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)

Hydrogen bond networks stabilize RNA secondary and tertiary structure and are thus essentially important for protein recognition. During structure refinements using either NMR or X-ray techniques, hydrogen bonds were usually inferred indirectly from the proximity of donor and acceptor functional groups. Recently, quantitative heteronuclear J(N,N)-HNN COSY NMR experiments were introduced that allowed the direct identification of donor and acceptor nitrogen atoms involved in hydrogen bonds. However, protons involved in base pairing interactions in nucleic acids are often not observable due to exchange processes. The application of a modified quantitative J(N,N)-HNN COSY pulse scheme permits observation of(2h)J(N,N) couplings via non-exchangeable protons. This approach allowed the unambiguous identification of the A27.U23 reverse Hoogsteen base pair involved in a U-A.U base triple in the HIV-2 transactivation response element-argininamide complex. Despite a wealth of NOE information, direct evidence for this interaction was lacking due to the rapid exchange of the U23 imino proton. The ability to directly observe hydrogen bonds, even in D(2)O and in the presence of rapid exchange, should facilitate structural studies of RNA.
 ...
PMID:Detection of N-H...N hydrogen bonding in RNA via scalar couplings in the absence of observable imino proton resonances. 1071 Apr 25

As part of an on-going study on the suitability of a formal therapeutic drug monitoring (TDM) of antiviral drugs for improving the management of HIV infection, a high-performance liquid chromatography method has been developed to quantify simultaneously in plasma five HIV protease inhibitors (PIs) (i.e., indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and the novel non-nucleoside reverse transcriptase inhibitor efavirenz. After viral inactivation by heat (60 degrees C for 60 min), plasma (600 microl), with clozapine added as internal standard, is diluted 1:1 with phosphate buffer, pH 7 and subjected to a solid-phase extraction on a C18 cartridge. Matrix components are eliminated with 2 x 500 microl of a solution of 0.1% H3PO4 neutralised with NaOH to pH 7. PIs and efavirenz are eluted with 3 x 500 microl MeOH. The resulting eluate is evaporated under nitrogen at room temperature and is reconstituted in 100 microl 50% MeOH. A 40-microl volume is subjected to HPLC analysis onto a Nucleosil 100, 5 microm C18 AB column, using a gradient elution of MeCN and phosphate buffer adjusted to pH 5.15 and containing 0.02% sodium heptanesulfonate: 15:85 at 0 min-->30:70 at 2 min-->32:68 at 8 min-->42:58 at 18 min-->46:54 at 34 min, followed by column cleaning with MeCN-buffer, pH 5.15 (90:10), onto which 0.3% AcOH is added. Clozapine, indinavir, amprenavir, saquinavir, ritonavir, efavirenz and nelfinavir are detected by UV at 201 nm at a retention time of 8.2, 13.0, 16.3, 21.5, 26.5, 28.7 and 31.9 min, respectively. The total run time for a single analysis is 47 min, including the washing-out and reequilibration steps. The calibration curves are linear over the range 100-10,000 ng/ml. The absolute recovery of PIs/efavirenz is always higher than 88%. The method is precise with mean inter-day relative standard deviations within 2.5-9.8% and accurate (range of inter-day deviations -4.6 to +4.3%). The in vitro stability of plasma spiked with PIs/efavirenz at 750, 3000 and 9000 ng/ml has been studied at room temperature, -20 degrees C and +60 degrees C. The method has been validated and is currently applied to the monitoring of PIs and efavirenz in HIV patients. This HPLC assay may help clinicians confronted to questionable compliance, side effects or treatment failure in elucidating whether patients are exposed to adequate circulating drug levels. The availability of such an assay represents an essential step in elucidating the utility of a formal TDM for the optimal follow-up of HIV patients.
 ...
PMID:Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir, nelfinavir and the non-nucleoside reverse transcriptase inhibitor efavirenz by high-performance liquid chromatography after solid-phase extraction. 1079 93

