Biomedical subjects

A F Cohen

Publications and source records attributed to A F Cohen.

At least 37 records · Page 2Linked to original sources

PubMed2004

The application of the principles of clinical drug development to pharmacological challenge tests of the serotonergic system.

Pharmacological challenge tests of the serotonergic system have extensively been used during the past 20 years and new tests are in development. It is of crucial importance to standardize challenge tests to ascertain that observed variability is due to the state of the challenged system and not caused by variability of the test itself. This is even more important now that challenge tests increasingly are used in complex studies (e.g. in combination with neuroimaging and in large population studies with repeated tests over time). The Guideline for Good Clinical Practice may be of great help in the standardization of these tests. This is a recently developed guideline for pharmaceutical drug-development, which increasingly is used as a reference for all research in humans. To exemplify the possible usefulness of this approach, we apply it to meta-chlorophenylpiperazine, one of the most commonly used drugs in serotonergic challenge tests. We conclude that much can be learned from the development of this particular challenge. In the discussion, we address general issues that emerged from this review and their relevance to the development of future challenge tests.

Animals↗

PubMed2004

Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients.

Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study.

Administration, Oral↗

PubMed2004

No evidence of the usefulness of eye blinking as a marker for central dopaminergic activity.

This study aimed to evaluate eye blinking as a marker for central dopaminergic activity by investigating the effects of sulpiride (D2-antagonist) and lisuride (D2-agonist) on spontaneous eye blinks. Twelve healthy subjects were included in a randomized, double-blind, placebo-controlled, three-period crossover trial. They received sulpiride 400 mg, lisuride 0.2 mg and placebo on different occasions. Eye blinks, prolactin, finger tapping, eye movements and visual analogue scales were measured at baseline and regularly for 12 h after administration. No effect of sulpiride or lisuride was observed on the number of eye blinks. Sulpiride caused an increase in prolactin (643 U/ml) [confidence interval (CI) 549-737). Lisuride caused a decrease in smooth pursuit eye movements (-4.1%) (CI -7.3 to -0.9) and visual analogue scales for mood (-2.1 mm) (CI -3.7 to -0.4). Spontaneous eye blink rate was not affected by sulpiride and lisuride, which makes eye blinking not suitable as a marker for central D2 activity.

Adult↗

PubMed2003

[European guideline for the quality of non-commercial clinical trials: elegant implementation in the Netherlands via the amended Dutch Medical Research Involving Human Subjects Act].

As of May 2004, the new European directive 2001/20/EC will require European member states to follow Good Clinical Practice rules for non-commercial academic clinical investigations. For several member states this poses a serious threat to such investigations. In the Netherlands however, most items of the new directive can be incorporated in the Dutch Medical Research Involving Human Subjects Act. In fact, many of the items are already covered by this Act, notably with respect to data integrity and patient safety. However, an extra effort is needed to implement the quality control standards to which the registration research already complies. The Dutch Medical Research Involving Human Subjects Act is currently being amended to comply with the new European directive. This is also an ideal opportunity for enhancing the national climate of clinical research and ensuring an improved translation of local research ideas into clinical trial protocols.

Clinical Protocols↗

PubMed2003

Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE).

OBJECTIVES: To compare the pharmacokinetic parameters and safety of the progestagen, Org 30659, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), and ethinyl estradiol (EE) in Caucasian and Japanese women after single and multiple doses. METHODS: This was an open-label parallel design of a single dose followed by a multiple dose period in healthy young Japanese and Caucasian subjects. RESULTS: The area under the curve (AUC) of Org 30659 after single dosing was increased by a factor of 1.75 [90% confidence interval (CI): 1.48-2.08] in Japanese women compared to Caucasian women. At steady state, this difference increased to a factor of 1.90 (90% CI: 1.60-2.25). The AUC of EE after single dosing was similar in Caucasian and Japanese women, but at steady state it was increased by a factor 1.38 (90% CI: 1.15-1.64) in the Japanese group. Weight normalization reduced, but did not remove, all the observed differences. Sex hormone binding globulin played no significant role in the differences between Caucasian and Japanese subjects. Both the single- and multiple-dose treatments with Org 30659/EE were generally well tolerated by all subjects. The Japanese population reported more and different treatment-related adverse events than the Caucasian population. CONCLUSIONS: The peak concentration and extent of exposure of Org 30659, and to a lesser extent of EE, in Japanese women are higher than in Caucasian women. Furthermore, the peak concentration and extent of exposure at steady state of Org 30659, and to a lesser extent of EE, are higher than would be predicted assuming linear pharmacokinetics over time. No major safety issues were observed.

