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Chemicals/CAS: calcium chloride, 10043-52-4; calcium, 7440-70-2; citric acid, 126-44-3, 5949-29-1, 77-92-9, 8002-14-0; edetic acid, 150-43-6, 60-00-4

For a period of 6 weeks, 76 healthy male volunteers consumed during their daily main meal the contents of one tin (~ 135 g) of either fish (mackerel) paste or meat paste. Fibrinolytic parameters were determined in plasma samples obtained at the beginning and at the end of the experimental period. No changes were found in plasminogen, α2-antiplasmin, tissue-type plasminogen activator (t-PA) antigen, and euglobulin t-PA activity. In the control group (n = 39), plasminogen activator inhibitor activity did not change. In the fish group (n = 37), however, total plasma PA inhibitor (PAI) activity increased by 45%, due to a 71% increase in PA inhibitor type-1. This increase could not be ascribed to a diet-induced acute phase-type reaction and could not be explained by changes in serum triglycerides or insulin. Chemicals/CAS: plasminogen activator inhibitor 1, 140208-23-7; Acute-Phase Proteins; Glycoproteins; Plasminogen Activators, EC 3.4.21.-; Plasminogen Inactivators

Insufficient daytime sleep may result in reduction of effectiveness and safety during overnight military missions. The usefulness of temazepam and zaleplon to optimize afternoon sleep and their effects on performance and alertness during a subsequent night shift were studied. Method: In a randomized double-blind within-subjects design, 11 subjects took 20 mg of temazepam, 10 mg of zaleplon, or placebo before a 5:30-10:00 p.m. sleep period. Sleep length and quality were measured. Subjects were kept awake throughout the night while alertness, cognitive performance, and muscle power were repeatedly measured. Results: Temazepam provided significantly longer and qualitatively better sleep than zaleplon or placebo. During the night, sleepiness increased and muscle power was impaired in all conditions. Better sleep was correlated with less sleepiness during the night. Conclusion: Temazepam is useful to optimize a 4.5-hour afternoon sleep before overnight missions. Irrespective of hypnotic treatment, sleepiness and fatigue increased during the night shift.

Too few drug discovery projects generate a marketed drug product, often because preclinical studies fail to predict the clinical experience with a drug candidate. Improving the success of preclinical-to-clinical translation is of paramount importance in optimizing the pharmaceutical value chain. Here, we advance the case for a molecular systems approach to crossing the preclinical-to-clinical translational chasm and for metabolomic analysis of readily accessible bodyfluids as a key technology in translational activities. © 2006.

Acute mountain sickness is thought to be triggered by cerebral hypoxemia and be prevented by acetazolamide (Actz). The effect of Actz on cerebral oxygenation at altitude remains unknown. In 16 members of the 2005 Dutch Cho Oyu (8201 m, Tibet) expedition, the influence of Actz and exercise (750 mg PO daily) on heart rate, peripheral and regional cerebral oxygen saturation (SaO2 and rSO2, the Lake Louise score (LLS), and psychomotor function were studied at 0 m 14 days prior to the expedition, after arrival at 3700 m on day 3, after arrival at 5700 m on day 29, and again at 5700 m before the end of the expedition on day 51. After arrival at 3700 m, the LLS of the climbers taking Actz (n = 8) was significantly lower compared to those who did not take Actz (n = 8): 0.75 ± 1.0 versus 2.9 ± 2.0, p < 0.05 (ANOVA). High LLSs were associated with low rSO2 values in rest and exercise (p < 0.01 and p < 0.001). With altitude, resting SaO2 and resting rSO2 decreased significantly (p < 0.001), irrespective of Actz use. Exercise at 3700 m and 5700 m reduced SaO2 and rSO2 even further compared to rest (p < 0.001), although at 3700 m the rSO2 was preserved better in those who took Actz (55.3 ± 4.3% versus 47.9 ± 5.7%, p < 0.05). Irrespective of Actz use, with altitude, the percentage of omissions in the vigilance and tracking test increased while the climbers' scores on vigor decreased (p < 0.05). In conclusion, at altitude, exercise-induced reduction in cerebral oxygenation is less in climbers on Actz compared to climbers not taking Actz. This effect is nullified after several weeks at altitude due to acclimatization in climbers not taking Actz.

