An update on the pharmacogenetic considerations when prescribing dopamine receptor agonists for Parkinson's disease.

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability. Thus, it has been suggested that pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease. AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease. EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

Comparative Pharmacokinetics and Bioequivalence Evaluation of Two Formulations of Pramipexole Dihydrochloride Extended-Release Tablets in Healthy Chinese Subjects Under Fasted and Fed States: A Randomized, Open-Label, Single-Dose, Two-Period Crossover Clinical Trial.

Background: Pramipexole dihydrochloride extended-release tablet is a novel long-acting form of non-ergot dopamine agonist indicated as one of main therapeutic approaches for Parkinson's disease. However, pharmacokinetic properties of extended-release pramipexole in healthy Chinese subjects remain unclear. Methods: A single-center, randomized, open-label, two-period crossover, single-dose study was performed to investigate comparative pharmacokinetics and evaluate bioequivalence of 0.375 mg test (Yangtze River Pharmaceutical Group Co., Ltd.) and reference (Trade name: Sifrol®, Boehringer Ingelheim Pharma GmbH & Co. KG) formulations of pramipexole dihydrochloride extended-release tablets in healthy Chinese subjects under fasted and fed states. Results: A total of 56 subjects (28 in each dietary trial) were enrolled and randomized. After single dose of 0.375 mg test and reference formulations under fasted condition, main pharmacokinetics of pramipexole were as follows: peak concentration (Cmax) were 409.33±95.93 and 413.77±132.03 pg/mL; plasma area under concentration-time curve from time 0 to last measurable concentration (AUC0-t) were 8801.95±1966.83 and 8646.37±2600.49 h*pg/mL; AUC from time 0 to infinity (AUC0-∞) were 9469.03±1991.61 and 9082.95±2666.26 h*pg/mL; elimination half-life (t1/2) were 11.98±3.91 and 9.85±2.63 h; both time to reach Cmax (Tmax) were about 4.50 h, respectively, for test and reference formulations. The 90% confidence intervals of geometric mean ratios (test/reference) of Cmax, AUC0-t and AUC0-∞ under fasted and fed conditions were all within 80-125%. Following administration under fed condition, Cmax and Tmax for both test and reference formulations slightly increased and prolonged to 5.0 h, respectively, but AUC approximately remained unchanged compared with dosing under fasted condition. Test and reference formulations showed similar bioequivalence and favorable safety under fasted and fed states. Conclusion: Test and reference formulations of pramipexole dihydrochloride extended-release tablets (0.375 mg) showed similar bioequivalence and well safety and tolerability in healthy Chinese subjects under fasted and fed states, which supports further investigations of test formulation in patients with Parkinson's disease.

Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole.

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype-phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype-phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity.

Relationships between dopamine D2/3 receptor availability and social-environmental factors in humans.

Social factors are associated with psychiatric outcomes and brain function. Relationships between local population data obtained from Social Explorer analyses of the American Community Survey (2014-2018) and dopamine D2/3 receptor (D2/3R) availability were explored in this retrospective analysis of [11C]PHNO positron emission tomography (PET) imaging data (n = 70). Larger local population size and lower percentage of the population with a bachelor's degree or higher were significantly associated with higher striatal D2/3R availability, suggesting that living in a populous area with fewer educational resources may be accompanied by stressors with concomitant dopaminergic changes. Future prospective, collaborative studies are needed to better understand the precise etiology of the observed relationships.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation.

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and ß-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.

Effect of pH on Iontophoretic Transport of Pramipexole Dihydrochloride across Human Epidermal Membrane.

PURPOSE: Drugs with higher molecular charges generally show higher flux enhancement when electromigration is the main mechanism in transdermal iontophoresis. This study evaluated the effect of decreasing the formulation pH to increase the positive charges of pramipexole dihydrochloride (PXCl) on its iontophoretic transport across skin. METHODS: In vitro transdermal iontophoresis of PXCl in buffer solution isotonized with either sodium chloride or mannitol were performed in a pH range of 3.0-7.0. Experiments of iontophoresis under symmetric condition with respect to donor and receiver pH and passive transport of the drugs after pretreatment with iontophoresis were conducted to investigate the transport mechanism involved. RESULTS: Iontophoretic permeation of PXCl was pH-dependent in drug solution isotonized with mannitol. The iontophoretic flux of PXCl with valence z = +2 at pH 3.0 was half of that of PXCl with z = +1 at pH 7.0. The results suggest that the decrease in PXCl delivery at higher valence at pH 3 was mainly due to pH-dependent selectivity of PX ion permeation across the skin and not electroosmosis. CONCLUSIONS: Skin permselectivity is a significant factor for iontophoretic transport of PXCl, and reducing formulation pH to increase the positive charges on PX ions did not enhance PXCl delivery.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia. OBJECTIVE: The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies. METHODS: Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics. RESULTS: The plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain. CONCLUSIONS: The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

An open-label, positron emission tomography study of the striatal D2/D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

PURPOSE: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg. METHODS: Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. RESULTS: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. CONCLUSION: By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT00805454 December 9, 2008.

Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands.

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (Ki = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.

Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease.

Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.

A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Absorption, Biokinetics, and Metabolism of the Dopamine D2 Receptor Agonist Hordenine (N,N-Dimethyltyramine) after Beer Consumption in Humans.

Hordenine, a natural constituent of germinated barley, is a biased agonist of the dopamine D2 receptor. This pilot study investigated the biokinetics of hordenine and its metabolites in four volunteers consuming beer equal to 0.075 mg hordenine/kg body weight. A new ultrahigh-performance liquid chromatography method coupled to electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method determined maximum plasma concentrations of 12.0-17.3 nM free hordenine after 0-60 min. Hordenine phase-II metabolism was first dominated by sulfation, but later by glucuronidation. The elimination half-lives in plasma were 52.7-66.4 min for free hordenine and about 60/80 min longer for hordenine sulfate and hordenine glucuronide. Urinary excretion peaked 2-3.5 h after consumption and accumulated to 3.78 µmol within 24 h, corresponding to 9.9% of the ingested dose. The observed hordenine levels in plasma seem too low to provoke direct interaction with the dopamine D2 receptor related to food reward, but synergistic or additive effects with alcohol or N-methyltyramine may occur.

Facile nose-to-brain delivery of rotigotine-loaded polymer micelles thermosensitive hydrogels: In vitro characterization and in vivo behavior study.

A rotigotine (ROT)-loaded polymer micelles thermosensitive gel (ROT-PM-TSG) delivery system was engineered to enhance the solubility of the drug, prolong the residence time, and increase the concentration of the drug in the brain tissue. First, ROT-loaded polymer micelles (ROT-PM) were tailored and optimized. The average particle size, encapsulation efficiency, and drug loading of the ROT-PM were (88.62 ± 1.47) nm, (93.5 ± 0.79) %, and (19.9 ± 0.60) %. The optimal ROT-PM-TSG formulation contained 22% P407 and 2% P188 with a gelation temperature of about 32.3 °C and a pH of 5.186. In vivo, the MRT of ROT-PM and ROT-PM-TSG nasal administration was 1.43 and 1.79 times extended than that of the intravenous. In comparison with the intravenous group, the distribution of ROT in olfactory bulb, cerebrum, cerebellum and striatum was 276.6%, 170.5%, 166.5% and 184.4%, respectively. In conclusion, the ROT-PM-TSG system has proven to be a potential application prospect as a ROT nose-to-brain delivery system.

Further in vivo characterization of [11 C]-(+)-PHNO uptake into a retina-like region of interest in humans.

The neurotransmitter dopamine is present in the retina and is involved in several modulatory functions. Unlike in rodents, dopamine D3 receptors are expressed in the retina of humans. Recently, uptake of the D3 receptor-preferring radiotracer [11 C]-(+)-PHNO has been observed in a retina-like region of interest (ROI) in humans. Here, we attempted to quantify [11 C]-(+)-PHNO uptake into this ROI using an independent sample, employing an extended scan acquisition time (120 min) and arterial kinetic modeling. Data from 14 healthy controls were analyzed (Mean Age: 38.41 ± 9.55, 3 female), 8 of which provided arterial line input function data (Mean Age: 41.07 ± 7.82, 3 female). Using Ichise's multilinear analysis (MA1) method, it was possible to quantify the volume of distribution (VT ) of [11 C]-(+)-PHNO in this retina-like region (Mean VT  = 13.56 ± 3.52; Mean χ2  = 2.08 ± 2.20). Notably, the shape of the time activity curve resembled closely that of the globus pallidus. Moreover, the VT values in the retina correlated well with binding potential (BPND ) values calculated using the simplified reference tissue model (Mean BPND  = 2.11 ± .94; Mean χ2  = 5.76 ± 2.56), employing the cerebellum as the reference region (r = .76, r2  = .58). In summary, we provide evidence that the in vivo uptake of [11 C]-(+)-PHNO into a retina-like ROI in humans can be quantified using both arterial blood sampling (VT ) and simplified reference tissue methods (BPND ).

Fenoldopam mesylate for treating psoriasis: A new indication for an old drug.

Fenoldopam, a highly selective dopamine receptor agonist, is available in clinics as Corlopam™ i.v. for the management of severe hypertension. Recent reports demonstrate its anti-proliferative activity in vitro in a dose dependent manner. However, stability issues of the drug due to its susceptibility to oxidation, pH sensitivity, poor transdermal flux, and the barrier properties of skin present challenges to develop a topical formulation of fenoldopam. The aim of the present study is to suggest a stable topical formulation of fenoldopam for the treatment of psoriasis. Water washable ointment and glycerin-based carbopol anhydrous gel of fenoldopam intended for topical delivery were prepared and evaluated in vitro and in vivo. Results from pH dependent stability studies suggest the necessity to maintain acidic pH in final formulations. The presence of an acidic adjuster in ointment and unneutralised carbopol dispersion of anhydrous gel maintain the desired acidic environment in the formulations. Stability studies of prepared formulations performed for 90 days indicate that the drug remains stable in formulations. In vivo studies demonstrate the applicability of the formulations for better skin penetration, skin compliance, and photosafety. Efficacy studies using an imiquimod induced psoriasis model confirm the promising application of developed fenoldopam topical formulations for psoriasis.