We describe solid state NMR measurements on frozen solutions of the complex of the 24-residue HIV-1 gp120 V3 loop peptide RP135 with the Fab fragment of the anti-gp120 antibody 0.5beta, using rotational echo double resonance (REDOR). In order to probe possible hydrogen bonding between arginine side chains and glycine backbone carbonyls in the region of the conserved Gly-Pro-Gly-Arg (GPGR) motif of the V3 loop, RP135 samples were prepared with 15N labels at the eta nitrogen positions of arginine side chains and 13C labels at glycine carbonyl positions and 13C-detected 13C-15N REDOR measurements were performed on peptide/antibody complexes of these labeled samples. Such hydrogen bonding was previously observed in a crystal structure of the V3 loop peptide/antibody complex RP142/59.1 [Ghiara et al. (1994) Science, 264, 82-85], but is shown by the REDOR measurements to be absent in the RP135/0.5beta complex. These results confirm the antibody-dependent conformational differences in the GPGR motif suggested by previously reported solid state NMR measurements of phi and psi backbone dihedral angles in the RP135/0.53 complex. In addition, we describe REDOR measurements on the helical synthetic peptide MB(i+4)EK in frozen solution that establish our ability to detect 13C-15N dipole-dipole couplings in the distance range appropriate to these hydrogen bonding studies. We also report the results of molecular modeling calculations on the central portion RP135, using a combination of the solid state NMR restraints of Weliky et al. [Nat. Struct. Biol., 6, 141-145, 1999] and the liquid state NMR restraints of Tugarinov et al. (Nat. Struct. Biol., 6, 331-335, 1999]. The dynamics calculations demonstrate the mutual compatibility of the two sets of experimental structural restraints and reduce ambiguities in the solid state NMR restraints that result from symmetry and signal-to-noise considerations.
 ...
PMID:Probing hydrogen bonds in the antibody-bound HIV-1 gp120 V3 loop by solid state NMR REDOR measurements. 1082 83

Substantial losses of total body protein (TBP) can occur in chronic diseases and in aging. Such losses impact negatively on immunity and quality of life, and on growth rates in children. Direct measurements of total body nitrogen (TBN) monitor the integrated changes in TBP over time and allow comparison with normal subjects. TBN assessment via neutron capture analysis is therefore the gold-standard method of TBP estimation, so that risk factors for protein deficit can be identified and patient management optimized. The nitrogen index (NI) can be used to predict prognostic outcome: an NI < 0.9 is associated with substantial wasting in HIV disease, an NI < 0.8 predicts significant pathophysiology in chronic renal failure, and a low NI is predictive of neutropenia in breast-cancer patients. These findings emphasize the central importance of adequate protein stores in recovery from disease or in maintaining quality of life. Aging appears to involve a gradual loss of TBP throughout adulthood. Cross-sectional data suggest that TBP declines curvilinearly with age, such that there is an accelerated decline after 65 years of age. However, longitudinal data are scarce, and little is known about the relative loss of visceral protein, as opposed to skeletal muscle protein. More clearly-defined data are essential if the effects of aging per se are to be separated from the effects of chronic disease. A further complication is the knowledge that physical activity also declines with age. Thus sarcopenia, the loss of skeletal muscle mass, could primarily result from disuse rather than aging. The economic impact of unsuccessful aging places a pressing need for multicompartment data in longitudinal study designs.
 ...
PMID:Total body protein in chronic diseases and in aging. 1086 69

