Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.105 (MDR)
 4,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.
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PMID:GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. 1206 91

The rise of multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis showing resistance to at least isoniazid and rifampicin, is a serious threat to tuberculosis control in some high prevalence countries and may have some impact on low prevalence regions as well. The World Health Organization estimates that 50 million people worldwide are infected with MDR-TB, and that, in the year 2000, 273,000 (3.1%) MDR-TB cases were among the 8.7 million new tuberculosis cases. In 1998, the highest MDR-TB rates among new cases and the highest combined (new and previously treated cases) MDR-TB rates were found in Estonia (14.1 and 18.1%), Henan province in China (10.8 and 15.1%), Latvia (9.0 and 12.0%), and Ivanovo Oblast (9.0 and 12.3%) and Tomsk Oblast (6.5 and 13.7%) in the Russian Federation. The risk factors for MDR-TB are previous treatment or relapse, originating from "hot spot" areas, a history of imprisonment, homelessness and possibly also human immunodeficiency virus. The treatment of multidrug-resistant tuberculosis is difficult due to side-effects and a treatment duration of up to 3 yrs, which is expensive and often unsuccessful. Therefore, strategies for the treatment and prevention of multidrug-resistant tuberculosis are urgently required. This requires functioning tuberculosis control programmes (directly observed treatment short course), and, in some high prevalence countries, the introduction of second-line drugs on the basis of appropriate susceptibility testing (directly observed treatment short course-Plus). Only the future will show whether this "ticking time bomb" can be defused.
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PMID:Strategies against multidrug-resistant tuberculosis. 1216 49

The authors carried out a comparative clinical and immunological study of different types of drug-resistance (mono-, poly-, MDR of primary and secondary genesis) and immunity in 54 patients with a specific process in the lung. The level of suppression, immunodeficiency, and the incidence of adverse effects were found to be on the increase in the group with the preserved sensitivity to the that with mono-, poly-, and MDR. Impaired immune homeostasis was more pronounced in patients with secondary MDR versus those with primary MDR.
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PMID:[Interaction of types of drug resistance and immunity in patients with pulmonary tuberculosis]. 1256 32

In the United States, many people erroneously think that tuberculosis (TB) is a disease of the past--an illness that no longer constitutes a public health threat. In reality, TB is one of the leading global causes of morbidity and mortality. According to the World Health Organization, which compiles annual country profiles of reported TB cases using standardized case definitions, 2.4 million cases were reported in 2001. However, because of underreporting, the number of new TB cases is estimated to be 8.3 million, including 1.8 million deaths. In the United States, after more than 3 decades of steady downward trends, an unprecedented resurgence of TB occurred between 1985 and 1992. This increase was associated with deficient infrastructure, the human immunodeficiency virus (HIV) epidemic, immigration, outbreaks in congregate settings, and widespread occurrence of multidrug resistant TB strains. The resultant increased concerns provided the impetus for the development of a national action plan to combat MDR and the mobilization of new resources. Consequently, the incidence of TB cases has decreased from 1992 through 2002. New challenges are evident and must be addressed to achieve the agreed-on goal of eliminating TB in the United States. This report describes the global epidemiology of TB and the epidemiology in the United States, and outlines future challenges to the elimination of TB in the United States.
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PMID:Epidemiology of tuberculosis. 1467 72

It has been proposed that the declining efficiency of antiretroviral agents in human immunodeficiency virus (HIV) infection may also depend on cellular factors at their site of action. Two in particular have been proposed: (i) the defective intracellular metabolism of NRTI in target cells and the altered uptake; and (ii) efflux of nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) by cellular transporter molecules. Several studies have shown that: changes in the activities of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogues, e.g. zidovudine, show significantly decreased activity of thymidine kinase (TK) compared with untreated HIV-infected people; and NRTI and PI are substrates for the multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P-glycoprotein (MDR), and the newly discovered family of multidrug resistance-associated proteins (MRP1-6), promote the active extracellular efflux of a wide variety of therapeutics drugs and overexpression of some of them lowers intracellular concentration of PI. In the very near future such mechanisms, also called 'cellular drug resistance', might be taken into account, together with other immunological, virological and behavioural factors, to explain the 'drug failure' and/or the variability of response in HIV patients undergoing antiretroviral treatment.
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PMID:Cellular issues relating to the resistance of HIV to antiretroviral agents. 1500 May 83

Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem because treatment is complicated, cure rates are well below those for drug-susceptible tuberculosis (TB), and patients may remain infectious for months or years, despite receiving the best available therapy. To gain a better understanding of MDR-TB, we characterized serial isolates recovered from 13 human immunodeficiency virus-negative patients with MDR-TB, by use of IS6110 restriction fragment-length polymorphism analysis, spacer oligonucleotide genotyping (i.e., "spoligotyping"), and sequencing of rpoB, katG, mabA-inhA (including promoter), pncA, embB, rpsL, rrs, and gyrA. For all 13 patients, chronic MDR-TB was caused by a single strain of Mycobacterium tuberculosis; 8 (62%) of the 13 strains identified as the cause of MDR-TB belonged to the W-Beijing family. The sputum-derived isolates of 4 (31%) of the 13 patients had acquired additional drug-resistance mutations during the study. In these 4 patients, heterogeneous populations of bacilli with different resistance mutations, as well as mixtures of drug-susceptible and drug-resistant genotypes, were observed. This genetic heterogeneity may require treatment targeted at both drug-resistant and drug-susceptible phenotypes.
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PMID:Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis. 1519 48

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

Mycobacterium (M.) tuberculosis is the most common individual causative agent of infectious disease in the world. It is responsible for 26% of preventable deaths in adulthood. Because the number of new cases grows at an annual rate of 2%, in 1993 WHO proclaimed tuberculosis a global health problem. The immediate cause for this was coinfection with causative agents of tuberculosis and human immunodeficiency virus, and spread of resistant and multiresistant strains of M. tuberculosis (MDR TB). It is estimated that 50 million people are infected with resistant strains of M. tuberculosis. Tuberculosis has emerged as a major public health problem for its high mortality (50%-80%) in the first 4-16 weeks of the disease and 100 times more expensive therapy for drug-resistant than for drug-susceptible tuberculosis. Mycobacteriologic laboratories play a fundamental role in the detection, combat and control of tuberculosis, especially in preventing the spread of drug-resistant tuberculosis. In this connection, there is an increased need of a rapid and reliable determination of the susceptibility of isolated strains of M. tuberculosis to the first- and second-line antituberculotic drugs.
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PMID:[Drug-resistant tuberculosis: resistance mechanisms and drug susceptibility of Mycobacterium tuberculosis]. 1570 Jun 89

The emergence of multidrug-resistant tuberculosis (MDR-TB) is increasing and is exacerbated by the human immunodeficiency virus (HIV) epidemic. The standard short-course regimen used for the treatment of tuberculosis is likely to be ineffective against MDR-TB, leading to the need for second-line drugs. In such situations, drug susceptibility testing (DST) is necessary to select an appropriate treatment regimen. In this study, DST of 99 MDR-TB strains isolated in Thailand was performed using a drug-impregnated disc method. The results showed that 94.95% of the strains were susceptible to amikacin and kanamycin, 90.91% to ciprofloxacin and ofloxacin, 85.86% to para-aminosalicylic acid, and 78.79% to ethionamide.
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PMID:Second-line drug susceptibilities of Thai multidrug-resistant Mycobacterium tuberculosis isolates. 1573 44


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