Adult↗

PubMed2003

Biomarkers for the effects of benzodiazepines in healthy volunteers.

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.

Benzodiazepines↗

PubMed2003

The effect of motilin on the rectum in healthy volunteers.

AIMS: The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored. METHODS: Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double-blind, randomized, cross-over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay. RESULTS: Baseline rectum volumes were similar between treatments: 185 +/- 62 mL (motilin) and 136 +/- 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) -3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg-1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings. CONCLUSION: Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.

Adult↗

PubMed2003

REM sleep effects as a biomarker for the effects of antidepressants in healthy volunteers.

The potential use of rapid eye movement (REM) sleep effects as a biomarker for the therapeutic effects of antidepressants in healthy volunteers is reviewed. A literature search was performed to select studies investigating the effects of antidepressants on REM sleep. To assess the specificity of REM sleep effects as a biomarker, the effects of other central nervous system drugs on REM sleep were also investigated. A significant REM sleep reduction was shown for 16 of 21 investigated antidepressants after single-dose (mean reduction 34.1%) and for 11/13 drugs after multiple-dose administration (mean reduction 29.2%). The median increase in REM latency was approximatety 60% after single- or multiple-dose administration. REM sleep effects were linearly normalized to therapeutic doses, by dividing the REM sleep effect by the investigated dose and multiplying by the therapeutic dose. Normalized REM sleep effects were highly variable (range -27.0% to 81.8% for REM sleep; range -17.0% to 266.3% for REM latency) and demonstrated no relationship with relevant pharmacological properties of the investigated drugs. No quantifiable dose-response relationship could be constructed after single and multiple dose administration. REM sleep effects were not specific for antidepressants. Benzodiazepines, for example, caused an average dose normalized REM sleep reduction of 8.7% and a median 8.6% increase of REM latency. This review demonstrates that although REM sleep effects occur with most of the antidepressants, it is by itself of limited value as a biomarker for antidepressant action. The specificity for antidepressants is limited, and it does not show a quantitative dose-response relationship to antidepressant agents. This is at least partly due to the complex relationships between drug pharmacokinetics and the variable time course of REM and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results.

Antidepressive Agents↗

PubMed2003

The psychomotor effects of carbamazepine in epileptic patients and healthy volunteers.

The effect of straight release carbamazepine monotherapy was studied in 12 well-controlled epileptic patients using adaptive tracking, smooth pursuit and saccadic eye movements, body sway, Digit Symbol Substitution Test (DSST) and Visual Analogue Scales. Patients were matched to healthy controls for age and gender. After patients had received their usual morning dose of carbamazepine, patient-control pairs were studied for 7 h. Compared to controls, the average DSST scores of patients were significant lower. No relationships were shown between DSST performance and plasma concentrations of carbamazepine and carbamazepine-epoxide. No significant differences were found for any of the other effect parameters. Variations in plasma concentrations were limited, contributing to the absence of systematic fluctuations in test results. Of the used tests, DSST is most clearly related to cognitive function. It is concluded that the difference in DSST performance appears to reflect a long-term small neurocognitive difference between subjects with and without epilepsy.

Adolescent↗

PubMed2002

[Class substitution of medicines--between cost reduction and the position of professionals in health care].

