Dopamine modulations of reward-driven music memory consolidation.

Music listening provides one of the most significant abstract rewards for humans because hearing music activates the dopaminergic mesolimbic system. Given the strong link between reward, dopamine, and memory, we aimed here to investigate the hypothesis that dopamine-dependent musical reward can drive memory improvements. Twenty-nine healthy participants of both sexes provided reward ratings of unfamiliar musical excerpts that had to be remembered following a consolidation period under three separate conditions: after the ingestion of a dopaminergic antagonist, a dopaminergic precursor, or a placebo. Linear mixed modeling of the intervention data showed that the effect of reward on memory-i.e., the greater the reward experienced while listening to the musical excerpts, the better the memory recollection performance-was modulated by both dopaminergic signaling and individual differences in reward processing. Greater pleasure was consistently associated with better memory outcomes in participants with high sensitivity to musical reward, but this effect was lost when dopaminergic signaling was disrupted in participants with average or low musical hedonia. Our work highlights the flexibility of the human dopaminergic system, which can enhance memory formation not only through explicit and/or primary reinforcers but also via abstract and aesthetic rewards such as music.

Alterations in EEG connectivity in healthy young adults provide an indicator of sleep depth.

Current sleep analyses have used electroencephalography (EEG) to establish sleep intensity through linear and nonlinear measures. Slow wave activity (SWA) and entropy are the most commonly used markers of sleep depth. The purpose of this study is to evaluate changes in brain EEG connectivity during sleep in healthy subjects and compare them with SWA and entropy. Four different connectivity metrics: coherence (MSC), synchronization likelihood (SL), cross mutual information function (CMIF), and phase locking value (PLV), were computed focusing on their correlation with sleep depth. These measures provide different information and perspectives about functional connectivity. All connectivity measures revealed to have functional changes between the different sleep stages. The averaged CMIF seemed to be a more robust connectivity metric to measure sleep depth (correlations of 0.78 and 0.84 with SWA and entropy, respectively), translating greater linear and nonlinear interdependences between brain regions especially during slow wave sleep. Potential changes of brain connectivity were also assessed throughout the night. Connectivity measures indicated a reduction of functional connectivity in N2 as sleep progresses. The validation of connectivity indexes is necessary because they can reveal the interaction between different brain regions in physiological and pathological conditions and help understand the different functions of deep sleep in humans.

Dopamine modulates the reward experiences elicited by music.

Understanding how the brain translates a structured sequence of sounds, such as music, into a pleasant and rewarding experience is a fascinating question which may be crucial to better understand the processing of abstract rewards in humans. Previous neuroimaging findings point to a challenging role of the dopaminergic system in music-evoked pleasure. However, there is a lack of direct evidence showing that dopamine function is causally related to the pleasure we experience from music. We addressed this problem through a double blind within-subject pharmacological design in which we directly manipulated dopaminergic synaptic availability while healthy participants (n = 27) were engaged in music listening. We orally administrated to each participant a dopamine precursor (levodopa), a dopamine antagonist (risperidone), and a placebo (lactose) in three different sessions. We demonstrate that levodopa and risperidone led to opposite effects in measures of musical pleasure and motivation: while the dopamine precursor levodopa, compared with placebo, increased the hedonic experience and music-related motivational responses, risperidone led to a reduction of both. This study shows a causal role of dopamine in musical pleasure and indicates that dopaminergic transmission might play different or additive roles than the ones postulated in affective processing so far, particularly in abstract cognitive activities.

Prevalence of Sleep Disorders in Adults With Down Syndrome: A Comparative Study of Self-Reported, Actigraphic, and Polysomnographic Findings.

