Sex differences in sleep after a single oral morning dose of olanzapine in healthy volunteers.

OBJECTIVE: Polysomnography abnormalities are frequent in schizophrenia and have been correlated with clinical variables. Because women with schizophrenia present a general better clinical outcome than men, we aimed to determine whether sex differences in antipsychotic-induced effects on sleep could contribute to this difference. METHODS: Single oral morning doses of olanzapine (5 mg) were administered to 10 men and 10 women. Sleep variables were evaluated using traditional polysomnography Rechstschaffen and Kales criteria and all-night sleep electroencephalogram spectral analysis. Drug plasma concentrations were also measured. RESULTS: Significant sex-by-drug interactions were obtained in slow-wave sleep. After olanzapine, women showed an increase in slow-wave sleep, whereas men showed a decrease. We did not observe sex differences in olanzapine-induced hypnotic effects. Neither did we find any significant differences in pharmacokinetic parameters between sexes. Significant sex effects were observed in deep sleep, with women showing longer periods than men. CONCLUSION: Our results showed significant pharmacodynamic differences in olanzapine sleep effects between men and women. Further studies in clinical populations are needed to assess if these sex-based differences suggest that optimal treatment and doses should differ between men and women.

Waking and sleep electroencephalogram variables as human sleep homeostatic process biomarkers after drug administration.

BACKGROUND/AIMS: The correlation between theta activity during wakefulness and slow-wave activity (SWA) during sleep observed after sleep deprivation suggests such patterns can be used as electroencephalogram (EEG) biomarkers of the sleep homeostasis process. Since these EEG components would be very useful objective measures to assess CNS drug effects, we investigated whether the relationship between sleep homeostatic EEG biomarkers could be reproduced after an experimental pharmacological intervention. METHODS: Seventeen healthy volunteers took part in a phase I randomized, double-blind, crossover design study. To increase sleep propensity, all participants received a single morning oral dose of olanzapine (5 mg) and placebo. Quantitative EEG analysis was done by power spectra calculations: theta activity (3.5-7.5 Hz) during wakefulness and SWA (0.5-4.0 Hz) during sleep. The relationship between the 2 EEG parameters was assessed by correlating the rise rate (percent/hour) of theta activity in wakefulness and the increase (percent) of SWA in the first non-REM sleep episode. RESULTS: Following olanzapine administration we observed increases in theta activity during wakefulness, and increases in total sleep time, sleep efficiency and slow-wave sleep time during sleep. However, a weak and unreliable correlation was observed between the increases in theta activity and changes in sleep SWA. CONCLUSIONS: From these results, we cannot affirm that these waking and sleep EEG variables behave as biomarkers of human sleep homeostasis after drug administration. It is possible that these EEG biomarkers reflect different physiological mechanisms if they are assessed during drug CNS effects.

Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients.

The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m(2). Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study.

AIM: The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS: Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS: Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION: Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

Treatment simplification to once daily darunavir/ritonavir guided by the darunavir inhibitory quotient in heavily pretreated HIV-infected patients.

BACKGROUND: We explored a treatment simplification strategy to darunavir/ritonavir 900/100 mg once daily guided by the darunavir virtual inhibitory quotient (vIQ) in patients receiving salvage therapy with darunavir/ritonavir 600/100 mg twice daily. METHODS: Open-label, randomized pilot study in HIV-infected patients on darunavir/ritonavir 600/100 mg twice daily (viral load <50 copies/ml; darunavir vIQ >2). Thirty patients were randomized to darunavir/ritonavir 900/100 mg once daily (once-daily group, n=15) or 600/100 mg twice daily (twice-daily group, n=15). Viral load, blood chemistry, and darunavir and ritonavir trough plasma concentrations (C(trough)) were determined up to 48 weeks. If the darunavir vIQ fell to <1.5, the dosage was switched to 600/100 mg twice daily. The primary end point was the percentage of 48-week treatment failure. RESULTS: Patients had taken a mean 11.6 (sd +/-3.9) antiretroviral regimens before darunavir/ritonavir administration. The proportion of patients without 48-week treatment failure was 86.7% in both groups. The median (interquartile range [IQR]) darunavir C(trough) decreased from 3.09 mg/l (IQR 2.43-3.93) at baseline to 1.60 mg/l (IQR 1.25-2.04) at week 48 (P=0.001) in the once-daily group. Three once-daily group patients switched to darunavir/ritonavir 600/100 mg twice daily. Fewer patients had triglyceride levels >200 mg/dl at week 48 in the once-daily group (20.0%) than in the twice-daily group (20.0% versus 57.1%; P=0.046). CONCLUSIONS: Treatment simplification to darunavir/-ritonavir 900/100 mg once daily guided by the darunavir vIQ in treatment-experienced HIV-infected patients receiving darunavir/ritonavir 600/100 mg twice-daily seems to be safe enough to be tested in adequately powered clinical trials.

