Adam Cohen

• MD PhD
• Professor at Centre for Human Drug Research

Objective The aim of the present study was to develop a neural network to characterize the effect of aging on the ECG in healthy volunteers. Moreover, the impact of the various ECG features on aging was evaluated. Methods & Results A total of 6228 healthy subjects without structural heart disease were included in this study. A neural network regres...

Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely m...

Introduction Drivers should be aware of possible impairing effects of alcohol, medicinal substance, or fatigue on driving performance. Such effects are assessed in clinical trials, including a driving task or related psychomotor tasks. However, a choice between predicting tasks must be made. Here, we compare driving performance with on-the-road dri...

Background Facioscapulohumeral dystrophy (FSHD) is a progressive muscle dystrophy disorder leading to significant disability. Currently, FSHD symptom severity is assessed by clinical assessments such as the FSHD clinical score and the Timed Up-and-Go test. These assessments are limited in their ability to capture changes continuously and the full i...

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disease. Its slow and variable progression makes the development of new treatments highly dependent on validated biomarkers that can quantify disease progression and response to drug interventions. Objective: We aimed to build a tool that estimates FSHD clin...

Aims Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20–40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine...

Cholinesterase inhibitors have been shown to improve cognitive functioning in patients with Alzheimer’s Disease (AD), but are associated with side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of a single dose of galantamine on CNS functioning in mild to mod...

Objective: Sleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present...

Rationale Car-driving performance is negatively affected by the intake of alcohol, tranquillizers, sedatives and sleep deprivation. Although several studies have shown that the standard deviation of the lateral position on the road (SDLP) is sensitive to drug-induced changes in simulated and real driving performance tests, this parameter alone migh...

Background Assessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper‐based diaries are often inconvenient and have limited reliability, particularly for outpatient trials. Objectives To investigate the utility of an electronic diary (e‐diary) application for patients wi...

Anxiety disorders arise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behaviora...

Aim: Salbutamol is used in the management of obstructive bronchospasm, including that of some elite athletes. It is claimed that high salbutamol (oral) doses may also have an anabolic effect. Therefore, inhalation of salbutamol is restricted by the World Anti-Doping Agency (WADA) to a maximal daily dose. Urine is tested for violations, but recent...

Objective: To develop a self-test to measure clinical fitness to perform in surgical residents, with alcohol-induced impairment as reference. Design: Observational, exploratory study to evaluate night shift-induced impaired performance in surgical residents followed by a randomized blinded, placebo-controlled, crossover study to evaluate impaire...

The first administration of a new compound in humans is an important milestone. A major source of information for the researcher is the 'investigator's brochure' (IB). Such a document, has a size of several hundred pages. The IB should enable investigators or regulators to independently assess the risk-benefit of the proposed trial but the size and...

Aim: Establishing a pharmacologic challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor. Methods: This randomized, double-blind, double-dummy, placebo-controlled, four way cross-over study examined...

Music performance anxiety (MPA) is a specific condition for musicians. Although it can have a negative influence on their music careers, little attention is paid to this phenomenon both in the professional environment and in stress research. In the current pilot study, insight was gained into the physiology of the autonomic stress response related...

Aims: To investigate the role of pharmacology in the design of first in man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015. Methods: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's b...

The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium–glucose cotransporter-2 (SGLT2) mRNA expression. It is developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administrat...

Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-control...

The Centre for Human Drug Research (CHDR) is a non-profit clinical research institute at the interface between academia and the pharmaceutical industry. CHDR hosts a research internship program for undergraduate (bio)medical students. The aim of this study was i) to investigate the student perceptions of the undergraduate research internship ii) qu...

New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical can...

Aim: Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the...

In this article, we consider the new drugs approved for the European market in 2015. We present a summary of the new mechanisms of action introduced and highlight three new mechanisms of action with a potentially high future impact: PCSK9 inhibition (alirocumab (Praluent (R)) and evolocumab (Repatha (R))) for hypercholesterolaemia, neprilysin inhib...

ISIS 388626 is an antisense SGLT2 inhibitor, designed to treat type 2 diabetes mellitus by induction of glycosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100 and 200 mg ISIS 388626 in humans. ISIS 38...

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature coul...

Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor remova...

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carbopl...

Oligonucleotides (ONs) are short fragments of nucleic acids, currently being investigated as therapeutic agents. When administered subcutaneously (sc) ONs cause a specific local reaction originating around the injection site, such as erythema, itching, discomfort and pain, including more severe manifestations such as ulceration or necrosis. These i...

