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41.
42.
Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: high affinity and selective A2B adenosine receptor antagonists 总被引:2,自引:0,他引:2
Kalla RV Elzein E Perry T Li X Palle V Varkhedkar V Gimbel A Maa T Zeng D Zablocki J 《Journal of medicinal chemistry》2006,49(12):3682-3692
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs. 相似文献
43.
Loussaïef C Toumi A Chakroun M Ben Brahim H Ben Romdhane F Bouzouaïa N 《La Tunisie médicale》2006,84(2):103-105
Psoas abscesses are rare. In the absence of specific symptoms and signs, their diagnosis was usually difficult. Medical imaging advances have helped in their diagnosis and treatment. Eleven cases of psoas abscess were reviewed retrospectively. We tried to determine epidemiologic and clinical features and therapeutic alternatives for this entity. Mean aged 27 years. Three of the 11 cases occurred in females. An underlying disease was observed in three cases. Associated clinical features were fever (n = 11), lumbar pain (n = 10), and psoOtis (n = 5). Diagnosis was confirmed by ultrasonography (n = 10) and computed tomography (n = 1). Blood culture was positive in 6 out of 11 cases: Staphylococcus aureus (n = 5) and Klebsiella pneumonia (n = 1) Staphylococcceus aureus was isolated in 6 abscess pus. Antibiotics were prescribed in all cases for a mean length of 61 days, in association with percutaneous drainage in 5 cases, surgical drainage in one case and abscess puncture in one case. Outcome was favourable in all cases. 相似文献
44.
Guianvarc'h D Duca M Boukarim C Kraus-Berthier L Léonce S Pierré A Pfeiffer B Renard P Arimondo PB Monneret C Dauzonne D 《Journal of medicinal chemistry》2004,47(9):2365-2374
A series of novel 4beta-substituted sulfonamide derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin has been synthesized. Their effects on human DNA topoisomerase II and, in some cases, on tubulin polymerization were evaluated. Compounds 8a, 8c, 8f, 8g, 8n, 8q, 8r, and 8s and the synthetic precursor 4 are potent topoisomerase II poisons that induce double-stranded breaks in DNA, with either improved or similar activity compared to etoposide. Only the amino precursor, compound 5, was slightly active in tubulin polymerization inhibition assays. We observed that the derivatives bearing an aromatic ring on the 4beta-sulfonamide substituent were either less cytotoxic or equivalent to the parent drug, while the sulfonamides containing an aliphatic side chain and the amino-sulfonamide derivatives, except 8d and 8g, exhibited increased cytoxicity compared to etoposide. In vivo, against the P388 leukemia and the A-549 orthotopic model of lung carcinoma, the most promising compounds were the morpholino- and the piperazino-containing sulfonamides derivatives 8r and 8s. 相似文献
45.
46.
Abu Elzein EM Gameel AA Ramadan RO Housawi FM 《Revue scientifique et technique (International Office of Epizootics)》1999,18(3):749-752
An eruptive moderate form of camelpox infection is reported in camels aged three to four years from the Al-Ahsa region of Saudi Arabia. The clinical signs were moderate in nature (between the 'mild' and the 'severe' form). The morbidity rate was 100% while the case fatality rate was 0%. Camelpox virus was isolated and identified using electron microscopy and serological analysis. 相似文献
47.
Purified protein A (PA) from Staphylococcus aureus was conjugated with the enzyme alkaline phosphatase. This reagent reacted well with pig, rabbit and guinea pig IgG and less well with mouse and bovine IgG. Radioactive 125I-labelled PA showed a similar affinity for the IgGs examined. Antibodies against foot-and-mouth disease virus contained in guinea pig, rabbit and pig serum were detected, using the enzyme-conjugated PA in indirect tests, which were of similar sensitivity to those using enzyme-conjugated anti-species antibody as tracer. 相似文献
48.
Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: a PET/[11C]raclopride study in healthy men. 总被引:4,自引:0,他引:4
Marco Leyton Isabelle Boileau Chawki Benkelfat Mirko Diksic Glen Baker Alain Dagher 《Neuropsychopharmacology》2002,27(6):1027-1035
Eight healthy men underwent two positron emission tomography (PET) [11C]raclopride scans, one following placebo, the second following d-amphetamine (0.30 mg/kg, p.o.). PET data were analyzed using: (1) brain parametric maps to statistically generate regions of significant change; and (2) a priori identified regions of interest (ROI) manually drawn on each individual's co-registered magnetic resonance (MR) images. Compared with placebo, d-amphetamine decreased [11C]raclopride binding potential (BP) with significant effects in ventral but not dorsal striatum. Change in BP in the statistically generated cluster correlated with self-reported drug-induced 'drug wanting' (r = 0.83, p =.01) and the personality trait of Novelty Seeking-Exploratory Excitability (r = 0.79, p =.02). The same associations were seen in the manually drawn ROI in ventral striatum but not in dorsal putamen or caudate. Changes in extracellular dopamine (DA) did not correlate with mood. Mesolimbic DA might mediate interest in obtaining reward rather than reward, per se. Individual differences in amphetamine-induced DA release might be related to predispositions to drug and novelty seeking. 相似文献
49.
