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)

Smear microscopy for acid-fast bacilli (AFB) remains the first priority for national tuberculosis programmes (NTPs) in high-prevalence countries. No other established technique offers the same advantages of accuracy, speed, appropriateness and accessibility. Its sensitivity may be reduced in HIV-positive cases or because of technical deficiencies, and it lacks specificity for viable bacilli in follow-up examinations. Its main problem is that it is tedious, necessitating an effective external quality assessment (EQA) system following international guidelines. Operational research is needed to optimise the staining he place of sputum concentration o define t and fluorescence microscopy, to challenge difficult and obsolete strategies and to streamline procedures. Culture is much more difficult to set up and is usually impossible to decentralise. Because of its lower yield and higher costs, its efficiency for case detection in NTPs will lag well behind that in industrialised countries. The technique should only be used as a preliminary to drug susceptibility testing (DST). DST should not be developed to the detriment of the AFB microscopy network and its EQA. It should be used mainly for monitoring drug resistance. Continuous monitoring of resistance in a representative sample of isolates from first-line failure and relapse cases may be more efficient and more accurate than periodic surveys among new cases, and can be used to identify MDR-TB, whose treatment should be standardised, because of considerable risk of error in the laboratory. A specialist service offering molecular techniques may be useful for exceptional cases, but it has no place in the routine work of NTPs.
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PMID:Tuberculosis bacteriology--priorities and indications in high prevalence countries: position of the technical staff of the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease. 1583 63

During a 2-year retrospective study, 195 non-HIV-infected patients with extrapulmonary tuberculosis (EPT) were diagnosed at the National Tuberculosis Center, Kuala Lumpur, representing 10% of all patients with tuberculosis. Their mean age was 39 (+/- SD) 14 years old (range 14-81). The largest age group was 25-34 years, while 78.5% were less than 50 years of age. The subjects were mainly female (50.3%), Malay (49.2%), married (61.5%), resided in Kuala Lumpur (51.0%), and were unemployed (50.3%). Regarding risk factors, they were smokers and/or alcohol users (21.0%), and injecting drug users (IDUs) (5.1%); they also had history of tuberculosis (3.6%) and contact with TB patients (9.2%). Lymphadenopathy was the most common sign (45.6%) shown in the medical records. 42% of x-ray findings (chest, spine, and hip) showed signs consistent with tuberculosis, while histopathology was the most useful diagnostic tool (52.3%) and lymph node was the most frequent specimen used (35.0%) in this study. The three main sites of involvement were lymph nodes (42.6%), miliary and disseminated (19.5%), and pleura (12.8%). The outcome of this study showed 72.8% of these patients had completed treatment for at least 6 months, whilst, only 4.6% of patients were still undergoing treatment, and unfortunately, 22.6% of them showed non-adherence to anti-tubercular therapy at a duration of less than 6 months. However, no MDR-TB or death cases were reported or registered in this study.
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PMID:Extrapulmonary tuberculosis in Peninsular Malaysia: retrospective study of 195 cases. 1590 32