Introduction: Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer...

Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received detailed prior safety review at both the local clinical research facility and at national drug regulatory authority level. The recent fatal SAE in the BIA-102474-101 clinical trial shows...

Olaparib is used to treat BRCA-associated, platinum-sensitive ovarian cancer. Olaparib inhibits poly(ADP-ribose) polymerase, thereby blocking the repair of single strand DNA breaks. This results in synthetic lethality in BRCA-associated cancer cells, which have a dysfunction of another DNA repair pathway: homologous recombination.

LDL-receptor expression is inhibited by the protease PCSK9, which is considered a pharmacological target to reduce LDL-C levels in hypercholesterolemic patients. We performed a first-in-human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9. In this randomized, placebo-controlled trial, twenty-four healthy volunteers received...

Good news from Emanuel and colleagues 1 —apparently, phase I clinical drug trials are safe. However, given the very low frequencies of serious adverse events, retrospective associations of trial characteristics with adverse events are of no use for predicting safety problems in future trials. None of these associations would have helped prevent the...

Soluble inflammatory markers obtained from non-invasive airway sampling such as induced sputum may be useful biomarkers for targeted pharmaceutical interventions. However, before these soluble markers can be used as potential targets, their variability and reproducibility need to be established in distinct study populations. This study aimed to ass...

In this series we draw attention to medicines that have entered the European market with an entirely new mechanism of action. Publication is not to be confused with endorsement of use in clinical practice. Copyright to the images belongs to Leiden University, but use of the images.

Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the B3-adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body. This article is protected by copyright. All rights reserved.

Innovative potential new medicines are a triumph of molecular design combined with advanced biological knowledge. The high tech products still often undergo painfully primitive assessments when they are finally tested in humans. TGN1412 was a chilling example of how such a sophisticated product could be destroyed by inadequate development.

AZD6280 is a novel γ-aminobutyric acid A receptor modulator with higher in vitro efficacy at the α2,3 subtypes as compared to the α1 and α5 subtypes. This study compared the pharmacodynamic effects of single oral dose AZD6280 10 mg and 40 mg on the central nervous system with 2 mg of lorazepam. Sixteen healthy males were enrolled into the double-bl...

Bedaquiline is used in the treatment of multidrug-resistant tuberculosis. It kills both replicating and non-replicating bacteria by a novel mechanism of action: the inhibition of the mycobacterial ATP synthase enzyme. This article is protected by copyright. All rights reserved.

Lomitapide is used in the treatment of homozygous familial hypercholesterolemia. It inhibits the microsomal triglyceride transfer protein, an enzyme involved in the production of very-low-density lipoprotein (VLDL). This lowers hepatic VLDL release and plasma levels of low-density lipoprotein. This article is protected by copyright. All rights rese...

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately d...

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 bee...

Fasting and postprandial hyperglucagonemia in type 2 diabetes mellitus (T2DM) patients cause excessive hepatic glucose production (HGP), suggesting that attenuation of hepatic glucagon action could be a therapeutic strategy for T2DM. In this study we evaluated the safety, tolerability, PK and pharmacodynamics in healthy human volunteers of single a...

Needs a few tweaks before implementation On 2 April 2014, the European Parliament approved the new European Union Clinical Trials Regulation.1 This regulation will replace the Clinical Trials Directive, which has failed to achieve its goal of simplifying the scientific and ethical review of clinical trials in the EU.2 3 Unlike the directive, the...

Aim: Anthracycline-induced cardiotoxicity is (partly) mediated by free radical overload. A randomized study was performed in breast cancer patients to investigate whether free radical scavenger super oxide dismutase (SOD) protects against anthracycline-induced cardiotoxicity as measured by changes in echo, electrocardiography and an array of bioma...

AZD7325 is a novel α2,3 -subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single-oral-dose AZD7325 2mg and 10mgon the central nervous system (CNS) compared to placeboand lorazepam2mg. Thisdouble-blind, randomized, 4-way-crossover studyenrolledsixteen healthymales and administeredtwo validated CNS-...

Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low-quality studies that use a surrogate end-point that relates to the clinical end-point in a partial manner at most. Such a medicine would surely not be recommended. The...

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...

Clinical Pharmacology in Neuroscience Drug Discovery in recent years has concentrated on First Time in Human safety and pharmacokinetics. The more traditional pharmacological research in humans has been reduced mainly as a response to the difficulty of developing human pharmacology models in neuroscience diseases. As a consequence, opportunities ar...

The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy vo...

