A. F. Cohen

Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

TPA023, a GABAA α2,3 αsubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound Lacks efficacy at the α1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with pLacebo and Lorazepam 2 mg (therapeutic anxioLytic dose). Twelve healthy maLe volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of Lorazepam. In contrast to Lorazepam, TPA023 had no detectabLe effects on saccadic Latency or inaccuracy. Also unlike Lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of Lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to Lorazepam, TPA023 caused no detectabLe memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABAA receptor subtypes.

Effect of intrapulmonary tetrahydrocannabinol administration in humans

This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano® vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano® vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano® vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of alertness (8 mg: -33.6 mm: 95% CI -41.6, -25.7), feeling high (8 mg: 1.09 U: 95% CI 0.85, 1.33), external perception (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4 - 84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.

The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A 2,3 selective agonist, in comparison with lorazepam in healthy volunteers

Abstract Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the γ-aminobutyric acidA 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

Modelling of the concentration—effect relationship of THC on central nervous system parameters and heart rate — insight into its mechanisms of action and a tool for clinical research and development of cannabinoids

Pharmacokinetics after pulmonary administration of δ-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic—pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration—effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.

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 Tmax of 0.78 h (range: 0.33—2.50) and t1/2 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 Emax 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 Emax 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.

Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy

IntroductionThe clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is difficult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac effects, with emphasis on course-to-course variation.MethodsEligible for study participation were patients, without known cardiologic abnormalities who did not use cardiotoxic medication (except for ANT-therapy), who had previously completed at least three cycles of anthracyclin-containing chemotherapy (nxa0=xa014) and patients who were ANT-naïve and who were scheduled to receive doxorubicin-containing chemotherapy (nxa0=xa012). Seven patients in this last group also completed at least three cycles and were available for follow-up assessments; thus a total population of 21 patients (12F/9M) completed at least three courses ANT-chemotherapy. In these patients blood samples and ECG-recordings were taken within 6xa0months after completion of ANT-therapy. In 12 patients (10F/2M) assessments were also done before, immediately afterwards and at 24xa0h after each course of ANT.Results and ConclusionsIn the patients who completed chemotherapy, NT-proBNP was 277% (nxa0=xa021; 95% CI: 86–661%, Pxa0<xa00.001) higher compared to healthy volunteers. During the first course NT-proBNP rose 269% (nxa0=xa012; 167–409%, Pxa0<xa00.0001) at 24xa0h post-administration. The linear corrected QT (QTcL) directly after the first administration of ANT increased by 9.56xa0ms (nxa0=xa012; 3.85–15.27, Pxa0<xa00.001) and this prolongation was still present at 24xa0h, 11.48xa0ms (nxa0=xa012; 5.61–17.34, Pxa0<xa00.0001). Both NT-proBNP and QTcL returned to baseline before the start of the next course and a similar pattern was observed during each course. NT-proBNP and QTcL may be useful markers for course-to-course evaluation of anthracyclin-induced cardiotoxicity.

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.

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery

Objective: The commonly used continuous intravenous (IV) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous IV furosemide therapy in children after cardiac surgery. Subjects and methods: Twelve paediatric patients (5F/7xa0M, age 0–33xa0weeks) post-cardiac surgery, who were to receive 3xa0days of continuous IV furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). Results: The mean starting dose of continuous IV furosemide was 0.093 (±0.016) mg/kg per hour. The mean dose was increased to 0.175 (±0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (±0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. Conclusions: This study extends the observation of the beneficial effects of continuous IV furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2xa0mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2xa0mg/kg per hour may be optimal.

Influence of obesity and body fat distribution on growth hormone kinetics in humans

We studied the kinetics of exogenous recombinant 22-kDa human growth hormone (rhGH) in premenopausal women with upper body obesity (UBO), lower body obesity (LBO), or normal body weight. A bolus of 100 mU rhGH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. GH kinetics were investigated with noncompartmental analysis of plasma GH curves. GH peak values in response to GH infusion and plasma half-life of GH were not significantly different between normal weight and obese subjects. In contrast, GH clearance was 33% higher in LBO women and 51% higher in UBO women compared with clearance in normal weight controls. The difference in clearance between LBO and UBO was not statistically significant. Altered GH clearance characteristics contribute to low circulating GH levels in obese humans. Body fat distribution does not appear to affect GH kinetics.We studied the kinetics of exogenous recombinant 22-kDa human growth hormone (rhGH) in premenopausal women with upper body obesity (UBO), lower body obesity (LBO), or normal body weight. A bolus of 100 mU rhGH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. GH kinetics were investigated with noncompartmental analysis of plasma GH curves. GH peak values in response to GH infusion and plasma half-life of GH were not significantly different between normal weight and obese subjects. In contrast, GH clearance was 33% higher in LBO women and 51% higher in UBO women compared with clearance in normal weight controls. The difference in clearance between LBO and UBO was not statistically significant. Altered GH clearance characteristics contribute to low circulating GH levels in obese humans. Body fat distribution does not appear to affect GH kinetics.

Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol

Central Nervous System (CNS) effects of talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of haloperidol and placebo. The study was randomised, double-blind, three-way crossover of talnetant 200 mg, haloperidol 3 mg or placebo. Twelve healthy males participated and EEG, saccadic and smooth pursuit eye movements, adaptive tracking, body sway, finger tapping, hormones, visual analogue scales (VAS) for alertness, mood and calmness and psychedelic effects, left/right distraction task, Tower of London and Visual and Verbal Learning Task were assessed. Haloperidol showed (difference to placebo; 95% CI; p-value) decreases in EEG α power (−0.87μV; −1.51/−0.22; p = 0.0110), saccadic inaccuracy (2.0%; 0.5/3.6; p = 0.0133), smooth pursuit eye movements (−7.5%; −12.0/−3.0; p = 0.0026), adaptive tracking (−3.5%; −5.4/−1.7; p = 0.0009), alertness (−6.8 mm; −11.1/−2.4; p = 0.0039), negative mood (−4.6 mm; −8.6/−0.6; p = 0.0266), the ability to control thoughts (1.2 mm; 0.2/2.3; p = 0.0214), and an increase of serum prolactin (ratio 4.1; 3.0/5.6; p < 0.0001). Talnetant showed decreased alpha power (−0.69 μV; −1.34/−0.04; p = 0.0390), improved adaptive tracking (1.9%; 0.1/3.7; p = 0.0370) and reduced calmness on VAS Bond and Lader (−4.5 mm; −8.0/−1.0; p = 0.0151). Haloperidol effects were predominantly CNS-depressant, while those of talnetant were slightly stimulatory. The results suggest that talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists.