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991.
García-Aparicio C Bonache MC De Meester I San-Félix A Balzarini J Camarasa MJ Velazquez S 《Journal of medicinal chemistry》2006,49(17):5339-5351
Here we describe a novel type of enzyme-based prodrug approach in which a dipeptide moiety is linked to a nonpeptidic therapeutic drug through an amide bond which is specifically cleaved by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme activity present in plasma and on the surface of certain cells. DPP IV has high substrate selectivity for peptides with a proline (or an alanine) at the penultimate amino acid position at the N-terminus but tolerates a wide range of natural amino acids at the amino terminal end. A variety of dipeptidyl amide prodrugs of anti-HIV TSAO molecules were synthesized and evaluated for their ability to act as substrates for the enzyme. Our data revealed that DPP IV/CD26 can efficiently recognize such prodrugs as substrates, releasing the parent compound. Moreover, it is possible to modify the half-life and the lipophilicity of the prodrugs by changing the nature of the dipeptide. All conjugates have shown marked in vitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety. 相似文献
992.
Sluis-Cremer N Hamamouch N San Félix A Velazquez S Balzarini J Camarasa MJ 《Journal of medicinal chemistry》2006,49(16):4834-4841
993.
994.
Giuliano C Fiore F Di Marco A Padron Velazquez J Bishop A Bonelli F Gonzalez-Paz O Marcucci I Harper S Narjes F Pacini B Monteagudo E Migliaccio G Rowley M Laufer R 《Xenobiotica; the fate of foreign compounds in biological systems》2005,35(10-11):1035-1054
The disposition of compound A, a potent inhibitor of the hepatitis C virus (HCV) NS5B polymerase, was characterized in animals in support of its selection for further development. Compound A exhibited marked species differences in pharmacokinetics. Plasma clearance was 44 ml min-1 kg-1 in rats, 9 ml min-1 kg-1 in dogs and 16 ml min-1 kg-1 in rhesus monkeys. Oral bioavailability was low in rats (10%) but significantly higher in dogs (52%) and monkeys (26%). Compound A was eliminated primarily by metabolism in rats, with biliary excretion accounting for 30% of its clearance. Metabolism was mainly mediated by cyclohexyl hydroxylation, with N-deethylation and acyl glucuronide formation constituting minor metabolic pathways. Qualitatively, the same metabolites were identified using in vitro systems from all species studied, including humans. The low oral bioavailability of compound A in rats was mostly due to poor intestinal absorption. This conclusion was borne out by the findings that hepatic extraction in the rat was only 30%, intraperitoneal bioavailability was good, and compound A was poorly absorbed from the rat isolated intestinal loop, with no detectable intestinal metabolism. Compound A was not an inhibitor of major human cytochrome P450 enzymes, indicating minimal potential for clinical drug-drug interactions. The metabolic clearance of compound A in rat, dog and monkey hepatocytes correlated with the systemic clearance observed in these species. Since compound A was very stable in human hepatocytes, the results suggest that it will be a low clearance drug in humans. 相似文献
995.
996.
997.
Jones CH; Newstead CG; Wills EJ; Davison AM 《Nephrology, dialysis, transplantation》1997,12(3):554-558
HYPOTHESIS: Trends in serum albumin concentration over time provide a
better prediction of clinical outcome in CAPD patients than a single mean
value. METHODS: This was a retrospective review of outcome at 36 months in
225 adult CAPD patients. Mean serum albumin was determined for the first
(SA1) and second (SA2) 6 months of treatment and patients grouped according
to SA1 (group I, > 37; group II, 34-37; group III, < 34 g/l) and
according to the change in serum albumin (delta SA) between the first and
second 6 months (increased/static or decreased). Patient (PS) and technique
(TS) survival were determined by Kaplan-Meier survival analysis. The effect
of SA1 and delta SA on survival were determined in a multivariate Cox
regression analysis model that included age and presence or absence of a
systemic disease. RESULTS: By SA1 group, PS and TS survival at 36 months
were 94 and 76% (group I), 64 and 53% (group II) and 70 and 52% (group
III). If delta SA increased/remained static, then SA1 did not predict PS
(group I, 100%; group II, 96%; group III, 74%; P = n.s.) or TS (group I,
72%; group II, 63%; group III, 65%; P = n.s.). If delta SA decreased, PS
was worse in groups II and III, both as compared to group I (PS group I,
88%; group II, 52%; group III, 34%; P = 0.02) and as compared to the groups
II and III when delta SA increased (PS group II, 74 vs 52%, P = 0.05; group
III, 82 vs 34%, P = 0.005) The same trend was seen for TS. In the
multivariate Cox regression model, age, direction of change in serum
albumin, and presence of a multisystem disease were significant predictors
of survival, whereas SA1 was not. CONCLUSION: Early hypoalbuminaemia in
CAPD only predicts a worse patient and technique survival if mean serum
albumin decreases further from the first to second 6 months of dialysis
therapy. Change in serum albumin between the first and second 6 months of
CAPD and the mean serum albumin over the first 6 months together offer
better discrimination of outcome than either alone.
相似文献
998.
PJ Beeby EJ Elliott DJ Henderson-Smart ID Rieger 《Archives of disease in childhood》1994,71(2):F93-F96
Compared with term infants, little information is available about the usefulness of the umbilical artery pH in relation to outcome in extremely preterm infants. This prospective study evaluates the relation between umbilical artery pH (UapH), Apgar scores, perinatal events, and outcome in infants born at less than 32 weeks' gestation. Six hundred and twenty three infants of < 32 weeks' gestation were studied. The median UapH was 7.25, with a range of 6.78-7.49. A low UapH was significantly associated with male sex, hyaline membrane disease, grade 3 or 4 intraventricular haemorrhage, and neonatal death. It was also associated with lower birth weight and lower birthweight centile. The relations between the UapH and outcomes of neonatal death, cerebral palsy, and developmental quotient at 1 year, and other perinatal risk factors were then examined using multiple logistic regression. After adjusting for other risk factors, UapH was not significantly associated with any outcome. In contrast, a low one minute Apgar (< 4) remained a significant risk factor, with odds ratios of 2.7 (95% confidence interval (CI) 1.5 to 5.2) for neonatal death and 3.8 (95% CI 1.4 to 10.4) for cerebral palsy. 相似文献
999.
1000.
Renal artery stenosis in kidney transplants 总被引:1,自引:0,他引:1
FC Fervenza RA Lafayette EJ Alfrey J Petersen 《American journal of kidney diseases》1998,31(1):142-148
Transplant renal artery stenosis (TRAS) is an increasingly recognized complication of renal transplantation, with a reported incidence of between 1% and 23%. The clinical features include refractory hypertension, new-onset hypertension, allograft dysfunction, and the presence of a bruit over the graft. In this report, we describe the investigation and treatment of one such patient and review the current diagnostic approaches and therapy in this setting. 相似文献