Class substitution (with cost reduction as the purpose) is only possible if there are equivalent drugs in terms of the pharmacological mode of action and safety both at the individual and population level, as well as per indication. Whether two drugs are found to be equivalent, is in part the consequence of the chosen clinically relevant margin in which equivalency can reasonably be assumed and the accuracy with which the outcome measure could be measured. Good data for carrying out class substitution will in many cases be lacking. It is for the health professional to decide which preparation is indicated for a certain patient whereby the pharmacist provides pharmacotherapeutic information and checks the prescribed treatment. The provision of education in medical and pharmaceutical curricula is the most effective manner for limiting drug costs.

Cost Allocation↗

PubMed2002

Exogenous motilin affects postprandial proximal gastric motor function and visceral sensation.

Our aim was to investigate the effect of motilin on postprandial proximal gastric motor and sensory function in healthy volunteers. Ten fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min. A liquid meal (200 ml) was ingested within 2 min at the start of the infusion. Proximal gastric volume was measured with a barostat device. Abdominal symptoms were scored by visual analog scales. Plasma motilin concentrations were measured using RIA. Endogenous motilin levels were not affected by meal ingestion. After meal intake, gastric relaxation was similar for motilin and placebo. After postprandial relaxation, motilin resulted in a faster return of gastric volume to baseline (P = 0.007). Motilin significantly increased postprandial feelings of nausea (P = 0.03) and tended to increase abdominal pain and abdominal tension. In conclusion, after normal postprandial gastric relaxation, motilin accelerated the return of gastric volume to baseline. In addition, motilin increased postprandial feelings of nausea.

Abdominal Pain↗

PubMed2002

Dose-related effects of motilin on proximal gastrointestinal motility.

AIM: To assess non-invasively the dose-response relations for the effects of exogenous motilin on antrum contraction frequency, gall-bladder volume and gastric myoelectrical activity. METHODS: In a double-blind, randomized, placebo-controlled, five-way crossover study, 10 fasted healthy volunteers were infused intravenously with synthetic human motilin (0.5, 1, 2 and 4 pmol x min/kg) or placebo for 60 min. Gall-bladder volume and antrum contractions were assessed by ultrasonography and gastric myoelectrical activity by electrogastrography. Motilin concentrations were measured using a radioimmunoassay. RESULTS: Baseline plasma motilin levels (60 pmol/L) were similar for all treatments. Motilin levels increased upon the start of infusion and rapidly returned to baseline after cessation of the infusion. At motilin doses of 2 and 4 pmol.min/kg, the antrum contraction frequency was significantly augmented, with maximum differences of two contractions per 2-min interval compared to placebo, while no changes in gastric myoelectrical activity were observed. Changes in gall-bladder volume were not significantly different for any of the motilin doses compared to placebo. CONCLUSIONS: Motilin increased antrum contraction frequency, whereas no effect on gastric myoelectrical activity was observed. Antrum contraction frequency appears to be a useful biomarker for motilin efficacy, and motilin doses of 2 and 4 pmol x min/kg were equally effective.

Adolescent↗

PubMed2002

Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin.

