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)

Practical approaches to the initial evaluation of solid organ transplant patients, BMT patients, and HIV-infected patients with pulmonary disease are summarized in Figures 2, 3, and 4. These algorithms are meant to be used as guidelines for the clinician. The clinical setting will ultimately determine the extent and speed of the evaluation. Patients who are recipients of solid organ transplants and have pulmonary symptoms may have focal or diffuse changes or may have normal chest radiographs. In all these groups, sputum is obtained by expectation. If a pathogen is found in any of the groups, it is treated. When no pathogen is found on sputum examination in patients with focal disease, empiric antibiotic therapy is given. If the patients do not improve on the empiric antibiotics, then bronchoscopy is performed. Some centers proceed directly to bronchoscopy before antibiotics are started in the hope of directing antibiotic therapy. Patients who have a normal CXR or diffuse infiltrates and no identified pathogen on examination of sputum undergo bronchoscopy, and the protocol is followed until a diagnosis is made (see Fig. 2). Patients who have received a BMT and who present with pulmonary symptoms are treated as shown in Figure 3. The CXR will reveal if the infiltrate is focal or diffuse. Those with focal infiltrates are treated with broad-spectrum antibiotics for 48 to 72 hours. If the symptoms and signs do not show some resolution, then bronchoscopy is usually performed. The effect of diffuse infiltrates in BMT patients depends to a large extent how far along in recovery from the transplant the patient is when they develop the infiltrates. During the first 30 days posttransplant, pulmonary edema commonly occurs, and the infiltrates may resolve with diuresis. If the patient is not clinically fluid overloaded or they do not respond to the diuretic therapy, then bronchoscopy with BAL is indicated. Finally, many HIV-infected patients may present with pulmonary symptoms. They may have a normal CXR or a diffuse or focal pattern (Fig. 4). All patients are subjected to sputum induction to identify a pathogen. If one is identified, it is treated. Should the patient not respond to treatment adequately or a pulmonary pathogen is not found, then bronchoscopy with BAL, protected specimen brush, or a transbronchial biopsy is attempted. The above schema is a general guideline to the initial evaluation of pulmonary disorders in the ICP. The respiratory abnormality is found in most of the cases if these algorithms are closely followed. If the patient does not improve or deteriorates further, additional diagnostic procedures such as video-assisted thorascopic lung biopsy or CT-directed transthoracic needle biopsy may be needed.
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PMID:The initial pulmonary evaluation of the immunocompromised patient. 1007 78

The differential diagnosis of pulmonary disorders in the HIV-infected individual is broad. Clinical features and chest radiographs may point towards a diagnosis but cannot reliably establish one. It is important to know the conditions in which bronchoscopy, BAL, and TBB are likely to be diagnostic, just as it is to know when other invasive or noninvasive procedures may be more useful. Finally, the incidence of transmission of infections such as tuberculosis during bronchoscopy and cross-contamination of patients with an improperly sterilized bronchoscope, cannot be overemphasized.
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PMID:Role of bronchoscopy in AIDS. 1020 18

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.
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PMID:Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. 1032 Oct 27

Efavirenz (SUSTIVA, DMP 266, EFV) is a novel non-nucleoside reverse transcriptase inhibitor, which shows good inhibitory activity against HIV-1. The pharmacokinetics of efavirenz allow for once daily dosing without regard to meals of normal composition. Efavirenz is a mild inducer of CYP 3A4. Clinically significant drug interactions have been reported with medications that are metabolised via the cytochrome P450 enzymes such as indinavir and saquinavir. Results from the studies collated for submission (003, 006, 020, 024 and ACTG 364) have demonstrated the potency and durability of once daily efavirenz in combination with zidovudine (AZT) + lamivudine (3TC), indinavir (IDV), nelfinavir (NFV), IDV + 2 NRTIs, and NFV + 2 NRTIs. Efavirenz was recently approved for commercial use in the USA and has received marketing authorisation in Europe and Canada.
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PMID:Clinical history of efavirenz. 1062 35

