Clozapine augmentation with antipsychotic drugs is widely used despite sparse evidence supporting this strategy. Sertindole is a nonsedating atypical antipsychotic drug with low affinity for cholinergic receptors, which makes it potentially suitable for augmentation of clozapine. The study design was a 12-week, double-blind, randomized, placebo-controlled study including patients with International Statistical Classification of Diseases, 10th Revision schizophrenia (F20.0-F20.3) and treated with clozapine for at least 6 months who had not achieved sufficient response. Patients were randomized 1:1 to either sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske Undersøgelser, World Health Organization Quality of Life Brief, Drug Attitude Inventory, fasting glucose, lipids, and electrocardiogram. Clozapine augmentation with sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude Inventory. No increased adverse effects compared with placebo were found. Four patients randomized to sertindole experienced a significant worsening of psychosis, and 2 of them required psychiatric admission. Metabolic parameters were unchanged during the study, but augmentation of clozapine with sertindole was associated with a 12-millisecond (SD, 20-millisecond) QTc prolongation compared with 0 millisecond (SD, 20 milliseconds) in the placebo group (P < 0.03). Augmentation with sertindole showed no benefits compared with placebo. Psychiatrists should be aware that augmentation might not add any benefits for the patients and in some cases worsen psychosis.

BACKGROUND This overview is aimed at clinicians working with patients in the fertile age who suffer from depressive disorders. The study of adverse effects of antidepressants on the foetus is hampered by difficulty in distinguishing between the behavioural changes that are related to the disorder itself and changes that accompany its treatment with antidepressants. The current lack of solid scientific knowledge and the implications, mainly emotional, of treating pregnant or breast-feeding women often raise anxiety and cause concern among patients and clinicians. METHODS Currently available data are evaluated and clinical recommendations given. RESULTS AND CONCLUSIONS Citalopram and sertraline can be used during pregnancy, while some controversy remains over in utero exposure to paroxetine and fluoxetine, which might be associated with an increased risk of foetal cardiovascular malformation. Less data is available concerning fluvoxamine and escitalopram use but current data does not indicate a specific risk. Citalopram, paroxetine and sertraline can be used during breast-feeding, while fluoxetine probably should be avoided. Nortriptyline, amitriptyline and clomipramine can be used during pregnancy and lactation, although data are more abundant for SSRI treatment. Venlafaxine can be used during pregnancy, while caution is advised during breast-feeding. Other antidepressants should be avoided because of lack of data on their effect. A strongly indicated lithium therapy should be continued. Close monitoring of lithium levels throughout pregnancy is mandatory, as is detailed foetal echocardiography in weeks 18-22 of gestation. Lithium should not be used during breast-feeding. Electroconvulsive therapy (ECT) is a valid option if indicated, both during pregnancy and breast-feeding.

OBJECTIVE The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). METHOD The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment. RESULTS The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54–4133 ng/ml, p = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months. CONCLUSION In a large cohort of type 2 diabetics, we either confirm or show for the first time:(a) an enormous (80-fold) variability in trough steady-state metformin plasma concentration,(b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.

  The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T/A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

PURPOSE Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. METHODS The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. RESULTS Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CONCLUSION CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

PURPOSE: To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol. METHODS: Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined. RESULTS: With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92)(P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol /(+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 /(+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed. CONCLUSIONS: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

BACKGROUND Clinical and epidemiological studies have associated selective COX-2 inhibitors with an increased risk of cardiovascular events. There are no clinical studies on the possible effects of these drugs on secondary hemostasis. The hypothesis for this study is that the use of selective COX-2 inhibitors could affect the secondary hemostasis and by that increase the risk of cardiovascular events in a population at high risk. METHODS An open-label randomized cross-over study was performed in 20 healthy male volunteers. The study consisted of two periods of each 21 days with medication, either celecoxib 100 mg b.i.d. or naproxen 250 mg b.i.d. Treatment periods were separated by a washout period of 28 days. Blood samples were obtained before the first medication period, and at the end of each medication period. Primary effect parameter was FXII level. Secondary effect parameters included a wide range of coagulation factors involved in secondary hemostasis. RESULTS There was no statistically significant effect of celecoxib or naproxen on the primary effect parameter. Protein C activity was significantly decreased after treatment with naproxen (P<0.01), compared to baseline. Platelet function, demonstrated as closure time (CT), was at baseline 118+/-24 sec.(mean+/-SD). Naproxen prolonged CT to 171+/-50 sec.(P<0.001). Celecoxib did not change CT significantly (119+/-24 sec.). CONCLUSIONS Neither the selective COX-2 inhibitor celecoxib, nor the non-selective NSAID naproxen caused any change in the primary effect parameter from the secondary hemostasis.

The objective of the study was to develop, implement and evaluate two treatment algorithms for schizophrenia and depression at a psychiatric hospital department. The treatment algorithms were based on available literature and developed in collaboration between psychiatrists, clinical pharmacologists and a clinical pharmacist. The treatment algorithms were introduced at a meeting for all psychiatrists, reinforced by the project psychiatrists in the daily routine and used for educational purposes of young doctors and medical students. A quantitative pre-post evaluation was conducted using data from medical charts, and qualitative information was collected by interviews. In general, no significant differences were found when comparing outcomes from 104 charts from the baseline period with 96 charts from the post-intervention period. Most of the patients (65% in the post-intervention period) admitted during the data collection periods did not receive any medication changes. Of the patients undergoing medication changes in the post-intervention period, 56% followed the algorithms, and 70% of the patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms. All of the 10 interviewed doctors found the algorithms useful. The treatment algorithms were successfully implemented with a high degree of satisfaction among the interviewed doctors. The majority of patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms.

