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Robert Litman,1,2 Dieter Naber,3 Lourdes Anta,4 Javier Martínez,4 Yuriy Filts,5 Christoph U Correll6– 8 1CBH Health LLC, Gaithersburg, MD, USA; 2Department of Psychiatry, Georgetown University Medical School, Washington, DC, USA; 3Department of Psychiatry and Psychotherapy, Hamburg-Eppendorf University, Hamburg, Germany; 4Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 5Communal Noncommercial Enterprise of Lviv Regional Council, Lviv Regional Clinical Psychiatric Hospital, Lviv, Ukraine; 6Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 7Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 8Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Javier Martínez, Laboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, Spain, Tel +34 91 375 63 36, Fax +34 91 304 78 81, Email jmartinez@rovi.esObjective: To analyze the effect of Risperidone ISM on social functioning and health-related quality of life (HR-QoL) in both short- and long-term treatment of patients with schizophrenia.Patients and Methods: This analysis was based on data from both phases of the PRISMA-3 study, including 433 relapsed patients from the double-blind (DB) phase of the PRISMA-3 trial who were treated for 12-weeks with once-monthly (every 28 days) intramuscular Risperidone ISM 75 mg or 100 mg (n = 288), or placebo (n = 145), as well as 174 patients transitioning from the DB to an open-label 52-week extension (OLE) phase, plus 41 de novo patients treated on a stable maintenance dose of oral risperidone. The clinician-administered Personal and Social Performance (PSP) scale and the patient-reported 20-item Subjective Well-being under Neuroleptics scale (SWN-20) were used to measure social functioning and HR-QoL outcomes, respectively.Results: Risperidone ISM significantly improved PSP total score from baseline to endpoint (Day 85) versus placebo in the DB phase with mean change total score (95% CI) of 10.7 (9; 12) compared to 4.8 (3; 7) for placebo (p < 0.0001). The statistically significant improvement was present from the first measurement time point (Day 29). SWN-20-measured HR-QoL increased on average in patients treated with Risperidone ISM in the DB phase. A significant improvement was also observed for PSP and SWN-20 scores from the OLE baseline to week 52 for patients transitioning from the DB phase. Stable de novo patients maintained similar PSP and SWN-20 scores during the whole OLE phase.Conclusion: Risperidone ISM provided a rapid and sustained improvement in personal and social functioning, and HR-QOL without need of oral risperidone supplementation or loading doses. These findings, along with a fast onset of efficacy, could contribute to reinforcing the therapeutic alliance and possibly an earlier discharge. Moreover, patient functioning continued improving or was maintained with long-term treatment.Keywords: risperidone, long-acting injectable, antipsychotics, schizophrenia, social functioning, quality of life

David P Walling,1 Howard A Hassman,2 Lourdes Anta,3 Lourdes Ochoa,4 Ignacio Ayani,3 Javier Martínez,3 Ibon Gutierro4 1Collaborative Neuroscience Network, LLC Garden Grove, Garden Grove, CA, USA; 2Hassman Research Institute, Berlin, NJ, USA; 3Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 4R&D Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, SpainCorrespondence: Javier MartínezLaboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, SpainTel + 34 91 375 63 36Fax + 34 91 304 78 81Email jmartinez@rovi.esIntroduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment.Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized.Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40– 65% and 38– 52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80– 1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16– 1.34], 1.17 [1.08– 1.27], and 1.25 [1.16– 1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone.Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.Keywords: bioequivalence, comparative bioavailability, long-acting injectables, LAIs, pharmacokinetic, risperidone, schizophrenia

Walling DP, Hassman HA, Anta L, et al. Drug Des Devel Ther. 2021;15:4371–4382. Page 4378, Table 2, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. Page 4379, Table 3, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. The authors apologize for the errors. Read the original article

