Center for Human Drug Research

Leiden, Netherlands

Center for Human Drug Research

Leiden, Netherlands

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Bergheanu S.C.,Center for Human Drug Research | Bergheanu S.C.,InterEuropa Clinical Research | Bodde M.C.,Leiden University | Jukema J.W.,Leiden University
Netherlands Heart Journal | Year: 2017

Recent years have brought a significant amount of new results in the field of atherosclerosis. A better understanding of the role of different lipoprotein particles in the formation of atherosclerotic plaques is now possible. Recent cardiovascular clinical trials have also shed more light upon the efficacy and safety of novel compounds targeting the main pathways of atherosclerosis and its cardiovascular complications. In this review, we first provide a background consisting of the current understanding of the pathophysiology and treatment of atherosclerotic disease, followed by our future perspectives on several novel classes of drugs that target atherosclerosis. The focus of this update is on the pathophysiology and medical interventions of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)). Abstract Recent years have brought a significant amount of new results in the field of atherosclerosis. A better understanding of the role of different lipoprotein particles in the formation of atherosclerotic plaques is now possible. Recent cardiovascular clinical trials have also shed more light upon the efficacy and safety of novel compounds targeting the main pathways of atherosclerosis and its cardiovascular complications. In this review, we first provide a background consisting of the current understanding of the pathophysiology and treatment of atherosclerotic disease, followed by our future perspectives on several novel classes of drugs that target atherosclerosis. The focus of this update is on the pathophysiology and medical interventions of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)). © The Author(s) 2017.


Cohen A.F.,Center for Human Drug Research | Cohen A.F.,Leiden University | Burggraaf J.,Center for Human Drug Research | Burggraaf J.,Leiden University | And 5 more authors.
Annual Review of Pharmacology and Toxicology | Year: 2015

The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development. ©2015 by Annual Reviews. All rights reserved.


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.


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.


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.


Moors E.H.M.,University Utrecht | Cohen A.F.,Center for Human Drug Research | Schellekens H.,University Utrecht
Drug Discovery Today | Year: 2014

Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development and the pharmaceutical industry, we identified the main factors causing this system failure. Although many solutions have been suggested to fix the drug development system, we believe that a combination of reforms of the regulatory and patent systems is necessary to make drug development sustainable. These reforms must be combined with a larger, open-access role for public research institutes in the discovery, clinical evaluation and safety evaluation of new drugs. © 2014 Elsevier 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.


Van Meer L.,Center for Human Drug Research | Moerland M.,Center for Human Drug Research | Cohen A.F.,Center for Human Drug Research | Burggraaf J.,Center for Human Drug Research
British Journal of Clinical Pharmacology | Year: 2014

Early detection of drug-induced kidney injury is vital in drug development. Generally accepted biomarkers such as creatinine and blood urea nitrogen (BUN) lack sensitivity and early injury responses are missed. Many new biomarkers to detect nephrotoxicity for pre-clinical utilization have been described and their use is adopted in regulatory guidelines. However, guidance on appropriate biomarkers for clinical trials is minimal. We provide an overview of potentially useful kidney biomarkers that can be used in clinical trials. This includes guidance to select biomarkers suitable to capture specific characteristics of the (expected) kidney injury. We conclude that measurement of urinary kidney injury marker-1 (KIM-1) serves many purposes and is often an appropriate choice. Cystatin C captures effects on glomerular filtration rate (GFR), but this marker should preferably be combined with more specific markers to localize the origin of the observed effect. Untoward effects on tubules can be captured relatively well with several markers. Direct detection of glomerular injury is currently impossible since specific biomarkers are lacking. Indirect assessment of toxic effects on glomeruli is possible by using carefully selected panels of other injury markers. We conclude that it is possible to obtain appropriate information on nephrotoxicity in clinical drug development by using carefully selected panels of injury markers and suggest that identification and validation of specific glomerular biomarkers could be of great value. © 2013 The British Pharmacological Society.


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.


Van Smeden J.,Leiden University | Boiten W.A.,Leiden University | Hankemeier T.,Leiden University | Rissmann R.,Center for Human Drug Research | And 2 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014

Ceramides (CERs), cholesterol, and free fatty acids (FFAs) are the main lipid classes in human stratum corneum (SC, outermost skin layer), but no studies report on the detailed analysis of these classes in a single platform. The primary aims of this study were to 1) develop an LC/MS method for (semi-)quantitative analysis of all main lipid classes present in human SC; and 2) use this method to study in detail the lipid profiles of human skin substitutes and compare them to human SC lipids. By applying two injections of 10 μl, the developed method detects all major SC lipids using RPLC and negative ion mode APCI-MS for detection of FFAs, and NPLC using positive ion mode APCI-MS to analyze CERs and cholesterol. Validation showed this lipid platform to be robust, reproducible, sensitive, and fast. The method was successfully applied on ex vivo human SC, human SC obtained from tape strips and human skin substitutes (porcine SC and human skin equivalents). In conjunction with FFA profiles, clear differences in CER profiles were observed between these different SC sources. Human skin equivalents more closely mimic the lipid composition of human stratum corneum than porcine skin does, although noticeable differences are still present. These differences gave biologically relevant information on some of the enzymes that are probably involved in SC lipid processing. For future research, this provides an excellent method for (semi-)quantitative, 'high-throughput' profiling of SC lipids and can be used to advance the understanding of skin lipids and the biological processes involved. © 2013 Elsevier B.V.

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