STUDY OBJECTIVES: Sleep problems are often undetected in adults with Down syndrome (DS). Our objective was to determine the prevalence of sleep disorders in adults with DS through self-reported and objective sleep measures. METHODS: We performed a community-based cross-sectional study of 54 adults with DS not referred for sleep disorders. Two polysomnography (PSG) sleep studies were performed. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the risk for the sleep apnea syndrome (OSA) was identified using the Berlin Questionnaire (BQ). Participants' sleep/wake pattern was assessed from sleep diaries and by wrist actigraphy. PSQI, ESS, and PSG measures were compared with 35 sex-, age-, and body mass index-matched patients in the control groups. RESULTS: In PSG measures, adults with DS showed lower sleep efficiency (69 ± 17.7 versus 81.6 ± 11; P < .001), less rapid eye movement sleep (9.4 ± 5.8 versus 19.4 ± 5.1; P < .001), a higher prevalence of OSA (78% versus 14%; P < .001), and a higher apnea-hypopnea index (23.5 ± 24.5 versus 3.8 ± 10.5; P < .001) than patients in the control group. In the DS group, the questionnaires (mean PSQI 3.7 ± 2.9; mean ESS 6.3 ± 4.5 and mean BQ 1 ± 0) did not reflect the sleep disturbances detected on the PSG. Actigraphy data recorded daytime sleep that was not self-reported (118.2 ± 104.2 minutes). CONCLUSIONS: Adults with DS show severe sleep disruption and a high prevalence of OSA, undetected by self-reported sleep measures. Actigraphy, PSG, and validated simplified devices for screening OSA should be routinely recommended for this population because treatment of sleep disorders can contribute to healthy aging.

Phytosterols and Omega 3 Supplementation Exert Novel Regulatory Effects on Metabolic and Inflammatory Pathways: A Proteomic Study.

Cardiovascular disease (CVD) remains one of the major causes of death and disability worldwide. In addition to drug treatment, nutritional interventions or supplementations are becoming a health strategy for CVD prevention. Phytosterols (PhyS) are natural components that have been shown to reduce cholesterol levels; while poly-unsaturated fatty acids (PUFA), mainly omega-3 (ω3) fatty acids, have shown to reduce triglyceride levels. Here we aimed to investigate whether the proteins in the main lipoproteins (low density lipoproteins (LDL) and high density lipoproteins (HDL)) as well as proteins in the lipid free plasma fraction (LPDP) were regulated by the intake of PhyS-milk or ω3-milk, in overweight healthy volunteers by a proteomic based systems biology approach. The study was a longitudinal crossover trial, including thirty-two healthy volunteers with body mass index (BMI) 25-35 kg/m² (Clinical Trial: ISRCTN78753338). Basal samples before any intervention and after 4 weeks of intake of PhyS or ω3-milk were analyzed. Proteomic profiling by two dimensional electrophoresis (2-DE) followed by mass spectrometry-(MALDI/TOF), ELISA, Western blot, conventional biochemical analysis, and in-silico bioinformatics were performed. The intake of PhyS-milk did not induce changes in the lipid associated plasma protein fraction, whereas ω3-milk significantly increased apolipoprotein (Apo)- E LDL content (p = 0.043) and induced a coordinated increase in several HDL-associated proteins, Apo A-I, lecitin cholesterol acyltransferase (LCAT), paraoxonase-1 (PON-1), Apo D, and Apo L1 (p < 0.05 for all). Interestingly, PhyS-milk intake induced a reduction in inflammatory molecules not seen after ω3-milk intake. Serum amyloid P component (SAP) was reduced in the LPDP protein fraction (p = 0.001) of subjects taking PhyS-milk and C-C motif chemokine 2 (CCL2)expression detected by reverse transcription polymerase chain reaction (RT-PCR) analysis in white blood cells was significantly reduced (p = 0.013). No changes were observed in the lipid-free plasma proteome with ω3-milk. Our study provides novel results and highlights that the PhyS-milk induces attenuation of the pro-inflammatory pathways, whereas ω3-milk induces improvement in lipid metabolic pathways.

Acute Sleep Deprivation Induces a Local Brain Transfer Information Increase in the Frontal Cortex in a Widespread Decrease Context.