A short-cut review was performed to evaluate whether steroids could be an effective therapy in hyper-emesis gravidarum. A database search revealed 9 papers relevant to this question and the details of each study methods and results were displayed in a table. The quality of these studies was generally low. There is only weak evidence that steroids could be an effective treatment for intractable hyper-emesis gravidarum.

Apathy in patients with dementia is common, underrecognized, and undertreated. We sought to improve understanding of the pharmacologic treatment of apathy in dementia by performing a systematic literature review of studies that used apathy outcome scales to document results of pharmacologic treatments for apathy. There is limited evidence of efficiency of pharmacotherapy for treatment of apathy in dementia. The best results were found for acetylcholinesterase inhibitors. There was some evidence of efficacy for memantine, but less evidence of efficacy for stimulants, calcium antagonists, and antipsychotics. There was no evidence to support the use of antidepressants or anticonvulsants. The research quality of studies was modest. Recommendations for standardizing research and for holistic evaluation and treatment are provided.

The suffix tree data structure plays an important role in the efficient implementations of some querying algorithms. This paper presents the fast Rep(eats)Seeker algorithm for repeats identification based on the improvements of suffix tree construction. The leaf nodes and the branch nodes are numbered in different ways during the construction of a suffix tree and extra information is added to the branch nodes. The experimental results show that improvements reduce the running time of the RepSeeker algorithm without losing the accuracy. The experimental results coincide with the theoretical expectations.

OBJECTIVE To study pre-treatment in determining total polysaccharide in flos Chrysanthemi Indici. METHOD The factors including the extraction temperature, extraction time, ratio of material to liquid were studied. The best extraction condition was found through the response surface design. RESULT The best extraction condition as follows: 81.0 degrees C of the extraction temperature, 1.6 h of extraction time, and the ratio of material to water as 1: 29. On these conditions the extraction rate of flos Chrysanthemi Indici was the best. CONCLUSION A model equation that can be used to predict the experiment is established through the response surface method.

The spectral resolution is a key index of evaluating the performance of the designed acousto-optic tunable filter (AOTF). We present a special double-filtering method of obviously enhancing the spectral resolution. We have discussed the main technique functional in the double-filtering method in detail. It is confirmed that the double-filtering method can effectively enhance the spectral resolution with good imaging quality. This study is significant in the imaging applications of AOTF.

OBJECTIVE To investigate the extraction process of Perilla frutescens flavonoids. METHODS Response surface method (RSM) was applied to a fractional design. The Perillafrutescens flavonoids were extracted by ultrasonic method. The influence factors of concentration of alcohol, ratio of liquid to solid, extraction times were evaluated. RESULTS The optimum extraction conditions were confirmed as follows: 60% alcohol extracted 4 times, 18 minutes every time and ratio of liquid to solid was 15:1. The extraction rate of flavonoids under this condition was 24. 65 mg/g. CONCLUSION Applying ultrasonic method to extract Perilla frutescens flavonoids is feasible.

Ongoing concerns about the emergence of an influenza pandemic continue as the number of avian and human infections with the H5N1 virus mount. Adequate amounts of vaccine or anti-virals are unlikely to be available early on in a pandemic, and the latter could become ineffective because of resistance. These factors have focused attention on the use of non-pharmaceutical public health interventions to inhibit human-to-human transmission.

Many experimental programs in chromatography involve the estimation of a second-order response surface. The paper focuses on the use of the methods of optimal experimental design to find efficient response surface designs. We give tables of the properties of designs with two, three and four factors. References are given to tables of designs and to SAS programs for their construction.

OBJECTIVE To optimize the extraction condition for the polysaccharides from Marasmius androsaceus Mycelium. METHODS The single factor tests and response surface methodology (RSM) were applied. Overall research was proceeded by rational desingn. Technological condition parameters were determined according to regression analysis by SAS. RESULTS The optimum condition was as follows: extraction temperature was 78 degrees C , extraction-duration was 1. 5h, water to material ratio was 36: 1. The optimum extracting rate for the polysaccharide was 11. 59%. CONCLUSION The RSM is for optimum extraction process and it will improve the extraction conditions of polysaccharides.

OBJECTIVE To study the feasibility of supercritical fluid extraction (SFE) for arctiin from the fruits of Arctium lappa. METHOD The extracts were analyzed by HPLC, optimum extraction conditions were studied by orthogonal tests. RESULT The optimal extraction conditions were: pressure 40 MPa, temperature 70 degrees C, using methanol as modifier carrier at the rate of 0.55 mL x min(-1), static extraction time 5 min, dynamic extraction 30 min, flow rate of CO2 2 L x min(-1). CONCLUSION SFE has the superiority of adjustable polarity, and has the ability of extracting arctiin.