Reproducibly emitting reference materials for volatile and semi-volatile organic compounds—using finite element modeling for emission predictions

Recent research into emissions of (semi-)volatile organic compounds [(S)VOC] from solid materials has focused on the development of suitable reference materials for quality assurance/quality control of emission test chamber measurements, which fulfill requirements such as homogenous and reproducible (S)VOC release. The approach of this study was to find a method for preparation of a material with predictable (S)VOC emission rates. A VOC (styrene) and an SVOC (2,6-diisopropylnaphthalene, DIPN), loaded into either vacuum grease or a 1:1 mixture of paraffin/squalane, have been tested. For the prediction of the emission rates, a model using the finite element method (FEM) was created to simulate the (S)VOC emission profiles. Theoretical and experimental results obtained in a Micro-Chamber/Thermal Extractor (μ-CTE?) and in 24 L emission test chamber measurements were in good agreement. Further properties were investigated concerning the material applicability, such as shelf life and inter-laboratory comparability. The maximum relative standard deviation in the inter-laboratory study was found to be 20%.     

Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator

AIMS: The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. METHODS: The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. RESULTS: Levormeloxifene was tolerated well after single doses in the range of 2.5--320 mg and multiple once daily dosing in the range of 20--160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20--160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19--25% and 28--35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2--3 h), a slow elimination (mean t1/2: 4.8--8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3--5). CONCLUSIONS: Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.     

Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study

The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size.     

Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first-episode schizophrenia patients

Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched controls. Three PPI measures [stimulus onset asynchrony (SOA) 30, 60, 120 ms] and habituation were assessed at baseline, and again after 6 yr. Sixteen patients and 17 healthy controls completed the study, and 13 patients and 17 healthy controls were included in the final analysis. The schizophrenia patients had PPI deficits compared to controls at baseline. After 6 yr, no significant group differences were found. PPI had increased significantly in the patients and had decreased significantly in controls. In addition, patients showed significantly less habituation than controls while habituation did not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors such as disease process, clinical state, or medication.