Sleep deprivation (SD) has adverse effects on mental and physical health, affecting the cognitive abilities and emotional states. Specifically, cognitive functions and alertness are known to decrease after SD. The aim of this work was to identify the directional information transfer after SD on scalp EEG signals using transfer entropy (TE). Using a robust methodology based on EEG recordings of 18 volunteers deprived from sleep for 36 h, TE and spectral analysis were performed to characterize EEG data acquired every 2 h. Correlation between connectivity measures and subjective somnolence was assessed. In general, TE showed medium- and long-range significant decreases originated at the occipital areas and directed towards different regions, which could be interpreted as the transfer of predictive information from parieto-occipital activity to the rest of the head. Simultaneously, short-range increases were obtained for the frontal areas, following a consistent and robust time course with significant maps after 20 h of sleep deprivation. Changes during sleep deprivation in brain network were measured effectively by TE, which showed increased local connectivity and diminished global integration. TE is an objective measure that could be used as a potential measure of sleep pressure and somnolence with the additional property of directed relationships.

Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naïve volunteers: effect of injection volume and dose on infectivity rates.

BACKGROUND: Controlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria. However, only a small number of research centres have the facilities required to perform such studies. CHMI by needle and syringe could help to accelerate the development of anti-malaria interventions by enabling centres worldwide to employ CHMI. METHODS: An open-label CHMI study was performed with aseptic, purified, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) in 36 malaria naïve volunteers. In part A, the effect of the inoculation volume was assessed: 18 participants were injected intramuscularly (IM) with a dose of 2,500 PfSPZ divided into two injections of 10 µL (n = 6), 50 µL (n = 6) or 250 µL (n = 6), respectively. In part B, the injection volume that resulted in highest infectivity rates in part A (10 µL) was used to formulate IM doses of 25,000 PfSPZ (n = 6) and 75,000 PfSPZ (n = 6) divided into two 10-µL injections. Results from a parallel trial led to the decision to add a positive control group (n = 6), each volunteer receiving 3,200 PfSPZ in a single 500-µL injection by direct venous inoculation (DVI). RESULTS: Four/six participants in the 10-µL group, 1/6 in the 50-µL group and 2/6 in the 250-µL group developed parasitaemia. Geometric mean (GM) pre-patent periods were 13.9, 14.0 and 15.0 days, respectively. Six/six (100%) participants developed parasitaemia in the 25,000 and 75,000 PfSPZ IM and 3,200 PfSPZ DVI groups. GM pre-patent periods were 12.2, 11.4 and 11.4 days, respectively. Injection of PfSPZ Challenge was well tolerated and safe in all groups. CONCLUSIONS: IM injection of 75,000 PfSPZ and DVI injection of 3,200 PfSPZ resulted in infection rates and pre-patent periods comparable to the bite of five PfSPZ-infected mosquitoes. Remarkably, it required 23.4-fold more PfSPZ administered IM than DVI to achieve the same parasite kinetics. These results allow for translation of CHMI from research to routine use, and inoculation of PfSPZ by IM and DVI regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT01771848.

Ibuprofen lysinate, quicker and less variable: relative bioavailability compared to ibuprofen base in a pediatric suspension dosage form.

