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Kumar AK Ramachandran G Kumar P Kumaraswami V Swaminathan S 《MedGenMed : Medscape general medicine》2006,8(4):53
Patient adherence to treatment is an important factor in the effectiveness of antiretroviral regimens. Adherence to treatment could be monitored by estimation of antiretroviral drugs in biological fluids. We aimed to obtain information on the quantity and duration of excretion of lamivudine in urine following oral administration of a single dose of 300 mg and to assess its suitability for adherence monitoring purposes. Spot urine samples were collected before dosing and at 4, 8, 12, 24, 28, 32, 48, 72, and 96 hours post dosing from 10 healthy subjects, and lamivudine was estimated by high-pressure liquid chromatography (HPLC). Lamivudine values were expressed as a ratio of urine creatinine. About 91% of the ingested drug was excreted by 24 hours, and the concentration thereafter in urine was very negligible. A lamivudine value of 0.035 mg/mg creatinine or less at 48 hours is suggestive of a missed dose in the last 24 hours. The study findings showed that estimation of urine lamivudine in spot specimens could be useful in monitoring patient adherence to antiretroviral treatment. However, this needs to be confirmed on a larger sample size and among patients on once-daily and twice-daily treatment regimens. 相似文献
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Reddy KK Singh SK Dessalew N Tripathi SK Selvaraj C 《Journal of enzyme inhibition and medicinal chemistry》2012,27(3):339-347
Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set (r(2)?=?0.92, SD?=?0.16, F?=?84.8, N?=?40) and for test set (Q(2)?=?0.71, RMSE?=?0.06, Pearson R?=?0.90, N?=?10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors. 相似文献
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Benjamin E. Blass Pravin Iyer Magid Abou-Gharbia Wayne E. Childers John C. Gordon Mercy Ramanjulu George Morton Premkumar Arumugam Joshodeep Boruwa John Ellingboe Sayan Mitra Rajashekar Reddy Nimmareddy Shalini Paliwal Jamallamudi Rajasekhar Savithiri Shivakumar Pratima Srivastava Raghuram S. Tangirala Konda Venkataramanaiah L. Krishnakanth Reddy 《Bioorganic & medicinal chemistry letters》2018,28(13):2270-2274
The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation. 相似文献
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Dihedral angle preferences of amino acid residues forming various non-local interactions in proteins
In theory, a polypeptide chain can adopt a vast number of conformations, each corresponding to a set of backbone rotation angles. Many of these conformations are excluded due to steric overlaps. Ramachandran and coworkers were the first to look into this problem by plotting backbone dihedral angles in a two-dimensional plot. The conformational space in the Ramachandran map is further refined by considering the energetic contributions of various non-bonded interactions. Alternatively, the conformation adopted by a polypeptide chain may also be examined by investigating interactions between the residues. Since the Ramachandran map essentially focuses on local interactions (residues closer in sequence), out of interest, we have analyzed the dihedral angle preferences of residues that make non-local interactions (residues far away in sequence and closer in space) in the folded structures of proteins. The non-local interactions have been grouped into different types such as hydrogen bond, van der Waals interactions between hydrophobic groups, ion pairs (salt bridges), and ππ-stacking interactions. The results show the propensity of amino acid residues in proteins forming local and non-local interactions. Our results point to the vital role of different types of non-local interactions and their effect on dihedral angles in forming secondary and tertiary structural elements to adopt their native fold. 相似文献
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Involvement of Ca2+ influx in F(-)-stimulated pepsinogen release from guinea pig gastric chief cells 总被引:2,自引:0,他引:2
T Matozaki C Sakamoto M Nagao H Nishizaki Y Konda S Baba 《Biochemical and biophysical research communications》1988,152(1):161-168
In isolated guinea pig gastric chief cells, pepsinogen release was stimulated by NaF in a dose-dependent manner. Cholecystokinin (CCK) and Ca2+ ionophore A23187 had no additional effect on NaF-stimulated pepsinogen release. CCK caused a rapid increase in intracellular free Ca2+ concentration ([Ca2+]i) monitored by Quin-2 and markedly stimulated inositol phosphate accumulation in chief cells. By contrast, NaF did not cause any change in [Ca2+]i. NaF, even at a maximal concentration for pepsinogen release, appeared to be relatively ineffective on inositol phosphate accumulation. On the other hand, NaF markedly stimulated Ca2+ influx into chief cells. These results suggest that F- stimulates pepsinogen release probably by increasing Ca2+ influx into chief cells. Since F- is a well known activator of guanine nucleotide regulatory proteins (G proteins), it is proposed that there may exist a G protein regulating the opening of Ca2+ channel in gastric chief cells. 相似文献
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Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. 总被引:16,自引:0,他引:16
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P. A. Zimmerman A. Buckler-White G. Alkhatib T. Spalding J. Kubofcik C. Combadiere D. Weissman O. Cohen A. Rubbert G. Lam M. Vaccarezza P. E. Kennedy V. Kumaraswami J. V. Giorgi R. Detels J. Hunter M. Chopek E. A. Berger A. S. Fauci T. B. Nutman P. M. Murphy 《Molecular medicine (Cambridge, Mass.)》1997,3(1):23-36
BACKGROUND: CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk. MATERIALS AND METHODS: Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk. RESULTS: CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors. CONCLUSIONS: The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy. 相似文献
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