Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro.

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.     

Critical analysis of jejunoileal bypass

This study analyzed a group of morbidly obese patients who underwent jejunoileal bypass over a 10 year period. Patients underwent either a Payne or Scott procedure. Weight loss was reported in terms of percent of excessive weight loss. Results showed that patients who had a Payne bypass had an average excess weight loss of 75 percent, whereas those with the Scott bypass had an average excess weight loss of 61 percent. All patients lost weight. Complications in this series were lower than what has been traditionally reported. The problem that occurred most often was kidney stones (8 percent of the patients). There has been only one death to date. The low incidence of complications can be attributed to the fact that the patients were evaluated, operated on, supervised, and followed by one doctor and his associated nurses. Thus, it is proposed that jejunoileal bypass, compounded with good patient care and careful patient selection, can produce positive results with a minimum number of problems.     

002 高血压及抗高血压药物与Ⅱ型糖尿病

本文采用前瞻性群体研究旨在确定降压药物的应用与继发Ⅱ型糖尿病的危险之间是否存在独立的相关性。 作者对12 550名(年龄45-64岁)无糖尿病的成年人进行全面健康评价(包括药物的使用及血压测定)。高血压判定标准为收缩压≥140mmH-g(1mmHg=0.1333 kPa)或舒张压≥90mmHg。确定高血压患者3 804例,根据使用降压药物的种类分为血管紧张素转化酶抑制剂(ACEI)162例,β阻滞剂543例,钙拮抗剂96例,噻嗪利尿剂458例,其它单一药物137例,多种药物(≥2种)934例,其余1 474例高血压患者未给予任何抗高血压药物治疗。随访3年及6年后,通过测定空腹血糖浓度[糖尿病判定标准为：空腹血糖≥126m/dl(≥7.0mmol/L)餐后血糖≥200m/dl(≥11.1mmol/L)]评价糖尿病新病例的发生率。     

Distribution of serogroups of Neisseria meningitidis and antigenic characterization of serogroup Y meningococci in Canada, January 1, 1999 to June 30, 2001.

The relative frequency of serogroups of Neisseria meningitidis associated with meningococcal disease in Canada during the period January 1, 1999 to June 30, 2001 was examined. Of the 552 strains of N meningitidis collected from clinical specimens of normally sterile sites, 191 (34.6%), 276 (50.0%), 61 (11.1%) and 23 (4.2%) were identified by serological and molecular methods as serogroups B, C, Y and W135, respectively. About half (50.8%) of the serogroup Y isolates were isolated in the province of Ontario. The two most common serotypes found were 2c and 14. Most of the serogroup Y strains isolated from patients in Ontario were serotype 2c, while serotype 14 was the most common serotype associated with disease in the province of Quebec. The two most common serosubtypes found among the serogroup Y meningococci were P1.5 and P1.2,5. Laboratory findings, based on antigenic analysis, did not suggest that these serogroup Y strains arise by capsule switching from serogroups B and C strains. This study documented a higher incidence of finding serogroup Y meningococci in clinical specimens from patients in Ontario compared to the rest of Canada, and parallels the increase in serogroup Y meningococcal disease reported in some parts of the United States.     

Not all nonpalpable breast cancers are alike.

Clinical and mammographic data of 1009 consecutive patients were correlated with histopathologic data of 1144 biopsy specimens of nonpalpable breast lesions to better define the presentation and biologic behavior of early breast cancer. Patients with malignant neoplasms (269 [24%] of 1144 specimens) were older (mean age, 62.1 years) than patients with benign lesions (mean age, 54.9 years). Furthermore, patients with invasive disease were older (mean age, 63.3 years) than patients with noninvasive disease (mean age, 58.5 years) with an overall increased risk of invasive cancer per year of 1.035. A 58% incidence of invasive cancer was detected for lesions characterized by calcifications, while the incidence of invasive cancer was 84% for isolated mass lesions (relative risk, 4.31 for masses). Isolated mammographic calcifications associated with cancer appeared in a younger population and were significantly associated with noninvasive ductal cancer. Breast cancer presenting as a mammographic mass appeared in an older group and was highly associated with the presence of invasive disease.     

The unusual cause of death--a special assignment for the doctor in emergency service

The emergeny physician summoned to a sudden, unexpected death is confronted by various uncommon problems such as the certification of death on the "frontline" without destroying important evidence, the estimation of time since death, deciding whether the death must be reported to the authorities as well as taking care of mourning relatives. To all this questions the authors offer answers and practical advices.