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61.
62.
DC Underwood S Bochnowicz RR Osborn CJ Kotzer MA Luttmann DW Hay PD Gorycki SB Christensen TJ Torphy 《Canadian Metallurgical Quarterly》1998,287(3):988-995
We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders. 相似文献
63.
IM Bell JM Erb RM Freidinger SN Gallicchio JP Guare MT Guidotti RA Halpin DW Hobbs CF Homnick MS Kuo EV Lis DJ Mathre SR Michelson JM Pawluczyk DJ Pettibone DR Reiss S Vickers PD Williams CJ Woyden 《Canadian Metallurgical Quarterly》1998,41(12):2146-2163
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases. 相似文献
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65.
AI Qureshi JI Suarez PD Parekh G Sung R Geocadin A Bhardwaj RJ Tamargo JA Ulatowski 《Canadian Metallurgical Quarterly》1998,43(1):22-6; discussion 26-7
OBJECTIVE: Risk factors that predispose to the formation of multiple intracranial aneurysms, which are present in up to 34% of patients with intracranial aneurysms, are not well defined. In this study, we examined the association between known risk factors for cerebrovascular disease and presence of multiple intracranial aneurysms. METHODS: We reviewed the medical records and results of conventional angiography in all patients with a diagnosis of intracranial aneurysms admitted to the Johns Hopkins University hospital between January 1990 and June 1997. We determined the independent association between various cerebrovascular risk factors and the presence of multiple aneurysms using logistic regression analysis. RESULTS: Of 419 patients admitted with intracranial aneurysms (298 ruptured and 121 unruptured), 127 (30%) had multiple intracranial aneurysms. In univariate analysis, female gender (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.1-3.3) and cigarette smoking at any time (OR = 1.8; 95% CI, 1.1-3.0) were significantly associated with presence of multiple aneurysms. In the multivariate analysis, cigarette smoking at any time (OR = 1.7; 95% CI, 1.1-2.8) and female gender (OR = 2.1; 95% CI 1.2-3.5) remained significantly associated with multiple aneurysms. Hypertension, diabetes mellitus, and alcohol and illicit drug use were not significantly associated with presence of multiple aneurysms. CONCLUSION: Cigarette smoking and female gender seem to increase the risk for multiple aneurysms in patients predisposed to intracranial aneurysm formation. Further studies are required to investigate the mechanism underlying the association between cigarette smoking and intracranial aneurysm formation. 相似文献
66.
L Zhang D Wang H Fischer PD Fan JH Widdicombe YW Kan JY Dong 《Canadian Metallurgical Quarterly》1998,95(17):10158-10163
Adeno-associated virus (AAV)-based vectors have been shown to be effective in transferring the cystic fibrosis gene (CFTR) into airway epithelial cells in animal models and in patients. However, the level of CFTR gene expression has been low because the vector cannot accommodate the CFTR gene together with a promoter. In this study, we described a strategy to reduce the size of the CFTR cDNA to allow the incorporation of an effective promoter with the CFTR gene into AAV vectors. We engineered and tested 20 CFTR mini-genes containing deletions that were targeted to regions that may contain nonessential sequences. Functional analyses showed that four of the shortened CFTRs (one with combined deletions) retained the function and the characteristics of a wild-type CFTR, as measured by open probability, time voltage dependence, and regulation by cAMP. By using an AAV vector with a P5 promoter, we transduced these short forms of CFTR genes into target cells and demonstrated high levels of CFTR expression. We also demonstrated that smaller AAV/CFTR vectors with a P5 promoter expressed the CFTR gene more efficiently than larger vectors or a vector in which CFTR gene was expressed from the AAV inverted terminal repeat sequence. The CFTR mini-gene with combined deletions was packaged into AAV virions more efficiently, generated higher titers of transducing virions, and more effectively transferred CFTR function into target cells. These new vectors should circumvent the limitations of AAV vector for CFTR expression. Our strategy also may be applicable to other genes, the sizes of which exceed the packaging limit of an AAV vector. 相似文献
67.
Fibro-osseous lesions of the sinonasal region are relatively frequent, but those strictly confined to the nasal cavity are rare. We report an atypical fibro-osseous lesion in the nasal cavity and describe its radiological features. The differential diagnosis is discussed. 相似文献
68.
XF Zhao T Colaizzo-Anas NJ Nowak TB Shows RW Elliott PD Aplan 《Canadian Metallurgical Quarterly》1998,47(2):319-322
OBJECTIVE: We prospectively compared the ability of two techniques--bone scintigraphy with single-photon emission computed tomography (SPECT) of the chest and CT of the chest--to reveal potential osteosarcoma metastases of the lung. SUBJECTS AND METHODS: Our study included 27 patients with osteosarcoma who prospectively underwent both bone scintigraphy with SPECT of the chest and CT of the chest. The imaging results were compared with outcome or pathologic analysis of any lung lesions found. RESULTS: Eight (30%) of the 27 patients had pulmonary metastases. Four of these eight patients had positive results on both CT studies and bone SPECT studies, with additional lesions detected with bone SPECT in two of these four patients. The other four patients with pulmonary metastases had positive results on CT studies, whereas the results of bone SPECT studies remained negative. The results of bone SPECT studies were negative in the 19 patients without pulmonary metastases. CT, however, showed abnormalities in seven (37%) of the 19 patients, which were eventually attributed to benign conditions. CONCLUSION: Negative results on a bone SPECT study of the chest should not be used to exclude the possibility of lung metastases. However, if the results are positive, a bone SPECT study can be used to confirm abnormalities seen on CT scans and may also reveal subtle lesions missed on CT scans. 相似文献
69.
70.
BACKGROUND: Topical antimicrobials have been considered for treatment of secondarily infected wounds because of the potential for reduced risk of adverse effects and greater patient convenience. We compared mupirocin cream with oral cephalexin in the treatment of wounds such as small lacerations, abrasions, or sutured wounds. METHODS: In 2 identical randomized double-blind studies, 706 patients with secondarily infected wounds (small lacerations, abrasions, or sutured wounds) received either mupirocin cream topically 3 times daily or cephalexin orally 4 times daily for 10 days. RESULTS: Clinical success at follow-up was equivalent in the two groups: 95.1% and 95.3% in the mupirocin cream and the cephalexin groups, respectively (95% confidence interval [CI], -4.0% to 3.6%; P = .89). The intention-to-treat success rate was 83% in both groups. Bacteriologic success at follow-up was also comparable: 96.9% in the mupirocin cream and 98.9% in the cephalexin groups (95% CI, -6.0% to 2.0%; P = .22). The occurrence of adverse experiences related to study treatment was similar for the 2 groups, with fewer patients in the mupirocin cream group reporting diarrhea (1.1% vs 2.3% for cephalexin). CONCLUSIONS: Mupirocin cream applied topically 3 times daily is as effective as oral cephalexin given 4 times daily for the treatment of secondarily infected wounds and was well tolerated. 相似文献