Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients

Summary— Zolpidem, an imidazopyridine derivative, is a chemically novel, non-benzodiazepine hypnotic agent. Many uraemic patients complain of sleep disorders and ask for hypnotic medication which is well tolerated both clinically and biologically in such patients. We studied the pharmacokinetics and pharmacodynamics of zolpidem in 12 end-stage renal patients regularly treated by hemodialysis three times a week. Zolpidem (10 mg) was given orally for 14 or 21 days. Pharmacokinetic and pharmacodynamic evaluations were repeated at the end of the study on day 14 or day 21. C_max, T_max, t1/2 and the area under the curve were not modified in hemodialyzed patients. After daytime dosing, zolpidem induced the same level of sleepiness after the first and last dose and was well tolerated as a hypnotic agent after the night-time dosing. From these results, it can be said that zolpidem may be administered safely to patients with severe renal impairment without any modification of the dosage regimen.     

Lung scar cancer—a reappraisal

A retrospective clinicopathological study of 100 necropsy cases of lung carcinoma revealed three scar cancers. The scarring in a further 11 probably occurred secondary to the tumour. The premise that lung scars initiate malignancy is questioned.     

Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.     

Changes in red blood cell membrane phosphate concentration during blood bank storage

The change in red blood cell membrane phosphate concentration of standard CPD whole blood stored in Fenwal blood bags at 4 C was measured daily for two weeks. Membrane phosphate concentrations increased rapidly when stored pH fell to 6.95. At the same time, the rate of K+ leakage from the cells increased, and transport of inorganic phosphate across the membrane decreased. It is concluded that gross uptake of phosphorus by the red blood cell membrane during blood bank storage may be in part responsible for physical changes in the membrane.     

从流行病学观点论精液分析

在《世界卫生组织人类精液分析实验室技术手册》(简称手册)第5版中,首次增加了人类精液特征的参考值范围。现阐述提供这些数据是否有助于平息就某些问题引发的广泛争议,如时间地点不同,精液计数差异明显;能否证实某些假设,如人类活动向环境中排放的化学物质损害男性生殖健康等。也解释了这些参考值并不能解决上述问题的原因。虽然既定的精液特征参考值对流行病学研究的价值有限,但世界卫生组织(WHO)手册对建立合适的研究方案极具价值。尽管精液分析有局限性,但仍然是流行病学研究的有用工具,而且至今尚无其他更好的方法能取而代之。     

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

Background

An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.

Methods

We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.

Results

The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.

Conclusions

We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.