OBJECTIVES: To assess and compare the bioavailability of ibuprofen enantiomers (R and S) of two different pediatric suspensions: the first one with ibuprofen lysinate (Algidrin® Pediátrico, FARDI S.A., Barcelona, Spain) and the second one with ibuprofen base (Dalsy®, Abbott Laboratories S.A., Madrid, Spain). METHODS: A randomized, open-label, single-dose, balanced, crossover study under fasting conditions was performed at the CIM-Sant Pau. 24 healthy volunteers received a single dose of ibuprofen lysinate (Algidrin® Pediátrico, FARDI S.A.) and ibuprofen base (Dalsy®, Abbott Laboratories S.A.) equivalent to 400 mg of ibuprofen. 18 blood samples were drawn and ibuprofen enantiomer plasma concentrations were determined using an enantioselective analytical method. An analysis of variance (ANOVA) model was used, and the 90% confidence intervals (CI) were calculated; further analyses were made regarding rate of absorption and variability. RESULTS: The pharmacokinetic parameters (Algidrin® Pediátrico vs. Dalsy® (Mean±SD)) were: S-enantiomer: Cmax=22.39±5.33 vs. 19.97±3.19 µg/mL; AUC0t=74.83±16.69 vs. 74.64±14.80 µg×h/mL, and AUC0∞=77.46±19.33 vs. 76.98±17.13 µg×h/mL; and for R-enantiomer: Cmax=21.74±3.76 vs. 15.20±2.03 µg/mL; AUC0t=57.55±10.17 vs. 46.13±9.61 µg×h/mL, and AUC0∞ value was 58.49±10.57 vs. 47.03±10.02 µg×h/mL. The tmax (Median) for S-enantiomer (active) were: 0.5 vs. 1.33 hours (p=0.001) and for R-enantiomer: 0.5 vs. 1.0 hours (p=0.004). Ibuprofen pharmacokinetic values may vary under fed state and in pediatric population. CONCLUSIONS: While S-ibuprofen shows a similar bioavailability for AUC0t, AUC0∞, and Cmax, R-ibuprofen shows suprabioavailability for the lysinate formulation. The rate of absorption of the ibuprofen lysinate suspension is quicker and less variable than that of the ibuprofen base reference suspension and it exhibits a shorter tmax, which is of particular interest for achieving a rapid and homogeneous analgesic and antipyretic effect.

Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres.

BACKGROUND: Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development. METHODS: An open-labelled, randomized, dose-finding study in 18-45 year old, healthy, malaria-naïve volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR. RESULTS: IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination. CONCLUSIONS: IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01624961 and NCT01771848 .

Lipidomic changes of LDL in overweight and moderately hypercholesterolemic subjects taking phytosterol- and omega-3-supplemented milk.

The benefits of dietary phytosterols (PhySs) and long-chain n-3 PUFA (ω3) have been linked to their effects as cholesterol- and triglyceride (TGL)-lowering agents. However, it remains unknown whether these compounds have further metabolic effects on LDL lipid composition. Here, we studied the effects of PhyS- or ω3-supplemented low-fat milk (milk) on the LDL-lipidome. Overweight and moderately hypercholesterolemic subjects (n = 32) were enrolled in a two-arm longitudinal crossover study. Milk (250 ml/day), enriched with either 1.57 g PhyS or 375 mg ω3 (EPA + DHA), was given to the participants during two sequential 28 day intervention periods. Compared with baseline, PhyS-milk induced a higher reduction in the LDL cholesterol (LDLc) level than ω3-milk. LDL resistance to oxidation was significantly increased after intervention with PhyS-milk. Changes in TGL and VLDL cholesterol were only evident after ω3-milk intake. Lipidomic analysis revealed a differential effect of the PhyS- and ω3-milk interventions on the LDL lipid metabolite pattern. Content in LDL-glycerophospholipids was reduced after PhyS-milk intake, with major changes in phosphatidylcholine (PC) and phosphatidylserine subclasses, whereas ω3-milk induced significant changes in the long-chain polyunsaturated cholesteryl esters and in the ratio PC36:5/lysoPC16:0, associated to a reduced inflammatory activity. In conclusion, daily intake of milk products containing PhyS or ω3 supplements induce changes in the LDL-lipidome that indicate reduced inflammatory and atherogenic effects, beyond their LDLc- and TGL-lowering effects.

Ritonavir boosting dose reduction from 100 to 50 mg does not change the atazanavir steady-state exposure in healthy volunteers.

