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131.
OBJECTIVE: To review the previously published studies on pharmacokinetics and pharmacodynamics of chiral drugs used in the treatment of asthma. DATA SOURCES: Primary and review articles were identified with a MEDLINE search (1980-May 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All English-language studies and reviews obtained from the MEDLINE search pertaining to stereoselective pharmacokinetics and pharmacodynamics of chiral anti-asthma drugs were assessed. DATA SYNTHESIS: Several anti-asthma drugs (e.g., beta(2)-adrenergic agonists, leukotriene modifiers) are chiral and marketed as racemates, which consist of equal proportions of 2 enantiomers. Significant stereoselectivity has also been reported in pharmacodynamics and pharmacokinetics of the beta(2)-agonists. The enantiomers of beta(2)-agonists in the R configuration are primarily responsible for the bronchodilating effects of the racemate. The plasma concentrations of the enantiomers of anti-asthma drugs may differ as a reflection of stereoselectivity in clearance, volume of distribution, and route of administration. CONCLUSIONS: Stereoselectivity in the pharmacokinetics of anti-asthma drugs may complicate the relationship between dose and/or plasma concentration of racemic drug versus effect relationship. An appreciation of the stereoselective pharmacokinetics and pharmacodynamics of chiral anti-asthma drugs may optimize the use of these agents in asthmatic patients. 相似文献
132.
Although absence of the common carotid artery (CCA) is a rare anomaly, the specific configuration in our case makes it extremely rare. Clinical, angiographic, ultrasonographic, and embryologic correlations of this anomaly are discussed after the case report. 相似文献
133.
Alon US Monzavi R Lilien M Rasoulpour M Geffner ME Yadin O 《Pediatric nephrology (Berlin, Germany)》2003,18(2):155-158
Hypertension has been anecdotally reported in children with familial hypophosphatemic rickets (XLH). To better identify and characterize the clinical and laboratory features of hypertensive XLH children, we reviewed the medical records of 41 XLH children, all treated with phosphate and vitamin D analogues. Eight children, who were originally normotensive, developed hypertension during the 2nd decade of life. At diagnosis of hypertension all had persistent secondary/tertiary hyperparathyroidism (HPTD), defined as high serum parathyroid hormone (PTH) for 12 months or longer. Seven had nephrocalcinosis (NC). Analysis of data showed that of 11 children with HPTD, 8 developed hypertension compared with 0 among 30 without HPTD (P<0.001). Of 40 children studied, 18 had NC that was significantly associated with both HPTD (P<0.01) and hypertension (P<0.025). At diagnosis of hypertension, serum calcium was elevated in 2. Plasma renin activity was high in 3 of 4 patients in whom it was measured. Doppler ultrasonography or renal scan was normal in the 5 children studied. Early echocardiography showed left ventricular hypertrophy in only 2 of 5 children studied. In 3 patients who underwent parathyroidectomy, hypertension persisted and 1 progressed to renal failure. Serum creatinine remained normal in all others. Successful treatment of hypertension consisted of beta-adrenergic blockers, angiotensin converting enzyme inhibitors, and Ca channel blockers as monotherapy or in combination. We conclude that hypertension in treated XLH children is closely associated with HPTD. Emphasis should therefore be placed on prevention of the development of HPTD as a complication of XLH treatment, and close monitoring for hypertension in those who do develop HPTD. 相似文献
134.
Valid, reliable and comparable measures of the health states of individuals and of the health status of populations are critical components of the evidence base for health policy. We need to develop population health measurement strategies that coherently address the relationships between epidemiological measures (such as risk exposures, incidence, and mortality rates) and multi-domain measures of population health status, while ensuring validity and cross-population comparability. 相似文献
135.