High long-term test-retest reliability for extrastriatal 11C-raclopride binding in healthy older adults.

In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.

Uso de asenapina en la práctica clínica: recomendaciones de un panel de expertos / Management of asenapine treatment in clinical practice: Recommendations from a panel of experts

Introducción: La selección del antipsicótico adecuado para el tratamiento de pacientes con trastorno bipolar (TB) debe basarse en los síntomas presentes, así como en las necesidades terapéuticas de cada paciente y en los posibles efectos adversos asociados al tratamiento. Asenapina es un antipsicótico de segunda generación indicado para el tratamiento de pacientes con TB de tipoI, cuyo perfil farmacocinético y farmacodinámico presenta características diferenciales con respecto al resto de antipsicóticos. Material y métodos: Este documento de recomendaciones ha sido elaborado por un panel de expertos con experiencia en el uso de asenapina en los ámbitos de la atención psiquiátrica de urgencias, hospitalaria y ambulatoria. Las recomendaciones se debatieron en una única reunión y fueron elaboradas a partir de la práctica clínica de los expertos y la evidencia proporcionada por la literatura científica. Resultados: Se describe el perfil de pacientes que mejor se ajusta a las características farmacodinámicas de asenapina, así como las ventajas y limitaciones del perfil farmacocinético asociado a la administración sublingual. Se abordan también las principales características de seguridad de asenapina, así como las posibles medidas a tomar para mitigar los efectos adversos más frecuentes. Finalmente, el documento proporciona una orientación acerca de la dosificación y el manejo general del fármaco, incluyendo las combinaciones con otros fármacos y el cambio de otros antipsicóticos a asenapina. Conclusiones: Este artículo proporciona una orientación para el uso adecuado de asenapina, así como para la identificación de los pacientes en los que este antipsicótico puede resultar más adecuado

Introduction: The choice of an antipsychotic should be based on bipolar disorder (BD) symptoms and the particular needs of each patient, as well as the adverse events potentially associated with treatment. Asenapine is an atypical antipsychotic indicated for the management of type-I BD, with distinct pharmacokinetic and receptor affinity profiles. Material and methods: Recommendations document developed by a panel of experts with extensive experience in the use of asenapine in psychiatric care, including emergency department, hospital, and outpatient care. Recommendations were discussed in a single meeting and were based on both the clinical experience of the panel of experts and the empirical evidence provided in the scientific literature. Results: The present document describes the patient profile that best suits the pharmacodynamic characteristics of asenapine, as well as the advantages and limitations of the pharmacokinetics associated with the sublingual route. The document also addresses the main safety issues of asenapine and suggests interventions aimed at mitigating the most frequent adverse reactions associated with asenapine treatment. Finally, the article provides advice on dosing and overall management of asenapine treatment, including the combination with other treatments and the switch from other antipsychotics to asenapine. Conclusions: In this recommendations document, we provide clinicians with guidance on the use of asenapine in real-life practice, including the identification of patients who best suit the characteristics of this antipsychotic

A novel approach to evaluate the pharmacodynamics of a selective dopamine D1/D5 receptor partial agonist (PF-06412562) in patients with stable schizophrenia.

BACKGROUND: PF-06412562 is an orally bioavailable, selective dopamine D1/D5 receptor partial agonist with a non-catechol structure under evaluation for treatment of cognitive impairment in schizophrenia. AIMS: This randomized, double-blind, placebo-controlled, parallel-group, Phase 1b study examined the pharmacokinetics and pharmacodynamics of three doses of PF-06412562 (3 mg, 9 mg, and 45 mg twice daily) over 15 days in patients with schizophrenia receiving antipsychotics. METHODS: Primary endpoints included adjunctive safety/tolerability and effects on MATRICS Consensus Cognitive Battery Working Memory domain and reward processing (Monetary Incentive Delay) tasks. Exploratory endpoints included other behavioral/neurophysiological tasks, including the N-back task. RESULTS: Among 95 subjects (78% male; mean age 34.8 years), baseline characteristics were similar across groups. The MATRICS Consensus Cognitive Battery Working Memory composite change from baseline on Day 13 improved in all groups, the smallest improvement was observed in the 45 mg group and was significantly smaller than that in the placebo group (two-sided p=0.038). For the Monetary Incentive Delay task (change from baseline in blood-oxygen-level-dependent functional magnetic resonance imaging activation in anterior ventral striatum for the contrast of cue gain>cue no gain on Day 15), no PF-06412562 dose was significantly different from placebo. No doses of PF-06412562 showed a significant difference on two-back task accuracy versus placebo. CONCLUSIONS: Adjunctive treatment with PF-06412562 was safe and well tolerated in patients with schizophrenia. PF-06412562 failed to show clinical benefit relative to placebo on assessments of cognition or reward processing in symptomatically stable patients over a 15-day treatment period. Numerous limitations due to the safety study design warrant further efficacy evaluation for this drug mechanism.