Background. Electroconvulsive therapy (ECT) is an effective and safe medical procedure that mainly indicated for depression, but is also indicated for patients with other conditions. However, ECT is among the most stigmatized and controversial treatments in medicine. Our objective was to examine social media contents on Twitter related to ECT to identify and evaluate public views on the matter. Methods. We collected Twitter posts in English and Spanish mentioning ECT between January 1, 2019 and October 31, 2020. Identified tweets were subject to a mixed method quantitative– qualitative content and sentiment analysis combining manual and semi-supervised natural language processing machine-learning analyses. Such analyses identified the distribution of tweets, their public interest (retweets and likes per tweet), and sentiment for the observed different categories of Twitter users and contents. Results. “Healthcare providers” users produced more tweets (25%) than “people with lived experience” and their“relatives”(including family members and close friends or acquaintances) (10% combined), and were the main publishers of “medical” content (mostly related to ECT’s main indications). However, more than half of the total tweets had “joke or trivializing” contents, and such had a higher like and retweet ratio. Among those tweets manifesting personal opinions on ECT, around 75% of them had a negative sentiment. Conclusions. Mixed method analysis of social media contents on Twitter offers a novel perspective to examine public opinion on ECT, and our results show attitudes more negative than those reflected in studies using surveys and other traditional methods. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an E max model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published E max model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations., (© 2024 Laboratorios Farmacéuticos ROVI. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Benzodiazepines are frequently prescribed drugs; however, their prolonged use can lead to tolerance, dependence, and other adverse effects. Despite these risks, long-term use remains common, presenting a public health concern. This study aims to explore the beliefs and opinions held by the public regarding benzodiazepines, as understanding these perspectives may provide insights into their usage patterns., Methods: We collected public tweets published in English between January 1, 2019, and October 31, 2020, that mentioned benzodiazepines. The content of each tweet and the characteristics of the users were analyzed using a mixed-method approach, including manual analysis and semi-supervised machine learning., Results: Over half of the Twitter users highlighted the efficacy of benzodiazepines, with minimal discussion of their side effects. The most active participants in these conversations were patients and their families, with health professionals and institutions being notably absent. Additionally, the drugs most frequently mentioned corresponded with those most commonly prescribed by healthcare professionals., Conclusions: Social media platforms offer valuable insights into users' experiences and opinions regarding medications. Notably, the sentiment towards benzodiazepines is predominantly positive, with users viewing them as effective while rarely mentioning side effects. This analysis underscores the need to educate physicians, patients, and their families about the potential risks associated with benzodiazepine use and to promote clinical guidelines that support the proper management of these medications., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

One of the most important challenges in the management of patients with schizophrenia is to ensure adherence to antipsychotic treatment. The contribution of long-acting injectables (LAI) is undeniable in this matter, but there are still some unmet medical needs not covered by these drugs (e.g. quick onset of action for patients with acute exacerbation of schizophrenia). This article summarises the pharmacokinetics, efficacy and safety of Risperidone ISM ( in situ microparticles). The aim of this review is to provide information about the potential uses of this new LAI formulation of risperidone for the treatment of schizophrenia, contextualising and diving into the published evidence. Risperidone ISM shows a rapid release which allows achieving within 12 h risperidone active moiety levels similar to those observed in the steady-state for oral risperidone treatment, achieving a mean average concentration of 38.63 ng/mL. The plasma concentration of active moiety achieved by Risperidone ISM comes with a predictable dopamine D2 receptor occupancy above 65% throughout the 28-day dosing period, which is accepted as a threshold for the efficacy of the antipsychotic treatment. This can be associated with the positive efficacy findings throughout its clinical development. In the short term, it provides an early and progressive reduction of symptoms in adult patients with acute exacerbation of schizophrenia without the need for loading doses or oral risperidone supplementation, which could contribute to reinforcing the therapeutic alliance between the patient and the psychiatrist. In addition, long-term treatment was effective, safe and well tolerated regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM during an acute exacerbation or switched from stable doses of oral risperidone. Improvement and maintenance of personal and social functioning and health-related quality of life were observed in each setting, respectively. All these findings endorse Risperidone ISM as a useful and valuable treatment for the acute and maintenance management of patients with schizophrenia., (© The Author(s), 2024.)