OBJECTIVES: To evaluate the pharmacokinetics, tolerability and safety of 300 mg of atazanavir boosted with 100 or 50 mg of ritonavir, both once daily, at steady state. METHODS: This was a single-blind, multiple-dose, crossover, sequence-randomized trial. Thirteen healthy HIV-1-negative men received witnessed once-daily doses of atazanavir (300 mg) and 100 or 50 mg of ritonavir for 10 days (15 day washout). Atazanavir and ritonavir plasma concentrations were determined for 24 h on day 10. Log-transformed individual pharmacokinetic parameters were compared between treatments (analysis of variance); the difference between treatments on the log scale and 95% CIs were calculated. Fasting cholesterol, triglycerides, glucose and bilirubin plasma levels were measured at the beginning and end of each period and compared (Wilcoxon signed rank test). Gastrointestinal symptoms and other events were recorded. RESULTS: Ritonavir C(max) and the AUC0₋24 were lower after the 50 mg booster dose than after 100 mg [geometric mean ratio (GMR) (95% CI), 0.40 (0.31-0.51) and 0.35 (0.29-0.42), respectively]. No differences were observed in atazanavir exposure with 50 or 100 mg of ritonavir [GMR C(max) (95% CI), 1.00 (0.79-1.28); GMR AUC0₋24 (95% CI), 0.98 (0.79-1.21)]. Atazanavir trough concentration was >0.15 mg/L in all volunteers. Total and low-density lipoprotein cholesterol increased 0.40 mM (P = 0.01) and 0.37 mM (P = 0.003) from their corresponding baseline value during the 100 mg dosing period; there were no significant changes on 50 mg. Mild increases in bilirubin were detected on day 10 after both treatments without differences between treatments. CONCLUSIONS: In spite of higher exposure to ritonavir with 100 mg, atazanavir exposure was equivalent; the lipid profile was better under the lower booster dose (50 mg).

Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study.

PURPOSE: Triflusal is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. It was initially marketed as capsules containing 300 mg of active substance. In 2006 a new 600 mg (10 ml) oral solution form of triflusal was authorized in Spain. The primary aim of this study was to compare the gastrointestinal safety of the new triflusal oral solution with triflusal capsules in healthy volunteers. METHODS: Sixty healthy subjects were randomly assigned, in a 2.5:2.5: 1 ratio, into one of three groups, with 25 subjects receiving one bottle of triflusal oral solution (600 mg) daily, 25 subjects receiving two triflusal capsules (600 mg) once daily, and ten subjects receiving two placebo capsules once daily, respectively, during 7 consecutive days. Gastroscopy was performed at baseline before the administration of study drugs and after 4-8 h of the last dose of study drugs. Effects on the esophagus, stomach, and duodenum were measured in accordance with a modified Lanza scale. RESULTS: No differences between groups were detected at baseline. After treatment, median global scores in the placebo, triflusal solution, and triflusal capsules groups were, respectively, 0, 1, and 3 (p = 0.003 for comparison between placebo and triflusal capsules and p = 0.042 for comparison between triflusal solution and triflusal capsules). There were no significant differences between the scores on the triflusal solution and placebo groups. All treatments were well tolerated. CONCLUSION: In healthy subjects, triflusal solution induced less endoscopically apparent gastrointestinal mucosal damage than triflusal capsules and did not induce more damage than the placebo in healthy volunteers.

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a 'thorough QT/QTc study' performed according to ICH guidelines.

AIMS: To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines. METHODS: This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day(-1), and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day(-1) was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative 'thorough QT/QTc study' is one where the main variable is around < or =5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms. RESULTS: The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported. CONCLUSIONS: This 'thorough QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.

Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments.

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

A comparison of ebastine 10 mg fast-dissolving tablet with oral desloratadine and placebo in inhibiting the cutaneous reaction to histamine in healthy adults.

BACKGROUND AND OBJECTIVE: Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed. METHODS: This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire. RESULTS: Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier. CONCLUSION: Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.

Pharmacokinetic profile of the somatostatin analogue lanreotide in individuals with chronic hepatic insufficiency.

