A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.     

Pharmacokinetics of trazodone and its major metabolite m-chlorophenylpiperazine in plasma and brain of rats

Sprague-Dawley rats were used as models for single trazodone administration (males), continuous adminstration and dose proportionality experiments (males, females, pregnant females). Plasma and brain tissue were analysed for trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). Fetal exposure to trazodone and m-CPP was assessed and differences in their steady-state plasma concentration were sought between adult males and females. Both trazodone and m-CPP rapidly appeared in plasma and brain tissue following a single intraperitoneal trazodone dose with brain concentrations exceeding those in plasma. Plasma concentrations of m-CPP were lower than those of trazodone but exceeded them in brain tissue. Chronic administration using osmotic mini-pumps revealed a significant linear relationship between trazodone concentration in plasma and brain at steady-state (r=0.96, p<0.0001). No simple relationship was found between plasma and brain tissue concentration for m-CPP. In contrast to observations following single trazodone administration, m-CPP concentrations at steady-state were lower than trazodone concentrations in brain tissue, suggesting a lack of stationarity in the disposition of trazodone over time. No significant differences in plasma or brain tissue drug concentrations relative to administered trazodone dose were observed between male and female rats, nor between pregnant and non-pregnant females. Trazodone and m-CPP were both detected in fetal and placental tissues, with placenta having the highest concentrations. The data suggest that neuropharmacological studies of trazodone could yield different results depending upon the route and schedule of drug administration. Maternally administered trazodone, like many other antidepressants, is distributed to fetal tissues in rodents, reaffirming the need for caution in treating pregnant women with psychoactive drugs.     

Diet and cancer prevention: the fiber first diet

Diet can play a major role in cancer prevention. The international differences in cancer incidence are largely accounted for by lifestyle practices that include nutrition, exercise, and alcohol and tobacco use. About 50% of cancer incidence and 35% of cancer mortality in the U.S., represented by cancers of the breast, prostate, pancreas, ovary, endometrium, and colon, are associated with Western dietary habits. Cancer of the stomach, currently a major disease in the Far East, relates to distinct, specific nutritional elements such as excessive salt intake. For these cancers, information is available on possible initiating genotoxic factors, promoting elements, and prophylactic agents. In general, the typical diet in the United States contains low levels of the potent carcinogenic agents, heterocyclic amines, formed during the cooking of meats. It provides only about half the potent appropriate fiber intake and is high in calories. About twice as many calories as would be desirable come from fat, certain kinds of which enhance the development of cancers. Other foods with functional properties, such as soy products and tea, can be beneficial. To achieve reduction in risk of certain cancers, diet must be optimized, primarily to reduce caloric intake and the fat component. The latter should be 20% or less of total caloric intake and fiber should be increased to 25- 35 g per day for adults. One approach to achieving these goals is the Fiber First Diet, a diet designed around adequate fiber intake from grains, especially cereals, vegetables, legumes, and fruits, which thereby reduces both calorie and fat intake. Such dietary improvements will not only reduce cancer and other chronic disease risks, but will contribute to a healthy life to an advanced age. A corollary benefit is a lower cost of medical care.      

Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease.

Serum gonadotropin, estrogen, and androgen levels were measured in samples obtained from 19 patients with polycystic ovarian disease (PCO) and from 10 normal women on day 2 to 4 of their menstrual cycles. In patients with PCO, the mean (plus or minus S.E.) concentration was significantly higher (P smaller than 0.001) than the concentrations found in the normal subjects for LH (35 plus or minus 4.6 vs. 12.7 plus or minus 2.6 m.I.U. per milliliter), but not for FSH (10.3 plus or minus 0.7 vs. 8.7 plus or minus 0.9 m.I.U. per milliliter). Estrone (E1) levels (92 plus or minus 4 vs. 52 plus or minus 5 pg. per milliliter) were also significantly higher (P smaller than 0.001), while estradiol (E2) concentrations (58 plus or minus 4 vs. 63 plus or minus 8 pg. per milliliter) were comparable. Testosterone (T) (468 plus or minus 41 vs. 325 plus or minus 34 pg. per milliliter, P smaller than 0.05), androstenedione (delta) (2,083 plus or minus 138 vs. 1,123 plus or minus 153 pg. per milliliter, P smaller than 0.001), and dehydroepiandrosterone sulfate (3.4 plus or minus 0.4 vs. 2.0 plus or minus 0.37 mug per milliliter, P smaller 0.02) were also significantly increased over the values in normal controls. The mean dehydroepiandrosterone (DHEA) was elevated in the patients with PCO (11.3 plus or minus 1.7 vs. 7.5 plus or minus 1.2 mug per milliliter), but was not significantly different. A positive correlation was found between LH levels and both E2 and E1 concentrations in the patients with PCO. These data show a distinct profile of gonadotropin, estrogen, and androgen levels in patients with PCO.     