Aims: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL 40 ), and several covariates using all data from five clinical studies., Methods: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL 40 ., Results: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL 40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data., Conclusions: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg., (© 2024 Laboratorios Farmaceuticos ROVI S.A. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Antidepressants are the foundation of the treatment of major depressive disorders. Despite the scientific evidence, there is still a sustained debate and concern about the efficacy of antidepressants, with widely differing opinions among the population about their positive and negative effects, which may condition people's attitudes towards such treatments. Our aim is to investigate Twitter posts about antidepressants in order to have a better understanding of the social consideration of antidepressants., Methods: We gathered public tweets mentioning antidepressants written in English, published throughout a 22-month period, between 1 January 2019 and 31 October 2020. We analysed the content of each tweet, determining in the first place whether they included medical aspects or not. Those with medical content were classified into four categories: general aspects, such as quality of life or mood, sleep-related conditions, appetite/weight issues and aspects around somatic alterations. In non-medical tweets, we distinguished three categories: commercial nature (including all economic activity, drug promotion, education or outreach), help request/offer, and drug trivialization. In addition, users were arranged into three categories according to their nature: patients and relatives, caregivers, and interactions between Twitter users. Finally, we identified the most mentioned antidepressants, including the number of retweets and likes, which allowed us to measure the impact among Twitter users., Results: The activity in Twitter concerning antidepressants is mainly focused on the effects these drugs may have on certain health-related areas, specifically sleep (20.87%) and appetite/weight (8.95%). Patients and relatives are the type of user that most frequently posts tweets with medical content (65.2%, specifically 80% when referencing sleep and 78.6% in the case of appetite/weight), whereas they are responsible for only 2.9% of tweets with non-medical content. Among tweets classified as non-medical in this study, the most common subject was drug trivialization (66.86%). Caregivers barely have any presence in conversations in Twitter about antidepressants (3.5%). However, their tweets rose more interest among other users, with a ratio 11.93 times higher than those posted by patients and their friends and family. Mirtazapine is the most mentioned antidepressant in Twitter (45.43%), with a significant difference with the rest, agomelatine (11.11%)., Conclusions: This study shows that Twitter users that take antidepressants, or their friends and family, use social media to share medical information about antidepressants. However, other users that do not talk about antidepressants from a personal or close experience, frequently do so in a stigmatizing manner, by trivializing them. Our study also brings to light the scarce presence of caregivers in Twitter.

Objective: To evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted., Methods: Eligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales., Results: Altogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed., Conclusion: Risperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone., (Copyright © 2021 Laboratorios Farmacéuticos Rovi, S.A. Published by Elsevier B.V. All rights reserved.)

Background: Antipsychotic medications are the first-line treatment for schizophrenia. However, non-adherence is frequent despite its negative impact on the course of the illness. In response, we aimed to investigate social media posts about antipsychotics to better understand the online environment in this regard. Methods: We collected tweets containing mentions of antipsychotic medications posted between January 1st 2019 and October 31st 2020. The content of each tweet and the characteristics of the users were analyzed as well as the number of retweets and likes generated. Results: Twitter users, especially those identified as patients, showed an interest in antipsychotic medications, mainly focusing on the topics of sexual dysfunction and sedation. Interestingly, paliperidone, despite being among one of the newest antipsychotics, accounted for a low number of tweets and did not generate much interest. Conversely, retweet and like ratios were higher in those tweets asking for or offering help, in those posted by institutions and in those mentioning cognitive complaints. Moreover, health professionals did not have a strong presence in tweet postings, nor did medical institutions. Finally, trivialization was frequently observed. Conclusion: This analysis of tweets about antipsychotic medications provides insights into experiences and opinions related to this treatment. Twitter user perspectives therefore constitute a valuable input that may help to improve clinicians' knowledge of antipsychotic medications and their communication with patients regarding this treatment., Competing Interests: JS-V was employed by IBM. RR-J has been a consultant for, spoken at events of, or received grants from the Instituto de Salud Carlos III, the Fondo de Investigación Sanitaria (FIS), the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), the Madrid Regional Government (S2010/BMD-2422 AGES, S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, and Angelini. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alvarez-Mon, Donat-Vargas, Santoma-Vilaclara, Anta, Goena, Sanchez-Bayona, Mora, Ortega, Lahera, Rodriguez-Jimenez, Quintero and Álvarez-Mon.)

