Objective gait assessment in individuals with knee osteoarthritis using inertial sensors: A systematic review and meta-analysis.

BACKGROUND: Objective assessment of gait using inertial sensors has shown promising results for functional evaluations in individuals with knee osteoarthritis (OA). However, the large number of possible outcome measures calls for a systematic evaluation of most relevant parameters to be used for scientific and clinical purposes. AIM: This systematic review and meta-analysis aimed to identify gait parameters derived from inertial sensors that reflect gait deviations in individuals with knee OA compared to healthy control subjects (HC). METHODS: A systematic search was conducted in five electronic databases (Medline, Embase, Web of Science, CINAHL, IEEE) to identify eligible articles. Risk of bias was assessed using a modified version of the Downs and Black scale. Data regarding study population, experimental procedures, and biomechanical outcomes were extracted. When a gait parameter was reported by a sufficient number of studies, a random-effects meta-analysis was conducted using the inverse variance method. RESULTS: Twenty-three articles comparing gait between 411 individuals with knee OA and 507 HC were included. Individuals with knee OA had a lower gait speed than HC (standardized mean difference = -1.65), driven by smaller strides with a longer duration. Stride time variability was slightly higher in individuals with knee OA than in HC. Individuals with knee OA walked with a lower range of motion of the knee during the swing phase, less lumbar motion in the coronal plane, and a lower foot strike and toe-off angle compared to HC. SIGNIFICANCE: This review shows that inertial sensors can detect gait impairments in individuals with knee OA. Large standardized mean differences found on spatiotemporal parameters support their applicability as sensitive endpoints for mobility in individuals with knee OA. More advanced measures, including kinematics of knee and trunk, may reveal gait adaptations that are more specific to knee OA, but compelling evidence was lacking.

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method.

BACKGROUND AND METHODS: This opinion paper expanded on the WHO "six-step approach to optimal pharmacotherapy," by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward "precision clinical pharmacology," as a prerequisite for precision medicine. RESULT: In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the "One Health" concept) and to reduce drug resistance. DISCUSSION AND CONCLUSION: As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.

Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.

Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

The use of biomarkers in human pharmacology (Phase I) studies.

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.

Determination of methylphenidate in plasma and saliva by liquid chromatography/tandem mass spectrometry.

Methylphenidate (MPH) is a phenethylamine derivative used in the treatment of attention-deficit hyperactivity disorder (ADHD). In adults, clinical monitoring of MPH therapy is usually performed by measuring plasma MPH concentrations. In children blood sampling is however undesirable. Saliva may be an alternative matrix for monitoring MPH concentrations with the advantage that it can be obtained non-invasively. Therefore, we developed an analytical method for the quantification of MPH in both plasma and saliva. We present the validation of a liquid chromatography-tandem mass spectrometric method using a hydrophilic interaction liquid chromatography column (HILIC). In 100 µL sample, proteins were precipitated with 750 µL acetonitrile/methanol 84/16 (v/v) containing d9-methylphenidate as the internal standard. Standard curves were prepared over the MPH concentration range of 0.5-100.0 µg/L. The total analysis time was 45 s. Accuracy and within- and between-run imprecision were in the range of 98-108% and less than 7.0%, respectively. Matrix effects were greater for plasma than saliva with 46% and 8% ionization suppression. The matrix effects were adequately compensated by the use of deuterated MPH as internal standard. MPH significantly degraded in plasma and saliva at room temperature and 5°C. Samples were stable at -20°C for at least 4 weeks. The method was successfully applied for the determination of MPH concentrations in plasma and saliva samples from an adult healthy volunteer. Using protein precipitation and hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry, this method allows fast, accurate and precise quantification of MPH in both plasma and saliva.

Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state.

GSK598809 is a novel selective dopamine D(3) receptor antagonist, currently in development for the treatment of substance abuse and addiction. In a blinded, randomized, placebo-controlled study, effects of single oral doses of 175 mg GSK598809 were evaluated in healthy volunteers. Pharmacokinetics, central nervous system (CNS) effects and potential for interactions with alcohol were evaluated, using an alcohol infusion paradigm and analysis of eye movements, adaptive tracking, visual analogue scales, body sway, serum prolactin and verbal visual learning test. Adverse effects of GSK598809 included headache, dizziness and somnolence. Plasma concentration of GSK598809 was maximal 2-3 hours postdose and decreased with a half-life of roughly 20 hours. CNS effects were limited to prolactin elevation and decreased adaptive tracking. Co-administration of GSK598809 and alcohol did not affect alcohol pharmacokinetics, but caused a 9% decrease of C (max) and a 15% increase of AUC of GSK598809. CNS effects of co-administration were mainly additive, except a small supra-additive increase in saccadic reaction time and decrease in delayed word recall. In conclusion, GSK598809 causes elevation of serum prolactin and a small decrease in adaptive tracking performance. After co-administration with alcohol, effects of GSK598809 are mainly additive and the combination is well tolerated in healthy volunteers.