BACKGROUND AND OBJECTIVES: The somatostatin analogue lanreotide is indicated for the treatment of acromegaly and to relieve the symptoms of neuroendocrine tumours. The objective of the present study was to compare the pharmacokinetic profile and safety of intravenous lanreotide in healthy volunteers and individuals with hepatic impairment. METHODS: Immediate-release lanreotide was administered at 7 microg/kg during a 20-minute intravenous infusion. Blood samples were collected over 24 hours and lanreotide serum levels determined by radioimmunoassay. Pharmacokinetic parameters were estimated by non-compartmental analyses. RESULTS: Two study centres recruited 53 individuals. Study A comprised 10 individuals with hepatic insufficiency Child-Pugh grade A (mild), 7 with grade B (moderate) and 12 healthy volunteers - all Caucasian. Study B comprised 4 individuals with hepatic insufficiency Child-Pugh grade A, 6 with grade B, 2 with grade C (severe) and 12 healthy volunteers - all Chinese. All participants were included in the safety analysis. The pharmacokinetic analysis included all participants from study B, but only 12 with hepatic impairment and 11 healthy volunteers from study A. Combined analysis of both studies showed an increased serum elimination half-life (57%; p < or = 0.001), mean residence time (53%; p < or = 0.001) and volume of distribution (at steady state, 57%; at terminal disposition phase, 64%; both p < or = 0.001) in individuals with mild hepatic insufficiency compared with healthy volunteers. These differences were more pronounced in individuals with moderate-to-severe hepatic insufficiency compared with healthy volunteers; additionally, the area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) was increased (23%; p < or = 0.05) and clearance (CL) decreased (19%; p < or = 0.05) compared with healthy volunteers. The peak serum concentration of lanreotide tended to be lower in individuals with hepatic insufficiency than in healthy volunteers (statistically non-significant). There were no pharmacokinetic differences between the two groups of healthy volunteers. Lanreotide was well tolerated with only two mild adverse events that were considered to be possibly related to treatment (both nausea and headache with either vomiting or dizziness). There were no clinically relevant changes in laboratory parameters or vital signs during the study. CONCLUSION: The pharmacokinetic profile of lanreotide depends on the severity of hepatic insufficiency with CL and AUC(infinity), which are only slightly altered with moderate-to-severe insufficiency. The changes in exposure do not, however, require dosage adjustment. Moreover, lanreotide is usually given as a prolonged-release microparticle or Autogel formulation, and terminal half-life and serum concentrations depend on the release properties of the formulation. Dosing is also adapted for each patient, based on therapeutic response. Thus, hepatic insufficiency does not require additional dosage adjustments.

Dealing with time-dependent pharmacokinetics during the early clinical development of a new leukotriene B4 synthesis inhibitor.

PURPOSE: The aim of this study was to explore the possibility of achieving a practical dosing regimen for 2,4,6-triiodophenol (AM-24), a new leukotriene B4 (LTB4) synthesis inhibitor. First, a model capable of dealing with the nonlinearity in its pharmacokinetic profile was built, and then it was combined with a pharmacodynamic model previously established with data from earlier phase I trials. METHODS: One week after the first 240-, 350-, or 500-mg oral dose of AM-24, six additional doses were given to 24 healthy volunteers once daily. A total of 33 blood samples were obtained from each individual. Different models, including enzyme turnover models, were fitted to the data by using the software NONMEM. RESULTS: Drug absorption was modeled with a first-order process. Drug disposition was described with a one-compartment model, and elimination with an (auto)inhibited and a noninhibited clearance. AM-24 inhibited the enzyme production rate to a maximum of 98%. Relative bioavailability was independent of the decrease in the amount of enzyme. The estimate of the enzyme turnover half-life was 8.5 h. CONCLUSIONS: Simulations have shown that steady-state conditions eliciting 90% of maximal LTB4 synthesis inhibition can be reached after 3 weeks during an oral treatment with AM-24 administered at the dosage of 500 mg once daily.

Pharmacokinetics of Dexketoprofen Trometamol in Healthy Volunteers After Single and Repeated Oral Doses.

The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg in 18 healthy volunteers. In the second study, the pharmacokinetics and tolerability of oral dexketoprofen trometamol in tablet form were evaluated after either a single 25 mg dose (24 volunteers) or a repeated dose of 25 mg twice daily for 7 days (12 volunteers). The absorption of dexketoprofen from dexketoprofen trometamol capsules was bioequivalent to that of ketoprofen. On the other hand, the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen. Dexketoprofen trometamol showed the most rapid absorption rate, with highest Cmax and shortest tmax values, whereas dexketoprofen free acid had the slowest absorption rate, and ketoprofen had an intermediate absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred. Dexketoprofen trometamol was well tolerated, with no clinically relevant adverse events reported.