We focused on tweets containing hashtags related to ADHD pharmacotherapy between 20 September and 31 October 2019. Tweets were classified as to whether they described medical issues or not. Tweets with medical content were classified according to the topic they referred to: side effects, efficacy, or adherence. Furthermore, we classified any links included within a tweet as either scientific or non-scientific. We created a dataset of 6568 tweets: 4949 (75.4%) related to stimulants, 605 (9.2%) to non-stimulants and 1014 (15.4%) to alpha-2 agonists. Next, we manually analyzed 1810 tweets. In the end, 481 (48%) of the tweets in the stimulant group, 218 (71.9%) in the non-stimulant group and 162 (31.9%) in the alpha agonist group were considered classifiable. Stimulants accumulated the majority of tweets. Notably, the content that generated the highest frequency of tweets was that related to treatment efficacy, with alpha-2 agonist-related tweets accumulating the highest proportion of positive consideration. We found the highest percentages of tweets with scientific links in those posts related to alpha-2 agonists. Stimulant-related tweets obtained the highest proportion of likes and were the most disseminated within the Twitter community. Understanding the public view of these medications is necessary to design promotional strategies aimed at the appropriate population.

This study characterized the pharmacokinetics, safety, and tolerability of Risperidone ISM, a new long-acting intramuscular formulation, for monthly administration without oral supplementation. Patients with schizophrenia received multiple intramuscular injections of 75 mg in the gluteal or deltoid muscle at 28-day intervals. Of the 70 randomized patients, 67 received at least one dose of study medication. The mean Cmax of the active moiety was achieved 24-48 h (tmax) after each administration, regardless of injection site. They ranged over four consecutive doses from 39.6 to 53.2 and 54.1 to 61 ng/ml, when given in gluteal or deltoid muscle, respectively. Active moiety achieved therapeutic levels by 2 h after dose, and the levels were maintained throughout the 4-week dosing period. No significant changes across the study were observed on either Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 (94%) patients experienced at least one treatment-emergent adverse event (TEAE). One serious TEAE (dystonia) was related to study treatment. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Risperidone ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-week dosing period over multiple intramuscular injections and was found to be safe and well tolerated.

Background: European guidelines recommend primary HPV testing for cervical cancer screening. However, the starting age remains to be defined, with an undecided window between 30 and 35 years. This pilot study compares the effectiveness of primary HPV testing to that of cytology for the detection of high-grade (CIN2+) lesions stratified by age., Methods: Cotesting with LBC cytology and APTIMA ® HPV (AHPV) was performed in 5053 women aged 25-65 in an opportunistic screening program in Madrid. AHPV-positive cases were referred to colposcopy and genotyped for HPV16 and 18/45 (AHPV-GT). Results were analyzed stratified in four age groups., Results: 454 cases (9.0%) were AHPV-positive. Women under 35 had a 30.2% CIN2+ rate, compared to 21.9% and 20.4% for women aged 35-44 or 45-54. There was a significant increase (P < .05) in the rate of CIN2+ in AHPV-GT-positive women when compared to that for other HPV types (AHPV-other), being 43.3% versus 15.7%. AHPV-GT-positive women under 35 had significantly higher rates of CIN2+ lesions than any other age-group. The sensitivity of cytology for cervical CIN2+ in APHV-positive women was 60.6%. All 4 carcinomas, including one AHPV-negative endometrial adenocarcinoma, had abnormal cytology. All cervical CIN2+ lesions biopsied were AHPV-positive., Conclusions: Aptima HPV shows a significantly higher sensitivity for cervical CIN2+ lesions than cytology alone. Unexpectedly, AHPV-positive women under 35 had the highest incidence of CIN2+ lesions, particularly when they are HPV16/18/45-positive. Reconsidering HPV primary screening before the recommended age of 35 is warranted., (© 2017 Wiley Periodicals, Inc.)

Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB-target genes in CD163 + tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man #166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The aim of this study was to characterize the pharmacokinetics and to evaluate the safety of risperidone ISM in patients with schizophrenia or schizoaffective disorder after a single gluteal intramuscular injection at three different dose strengths (50, 75, and 100 mg). A total of 36 patients were randomized and blood samples were collected to measure the plasma concentrations. The pharmacokinetic of the active moiety was biphasic for all three dose groups, and the mean plasma concentration was 21.45, 24.60, and 29.68 ng/ml in the 50, 75, and 100 mg group, respectively, 24 h after dose administration; 22.81, 24.57, and 31.41 ng/ml in the 50, 75, and 100 mg group, respectively, 48 h after dose administration, and 12.26, 17.31, and 20.01 ng/ml in the 50, 75, and 100 mg group, respectively, 30 days after dose administration. Overall, 34 patients experienced at least one treatment-emergent adverse event (TEAE). Two patients experienced a serious TEAE and no deaths occurred. There were no extrapyramidal symptoms-related serious TEAEs and no significant changes in any Columbia Suicide Severity Rating Scale parameter were observed during the study. Risperidone ISM provided a sustained release of risperidone that achieved therapeutic plasma levels within the first day. Risperidone ISM was safe, well tolerated, and should be suitable for a 4-weekly administration without oral supplementation.

Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIV-infected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population., Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 person-years (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender., Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997-2003)., Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection.

Objective: Rilpivirine (RPV) is the latest approved nonnucleoside reverse transcriptase inhibitor (NNRTI). It displays in-vitro activity extending over other NNRTI-resistant HIV strains. There is scarce information about the rate of RPV resistance-associated mutations (RAMs) in patients failing other NNRTIs., Methods: RPV RAMs were examined in plasma samples collected from HIV patients that had recently failed NNRTI-based regimens at 22 clinics in Spain., Results: Resistance tests from a total of 1064 patients failing efavirenz (EFV) (54.5%), nevirapine (NVP) (40%) or etravirine (ETR) (5.5%) were examined. The prevalence of RPV RAMs was K101E (9.1%), K101P (1.4%), E138A (3.9%), E138G (0.3%), E138K (0.3%), E138Q (0.8%), V179L (0.2%), Y181C (21.8%), Y181I (0.5%), Y181V (0.2%), H221Y (8.3%), F227C (0.1%) and M230L (1.5%). K101E/M184I was seen in 1%. E138K/M184I were absent. Mutations L100I and V108I were significantly more frequent in patients failing EFV than NVP (7.9 vs. 0.2 and 12.2 vs. 7.3%, respectively). Conversely, Y181C, Y181I, V106A, H221Y and F227L were more prevalent following NVP than EFV failures. Using the Spanish resistance interpretation algorithm, 206 genotypes (19.3%) from patients failing NNRTI (NVP 52%, EFV 40.8% and ETR 7.8%) were considered as RPV resistant. In patients with ETR failure, cross-resistance to RPV was seen in 27.6%, mainly as result of Y181C (81.3%), V179I (43.8%), V90I (31.3%) and V108I (18.8%)., Conclusion: RPV resistance is overall recognized in nearly 20% of patients failing other NNRTIs. It is more common following ETR (27.6%) or NVP (25%) failures than EFV (14.5%). E138 mutants are rarely seen in this context.