AIMS: To investigate the pharmacokinetic and pharmacodynamic interaction of the antithrombotic pentasaccharide fondaparinux (Org31540/SR90107A), given subcutaneously, and oral warfarin in healthy subjects. METHODS: This study was performed according to a randomised, three-way cross-over, placebo-controlled, double-blind design in 12 healthy male subjects. The treatment consisted of five subcutaneous (s.c.) injections of fondaparinux (4 mg) or placebo at 24 h intervals. Oral dosing of warfarin or placebo was added to the fourth (15 mg) and fifth (10 mg) s.c. injection. Blood samples for pentasaccharide assay, PT and APTT were drawn before the first s.c. dose of the pentasaccharide and over a 6 day period thereafter. RESULTS: Fondaparinux administered to healthy male volunteers alone or in combination with oral warfarin was well tolerated and no serious adverse events were observed. No differences were found in the AUC (43 vs 44 mg l(-1) h), Cmax (645 vs 678 ng ml(-1)) or elimination half-life (13.8 vs 14.1 h) of fondaparinux between the pentasaccharide-only and the combination treatment. The effect of warfarin on PT (mean maximal increase: 8.2 s.) was not influenced by the presence of the pentasaccharide (mean maximal increase in PT: 9.1 s.). After all treatments a small rise in APTT was seen. No further differences could be detected in the pharmacodynamic parameters following the three treatments. CONCLUSIONS: The coadministration of warfarin did not influence the pharmacokinetics of fondaparinux in healthy subjects. PT can still be used to monitor the effect of oral anticoagulants during the switch from antithrombotic treatment with pentasaccharide to full oral anticoagulant therapy.

Administration, Oral↗

PubMed2002

CNS effects of sumatriptan and rizatriptan in healthy female volunteers.

This study investigates the CNS effects of sumatriptan and rizatriptan, with temazepam as an active comparator, in healthy female volunteers. Sixteen volunteers completed a randomized, double-blind, crossover study and on four separate occasions received either 100 mg sumatriptan, 20 mg rizatriptan or 20 mg temazepam. The main parameters were eye movements, EEG, body sway, visual analogue scales and a cognitive test battery. Rizatriptan and sumatriptan decreased saccadic peak velocity by 18.3 (95% CI: 5.7, 30.8) and 15.0 (2.2, 27.9) degrees/sec, respectively, about half the decrease induced by temazepam (35.0 (22.1, 47.8) degrees/sec). Body sway increased (30% for rizatriptan (16%, 45%) and 14% for sumatriptan (1%, 27%), respectively). Temazepam caused larger, similar effects. In contrast to temazepam, sumatriptan and rizatriptan decreased reaction times of recognition tasks and increased EEG alpha power (significant for sumatriptan, 0.477 (0.02, 0.935). Therapeutic doses of sumatriptan and rizatriptan caused CNS effects indicative of mild sedation. For EEG and recognition reaction times the effects were opposite to temazepam, indicating central stimulation.

Adult↗

PubMed2002

Evaluation of tests of central nervous system performance after hypoxemia for a model for cognitive impairment.

The sensitivity of several neurophysiological and cognitive tests to different levels of hypoxia was investigated. Cerebral hypoxia in healthy volunteers may be a disease model for dementia or other forms of brain dysfunction. Twelve healthy subjects were included in a randomized, single-blind, placebo-controlled, three-period cross-over trial. They received three air/N2 gas mixtures via mask breathing [aimed at peripheral oxygen saturation (SPO2) values of > 97% (placebo), 90% and 80%, with normal end-tidal CO2]. Central nervous system effects were tested regularly for 130 min by saccadic and smooth pursuit eye movements, electro-encephalogram, visual analogue scales and cognitive tests. Treatments were well tolerated. Compared to SPO2 90%, SPO2 80% reduced saccadic peak velocity by 16.4 degrees/s [confidence interval (CI) -26.3, -6.4], increased occipital delta power by 14.3% (CI 3.6, 25.1), and significantly increased most cognitive reaction times. SPO2 80% also decreased correct responses for the binary choice task and serial word recognition [-1.3 (-2.2, -0.3) and -3.5 (-6.2, -0.8), respectively] compared to SPO2 90%. Cognitive performance was decreased by SPO2 80% and increased by SPO2 90% compared to placebo. Sensitive effect measurements can be identified for these interventions. The applicability as a model for cognitive impairment should be investigated further.

Adult↗

PubMed2001

[Medical research and the pharmaceutical industry. Uneasy bedfellows or a prenuptial agreement?].