Tuberculosis is a global burden disease, most possibly ranking high among diseases over the coming several decades, with 2 million deaths and over 8 million new cases annually. How can TB be controlled and eradicated quickly in the world? A major answer will be the wider application of the most effective control programme, i.e. DOTS recommended by WHO. But it has been developed in the long try and error efforts, including the ones by Dr. K. Styblo of IUATLD in African countries. The key components of successful TB programme are summarised as follows, which Dr. Kochi of WHO adopted as a global policy package. They are; 1) political commitment, 2) case finding by sputum microscopy, 3) use of short course chemotherapy under supervision, 4) a secured supply of anti-TB drugs, and 5) a standardised recording, reporting and monitoring system. The targets by 2005 are set 85% cure rate and 70% detection rate. By 2002, however, only half the targets have been achieved, and global expansion of DOTS with other strategies need to be strengthened. Emerging threats are HIV epidemic, MDR-TB increase and health sector reform taking place in the world. Stop TB partnership with its office in WHO has been formed to strengthen a global capacity, mobilizing various technical and financial partners. Japan's contribution to the global TB problem started in early 1960s. In the last 40 years, technical cooperation in national TB programme (NTP) has been made through JICA in over 15 countries, including United Arab Emirates. Thailand, Nepal, Afghanistan, Tanzania, Indonesia, Solomon Islands, Yemen, Philippines, Cambodia, Myanmar, Pakistan, Zambia, and China (TB project is on-going in underlined countries). In these projects, capacity strengthening of NTP has been given priority, including construction of national TB center, a model area development, nationwide DOTS expansion in collaboration with WHO or others, supply of anti-TB drugs, TB laboratory network with QA, collaborative operational research. An operational research for community based DOTS and ART is newly started in Zambia under JICA project. Besides, over 1800 doctors and technologists from 90 countries have been trained at Research Institute of Tuberculosis (RIT) through its international training courses in the last 40 years. These courses are organised collaboratively with WHO or other agencies, inviting globally renowned lecturers and ex-participants, and have been reputed widely. We aim not only to teach skills and knowledge but also to motivate them to do something new. This becomes possible only through human relationship in the course. I may need to mention about my personal commitment: First, I have worked to develop a community based TB programme model utilising village health volunteers in Bangladesh in 1980s. This system has now covered over 70% of the total patients in the country through BRAC, local NGO. Secondly, the application of participatory action research (PAR) method in introducing or expanding DOTS in Bangladesh and other countries. Staff members of NTP and local/ peripheral workers participate in the trials and discuss actively in the workshops periodically. This PAR approach empowers both NTP managers and peripheral staff. Through the international cooperation, we aim ultimately at 1) support for self-reliance, 2) empowerment (capacity building for problem finding and solution) of the people concerned, and 3) promotion of global peace without arms.
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PMID:[How to cope with the global tuberculosis burden--experiences and perspectives for Japan's international cooperation]. 1592 Sep 81

This retrospective study was conducted at the National Tuberculosis Center (NTBC) where 252 HIV-positive patients coexisting with tuberculosis (TB/HIV) were examined. We found that patients with pulmonary (PTB) and extrapulmonary tuberculosis (EPT) had similar mean age. A higher sex ratio between male to female (10.7:1) was observed in patients with PTB. The other characteristics of patients with pulmonary and extrapulmonary tuberculosis were not statistically different from each other. Cough (88%) and hemoptysis were the most common presenting symptoms, significantly related to patients with PTB. Lymphadenopathy (33.5%) was the most common sign in patients with EPT. The majority of patients with pulmonary and extrapulmonary tuberculosis had CD4 cell counts of less than 200 cells/mm3 (range 0-1,179 with a median of 57 cells/mm3). Lung (89%) and miliary (55.6%) forms were the most frequent disease locations in patients with PTB and EPT, respectively. A higher percentage of patients with PTB (42%) were treated successfully with short-course (6 months) therapy, whereas in patients with EPT (43%) needed a longer period (9 months) for successful treatment. Of the patients who defaulted treatment, a higher proportion (87%) had PTB. No MDR-TB or relapse cases were found in this study.
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PMID:Tuberculosis in HIV/AIDS patients: a Malaysian experience. 1629 50