The effect of experimentally-induced renal failure on accumulation of bupropion and its major basic metabolites in plasma and brain of guinea pigs

Dosage regimen adjustments because of poor renal function are often assumed to be unnecessary for extensively metabolized antidepressants. This assumption is being increasingly questioned in recognition of the role of active drug metabolites. The purpose of this study was to assess the steady-state accumulation of the new antidepressant bupropion and its three major basic metabolites in guinea pigs, with and without experimentally-induced renal guinea pigs, with and without experimentally-induced renal failure. Two groups of guinea pigs were treated by intraperitoneal (IP) implantation of mini-osmotic pumps containing bupropion hydrochloride. Immediately after surgery, one group of animals received an injection of uranyl nitrate. After 4 days, all animals were sacrificed by decapitation following blood removal by cardiac puncture. Analysis of plasma and brain samples by high performance liquid chromatography (HPLC) for concentrations of bupropion (BUP) and its major basic metabolites, the erythro-amino alcohol (EB), the threo-amino alocohol (TB) and the hydroxy metabolite (HB) revealed greater accumulation of BUP, TB, and HB in plasma and brain of the animals with renal failure compared to controls. No difference was found between groups in the concentrations of the EB metabolite. As the guinea pig shows a BUP and metabolite plasma concentration profile similar to that seen in human studies, these results suggest that further studies of bupropion and its major metabolites are warranted in patients with impaired renal function to assess possible excessive drug and metabolite accumulation.     

Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose

The pharmacokinetics of bupropion (BUP) and its three major basic metabolites (the erythroamino alcohol [EB], the threoamino alcohol [TB], and the hydroxy [HB] metabolites) were characterized after a single, oral, 200 mg dose of BUP in six healthy men. Twenty-one sequential plasma samples for analysis by HPLC were drawn from each subject over the 56-hour period after dosing. Pharmacokinetic analyses were by noncompartmental methods. The mean elimination t1/2 values of BUP, TB, EB, and HB were 9.8, 19.8, 26.8, and 22.2 hours, respectively. The mean plasma AUCs of TB and HB were 2.4 and 10.3 times greater, respectively, than that for BUP. Because of the substantial presence of these metabolites in systemic circulation, further studies are recommended to understand further their roles in the clinical profile of this new antidepressant.     

骨形态发生蛋白2表达异常与脊柱的融合

目的:综述近几年来国内外对骨形态发生蛋白2表达异常及其基因突变的研究,重点分析突变对脊柱融合的影响,为基因重组骨移植提供理论依据。资料来源:应用计算机检索Medline和Science Direct Online数据库1989-01/2007-01期间与骨形态发生蛋白2表达异常及脊柱融合相关的文章,检索词为"BMP2,BMP,gene mutation,mutation,gene expression,abnormal expression,spinal fusion,bony fusion,bone transplantation",限定文章语言种类为English。同时计算机检索中国期刊全文数据库2000-01/2007-01期间与骨形态发生蛋白2表达异常及脊柱融合相关的文章,检索词为"骨形态发生蛋白2,脊柱融合,骨移植,基因突变,表达异常",限定文章语言种类为中文。资料选择:对资料进行初审,选择有关骨形态发生蛋白2生物学活性、信号转导机制、基因突变、与骨诱导的关系、在脊柱融合中的研究进展的文献,共收集到121篇,排除综述类及重复研究。资料提炼:选择其中有代表性的30篇进行综述,涉及到骨形态发生蛋白2的生物学活性、诱导成骨机制、突变的分子学基础、基因突变及影响蛋白表达异常的其他因素。资料综合:骨移植植骨融合的形成是一个多因子、多基因的过程,涉及到骨生成、骨诱导和骨传导3个环节。骨形态发生蛋白2是骨发育和修复的关键调节剂,骨折愈合时尤其需要。国内外学者对于骨形态发生蛋白2基因的自身突变研究取得了很大进展,已检测出不同部位多个位点的突变。基因变异导致所编码氨基酸发生改变,从而引起相应多肽结构发生变异,影响蛋白质的理化性质。无论是体内的骨形态发生蛋白2抑制因子,突变导致的生物活性改变,还是其增龄性效应,最终都将引起局部骨形态发生蛋白2含量下降及生物学活性减退,可能直接导致脊柱融合术后植骨愈合不良或植骨不愈合的发生。结论:对骨形态发生蛋白2表达异常尤其对其基因进行突变分析,寻找影响植骨融合的遗传学因素,具有非常重要的临床意义。     

Sensitivity and specificity of four assays to detect human T− lymphotropic virus type I or type I/II antibodies

BACKGROUND: Assays that detect human T-lymphotropic virus type I and type II antibody (HTLV-I/II) are widely used in the routine screening of blood donors. STUDY DESIGN AND METHODS: Four commercially available anti-HTLV-I (Fujirebio and Organon Teknika) or -HTLV-I/II assays (Murex and Ortho) were evaluated in various serum panels: A) HTLV-I-positive specimens (n = 41), confirmed by Western blot and polymerase chain reaction; B) a commercially available anti-HTLV-I/II panel; C) serial dilutions of sera from HTLV-I-positive individuals (n = 30), confirmed by immunofluorescence assay and Western blot: D) serial dilutions of HTLV-II-positive blood donors (n = 20), confirmed by Western blot and polymerase chain reaction, and E) sera from first-time blood donors (n = 1055). RESULTS: All four assays elicited reactions in all 82 HTLV-I- positive samples in Panels A, B, and C. Of 32 HTLV-II-positive specimens in Panels B and D, 31 (96.9%) reacted in the Organon Teknika assay and all 32 reacted in the remaining tests. Probit analysis of test results in Panels C and D indicated that the Fujirebio test was the most sensitive assay, followed by Organon Teknika, Ortho, and Murex. The specificities of Fujirebio, Murex, Organon Teknika, and Ortho tests in 1055 first-time blood donors were 99.9, 100, 99.6, and 99.9 percent, respectively. CONCLUSION: All four studied assays for detecting HTLV-I or HTLV-I/II antibodies are appropriate as screening tests.