Several studies have been performed to investigate the appropriate dose of efavirenz (SUSTIVA, DMP 266, EFV) for the treatment of HIV infection. When considering the most appropriate dose, virological, pharmacological, clinical and safety data from these studies were examined. Efavirenz 600 mg once daily is the recommended dose of efavirenz for combination therapy in adults. Efavirenz 600 mg once daily adjusted for body size is the appropriate dose for combination therapy in children three years of age or older.
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PMID:Dose-ranging studies. 1062 36

An isothermal microcalorimeter was utilized to characterize a model solid-state interaction. The degradation of the HIV protease inhibitor, DMP 450, in a binary mixture with hydrous lactose was followed in the presence of 5% additional water. Heat produced in the microcalorimeter sample vessel from either chemical or physical change is channeled through extremely sensitive thermopile blankets and is measured as it flows into infinite heat sinks. Solid-state 1:1 mixtures of DMP 450 and hydrous lactose each with 5% water added were analyzed in the microcalorimeter at 50, 60 and 65 degrees C. The resulting heat flow profiles were consistent with an autocatalytic rate law. An activation energy of 26.12 kcal mol(-1) for the DMP 450:lactose mixture was determined from the slope of the Arrhenius plot of the microcalorimetry heat flow maximum value versus the reciprocal of the absolute temperature. The activation energy determined by the traditional method with HPLC analysis was found to be in excellent agreement with the microcalorimetry value at 26.38 kcal mol(-1).
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PMID:Utility of microcalorimetry in the characterization of the browning reaction. 1070 46

Protease inhibitors are widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected individuals and show a drastic effect on the reduction of virus load. We previously reported that doughnut-shaped, protease-defective gp120-containing HIV-1 particles from an L-2 cell clone, carrying a provirus with mutations at the pol (protease), env (gp41) and nef genes, rapidly and more effectively induces virus particle-mediated syncytia formation of uninfected T-cells, than a parental wild-type laboratory strain of HIV-1 (LAI). In this study, we examined the possibility of whether enhanced syncytia formation is mediated by morphologically similar doughnut-shaped particles obtained after treatment of LAI-infected cells with the protease inhibitors L-689, 502, DMP-323, RO-31-8959, and KNI-272. Utilizing such protease inhibitor-induced particles and a clone of MOLT-4 cells, we could not detect any enhancement of syncytia formation, over that seen with wild-type LAI particles. This result should alleviate concerns of patients on highly active antiretroviral therapy (HAART), that protease inhibitors might accelerate progression of the disease through enhanced production of defective, 'immature'-appearing particles.
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PMID:Fusion of uninfected T-cells occurs with immature HIV-1 protease-mutant, but not morphologically similar protease inhibitor derived particles. 1072 46

To test the hypothesis that beta-chemokine levels may be relevant to the control of HIV in vivo, we compared RANTES, MIP-1alpha, and MIP-1beta production from purified CD8(+) T cells from 81 HIV-infected subjects and from 28 uninfected donors. Asymptomatic HIV(+) subjects produced significantly higher levels of MIP-1alpha and MIP-1beta, but not RANTES, than uninfected donors or patients that progressed to AIDS. In contrast, beta chemokines in plasma were either nondetectable or showed no correlation with clinical status. The high beta-chemokine-mediated anti-HIV activity was against the macrophage tropic isolate HIV-1(BAL), with no demonstrable effect on the replication of the T-cell tropic HIV-1(IIIB). These findings suggest that constitutive beta-chemokine production may play an important role in the outcome of HIV-1 infection.
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PMID:Higher macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels from CD8+ T cells are associated with asymptomatic HIV-1 infection. 1109 21

Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.
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PMID:Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. 1133 79

DMP 266, a nonnucleoside reverse transcriptase inhibitor, has been effective as a monotherapeutic agent in reducing viral load. How long it remains effective is unknown, and resistance development is a problem. Two trials testing combinations with DMP 266 are beginning. One test using DMP 266 with indinavir is already considered flawed because indinavir is provided as a monotherapy first. Indinavir monotherapy is believed to help HIV resistance to evolve, especially in people with high baseline viral loads. Participants who are on the monotherapy risk not receiving the full benefit from indinavir and other protease inhibitors because they trigger similar resistance mutations.
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PMID:DMP 266: keep the drug but dump the trial? 1136 85


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