In cancer and AIDS, overexpression of the MDR1 gene has important implications in the design of chemotherapy protocols because of the ability of its product, the ATP-dependent drug efflux pump P-glycoprotein (Pgp), to confer selective advantage to tumor and HIV-infected cells in the form of multidrug resistance. To study Pgp expression and physiology, we designed a translational fusion between the MDR1 and enhanced green fluorescent protein (EGFP) genes. The chimeric protein, Pgp-EGFP, was concentrated mainly in the plasma membrane and in the Golgi when expressed in drug-sensitive KB-3-1 cells. Doxorubicin, daunorubicin and rhodamine-123 efflux assays confirmed function of the chimeric pump. Also, at the single-cell level, an inverse relationship between Pgp-EGFP expression and nuclear doxorubicin accumulation was demonstrated. Polarized Pgp expression on the apical cell surface was confirmed by transfection of the MDR-EGFP fusion gene into MDCK cells. However, after colchicine selection, Pgp-EGFP was also detectable in the lateral domain of the transfected MDCK monolayers. These results indicate that drug selection affects not only expression, but cellular localization of Pgp. Furthermore, using a tet-based inducible expression system for Pgp-EGFP, we confirmed the stable nature of Pgp (t(1/2 total Pgp-EGFP) = 2.2 days), but revealed that surface-Pgp acquires extra stability as an active pump (t(1/2 surface Pgp-EGFP) = 3.7 days).
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PMID:An MDR-EGFP gene fusion allows for direct cellular localization, function and stability assessment of P-glycoprotein. 1630 69

According to recent epidemiological reports, almost 40% of American population use complimentary and alternative medicine (CAM) during their lifetime. Patients detected with HIV or cancer often consume herbal products especially St. John's wort (SJW) for antidepressants in combination with prescription medicines. Such self-administered herbal products along with prescribed medicines raise concerns of therapeutic activity due to possible drug-herbal interactions. P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) together constitute a highly efficient barrier for many orally absorbed drugs. Available literature, clinical reports and in vitro studies from our laboratory indicate that many drugs and herbal active constituents are substrates for both P-gp and CYP3A4. Results from clinical studies and case reports indicate that self-administered SJW reduce steady state plasma concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, amprenavir, indonavir, lopinavir, ritonavir, saquinavir, benzodiazepines, theophyline, irinotecan, midazolan and warfarin. This herbal agent has been also reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral contraceptives. Most of these medicinal agents and SJW are substrates for P-gp and/or CYP3A4. In vitro studies from our laboratory suggest that short-term exposure with pure herbal agents such as hypericin, kaempferol and quercetin or extract of SJW resulted in higher uptake or influx of ritonavir and erythromycin. Hypericin, kaempferol and quercetin also caused a remarkable inhibition of cortisol metabolism with the percent intact cortisol values of 64.58%, 89.6% and 90.1%, respectively, during short-term in vitro experiments. Conversely, long-term exposure of herbal agents (hyperforin, kaempferol and quercetin) showed enhanced expression of CYP3A4 mRNA in Caco-2 cells. In another study, we observed that long-term exposure of hypericin, kaempferol, quercetin and silibinin resulted in higher MDR-1 mRNA expression in Caco-2 cells. Therefore, herbs can pharmacokinetically act as inhibitors or inducers. Medicinal agents that are substrates P-gp-mediated efflux and/or CYP-mediated metabolism are likely to be potential candidates for drug-herbal interactions. The duration of exposure of cells/healthy volunteers/animals to herbals appears to be critical for drug-herbal interaction. An increase in plasma drug concentration is possible during concomitant administration of SJW and prescribed drugs. In contrast, prolonged intake of herbal supplement followed by drug administration may result in subtherapeutic concentrations. Therefore, clinical implications of such drug herbal interactions depend on a variety of factors such as dose, frequency and timing of herbal intake, dosing regimen, route of drug administration and therapeutic range. In vitro screening techniques will play a major role in identifying possible herb-drug interactions and thus create a platform for clinical studies to emerge. Mechanisms of drug-herbal interaction have been discussed in this review article.
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PMID:MDR- and CYP3A4-mediated drug-herbal interactions. 1644 30