The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol.

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, double-dummy study the effects of 25 mg of a novel H3RIA (MK-0249) and a stable alcohol level (0.6 g L(-1)) were compared with placebo, in 18 patients with ET. Tremor was evaluated using laboratory tremorography, portable tremorography and a clinical rating scale. The Leeds Sleep Evaluation Questionnaire (LSEQ) and a choice reaction time (CRT) test were performed to evaluate potential effects on sleep and attention, respectively. A steady state of alcohol significantly diminished tremor as assessed by laboratory tremorography, portable tremorography and clinical ratings compared with placebo. A high single MK-0249 dose was not effective in reducing tremor, but caused significant effects on the LSEQ and the CRT test. These results suggest that treatment with a single dose of MK-0249 does not improve tremor in alcohol-responsive patients with ET, whereas stable levels of alcohol as a positive control reproduced the commonly reported tremor-diminishing effects of alcohol.

The effects of TPA023, a GABAAα2,3 subtype-selective partial agonist, on essential tremor in comparison to alcohol.

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 are involved in the therapeutic effects of benzodiazepines in ET. The effects of 2 mg TPA023, a GABA(A) α2,3 subtype-selective partial agonist, on ET were compared to the effects of a stable alcohol level (0.6 g/L) and placebo in nine patients with ET. Tremor evaluation included laboratory accelerometry and a performance-based scale. Additional measurements were performed to evaluate other effects on the central nervous system (CNS). Alcohol significantly diminished tremor symptoms in the postural and kinetic condition, as assessed by laboratory accelerometry, but the performance-based rating scale was unaffected. Tremor was also reduced after TPA023 treatment in the kinetic condition, albeit not significantly. Additionally, TPA023 decreased saccadic peak velocity, while alcohol decreased subjective feelings of alertness. This study showed that alcohol reduced maximum tremor power, as assessed by laboratory accelerometry, unlike TPA023, which decreased tremor symptoms to some extent but not significantly. This study showed that treatment with an α2,3 subunit-selective GABA(A) partial agonist was less effective than a stable level of alcohol in reducing ET symptoms. These results provide no support for a therapeutic role of TPA023 in the suppression of ET symptoms.

Acute psychomotor, memory and subjective effects of MDMA and THC co-administration over time in healthy volunteers.

In Western societies a considerable percentage of young people expose themselves to the combination of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') and cannabis. The aim of the present study was to assess the acute effects of co-administration of MDMA and THC (the main psychoactive compound of cannabis) on pharmacokinetics, psychomotor performance, memory and subjective experience over time. We performed a four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (12 male, four female) between the ages of 18 and 27. MDMA (100 mg) was given orally, THC (4, 6, and 6 mg, interval of 90 min) was vaporized and inhaled. THC induced more robust cognitive impairment compared with MDMA, and co-administration did not exacerbate single drug effects on cognitive function. However, co-administration of THC with MDMA increased desired subjective drug effects and drug strength compared with the MDMA condition, which may explain the widespread use of this combination.

Desmopressin as a pharmacological tool in vasopressinergic hypothalamus-pituitary-adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects.

Arginine-vasopressin (AVP) is a physiological co-activator of the hypothalamus-pituitary-adrenal (HPA) axis, together with corticotrophin releasing hormone (CRH). A synthetic analogue of AVP, desmopressin (dDAVP), is often used as a pharmacological tool to assess co-activation in health and disease. The relation between dDAVP's neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic and non-specific stress effects has not been studied. A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers (6 : 6). dDAVP was administered intravenously as a 10 µg bolus (over 1 min) or a 30 µg incremental infusion (over 60 min). Neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic effects and adverse events (AEs) were recorded, and autonomic nervous system (ANS) activation evaluated. The incremental infusion reached 1.8-fold higher dDAVP concentrations than the bolus. Neuroendocrine effects were similar for the 10 µg dDAVP bolus and the 30 µg incremental infusion, while cardiovascular and coagulatory effects were greater with the 30 µg dose. Osmolality and ANS activity remained uninfluenced. AEs corresponded to dDAVP's side-effect profile. In conclusion, the neuroendocrine effects of a 10 µg dDAVP bolus administered over 1 min are similar to those of a 30 µg incremental infusion administered over one hour, despite higher dDAVP concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10 µg dDAVP bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen.

A pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal axis more integrally in healthy volunteers.

