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Leiden, Netherlands

Oei N.Y.L.,Leiden University | Rombouts S.A.,Leiden University | Soeter R.P.,Leiden University | Van Gerven J.M.,Center for Human Drug Research | Both S.,Leiden University
Neuropsychopharmacology | Year: 2012

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the reward system. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate wanting in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication. © 2012 American College of Neuropsychopharmacology.


Cohen A.F.,Leiden University | Cohen A.F.,Center for Human Drug Research
Nature Reviews Drug Discovery | Year: 2010

New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I- Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management. © 2010 Macmillan Publishers Limited. All rights reserved.


Osanto S.,Leiden University | Van Poppel H.,Catholic University of Leuven | Burggraaf J.,Center for Human Drug Research
Future Oncology | Year: 2013

Tasquinimod, an oral quinolone-3-carboxamide with anti-tumor activity in preclinical models of prostate cancer, has been tested in patients with minimally symptomatic castration-resistant prostate cancer (CRPC), showing promising inhibitory effects on the occurrence of metastasis and delayed disease progression. Although its mode of action is not fully understood, tasquinimod presumably exerts its unique anti-tumor action through inhibition of angiogenesis and immunomodulation. In clinical studies, tasquinimod demonstrated anti-tumor activity in prostate cancer in combination with a mild-to-moderate side effect profile. With single-agent tasquinimod, dose-limiting toxicity was amylase elevation without signs of pancreatitis and sinus tachycardia. The maximum tolerated dose in Phase I studies in patients with CRPC was once daily administration of 0.5-1-mg tasquinimod orally. In a Phase II trial, significant clinical activity has been demonstrated in asymptomatic or minimally symptomatic, chemotherapy-naive, metastatic CRPC (mCRPC) patients. Men were randomized to tasquinimod or placebo in a 2:1 fashion; treatment with tasquinimod resulted in significant improvement of median progression-free survival (7.6 vs 3.3 months with placebo; p = 0.0042). Based on these encouraging effects, a randomized, double-blind, placebo-controlled trial in men with minimally symptomatic mCRPC has been designed. This large Phase III trial, powered for a primary end point of progression-free survival, has now enrolled the target number of 1200 men. If the Phase II data are validated in the Phase III trial a new compound with a unique mode of action might become approved as a future therapy for minimally symptomatic mCRPC patients. © 2013 Future Medicine Ltd.


Gerrits M.G.F.,Merck And Co. | Schnabel P.G.,Merck And Co. | Post T.M.,Merck And Co. | Peeters P.A.M.,Merck And Co. | Peeters P.A.M.,Center for Human Drug Research
Contraception | Year: 2013

Background: The pharmacokinetics of the monophasic oral contraceptive nomegestrol acetate (NOMAC) plus 17β-estradiol (E2) were investigated after a single dose and multiple dosing. Study design: NOMAC/E 2 (2.5 mg/1.5 mg) was administered daily to healthy women (18-50 years, n= 23) for 24 days; blood samples for pharmacokinetic analysis were obtained on Day 24 and again, after a 10-day pill-free interval, on Day 35 after a single dose. Results: NOMAC reached steady state after 5 days with mean ± standard deviation (SD) trough NOMAC concentration (Cav) of 4.4±1.4 ng/mL. On Day 24, mean±SD peak NOMAC concentration (C max, 12.3±3.5 ng/mL) was reached in mean 1.5 h (t max); the mean±SD elimination half-life (t) was 45.9±15.3 h. After a single dose, NOMAC mean±SD Cmax was 7.2±2.0 ng/mL and mean±SD t was 41.9±16.2 h. On Day 24, E2 mean±SD Cav was 50.3±25.7 pg/mL; mean±SD Cmax was 86.0±51.3 pg/mL. After a single dose, mean±SD E2 Cmax was 253±179 pg/mL. Conclusions: These data demonstrate that NOMAC/E2 has a pharmacokinetic profile consistent with once-daily dosing. © 2013 Elsevier Inc.


Sidharta P.N.,Actelion Pharmaceuticals | Diamant Z.,Center for Human Drug Research | Dingemanse J.,Actelion Pharmaceuticals
Fundamental and Clinical Pharmacology | Year: 2014

Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders. © 2014 Société Française de Pharmacologie et de Thérapeutique.

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