The introduction of HIV-1 protease (HIV-PR) inhibitors has led to a dramatic increase in patient survival; however, these gains are threatened by the emergence of multi-drug-resistant strains. Design of inhibitors that overcome resistance would be greatly facilitated by deeper insight into the mechanistic events associated with binding of substrates and inhibitors, as well as an understanding of the effects of resistance mutations on the structure and dynamic behavior of HIV-PR. We previously reported a series of simulations that provide a model for HIV-PR dynamics, with spontaneous conversions between the bound and unbound crystal forms upon addition or removal of an inhibitor. Importantly, the unbound protease transiently sampled a third fully open state that permits entry to the active site, unlike both crystallographic forms. Recently, a crystal structure of unbound HIV-PR was reported for the MDR 769 isolate (PDB: 1TW7); unlike all previous experimental structures, the binding pocket is open. It is suggested that drug resistance in this strain arises at least in part from the inability of inhibitors to induce closing. We carried out simulations of the MDR 769 HIV-PR mutant and observed that the reported structure is unstable in solution and rapidly adopts the semi-open conformation observed for the unbound wild-type protease in solution. Further analysis suggests that the wide-open structure observed for MDR 769 arises not from sequence variation, but instead is an artifact from crystal packing. Thus, despite being the first experimental structure to reveal flap opening sufficient for substrate access to the active site, this structure may not be directly relevant to studies of inhibitor entry or to the cause of HIV-PR drug resistance.
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PMID:The open structure of a multi-drug-resistant HIV-1 protease is stabilized by crystal packing contacts. 1703 40

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)
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PMID:[Development of antituberculous drugs: current status and future prospects]. 1724 Sep 21

Current treatments for patients infected with HIV are suboptimal. There is a need for new HIV therapies that act through different mechanisms than current treatments. We investigated the in vitro efficacy, safety and mechanism of action of the benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10), a potential new HIV treatment. When HIV-1-responsive engineered HeLa cells were pre-incubated for 48 h with either SP-10 or zidovudine (AZT), SP-10 was able to inhibit viral replication at much lower concentrations (IC50 = 0.036 nM) than AZT (IC50 = 27.4 nM). In contrast to AZT, SP-10 also inhibited replication of the multidrug-resistant HIV-1 strain MDR-769 in the HeLa cell model. In co-incubation experiments, SP-10 also inhibited the CCR5-sensitive HIV-1 BaL virus replication in human peripheral blood mononuclear cells. SP-10 displayed very low toxicity compared with current antiviral treatments. Confocal laser scanning microscopy and immunoprecipitation studies showed that SP-10 reduced the expression of CD4 and CCR5 on the surface of the host cell. SP-10 also reduced the level of gp120 binding to the cell surface. Confocal laser scanning microscopy studies showed that SP-10 blocked the formation of actin filaments (F-actin) and altered actin accumulation near the cell surface. These promising results suggest that SP-10 has a novel mechanism of action that enables effective inhibition of HIV-1 binding and cell entry. Further development of SP-10 as a new HIV treatment appears warranted.
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PMID:The benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10) reduces HIV-1 infectivity in vitro by modifying actin dynamics. 1724 47

As shown in a previous study, the outcome of multidrug-resistant tuberculosis (MDR-TB) in France is not satisfactory (41% success rate). To improve the management and outcome of patients with MDR-TB, a prospective intervention study was carried out in 1998-1999 by National Reference Centre (NRC) staff. NRC staff contacted (i) the microbiologists reporting MDR-TB patients in order to offer second-line drug testing and (ii) physicians to help tailor treatment regimens based on World Health Organization guidelines. A total of 45 MDR-TB patients were followed, including 33 for whom NRC staff successfully interacted with the physicians in charge and 12 patients managed without NRC collaboration. The crude proportion of favourable outcomes was 58%, and this proportion reached 70% for patients managed in collaboration with the NRC. Among the latter 33 patients, 32 were treated with at least three active drugs for a median duration of 12 months. In multivariate analysis, HIV-positive status was associated with treatment failure (hazard ratio (HR) 4.3), whereas NRC intervention was associated with a favourable outcome (HR 0.2). However, even in the NRC intervention group the median duration of treatment was shorter than planned (median 12 months) and 12% of patients were lost to follow-up. This intervention study provides encouraging results and should be continued until reference teams and a directly observed treatment strategy (DOTS) are implemented to improve patient management further.
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PMID:An intervention programme for the management of multidrug-resistant tuberculosis in France. 1730 Sep 20


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