Introduction: HIV therapy has evolved rapidly since the 1990s; the arrival of more potent and safer antiretroviral drugs has transformed HIV infection into a chronic condition, which is rarely fatal. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are frequently used as a third agent - as part of a triple-combination therapy. Side effects and low barriers to resistance have been the major drawbacks of NNRTIs. Rilpivirine (RPV) is a next-generation non-nucleoside analogue, the unique features of which might favor choosing this drug over other NNRTIs. RPV is the latest NNRTI approved for the treatment of HIV infection. Along with its high efficacy and good safety profile, data on pharmacokinetics and drug interactions make RPV particularly attractive., Areas Covered: This article aims to provide an in-depth analysis of the main features and data available from recent clinical trials that have tested the performance of RPV., Expert Opinion: RPV is a safe and efficacious antiretroviral drug with a better neuropsychiatric and metabolic profile than efavirenz, which is currently the most widely used NNRTI. The availability of a fixed-dose coformulation of RPV with tenofovir/emtricitabine makes the use of RPV even more attractive. The efficacy of RPV in patients with a high baseline viral load remains to be clarified in further trials.

Increased and decreased levers of platelet monoamine oxidase (MAO) activity have been reported in patients with eating disorders, indicating abnormalities of the serotonin turnover. However, whether these findings are related to eating disorders or are rather reflecting the pathophysiology of borderline personality traits in these patients is still unknown. Platelet MAO activity and comorbid personality disorders were investigated in 72 patients with different subtypes of eating disorders (ED) and in a group of 28 healthy controls. ED patients comprised the following subtypes: 25 anorexia nervosa (AN) restrictive, 14 AN binge eating-purging (AN b-p), 3 anorexia nervosa not otherwise specified (AN NOS) and 30 bulimia nervosa (BN). Personality disorders and traits were assessed with the Structured Interview for Personality Disorders (SCID-II), the Zanarini Rating Scale for Borderline Personality Disorder, and the Barrat Impulsiveness Scale. Platelet MAO activity was significantly lower in ED patients with comorbid borderline personality disorder (BPD) than in ED without Borderline personality disorder (BDP). Platelet MAO activity was significantly and inversely correlated with the number and severity of BPD clinical features. In the subsample of patients with binge eating-purging symptoms (AN b-p, AN NOS and BN), platelet MAO activity was significantly lower in binge-purge patients with comorbid BPD than in binge-purge patients without BPD. The whole group of eating disorders had a significantly reduced lever of platelet MAO activity compared with the control group. The results suggest that low platelet MAO activity might characterize eating disorders with comorbid borderline personality traits, reflecting greater serotonin dysfunction in these patients. The role of decreased platelet MAO as an endophenotype with specific clinical manifestations should be explored in future studies., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Immigration from developing regions to Western countries has resulted in an increased rate of non-B subtypes in the HIV population. However, it is unclear whether these HIV variants remain confined to foreigners or are already spreading among natives. Since many immigrants come from regions in which hepatitis B virus (HBV) and hepatitis C virus (HCV) are endemic, HIV-hepatitis coinfection might be more frequent in newly diagnosed HIV persons. Herein, we report changes in the prevalence and distribution of HIV-1 subtypes in Madrid, Spain over the past 10 years as well as the rate of chronic HBV and HCV coinfection in 1854 newly diagnosed HIV-1 individuals. Overall 18.2% carried HIV-1 non-B subtypes, although the prevalence increased over time reaching a peak of 19.4% in the last period (2007-2010). The most common non-B variants were CRF02&#95;AG (37%), G (12%), A (9.9%), and C (7.8%). In native Spaniards the rate of non-B subtypes increased from 1.5% in 2000-2002 to 7.2% in 2003-2006 and to 11.4% in 2007-2010 (p = 0.04). Chronic hepatitis B and C were found, respectively, in 4.2% and 8.3% of the study population. While the prevalence of chronic hepatitis B has remained fairly stable over time across distinct populations, the rate of chronic HCV infection has experienced a significant decline, mainly in native Spaniards as a result of a reduction in intravenous drug use. In summary, the prevalence of HIV-1 non-B subtypes is rising in newly diagnosed HIV-1 individuals in Spain, including the native population. In contrast, the rate of HBV coinfection remains unchanged and the rate of HCV coinfection has declined.