Interferon (IFN)-β treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18, tumor necrosis factor-α (TNFα), IFNγ, IL-10, IL-4, or transforming growth factor-β in unstimulated whole blood of 26 RR-MS patents changed during 6 months of IFNβ-1b treatment. In these patients, a significant change was found in TNFα mRNA, whereas changes in IL-12 receptor-β2 and IL-10 mRNA showed a trend. IFNβ-1b-related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR-MS patents classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNβ-1b treatment with respect to IL-10, TNFα, and IL-18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFα and IL-18 mRNA as well as a transient increase in IL-10 mRNA. Baseline levels of IL-12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patents under investigation. Chemicals/CAS: interferon beta 1a, 145258-61-3; interferon beta-1b, 145155-23-3; Interferon-beta, 77238-31-4; Interleukin-12, 187348-17-0; RNA, Messenger

We showed previously that amifostine (WR 2721; Ethyol), a protector against carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice. In the present study, the influence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three doses of amifostine, administered just before the carboplatin infusion and 2-4 h thereafter. Compared with a control group of patients who received carboplatin alone, the patients receiving the combination had a longer final half-life of ultrafilterable platinum species [5.0 h versus 3.5 h in patients with a normal creatinine clearance (Clcr > 80 ml/min); 5.6 h versus 4.2 h in those with an impaired renal function (50 < Clcr < 80 ml/min)]. This might be caused by an influence of amifostine on the renal clearance of carboplatin as suggested by a transient increase in serum creatinine levels 24 h after treatment in the patients receiving the combination (mean ± SD: 34.1% ± 17.2% versus - 1.8% ± 16.5% in patients treated with carboplatin alone). The impact of these changes on the area under the concentration-time curves of the ultrafilterable platinum species was hardly noticeable in patients with a normal renal function but led to a significant increase in patients with an impaired renal function (395 ± 59 pmol/l·h versus 280 ± 62 μmol/l·h in patients receiving carboplatin alone). The clinical relevance of this influence is unclear, although theoretically it may result in an increase in the efficacy of carboplatin, as has been observed in tumor-bearing nude mice.

Chemicals/CAS: Ascorbic Acid, 50-81-7; Calcifediol, 19356-17-3; Vitamin A, 11103-57-4; Vitamin B 12, 68-19-9; Vitamin E, 1406-18-4; Vitamins

The optimum conditions (duration and concentration) of a fixed dose, intra-arterial melphalan infusion in relation to its antitumor effect and toxicity in the liver were investigated in a rat colon tumor model (CC531) of liver metastases. We studied the difference in tumor and liver uptake, as well as antitumor effect and hepatotoxicity after 5- and 20-min hepatic arterial infusion (HAI) of a fixed melphalan dose. Melphalan content in perfusate, liver, and tumor tissue was analyzed by high-performance liquid chromatography. The antitumor effect and hepatotoxicity in rats treated either systemically or with 5- and 20-min HAI, with a fixed dose melphalan (4.4 μmol), were assessed 2 weeks after treatment. No difference in melphalan content of tumor/ liver tissue or antitumor effect was observed between rats treated with 5- and 20-min HAI. Hepatotoxicity was strongly affected by perfusion duration/concentration, however. Rats treated with 5-min HAI weighed significantly less, and liver toxicity parameters were significantly increased compared with those of all other groups; eight of nine rats showed severe cholangiofibrosis. Body weights and liver toxicity parameters of the rats treated with 20-min HAI were not statistically different from the control group. In conclusion, duration of HAI with 4.4 μmol of fixed dose melphalan did not affect tumor uptake and antitumor effect, but the resulting increase in melphalan concentration had major impact on hepatobiliary toxicity. Therefore, in a clinical setting, caution should be taken when infusion duration and concentration of melphalan are changed.