Pharmacological function tests consisting of 100 µg hCRH (corticorelin) and 10 µg dDAVP (desmopressin) mimic endogenous hypothalamus-pituitary-adrenal (HPA) axis activation. However, physiological CRH concentrations preclude informative vasopressinergic co-activation (using dDAVP) and independent quantification of both corticotrophinergic (using hCRH) and vasopressinergic (using dDAVP) activation is limited due to administration on separate occasions. This randomized, double-blind, placebo-controlled, partial five-way crossover study in healthy males and females (six : six) examined whether (1) concomitant administration of dDAVP and hCRH provides more informative vasopressinergic co-activation than dDAVP alone; and (2) whether the administration of dDAVP followed two hours later by hCRH can quantify both vasopressinergic and corticotrophinergic activation on a single test day. Combining 10 µg dDAVP with 10 µg and 30 µg hCRH caused dose-related ACTH and cortisol release which was larger than with 10 µg dDAVP alone and respectively comparable to and greater than that induced by 100 µg hCRH. Using 10 µg dDAVP alone demonstrated limited ACTH release while the effects of 100 µg hCRH two hours later were three times as large. ACTH and cortisol released by 10 µg dDAVP returned to baseline prior to 100 µg hCRH administration and dDAVP did not influence the response to subsequent hCRH administration. Dose-related vasopressinergic co-activation of the HPA axis was induced by combining 10 µg dDAVP with 10 µg and 30 µg hCRH. Combining 10 µg dDAVP with 10 µg hCRH induced the potentially most informative vasopressinergic co-activation since it is not restricted by ceiling or flooring effects. The hCRH response was not affected by prior dDAVP, allowing for a practical function test examining both HPA activation routes on the same day.

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis: a study in healthy volunteers.

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant.

Almorexant, a dual orexin receptor antagonist potentially representing a new class of sleep-promoting compounds, was administered in an ascending single-dose study to evaluate tolerability, pharmacokinetics, and pharmacodynamics. Seventy healthy male subjects were enrolled in this double-blind, placebo- and active-controlled study. Each dose level (1-1,000 mg) was investigated in a separate group of 10 subjects (6 on almorexant, 2 on placebo, 2 on zolpidem 10 mg). Almorexant was well tolerated with no signs of cataplexy. Peak plasma concentration (C(max)) was quickly attained (median time to maximum concentration (t(max)) ranged from 0.7 to 2.3 h), and plasma concentrations subsequently decreased quickly to ~20% of C(max) over the course of 8 h. Vigilance, alertness, and visuomotor and motor coordination were reduced following daytime administration of zolpidem or almorexant at doses of > or =400 mg. Population pharmacokinetic/pharmacodynamic modeling suggested that doses of ~500 mg almorexant and 10 mg zolpidem are equivalent with respect to subjectively assessed alertness.

Hypothalamic glutamate levels following serotonergic stimulation: a pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers.

INTRODUCTION AND PURPOSE: Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers. METHODS: A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4h and MRS scans at 7T were performed every 30min over 3h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios. RESULTS: In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180min but induced a significant decrease of Glx at 60min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E(max) of 60.2ng/L at 80min followed by cortisol with an E(max) of 246.4ng/mL at 110min. CONCLUSIONS: The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.

The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects.

In this study the effects of R213129, a selective glycine transporter 1 inhibitor, on central nervous system function were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, 4-period crossover ascending dose study evaluating the following endpoints: body sway, saccadic and smooth pursuit eye movements, pupillometry, electroencephalography, visual analogue scales for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Visual and Verbal Learning Task, Stroop test, hormone levels and pharmacokinetics. R213129 dose levels were selected based on exposure levels that blocked the GlyT1 sites >50% in preclinical experiments. Forty-three of the 45 included subjects completed the study. Scopolamine significantly affected almost every central nervous system parameter measured in this study. R213129 alone compared with placebo did not elicit pharmacodynamic changes. R213129 had some small effects on scopolamine-induced central nervous system impairments. Scopolamine-induced finger tapping impairment was further enhanced by 3 mg R213129 with 2.0 taps/10 seconds (95% CI -4.0, -0.1), electroencephalography alpha power was increased by 10 mg R213129 with respectively 12.9% (0.7, 26.6%), scopolamine-induced impairment of the Stroop test was partly reversed by 10 mg R213129 with 59 milliseconds (-110, -7). Scopolamine produced robust and consistent effects in psychomotor and cognitive function in healthy volunteers. The most logical reason for the lack of R213129 effects seems to be that the central nervous system concentrations were too low. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

The effects of a glycine reuptake inhibitor R231857 on the central nervous system and on scopolamine-induced impairments in cognitive and psychomotor function in healthy subjects.