Early detection of drug-induced kidney injury is vital in drug development. Generally accepted biomarkers such as creatinine and 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, guidanc...

Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4...

Background/aims: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. Methods: In 40 children referred for an oral cl...

Je bent zaalarts op de afdeling Oncologie. Een patiënt die twee jaar geleden werd behandeld voor borstkanker wordt weer opgenomen; een recidief, metastasen. Einde verhaal. Er gaat van alles door je hoofd: ‘Waarom nou juist zij? Zou je van tevoren kunnen voorspellen wie een recidief krijgt? En kun je dat dan ook voorkómen? Dat moet iemand uitzoeken!...

AIM & METHODS: Imagine a medicine that is expected to have very limited effects based upon knowledge of pharmacology and (patho)physiology, is studied in the wrong population, with low quality studies that use a surrogate endpoint that relates to the clinical endpoint in a partial manner at most. Such a medicine would surely not be recommended. Rec...

Aims: To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects. Methods: Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the...

Unlabelled: OBJECTIVE & STUDY DESIGN: In a parallel design, 23 and 22 healthy pre-menopausal women were randomly administered a contraceptive vaginal ring (CVR) delivering 150/15 μg Nestorone®/ethinyl estradiol (EE) daily or an oral contraceptive (OC) containing levonorgestrel and EE (150/30 μg) for three cycles, to compare the effects on C-reacti...

In general, Japanese and Caucasians differ in their response to alcohol. To investigate these differences the alcohol clamping method can be used. This strictly controlled infusion regimen provides a reliable tool to study contrasts in central nervous system (CNS) effects and/or alcohol disposition. In this study, twelve Japanese and twelve Caucasi...

Discriminant analysis (DA) was performed on data of two combined hormonal contraceptives (CHC) differing in estrogen ratio to explore whether a combination of variables rather than a single variable distinguishes CHCs better. Data were used of a parallel study in premenopausal women treated for three cycles (21 days on, 7 days off) with a contracep...

The variability of drug response in different patients can be caused by various factors including age, change in renal function, co-medication and genotype. Traditionally, these personal variables are considered by clinicians prior to issuing a prescription. This paper provides an overview of a process to individualize prescribing for a patient wit...

JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other...

To evaluate the effectiveness of 6 months treatment with ibopamine eye drops in raising the intraocular pressure in patients with therapy-resistant hypotony after vitreoretinal surgery for proliferative vitreoretinopathy secondary to rhegmatogenous retinal detachment or penetrating trauma. A 2% ibopamine eye drop was topically administered 3 times...

Essential tremor (ET) is a relatively frequent neurological disorder that responds in some patients to gamma-aminobutyric acid A (GABA(A)) agonists such as the benzodiazepines. Partial subtype-selective GABA(A) agonists may have an improved side effect profile compared to non-selective GABA(A) agonists. However, it is unknown which GABA(A) subtypes...

Using the rate of dissociation from the D(2) receptor as a means to screen novel compounds for antipsychotic drug candidates, the centrally acting and fast-dissociating selective dopamine D(2) receptor antagonist JNJ-37822681 was developed. In a blinded, placebo-controlled, randomized first-in-human study, JNJ-37822681 was administered orally to 27...

Lifestyle modifications, including diet, are important in the prevention and management of type 2 diabetes mellitus (T2DM). However, limited information is available on the effects of single doses of meal replacements, particularly with regard to their effect on postprandial glucose. Therefore, a study was performed comparing the effects of a singl...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several lines of evidence suggest a possible role of 5-HT6 receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB-742457 is a potent 5-HT6 antagonist and has shown efficacy in different animal models of cognitive impairment. It is currently in development as a cognitive enhancer. Ri...

To compare the effects of a combined oral contraceptive (COC) taken continuously with those of one of similar composition taken cyclically on 30 variables related to haemostasis, lipids, carbohydrates, bone metabolism, and sex hormone-binding globulin (SHBG). Randomised, open-label, multicentre, comparative substudy of a larger phase 3 trial involv...

Procedures for verification of data from clinical studies are intended to maintain reliability for clinical trial results. Guidelines or legislations relating to clinical data management are of limited value and no study has yet demonstrated its effectiveness. Sponsor queries and dual entry procedures from one CRO on three different phase I trials...

Essential tremor (ET) is a common movement disorder. Animal studies show that histaminergic modulation may affect the pathological processes involved in the generation of ET. Histamine-3 receptor inverse agonists (H3RIA) have demonstrated attenuating effects on ET in the harmaline rat model. In this double-blind, three-way cross-over, single-dose,...