Impact of race on outcome after definitive radiotherapy for squamous cell carcinoma of the head and neck 总被引:1,自引:0,他引:1
BACKGROUND: The objective of the current study was to evaluate the impact of race (black vs. white) on the outcome of patients with invasive squamous cell carcinoma of the head and neck. METHODS: Between 1983 and 1997, 686 patients completed definitive, twice-daily radiotherapy (RT) alone or combined with a planned neck dissection; no patients received adjuvant chemotherapy. The minimum follow-up was 2 years, and median follow-up was 7 years for living patients. No patients were lost to follow-up. Fifty-five patients were black (8%). RESULTS: Although the two groups had similar 5-year local-regional control rates (black patients vs. white patients: 70% vs. 76%, respectively; P = 0.275), black patients had double the risk for distant recurrence compared with white patients (27% vs. 13%; P = 0.012). The 5-year cause-specific and absolute survival rates were lower for black patients (52% vs. 74% [P = 0.001] and 29% vs. 52% [P < 0.001], respectively). Multivariate analyses revealed that race was an independent predictor of freedom from distant metastasis (P = 0.013), cause-specific survival (P = 0.005), and absolute survival (P < 0.001). CONCLUSIONS: Although equal local-regional control rates can be achieved in black patients and white patients with squamous cell carcinoma of the head and neck, the risk of distant recurrence was significantly higher in black patients and resulted in decreased survival. Reevaluation of current strategies for pretreatment metastatic work-ups and development of more effective systemic therapy will be key to improving the survival disparity in this group. 相似文献
136.
PURPOSE: To analyze parameters that influence the risk of distant metastases after definitive radiotherapy. METHODS: Between 1983 and 1997, 873 patients were treated with definitive radiotherapy and had follow-up for 2 years or more. Univariate and multivariate analyses were performed to evaluate risk factors that might influence the risk of distant metastases. RESULTS: The 5-year distant metastasis-free survival rate was 86%. Univariate analyses revealed that the risk of distant metastases was significantly influenced by gender (p =.0092), primary site (p =.0023), T stage (p <.0001), N stage (p <.0001), overall stage (p <.0001), level of nodal metastases in the neck (p <.0001), histologic differentiation (p =.0096), control above the clavicles (p <.0001), and time to locoregional recurrence (p <.0001). Multivariate analysis of freedom from distant metastases revealed that gender (p =.0390), T stage (p <.0001), N stage (p =.0060), nodal level (p <.0001), and locoregional control (p <.0001) significantly influenced this end point. Multivariate analysis revealed that gender (p =.0049), T stage (p <.0001), N stage (p <.0001), and locoregional control (p <.0001) significantly influenced cause-specific survival. CONCLUSIONS: The risk of distant metastases after definitive radiotherapy is 14% at 5 years and is significantly influenced by gender, T stage, N stage, nodal level, and locoregional control. 相似文献
137.
PURPOSE: To evaluate feeding tube use. MATERIALS AND METHODS: Nine hundred thirty-four patients were treated with radiotherapy (RT). RESULTS: Feeding tubes were placed in 235 patients (25%): 212 patients (22.5%) for acute toxicity, 18 patients (2%) for late effects, and 5 patients (0.5%) for both. Median duration of tube dependence for acute toxicity was 3.8 months. Multivariate analysis revealed that feeding tube placement for acute toxicity was increased with higher RT dose (p <.0001), adjuvant chemotherapy (p =.0002), advanced age (p =.0002), and the presence of neck disease (p =.0045). The risk of a feeding tube for late effects was 2% at 5 years. The likelihood of feeding tube placement for late effects was greater for women (p =.0293), higher RT dose (p =.0345), and primary sites, including the hypopharynx and multiple synchronous primary tumors (p =.0360). Feeding tube placement for late effects was unrelated to tube placement for acute toxicity. CONCLUSION: Likelihood of long-term feeding tube dependence was low and unrelated to placement for acute effects. 相似文献
138.
Purpose. To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine.
Methods. We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl--cyclo-dextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and 51Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used.
Results. Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered.
Conclusions. Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage. 相似文献
139.
Astles PC Brown TJ Halley F Handscombe CM Harris NV Majid TN McCarthy C McLay IM Morley A Porter B Roach AG Sargent C Smith C Walsh RJ 《Journal of medicinal chemistry》2000,43(5):900-910
The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ET(A) receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ET(A) antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC(50) 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC(50) of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 micromol/kg) and was duly proposed and accepted as a development candidate. 相似文献
140.