The effects of the selective inhibitor of the glycine transporter 1, R231857, in development for schizophrenia, on the central nervous system (CNS) were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, four-period crossover ascending dose study. Pharmacokinetics, body sway, saccadic and smooth pursuit eye movements, pupillometry, pharmacoelectroencephalogram (EEG), Visual Analogue Scales (VAS) for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Stroop test, Visual and Verbal Learning Task (VVLT) and hormone levels were assessed. R231857 was administered alone and together with scopolamine to investigate the potential reversal of anticholinergic CNS impairment by the glycine reuptake inhibitor. Forty-two of the 45 included subjects completed the study. Scopolamine significantly affected almost every CNS parameter measured in this study. R231857 alone showed some pharmacodynamic changes compared with placebo. Although these effects might be an indication that R231857 penetrated the CNS, they were not consistent or dose-related. R231857 had some small effects on scopolamine-induced CNS-impairment, which were also not clearly dependent on dose. Scopolamine proved to be an accurate, reproducible and safe model to induce CNS impairment by an anticholinergic mechanism. R231857 lacked consistent dose-related effects in this study, probably because CNS concentrations were too low to produce significant/ reproducible CNS-effects or to affect the scopolamine challenge in healthy volunteers. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

Method development studies for repeatedly measuring anxiolytic drug effects in healthy humans.

Human experimental models for anxiety may serve as translational tools for translating preclinical psychopharmacological investigations into human studies. For the evaluation of drugs of which pharmacokinetics and pharmacodynamics are unidentified, repeating measurements after drug administration is necessary for characterising the time course of drug effects. In experiment 1, a threat-of-shock paradigm and adaptations of the Trier mental arithmetic test and the Stroop colour naming test were repeated four times within a day to evaluate whether anxiety responses to this test battery remain stable after repeated testing. This procedure was repeated on 4 days in a second experiment to evaluate suitability of the paradigm for a crossover design with multiple sessions. Results indicate no reductions or changes in fear potentiated startle, the main outcome measure for the threat paradigm, over test sessions or days. Skin conductance responses and subjective ratings under threat-of-shock showed significant fluctuations but also no systematic decline over time. Finally, the threat paradigm and Stroop test resulted in small increases in reported state anxiety while mental arithmetic produced larger effects that diminished after the first test day. It is concluded that especially the startle paradigm could be a useful new instrument for screening new anxiolytic drugs.

Ethanol co-administration moderates 3,4-methylenedioxymethamphetamine effects on human physiology.

Alcohol is frequently used in combination with 3,4-methylenedioxymethamphetamine (MDMA). Both drugs affect cardiovascular function, hydration and temperature regulation, but may have partly opposing effects. The present study aims to assess the acute physiologic effects of (co-) administration of MDMA and ethanol over time. A four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (9 male and 7 female) between the ages of 18 and 29. MDMA (100 mg) was given orally and blood ethanol concentration was maintained at pseudo-steady state levels of 0.6 per thousand by a three-hour 10% intravenous ethanol clamp. Cardiovascular function, temperature and hydration measures were recorded throughout the study days. Ethanol did not significantly affect physiologic function, with the exception of a short lasting increase in heart rate. MDMA potently increased heart rate and blood pressure and induced fluid retention as well as an increase in temperature. Co-administration of ethanol with MDMA did not affect cardiovascular function compared to the MDMA alone condition, but attenuated the effects of MDMA on fluid retention and showed a trend for attenuation of MDMA-induced temperature increase. In conclusion, co-administration of ethanol and MDMA did not exacerbate physiologic effects compared to all other drug conditions, and moderated some effects of MDMA alone.

Acute psychomotor effects of MDMA and ethanol (co-) administration over time in healthy volunteers.

In Western societies, a considerable percentage of young people use 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). The use of alcohol (ethanol) in combination with ecstasy is common. The aim of the present study was to assess the acute psychomotor and subjective effects of (co-) administration of MDMA and ethanol over time and in relation to the pharmacokinetics. We performed a four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (nine men, seven women) between the ages of 18 and 29. MDMA (100 mg) was given orally while blood alcohol concentration was maintained at pseudo-steady state levels of approximately 0.6 per thousand for 3 h by a 10% intravenous ethanol clamp. MDMA significantly increased psychomotor speed but did not affect psychomotor accuracy and induced subjective arousal. Ethanol impaired both psychomotor speed and accuracy and induced sedation. Coadministration of ethanol and MDMA improved psychomotor speed but impaired psychomotor accuracy compared with placebo and reversed ethanol-induced sedation. Pharmacokinetics and pharmacodynamics showed maximal effects at 90-150 min after MDMA administration after which drug effects declined in spite of persisting MDMA plasma concentration, with the exception of ethanol-induced sedation, which manifested itself fully only after the infusion was stopped. In conclusion, results show that subjects were more aroused when intoxicated with both substances combined compared with placebo, but psychomotor accuracy was significantly impaired. These findings may have implications for general neuropsychological functioning as this may provide a sense of adequate performance that does not agree with a significant reduction in psychomotor accuracy.