Malnutrition is common in HIV infection. Early studies demonstrated a disproportionate depletion of body cell mass compared to body weight, plus relative expansion of extracellular water volume. Neutron activation studies showed that both potassium and nitrogen were depleted in the HIV+ subjects, whereas cross-sectional imaging documented depletion of skeletal muscle mass. The etiology of malnutrition affects the composition of lost weight. Malnutrition is associated with adverse outcomes, whereas clinical stability is associated with nutritional stability. Increasingly, body composition studies are being incorporated into clinical trials. Hypercaloric feeding promotes gains in weight and body fat, but not in lean mass. Adjunctive therapies include anabolic agents, both steroids and recombinant human growth hormone (rhGH), cytokine inhibitors, and resistance training exercise. In addition to increasing fat-free mass, these therapies also have benefits in quality of life, notably functional performance, as well as physical function. Current research on alterations in body composition in HIV have noted a redistribution of fat, with visceral obesity in patients receiving highly active antiretroviral therapies.
 ...
PMID:Body composition studies in HIV-infected individuals. 1086 3

Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump. The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p2 1.0-21.1. Point mutations after cross-resistance patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticancer drugs, transfection with oncogenes, HIV-I, and UV-irradiation. An alternative hypothesis to the efflux pump claims that P-gp modifies the intracellular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp drug extrusion are generally lipid-soluble at physiological pH, possess a basic nitrogen atom and at least two co-planar rings. P-gp blocking does not depend on drug chirality. This opens the way of treating P-gp related MDR with chiral versions of drugs relatively harmless in terms of side-effects. We believe that resistance modifiers combined with cytostatics will chemotherapeutically be more effective for cancer patients.
 ...
PMID:Reversal of multidrug resistance of tumor cells. 1120 56

DNA is a well characterized intracellular target but its large size and sequential nature make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this respect the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in diagnosis and treatment of cancers as well as in molecular biology. Recent progress in the development of cross linked lexitropsin oligopeptides and hairpins, which bind selectively to the minor groove of duplex DNA, is discussed. Bis-distamycins and related lexitropsins show inhibitory activity against HIV-1 and HIV-2 integrases at low nanomolar concentrations. Benzoyl nitrogen mustard analogs of lexitropsins are active against a variety of tumor models. Certain of the bis-benzimidazoles show altered DNA sequence preference and bind to DNA at 5'CG and TG sequences rather than at the preferred AT sites of the parent drug. A comparison of bifunctional bizelesin with monoalkylating adozelesin shows that it appears to have an increased sequence selectivity such that monoalkylating compounds react at more than one site but bizelesin reacts only at sites where there are two suitably positioned alkylation sites. Adozelesin, bizelesin and carzelesin are far more potent as cytotoxic agents than cisplatin or doxorubicin. A new class of 1,2,9,9a-tetrahydrocyclo-propa[c]benz[e]indole-4-one (CBI) analogs i.e., CBI-lexitropsin conjugates arising from the latter leads are also discussed.A number of cyclopropylpyrroloindole (CPI) and CBI-lexitropsin conjugates related to CC-1065 alkylate at the N3 position of adenine in the minor groove of DNA in a sequence specific manner, and also show cytotoxicities in the femtomolar range. The cross linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin, and melphalan. A new class of PBD-lexitropsin conjugates is also discussed. Certain functional models of the bleomycins (BLMs) show outstanding DNA cleavage activity comparable with that of and positionally distinct from natural BLM.
 ...
PMID:Recent developments in sequence selective minor groove DNA effectors. 1128 37

Recombinant human growth hormone (rhGH) and its primary induced product, insulin-like growth factor-I (IGF-I), have beneficial effects on a myriad of syndromes associated with catabolic metabolism in children and in adults. Their ability to promote nitrogen retention and protein synthesis and to enhance lipolysis has translated into significant increases in body weight, lean body mass, and sense of well-being among HIV+ individuals with wasting syndromes. These changes, first observed in limited phase I studies, have now been confirmed by two large, controlled clinical trials. The alterations are consistent with the low GH and/or IGF-I levels observed in HIV infection, as well as the relative resistance to GH. Whether long-term outcome in HIV disease is altered by such therapies remains to be determined, however. The ability of GH to augment cellular immune function and modulate T lymphocyte trafficking in animal models of immune suppression has also led to examination of its impact on CD4+ T cell counts and viral load in HIV infection. There is currently little evidence that short-term rhGH administration has any lasting impact on T cell biology in the setting of HIV disease. However, preliminary reports that, in vitro, GH alters immune cell apoptosis and enhances the efficacy of Zidovidine (AZT), similar to changes observed with granulocyte-macrophage colony-stimulating factor, may lead to additional uses for GH. Studies to define the mechanism of action of GH and IGF-I on normal and abnormal immune homeostasis in children and adults should enhance our ability to design effective treatments for those with acquired immune deficiency syndrome (AIDS) and perhaps other wasting and immune suppressive disorders.
Pediatr AIDS HIV Infect 1995 Oct
PMID:Growth hormone in HIV/AIDS: current uses and future prospects. 1136 93

