international partners have formed the DOTS-Plus Working Group, which is attempting to determine the best possible strategy to manage MDR-TB. One of the goals of DOTS-Plus is to increase access to expensive second-line anti-TB drugs for WHO-approved TB control programmes in low- and middle-income countries.
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PMID:[Multiple drug resistance: a threat for tuberculosis control]. 1533 67

Efavirenz treatment has been associated with increases in HDL-cholesterol concentrations, and the circulating levels of the drug have been related to the multidrug resistance gene 1 (MDR-1) C3435T polymorphism. The changes in the measured lipid parameters were evaluated in 59 HIV-infected patients initiating efavirenz-based treatment at baseline and at 12 months of follow-up. Efavirenz treatment increased HDL-cholesterol. The changes in concentrations appeared to be influenced by the MDR-1 gene polymorphism, in which CC > CT > TT.
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PMID:The efavirenz-induced increase in HDL-cholesterol is influenced by the multidrug resistance gene 1 C3435T polymorphism. 1571 46

From August to December 1998, over a period of 5 months, a cross-sectional study had been carried out in Abidjan in order to analyze the epidemiological and microbiological features of BAAR+ TB patients in situation of failure or relapse after specific treatment. We investigated 79 patients enrolled in the departments of pulmonary disease of two general hospitals in Abidjan (CHU of Cocody and Treichville) and a TB outpatients' clinic. From 45 strains of Mycobacterium obtained by culture, 33 antibiograms were performed. The rate of multi-drug-resistance (MDR-TB) was 79%. Among MDR--TB patients, those aged of 20-40 years were the most concerned age group (72%) with a clear male predominant rate (sex ratio: 3). Among them 49/79 (62%) had an educational level lower or equal to primary school standarts and most of them lived in dwellings with common yard (67%). In their medical history only 40% had tuberculosis and 2 cases of self-medication were reported. MDR--TB prevailed among patients having at first a positive bacilloscopy. No link between HIV infection and MDR--TB was found.
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PMID:[Epidemiological, clinical and biological profile of resistant or recurrent pulmonary tuberculosis in Abidjan]. 1578 67


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