Recent publications in medical journals and the media seem to indicate that there are a number of major problems in the relationship between researchers and the pharmaceutical sector. Results of research allegedly are influenced or manipulated, the right to publish the results are taken away from the researchers, and all this for money. The underlying data do not seem to indicate that this is a very common problem, but rather a generalisation of incidents. To efficiently develop medicines in future requires an ever-growing amount of academic know-how that these companies simply lack; in modern pharmaceutical development there are many opportunities to connect academic and industrial research programmes, resulting in synergy rather than an academic sell-out. All parties concerned should make transparent and clear agreements.

Conflict of Interest↗

PubMed2001

No Influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers.

Dietary effects on liver blood flow may have biased the previously observed effects of hypertriglyceridemia on systemic tissue-type plasminogen activator (t-PA) concentrations. Therefore, in this study the effects of hypertriglyceridemia on plasma t-PA were determined by inducing hypertriglyceridemia with an intravenous fat emulsion (Intralipid) infusion. In a randomised crossover fashion, eight healthy male volunteers received Intralipid 10% (1.5 ml/min) or 0.9% saline for 2 h and 45 min. After 2 h of infusion, t-PA antigen, t-PA activity, t-PA/plasminogen activator inhibitor (PAI-1) complex, and PAI-1 activity were determined. Concomitantly, the effects of Intralipid t-PA clearance were determined from steady-state t-PA antigen concentrations of a 45-min recombinant tissue-type plasminogen activator (rt-PA) infusion (31.25 microg/min). Liver blood flow was assessed from steady-state concentrations of a continuous sorbitol infusion. Differences between treatments were calculated using the prevalue as the covariate. No significant differences were observed in mean+/-S.D. endogenous concentrations of t-PA antigen, 4.5+/-0.9/4.1+/-0.9 ng/ml (Intralipid vs. saline infusion; difference of 0.3 ng/ml, 95% confidence interval, CI: -0.2, 0.8); t-PA activity, 0.69+/-0.21/0.68+/-0.21 U/ml (difference of 0.04 U/ml, CI: -0.17, 0.25); t-PA/PAI-1 complex, 2.0+/-1.3/1.6+/-1.0 ng/ml (difference of 0.1 ng/ml, CI: -0.8, 0.6); and PAI-1 activity, 7.3+/-5.1/7.1+/-5.1 U/ml (difference of 0.26 U/ml, CI: -3.7, 4.3). Mean t-PA clearance and liver blood flow were unaffected by the Intralipid infusion. These results indicate that acute hypertriglyceridemia does not alter plasma fibrinolytic parameters in healthy male volunteers.

Acute Disease↗

PubMed2001

Cognitive performance and serotonergic function in users of ecstasy.

RATIONALE: (+/-) 3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to cause long term damage to serotonergic cerebral neurons in animals. The neurotoxic effects in humans are less clear and little is known about the functional consequences, although some studies suggest memory impairment. Given the widespread use of MDMA, our lack of knowledge raises concerns. OBJECTIVE: We investigated, in humans, the relation between past use of ecstasy and cognitive performance as well as serotonergic function. METHODS: Two groups of 21 males with moderate and heavy recreational use of MDMA, respectively, and a control group of 20 males without use of MDMA were compared. All were from the same subculture. Reaction time, direct recall, and recognition were assessed. Serotonergic function was measured by the neuro-endocrine response to a placebo-controlled, crossover challenge with dexfenfluramine. RESULTS: Ecstasy users showed a broad pattern of statistically significant, but clinically small, impairment of memory and prolonged reaction times. Heavy users were affected stronger than moderate users. Release of cortisol but not of prolactin after dexfenfluramine administration was significantly reduced in both groups of ecstasy users compared with the controls. Analyses of covariance showed that likely confounding variables including recent exposure to ecstasy, psychosocial profiles and use of other drugs did not explain the differences found between the groups. CONCLUSIONS: These results provide further evidence that use of ecstasy may be associated with impairment of memory and of serotonergic function. These findings are compatible with neurotoxicity of ecstasy as shown in animals.

Adolescent↗