Historically, many cases of demonic possession have masked major psychiatric disorder. Our aim is to increase awareness that symptoms of schizophrenia are still being classified as demonic possession by priests today. We report the case of a 28-year-old patient who had been diagnosed 5 years previously with paranoid schizophrenia (treated with clozapine, risperidone, ziprasidone and onlanzapine without a complete response) and was also receiving treatment in a first episode psychosis unit in Spain. The patient was led to believe by priests that her psychotic symptoms were due to the presence of a demon. This was surprising because some of the priests were from the Madrid archdiocese and knew the clinical situation of the patient; however, they believed that she was suffering from demonic possession, and she underwent multiple exorcisms, disrupting response to clinical treatment. Patient insight is an important factor in response to treatment, so religious professionals should encourage appropriate psychiatric treatment and learn about mental illnesses.

There are numerous studies demonstrating a direct association between the ingestion of soybean and low cancer incidence. This fact has been related to the presence of Bowman-Birk inhibitor (BBI) and lectin in soybean. The simultaneous and fast determination of BBI and lectin in soybean is proposed, for the first time, in this work. Two different strategies were designed for the extraction of BBI and lectin: extraction of soybean proteins using a Tris-HCl buffer followed by isolation of BBI and lectin by the isoelectric precipitation of other soybean proteins (method I) or by the direct extraction of BBI and lectin using an acetate buffer (method II). The effect of the previous soybean defating on the extraction of BBI and lectin was also studied. Moreover, the possibility of using a high-intensity focalized ultrasonic probe for accelerating the extraction was explored and an optimization of the extraction time and ultrasound amplitude was performed. The extracts obtained were analysed by RP-HPLC-ESI-MS for the correct identification of BBI and lectin in soybean. Moreover, a fast chromatographic methodology using a perfusion column and UV detection was optimized for the rapid determination of BBI and lectin in soybean. After evaluating its analytical characteristics (linearity, precision, and recovery), the method was applied to the quantitation of BBI and lectin in different soybean varieties., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The presence of resistance mutations in patients failing tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs.

The case of a 5-year-old child diagnosed as having pervasive developmental disorder (PDD), autistic type, from age 1 is reported. After surgery of vegetation in middle ear for repetitive otitis, the child presented an improvement in autistic behaviours, previously expressed as impaired social interactions, qualitative abnormalities in communication, a marked delay in language development, echolalia, stereotypies and self-aggressive behaviours. The aim of this paper is to bring attention to occurrences of misdiagnosis of PDD, which can occur when an adequate screening of the autistic syndrome is not realised. The result of the surgery was an improvement in autistic behaviours, despite the persistence of less severe autistic traits that may be more closely related to Asperger's syndrome.

The prevalence of etravirine resistance mutations was examined in genotypes derived from 1343 HIV-infected patients failing nevirapine or efavirenz in the resistance database of the Spanish AIDS Research Network (ResRIS). Overall, etravirine-resistant genotypes were recognized in 18.7% of patients, with no significant differences between failures under nevirapine or efavirenz. Thus, more than 80% patients with prior failure to nonnucleoside reverse transcriptase inhibitors could potentially benefit from etravirine rescue therapy.