Clinicians have had some success in treating or preventing several rarely discussed opportunistic infections. The author discusses seven infections, outlining the disease and possible treatments. Aspergillosis, a fungal infection found in the lungs and sinuses, can be treated with intravenous amphotericin B. However, researchers are studying oral itraconazole as an alternative treatment. B-19 parvovirus is a viral infection that may cause severe anemia, a decrease in red blood cell count or hemoglobin. A small study suggests that IVIG (intravenous immune globulin) was effective in reversing B-19 parvovirus-related anemia in seven HIV-positive patients. Coccidioidomycosis, an uncommon fungal infection usually seen in the lungs, has symptoms closely resembling those of PCP. Treatments include amphotericin B, or ketoconazole or fluconazole for mild cases. Histoplasmosis usually occurs in AIDS patients with fewer than 100 CD4 cells. A fungal infection, histoplasmosis can be treated with amphotericin V and itraconazole. Isosporiasis invades the intestines, causing persistent, watery diarrhea and other symptoms resembling cryptosporidiosis. Sulfadoxine and pyrimethamine combined can prevent the return of the organism. Molluscum contagiosum is a viral infection that produces small, white wart-like bumps on the skin. Bumps can be removed with an electrical charge or with liquid nitrogen. Progressive multifocal leukoencephalopathy (PML) is a life-threatening brain disorder. A very small study suggests that patients who received cytosine arabinoside (ara-C, cytarabine) stabilized and improved after treatment.
 ...
PMID:Out of sight, but not out of mind. 1136 70

HIV-related Kaposi's sarcoma is a progressive, frequently visceral disease that is postulated to be infectious. Its growth is accelerated by corticosteroids, Oncostatin M, the HIV-tat protein, Interleukin-6, fibroblast growth factor, interleukin-1, and tumor necrosis factor. It represents a proliferative disorder of mesenchymal cells in response to HIV and dysregulation of immune mediators from HIV infection, in conjunction with an unidentified infectious agent. It is multicentric and has varying rates of progression, though rapid growth may occur during heightened immunosuppression. Problematic lesions can cause alterations in appearance, result in edema, or occur in the lungs or gastrointestinal tract. Epidemic Kaposi's sarcoma is incurable. Immediate initiation of therapy is not necessary, but is justified by life-threatening or symptomatic disease, or a cosmetically unacceptable lesion. Small, localized lesions may be treated with intralesional vinblastine, topical liquid nitrogen, and modest doses of radiation therapy. Palliation is usually temporary, and tumors may soon recur in previously treated sites. Extensive or rapidly progressive disease, especially when involving internal organs, can be treated with single and combination therapies. Initial treatment involves the well-tolerated vincristine, vinblastine, and bleomycin; and etoposide, doxorubicin or interferon-a are used when disease progresses. The best results are seen in patients with CD4+ counts greater than 200/ml, who are less likely to suffer from therapy-induced bone marrow suppression and hair loss. Promising new treatments, particularly liposomal doxorubicin and LGD 1069, are being investigated.
 ...
PMID:The epidemiology, pathogenesis and treatment of Kaposi's sarcoma. 1136 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>