Lindberg JS Husserl FE Ross JL Jackson D Scarlata D Nussbaum J Cohen A Elzein H 《Nephrology news & issues》2005,19(3):35-6, 41-3
BACKGROUND: The Ochsner Clinic Foundation initiated the Healthy Start Clinic to identify, educate, and refer chronic kidney disease patients to nephrologists earlier in the course of their disease. This study investigated the impact of a structured educational session on the type and timing of permanent vascular access placement in patients receiving hemodialysis. METHODS: Before initiating dialysis, the HSC patient group received a general overview of the kidney and kidney disease, plus one-on-one instruction from a registered nurse, a dietitian, and a social worker. The HSC group was compared with a concurrent, conventionally prepared group of CKD patients who initiated dialysis during the same study period. RESULTS: Of the 147 patients initiating hemodialysis at OCF between April 1997 and December 2000, 61 had received structured HSC education, and 86 had received conventional care. In HSC-educated patients, the incidence of PVAs placed before hemodialysis initiation was twofold greater than in patients who received conventional care (77% HSC; 36% non-HSC, p < 0.001), and more HSC-educated patients initiated hemodialysis using their PVA (49% HSC; 23% non-HSC, p < 0.01). In addition, five times more patients who received HSC education received arteriovenous fistulas (52% HSC; 10% non-HSC, p < 0.001). Finally, significantly fewer HSC-educated patients initiated dialysis on a temporary catheter (51% HSC; 77% non-HSC, p < 0.001). CONCLUSIONS: Education programs for CKD patients help increase the number of patients receiving early PVA placement, as well as the proportion of patients receiving AVFs as opposed to grafts or temporary catheters. 相似文献
50.
Berns JS Elzein H Lynn RI Fishbane S Meisels IS Deoreo PB 《Kidney international》2003,64(4):1514-1521
BACKGROUND: Understanding the clinical variability of hemoglobin measurements in epoetin-treated hemodialysis patients is important, particularly when this therapy is aimed at maintaining patient hemoglobin levels within a narrow range, such as the 11 to 12 g/dL range recommended in National Kidney Foundation Kidney Dialysis Outcomes Quality Initiative (NKF-K/DOQI) guidelines. This study examines hemoglobin variability under conditions of standard clinical practice in epoetin-treated hemodialysis patients. METHODS: We studied 987 hemodialysis patients participating in an observational retrospective study that evaluated anemia management practices from October 1, 1996 to December 31, 1997 at 11 United States dialysis centers that were randomly selected from a pool of nearly all United States dialysis facilities. Each participating facility maintained its own anemia management protocols without specific anemia management recommendations or interventions made as part of this study. Hemoglobin variability was determined by calculating the 1-month and 2- to 6-month rolling average hemoglobin for each patient. The range of mean hemoglobin values that included the middle 50% (25th to 75th percentile), 80% (10th to 90th percentile), and 90% (5th to 95th percentile) of values were determined. The hemoglobin ranges that included 1 standard deviation (SD) (67%) of the study values and 2 SD (95%) of the study values for each time period were calculated. RESULTS: The mean hemoglobin was between 10.9 and 11.2 g/dL throughout the study. The hemoglobin range encompassing 50%, 80%, and 90% of values from a single month was 1.7, 3.3, and 4.4 g/dL, respectively. A progressive narrowing in the range of hemoglobin values encompassed by each percentile grouping (i.e., hemoglobin variability) was observed as longer rolling intervals were averaged. The hemoglobin range within the 25th to 75th percentile was 1.7 g/dL using single-month hemoglobin values and 1.1 g/dL using a 6-month rolling average. The range of hemoglobin values that encompassed 90% of patients was 4.4 g/dL using single-month values, 3.7 g/dL using 3-month rolling averages, and 3.2 g/dL using 6-month rolling averages. Fewer than 50% of patients had hemoglobin values within the 1.0 g/dL NKF-K/DOQI recommended range, even when a 6-month rolling average was applied. When hemoglobin values were measured for 1 month, 1 SD was 1.4 g/dL; for the 3-month rolling average, 1 SD was 1.1 g/dL; and for the 4-, 5-, and 6-month rolling averages, 1 SD was 1.0 g/dL. Greater hemoglobin variability correlated with higher mean corpuscular hemoglobin (P = 0.003) and serum ferritin (P = 0.047), and inversely correlated with age (P = 0.006) and serum albumin (P = 0.0001). CONCLUSION: Substantial variability occurs in hemoglobin values in epoetin-treated hemodialysis patients. The NKF-K/DOQI recommended hemoglobin range appears to be too narrow in clinical practice. Expanding the target range and use of rolling average hemoglobin intervals of 3 to 6 months as a clinical and quality assurance measure avoids clinical variability inherent with the use of isolated hemoglobin values or single-month hemoglobin averages. 相似文献