Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects.

AIMS: The aim of this study was to use data from an experimental induced blood stage malaria clinical trial to characterize the antimalarial activity of the new compound Actelion-451840 using pharmacokinetic/pharmacodynamic (PK/PD) modelling. Then, using simulations from the model, the dose and dosing regimen necessary to achieve cure of infection were derived. METHODS: Eight healthy male subjects were infected with blood stage P. falciparum. After 7 days, a single dose of 500 mg of Actelion-451840 was administered under fed conditions. Parasite and drug concentrations were sampled frequently. Parasite growth and the relation to drug exposure were estimated using PK/PD modelling. Simulations were then undertaken to derive estimates of the likelihood of achieving cure in different scenarios. RESULTS: Actelion-451840 was safe and well tolerated. Single dose treatment markedly reduced the level of P. falciparum parasitaemia, with a weighted average parasite reduction rate of 73.6 (95% CI 56.1, 96.5) and parasite clearance half-life of 7.7 h (95% CI 7.3, 8.3). A two compartment PK/PD model with a steep concentration-kill effect predicted maximum effect with a sustained concentration of 10-15 ng ml(-1) and cure achieved in 90% of subjects with six once daily doses of 300 mg once daily. CONCLUSIONS: Actelion-451840 shows clinical efficacy against P. falciparum infections. The PK/PD model developed from a single proof-of-concept study with eight healthy subjects enabled prediction of therapeutic effects, with cure rates with seven daily doses predicted to be equivalent to artesunate monotherapy. Larger doses or more frequent dosing are not predicted to achieve more rapid cure.

One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: investigation of neural correlates with BOLD MRI.

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

The effect of aging on the inhibitory function in middle-aged subjects: a functional MRI study coupled with a color-matched Stroop task.

OBJECTIVE: The effects of aging on the inhibitory function are largely described in the neuroimaging literature but little data is available on the beginning of this age-related impairment. METHODS: In this study, we described the cortical activation of middle-aged (mean age +/- standard error to the mean, 51.7 +/- 3.1) subjects compared to young (26.8 +/- 3.4) and elderly subjects (62.8 +/- 3) while they performed a color-matched Stroop task during functional magnetic resonance imaging. The task consisted in identifying the printing color of a word regardless of its meaning. Three conditions were defined depending on the meaning of this word; neutral (no meaning), congruent (color name matching the printing color), incongruent (color name mismatching the printing color), with interference effect in the latter. RESULTS: Middle-aged subjects were as slow as elderly compared to young for all conditions and both were less accurate than young subjects during interference condition. Elderly showed an activity more bilateral and greater in the parietal lobule, the dorsolateral and ventrolateral prefrontal cortex (DLPFC, VLPFC) during both congruent and incongruent conditions compared to young. Middle-aged showed an intermediary level of activity between those of elderly and young subjects in the left DLPFC, VLPFC and parietal lobule only during incongruent condition. CONCLUSION: These results suggested that the age-related impairment of the inhibitory process could already occur around the age of 50 years and consist in an increase of the activity in the left prefrontal and parietal cortex before increasing more and becoming bilateral around the age of 60 years.

Test-retest reliability of a functional MRI anticipatory anxiety paradigm in healthy volunteers.

PURPOSE: To evaluate the reproducibility of neural activations induced by an anticipatory anxiety provocation challenge in healthy volunteers. MATERIALS AND METHODS: Fourteen healthy male volunteers participated in two separate functional MRI (fMRI) sessions in which they underwent a paradigm based on anticipation of aversive transcutaneous electrical nerve stimulations. This paradigm consisted of alternating presentation of red circles associated with the likelihood that aversive stimuli may be given and blue circles during which the subjects knew that no shock could be given. Anxiety state was compared before the fMRI sessions and during the threat periods using clinical scales (Hamilton, STAI-Y1), the Bond and Lader Visual Analogue Scale, and self-rating scales of apprehension and stimulus aversivity. RESULTS: The selected paradigm induced anticipatory anxiety of moderate intensity as suggested by clinical scales and apprehension rating, without any habituation to the somatosensory stimulus across sessions. Compared to rest periods, threat of the aversive stimulus induced clear brain activation in anticipatory anxiety-related areas: frontal/prefrontal cortex, insula, lentiform nucleus, temporal pole, and cingulate cortex. Anxiety symptoms and cerebral activity were reproducible across sessions. CONCLUSION: The fMRI paradigm and its assessment method include all criteria to speed up the evaluation and the development of new anxiolytics.

Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety.

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.