Natural genetic variability at the pol gene may account for differences in drug susceptibility and selection of resistance patterns across HIV-1 clades. Spread of non-B subtypes along with changes in antiretroviral drug use may have modified drug resistance patterns in recent years. All HIV-1 clinical samples sent to a reference laboratory located in Madrid for drug resistance testing since January 2000 were analyzed. The pol gene was sequenced and HIV-1 subtypes were assigned using the Stanford algorithm and phylogenetic analyses for non-B subtypes. Drug resistance mutations were recorded using the IAS-USA mutation list (April 2008). A total of 3034 specimens from 730 antiretroviral-naive individuals (92 with non-B subtypes) and 1569 antiretroviral-experienced patients (97 with non-B subtypes) were examined. The prevalence of HIV-1 non-B subtypes in the study period increased from 4.4% (2000-2003) to 10.1% (2004-2007) (p < 0.01). The most predominant variants were CRF02&#95;AG (41.8%) and G (17.5%). Thymidine analogue mutations (TAMs) were more prevalent in B than non-B subtypes, in both drug-naive (6.2% vs. 1%; p < 0.01) and treatment-experienced patients (49% vs. 30%, p < 0.01). K103N was most frequent in B than non-B subtypes (34% vs. 21%; p < 0.01); conversely, 106A/M was more prevalent in non-B than B clades (11% vs. 5%). Codon 179 mutations associated with etravirine resistance were more frequent in non-B than B subtypes. Finally, secondary protease resistance mutations were more common in non-B than B clades, with a potentially significant impact at least on tipranavir. The prevalence of HIV-1 non-B subtypes has increased since the year 2000 in a large drug resistance database in Spain, determining changes in drug resistance patterns that may influence the susceptibility to new antiretroviral drugs and have an impact on genotypic drug resistance interpretation algorithms.

Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of > or = 1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (C(trough))/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society-USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hépatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR-) [LHR+ = sensitivity/(1-specificity); LHR- = (1-sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV C(trough), vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV C(trough), and 1.3 for the IAS-USA and RESIST scores. The values of LHR- were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV C(trough). HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.

Interpreting the results of drug resistance tests for HIV-1 is one of the most difficult tasks for both clinicians and virologists. There are many amino acid changes in viral proteins influencing the susceptibility to specific drugs, causing loss of activity or conversely hypersusceptibility. Moreover, the results of interactions derived from complex mutational patterns are difficult to predict. Different interpretation algorithms have been developed to facilitate the translation of information obtained in the genotypes to clinicians. Controversy exists, however, regarding the impact of genotypic changes over the activity of many antiretroviral drugs. Based on virologic outcomes, scientific literature, and expert opinion, the Drug Resistance Platform of the Spanish AIDS Research Network (RIS, Red de Investigación en SIDA) has developed over the last years its own interpretation system. Herein, we present the 2009 guidelines, in which special efforts have been made to standardize the criteria for interpreting resistance mutations for compounds within the same drug family and to facilitate the clinical interpretation of HIV-1 resistance genotypes.

In order to explore the bactericidal activity of concentrations similar to the peak serum concentrations obtained after a single i.v. dose of 2,000/200 mg co-amoxiclav and 500 mg vancomycin, killing curves with co-amoxiclav (69/10 microg/ml), amoxicillin (69 microg/ml), clavulanic acid (10 microg/ml), and vancomycin (15 microg/ml) were performed against two isogenic (ss-lactamase positive and negative) methicillin-resistant Staphylococcus aureus strains in cation-supplemented Mueller-Hinton broth with 2% NaCl incubated at 35 degrees C. Colony counts were performed at 0, 1, 2, 3 and 4 hours in Mueller- Hinton plates supplemented with 4% NaCl and 25 microg/ml oxacillin to measure the resistant population. Similar initial inocula reductions were obtained for amoxicillin-clavulanic acid and vancomycin for both strains, and significant differences were found in comparison to the control. Clavulanic acid decreased the growth rate of the ss-lactamase negative strain when compared to control curves. The penicillin-binding protein 2a affinity of old ss-lactams in conjunction with clavulanic acid overcoming ss-lactamase resistance may explain these results.