Pharmacokinetics and pharmacodynamics following single and repeated nightly administrations of loprazolam, a new benzodiazepine hypnotic.

The pharmacokinetics of oral loprazolam and pharmacodynamic responses on the morning following nightly drug administration were examined after single and after seven consecutive 1 mg doses in six non-fasting healthy subjects. The serum concentration-time profiles for unchanged loprazolam measured by a specific high pressure liquid chromatography/gas chromatography (h.p.l.c./g.c.) method and for benzodiazepine material measured by radioimmunoassay (RIA) were qualitatively similar although RIA levels were consistently higher. Approximate elimination half-life of unchanged loprazolam after single doses was 8.0 h. For RIA measured material, approximate half-life was 11.7 h following acute administration and 12.8 h after seven consecutive doses. Compared to results after single doses, maximum serum concentration and AUC were greater following 1 week's treatment. Using RIA results, the increases were 27.2% (95% CL 6.9 to 47.4%) and 35.1% (95% CL 15.8 to 54.3%) respectively and using h.p.l.c./g.c. data, 11% (95% CL - 22.6% to 44.5%) and 41% (95% CL - 50.9 to 133.0%). After repeated doses of loprazolam, there were no significant changes with respect to results after single doses in psychomotor function assessed objectively by critical flicker fusion threshold or choice reaction time, or in sleep quality or behaviour on awakening assessed subjectively by 10 cm analogue scales. Mean time to maximum serum concentration was 4.95 h with considerable inter-individual variability (range 1-12 h) and there was a lag time of 1-1.5 h before drug was detectable in blood.(ABSTRACT TRUNCATED AT 250 WORDS)     

Screening for prostate cancer with prostate-specific antigen: beware the biases

BACKGROUND: The evidence relating to the use of prostate-specific antigen (PSA) as a screening test is a highly controversial, as demonstrated by the lack of agreement among experts. There may be biases associated with various studies. ISSUES: The main controversy is the relatively high prevalence of prostate cancer (PC) found at autopsy compared with the relatively low death rate from the disease. The lack of modifiable risk factors has led to early detection as a strategy to reduce mortality, as there is evidence for a significant burden of disease. Important issues are the accuracy of current screening tests, some attempts to improve on them, and whether there are good prognostic markers. The consequences of PSA testing (usually further testing including biopsy) and outcomes of treatment are presented in terms of mortality and morbidity; quality of life (QOL) must also be considered. Also important are the benefits from, and the difficulties associated with the "informed choice" approach to PSA screening. CONCLUSION: There is evidence to suggest that biases can have a significant impact on the utility of PSA as a screening test for PC.     

Efficacy of intracoronary or intravenous VEGF165 in a pig model of chronic myocardial ischemia

OBJECTIVES: We sought to optimize vascular endothelial growth factor (VEGF) treatment for therapeutic angiogenesis in myocardial ischemia, we explored the efficacy of five different regimens. BACKGROUND: Although VEGF165 is one of the most potent pro-angiogenic growth factors, VEGF165 treatment for myocardial ischemia has been hampered by low efficacy and dose-limiting hypotension after systemic or intracoronary delivery. METHODS: This study evaluated the effect of intravenous or intracoronary rhVEGF165 in the presence or absence of nitric oxide (NO) synthase inhibition in a porcine model of chronic myocardial ischemia. Forty-two Yorkshire pigs with chronically occluded left circumflex coronary arteries were randomly assigned to receive 10 microg/kg of VEGF165: 1) rapid (40 min) intravenous VEGF165 0.25 microg/kg/min, 2) slow (200 min) intravenous VEGF165 0.05 microg/kg/min, 3) rapid intracoronary VEGF165 0.25 microg/kg/min, 4) rapid intracoronary VEGF165 0.25 microg/kg/min + nitro-L-arginine methyl ester hydrochloride (L-NAME) or 5) rapid vehicle infusion. RESULTS: Intracoronary and intravenous VEGF165 induced hypotension. Intracoronary VEGF-induced hypotension was blocked by L-NAME. Coronary angiography three weeks after treatment showed improvement in collateral index in both intracoronary groups but not the intravenous VEGF165 groups. Likewise, myocardial blood flow and microvascular function in the ischemic territory improved in both intracoronary groups but not in the intravenous groups. Global and regional myocardial function showed no significant improvements in any groups. CONCLUSIONS: Intracoronary infusion of VEGF165 significantly improves blood flow to the ischemic myocardium. Concomitant administration of L-NAME inhibits VEGF-induced hypotension while most likely preserving VEGF-induced angiogenesis. Intravenous infusion of VEGF165 was not effective in augmenting either myocardial flow or function in this model.     

Montgomery Thyroplasty Implant for vocal fold immobility: phonatory outcomes

Forty-three patients with a diagnosis of unilateral vocal fold immobility underwent thyroplasty type I with the Montgomery Thyroplasty Implant System. Preoperative and postoperative evaluations were completed by means of videostroboscopic, acoustic, and aerodynamic measures. Clinicians' perceptions of vocal quality and patients' satisfaction with the surgery and vocal quality were determined. Improvements after surgery were observed for glottal closure, vocal fold amplitude, mucosal wave activity, average intensity, maximum intensity range, maximum phonation time, glottal airflow, average sound pressure, and subglottal pressure. Average postsurgical fundamental frequency values fell within normal limits and did not display significant changes relative to presurgical values. The clinicians' perceptual evaluations indicated an improvement in voice quality for most patients. A majority of patients expressed satisfaction with the surgery and resulting voice quality. The results of the present study, in combination with the surgical advantages that have been described for the Montgomery Thyroplasty Implant System, support the view that this approach offers an attractive alternative for treating unilateral vocal fold immobility.     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.     

Less severe retinopathy of prematurity induced by surfactant replacement therapy

To assess the effect of surfactant replacement therapy (SRT) on the prevalence and severity of retinopathy of prematurity (ROP), we compared data from 160 SRT-treated preterm infants with data from 230 historic controls. The prevalence of ROP was 30.6% in the treatment group and 23.4% in the control group. Severe ROP (stages 3-4) was seen in 6.1% of the infants with ROP in the treatment group and 20.3% of the ROP patients in the control group. Surfactant therapy had no influence on the prevalence of ROP (odds ratio 1.4, 95% confidence interval 0.797-2.459, p = 0.242). However, SRT was associated with a decreased risk for severe ROP, compared to mild ROP (odds ratio 0.226, 95% confidence interval 0.056-0.905, p = 0.036). These data suggest that SRT is associated with a decreased risk for severe ROP.     

金刚大化学成分的研究

从百部科黄精叶钩吻属植物金刚大(Croomia japonica Miq)的根部分得五个成分,分别为粉蕊黄杨胺A(pachysamine A,Ⅰ)、金刚大啶(croomionidine,Ⅱ)、金刚大碱(croomme,Ⅲ)、脱氢金刚大碱(didehydrocroomine,Ⅳ)和β-谷甾醇。应用波谱(IP,MS,¹HNMR和¹³CNMR等)分析、理化数据测定和化学转化,确定丁它们的结构,其中金刚大啶为新甾体生物碱。