Elevated levels of plasma total homocysteine are associated with a higher risk of cardiovascular disease. Betaine and 5-methyltetrahydrofolate can remethylate homocysteine into methionine via independent reactions. We determined the effect of daily betaine supplementation, compared with both folic acid and placebo, on plasma concentrations of total homocysteine after an overnight fast and after methionine loading in men and women with mildly elevated homocysteine. Groups of twelve subjects ingested 6 g betaine, 800 μg folic acid with 6 g placebo or 6 g placebo each day for 6 wk. A methionine-loading test (i.e., ingestion of 100 mg L-methionine/kg body mass) was performed before and after 6 wk of supplementation. Fasting plasma homocysteine decreased by 1.8 μmol/L (95% confidence interval [CI]; -3.6, 0.0, P < 0.05) in the betaine group and by 2.7 μmol/L (95% CI: -4.5, -0.9, P < 0.05) in the folic acid group. These changes are relative to the change in the placebo group, in which fasting plasma homocysteine rose by 0.5 μmol/L. Furthermore, betaine suppressed the total area under the plasma homocysteine-time curve after methionine loading by 221 μmol. 24 h/L (95% CI: -425, -16, P < 0.05) compared with placebo, whereas folic acid had no effect. In conclusion, betaine appears to be highly effective in preventing a rise in plasma homocysteine concentration after methionine intake in subjects with mildly elevated homocysteine. It is not known whether this potential of betaine to "stabilize" circulating homocysteine concentrations lowers the risk of cardiovascular disease.

Background The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ∼15-40% and increases HDL-C by ∼40-140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE∗3Leiden.CETP mice. Methods and results Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59 to -100%, P < 0.001), thereby decreasing non-HDL-C (-24 to -45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (-41 to -92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, P < 0.001) and severity. Analysis of covariance showed that both anacetrapib (P < 0.05) and non-HDL-C (P < 0.001), but not HDL-C (P = 0.76), independently determined lesion size. Conclusion Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability. © The Author 2014. Chemicals/CAS: anacetrapib, 875446-37-0; atorvastatin, 134523-00-5, 134523-03-8

Vaccine research and development is a heterogeneous and intensely active area, encompassing the development of many different kinds of novel preventive and therapeutic vaccines (eg, against infectious, allergic, and autoimmune diseases, cancer, etc). Included in this is the development of different types of vaccines (eg, DNA vaccines, novel routes of administration, novel adjuvants, and immune system modulation). This poses challenges regarding approaches to preclinical evaluation of these products. Published regulatory guidance has not always kept up with scientific advances and innovation in this area and, at the same time, many vaccine developers are interested in better understanding and meeting regulatory expectations. It was in this context that in June 2007 a workshop was organized and held in Amsterdam (DIA International Workshop on Nonclinical Testing of Vaccines) to discuss the nonclinical aspects of vaccine development. This article provides a short historical overview of preclinical testing of vaccines and reviews and summarizes the discussions held during the June 2007 meeting. Copyright © 2009 Drug Information Association, Inc.

Hypertension or high blood pressure is a significant health problem worldwide. Typically, lifestyle changes, including adopting a healthy diet, are recommended for people with an elevated blood pressure. Lactotripeptides are bioactive milk peptides with potential antihypertensive properties in man. These peptides, as part of a food product or as nutraceutical, may contribute to the prevention and treatment of hypertension. This paper reviews the current evidence of the blood pressure control properties of lactotripeptides in man. Blood pressure-lowering effects of lactotripeptides are typically measured after 4-6 weeks of treatment. However, in some cases, a blood pressure response has been observed after 1-2 weeks. Maximum blood pressure reductions approximate 13 mmHg (systolic blood pressure) and 8 mmHg (diastolic blood pressure) after active treatment compared with placebo, and are likely reached after 8-12 weeks of treatment. Effective dosages of lactotripeptides range from 3.07 to 52.5 mg/d. Evidence indicates that lactotripeptides are only effective at elevated blood pressure; no further lowering of normal blood pressure has been observed. Concomitant intake of antihypertensive medication does not seem to influence the potency of lactotripeptides to lower blood pressure. Similarly, ethnicity has not been found to influence the extent of lactotripeptide-induced blood pressure lowering. Based on the currently available data, lactotripeptides appear to be safe and effective. Thus, they can be part of a healthy diet and lifestyle to prevent or reduce high blood pressure.