Nuevos hipnóticos, desde la perspectiva del farmacólogo / New hynotics, from the pharmacologist perspective

El insomnio es una condición extremadamente común con importantes consecuencias personales, sociales y económicas. El tratamiento farmacológico actual se centra principalmente en el GABA, el neurotransmisor inhibidor más importante del sistema nervioso central. Los agonistas del receptor benzodiacepínico han sido el pilar de la farmacoterapia de este trastorno. Las clásicas benzodiacepinas y los hipnóticos Z comparten un modo de acción similar, potenciando alostéricamente las corrientes de cloro a través de los receptores GABAA. A pesar del avance que supuso su descubrimiento en los 1960s, en relación a los tratamientos previos disponibles en cuanto al “cociente riesgo/beneficio”, todavía no se dispone de ningún compuesto que presente las propiedades que debería tener un “hipnótico ideal”. Diversas son las estrategias seguidas para mejorar la situación actual. Se continúan desarrollando fármacos GABAérgicos, mejorando sus perfiles farmacocinéticos (duración, inicio) o haciéndolos más específicos (selección del enantiómero óptimo a partir del racémico o selectividad con relación a los subtipos de receptor con los que interactuar), pero también se están desarrollando compuestos que actúan a través de nuevas dianas neuroquímicas, identificadas merced a los avances en los conocimientos sobre la estructura del sueño y sus bases neurobiológicas. Así hay compuestos en desarrollo que interactúan con determinados subtipos de receptores de otros sistemas de neurotransmisión, como el melatoninérgico y el serotoninérgico, e incluso fármacos que lo hacen con sistemas desconocidos hasta hace relativamente poco, como la neurotransmisión mediada por orexinas. Están apareciendo nuevos términos que permiten discernir diferencias en el perfil de efectos que se asocia a la actividad principal como productores de sueño y que sin duda en un futuro tendrán una importante traducción clínica con el objetivo de ofrecer una mejor, más segura e individualizada opción terapéutica para los pacientes. Además de hipnóticos, se empiezan a identificar: promotores del sueño, intensificadores del sueño, modificadores de la biestabilidad o cronobióticos (AU)

Insomnia is an extremely common condition with major personal, social and economic consequences. Current pharmacological treatments focus primarily on GABA, the major inhibitory neurotransmitter in the central nervous system. Benzodiazepine receptor agonists have been a mainstay of the pharmacotherapy of this disorder. Classical benzodiazepines and Z-hypnotics share a similar mode of action and allosterically enhance chloride currents through the GABAA receptor. In spite of the advance that its discovery in 1960s supposed, in relation to the previous available treatments as for the “risk/benefit ratio”, there is no existing compound with the characteristics of an “ideal hypnotic” yet. Several strategies have been followed in order to improve the current situation. There are still other drugs being developed to target the GABAergic system, with better pharmacokinetic profiles (duration, onset) or with more specificity (optimal enantiomer selection from the racemic or receptor subtype selectivity through which to interact). Other approaches take advantage to develop compounds which bind to new neurochemical targets, that have been identified thanks to the acquired knowledge about sleep structure ant its neurobiological bases. Thus, there are compounds under development that interact with certain receptor subtypes from other neurotransmitter systems, as the melatoninergic or the serotoninergic, and even drugs that interact with systems that have been unknown until recently, as the neurotransmission through orexins. New expressions are turning up that allow distinguish differences in the effect profile associated with the sleep producers major activity and that undoubtedly in a future they will have important clinical consequences with the objective to provide to patients the best, safer and individualized therapeutic option. In addition to hypnotics, the following labels start to be used: sleep promoters, sleep intensificators, bistability modifiers or chronobiotics (AU)

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.

Simultaneous population pharmacokinetic model for lopinavir and ritonavir in HIV-infected adults.

BACKGROUND: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients. OBJECTIVE: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds. METHODS: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques. RESULTS: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision. CONCLUSION: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis.

BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Variability in non-nucleoside reverse transcriptase and protease inhibitors concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in plasma trough concentrations of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in an outpatient routine clinical practice setting. METHODS: The study included 117 patients who attended our clinic for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. Patients were not informed that drug concentrations were going to be assessed until blood sampling. The time of the last antiretroviral treatment intake and blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective concentration. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were higher than 4.0 mg l(-1), 6.0 mg l(-1), and 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability in NNRTI and PI plasma concentrations was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Inappropriate adherence only explained 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. Therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. METHODS: One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were > 4.0 mg l(-1), > 6.0 mg l(-1) and > 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Quantitative evaluation of automatic ocular removal from simulated EEG signals: regression vs. second order statistics methods.

Analysis of the EEG by means of spectral parameters permit to evaluate the influence of a drug and to diagnose dysfunctional states in neurology, psychiatry and psychopharmacology. Eye movement artifacts contaminate EEG signals and can produce errors in this analysis. Regression based technique is considered the 'gold standard' artifact removal procedure and other techniques have been developed the last years, but few works have shown an objectively evaluation of the efficiency of these methods because it is impossible to record pure EEG and EOG signals. In this study, an artificially reproduction of bidirectional contaminated EEG and EOG data is proposed in order to simulate a real case. A comparative study between automatic second-order statistics techniques (PCA, AMUSE and SOBI) and multiple regression analysis is performed. Effectiveness of removal techniques is evaluated by calculating the errors in spectral parameters between sources and corrected EEG signals. Average values and topographic brain distribution of these errors are considered. Errors are located in the anterior leads especially in the frontopolar ones. Results show that AMUSE and SOBI methods preserve more cerebral activity than other techniques. We conclude that AMUSE and SOBI algorithms overcome the limitations of the regression based approach in the bidirectional contamination between ocular and neural activity.

Variability of sleep parameters across multiple laboratory sessions in healthy young subjects: the "very first night effect".

Many studies have been carried out to assess the variability of sleep parameters. The first night effect is one of the most important factors in this variability and has been extensively studied. However, the readaptation phenomenon when subjects returned to the sleep laboratory after spending a certain period of time at home has been not systematically evaluated. To investigate this phenomenon across multiple sleep laboratory sessions, polysomnographic data from 12 healthy young subjects for 12 nights (three periods each of 4 consecutive nights, with a minimum of 1 month between them) were collected. The first night effect was present only in the first night of the first period ("very first night") and was significant only for REM sleep-related variables. We conclude that the results from the first nights of consecutive periods within a specific protocol with healthy young subjects need not be discarded in subsequent analyses.