To date, treatment of organophosphate (OP) poisoning shows several shortcomings, and OP-victims might suffer from lasting cognitive deficits and sleep–wake disturbances. In the present study, long-term effects of soman poisoning on learning ability, memory and neurogenesis were investigated in rats, treated with the anticholinergic atropine and the oxime HI-6 for reactivation of soman-inhibited acetylcholinesterase. We also investigated whether sub-chronic treatment with the reported neurogenesis enhancer olanzapine would stimulate neurogenesis and possibly normalize the anticipated long-term deleterious effects of soman intoxication. Animals were treated with HI-6 (125 mg/kg i.p.), followed after 30 min by soman (200 mg/kg s.c.) and atropine sulphate (16 mg/kg i.m.) 1 min thereafter. Soman poisoning led to an elevation of extracellular acetylcholine levels to 1500% over baseline values as assessed by striatal microdialysis. Brain acetylcholinesterase was inhibited over 95%. This was accompanied by short recurrent seizures lasting for 40 min. Osmotic minipumps releasing olanzapine (7.5 mg/kg/day) or vehicle were subcutaneously implanted 24 h post-intoxication. After drug delivery for 4 weeks, newborn cells were BrdU labeled. Learning and memory performance were assessed 8 weeks after soman poisoning, followed by analysis of surviving newborn cells (BrdU) and neurogenesis (doublecortin, DCX). Eight weeks after soman-intoxication a significantly impaired learning ability was found that was paralleled by significantly lower numbers of DCX-positive cells but no changes in the number of BrdU-labeled cells. Apparently, the present Olanzapine regime was ineffective. We conclude that soman poisoning has long lasting effects on learning ability, a finding that was accompanied by impaired neurogenesis. Although we confirm a correlation between impaired neurogenesis and cognitive deficits, establishing the true causal relationship between these processes in OP exposed animals awaits future research.

A proof-of-concept study to assess the safety and efficacy of a traditional Chinese medicine formula as treatment for primary dysmenorrhea showed no statistically significant benefit over placebo. However, some efficacy parameters suggested possible superiority of the active treatment and so a larger study needs to be performed to determine whether this remedy has a role in the treatment of dysmenorrhea. © 2006 American Society for Reproductive Medicine.

Objective. Assessing whether the initiation of insulin therapy in patients with diabetes mellitus type 2 can be delivered as effectively in a structured transmural care model as in the more usual outpatients structure. Design. Retrospective comparative cohort study. Method. In 1997 data were collected from 52 patients with diabetes mellitus type 2 all of whom were above 40 years of age and transferred to insulin therapy in 1993: 25 in a transmural care setting and 27 in an outpatients setting, both in Amsterdam, the Netherlands. Both groups were treated according to one protocol concerning the initiation and monitoring of insulin therapy, treatment goals and follow-up. Outcome measures were: percentage of glycated haemoglobin (HbA1c), health status, self-care behaviour and patient satisfaction. In 1993 the mean age was (transmural/outpatients setting): 67.5/65.3 years; percentage of men: 32%/48%; mean duration of diabetes: 7.3/10.6 years; HbA1c: 9.1%/9.3%; mean body mass index: 27.4/29.1 kg/m2. Results. In the period 1993-1997 the mean HbA1c decreased from 9.1% to 7.2% in the transmural care group and from 9.3% to 7.6% in the outpatients care group (both: p = 0.000). The percentage of patients with poor glycaemic control (HbA1c > 8%) decreased from 60 to 8 in the transmural care group and from 59 to 15 in the outpatients care group. The percentage of patients with good glycaemic control (HbA1c < 7%) increased from 4 to 52 in the transmural care group and from 11 to 30 in the outpatients care group. No statistically significant differences were found between the patient groups with respect to health status, self-care behaviour and patient satisfaction. Conclusion. The transfer of patients with diabetes mellitus type 2 insulin therapy in a shared care setting was at least as effective as in an outpatients setting. Chemicals/CAS: Hypoglycemic Agents; Insulin, 11061-68-0

Chemicals/CAS: Recombinant Proteins; Tissue Plasminogen Activator, EC 3.4.21.68