Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Photoswitchable allosteric ligands to modulate metabotropic glutamate receptors

[eng] Photopharmacology has the main purpose to allow the control of protein activity with light. The most exploited strategy used to achieve this objective is the freely diffusible photopharmacology and it is based in the use of photosensitive ligands. These ligands are small bioactive molecules, which include a part of their structure (i.e. photoswitch) that can experience molecular changes upon illumination with a determined wavelength of light. These ligands can freely diffuse and they can be applied with systems expressing native proteins. Azobenzene is the most common photoswitch used in photopharmacology and it can switch with near UV light from the flat and long trans isomer to a shorter bent cis configuration. The reverse photoisomerization can be achieved either with visible light or thermally with light. Thus, if we include azobenzene in the molecular scaffold of a ligand by means of a replacement of a particular moiety (azologization), we can obtain new azo compounds that will resemble to the original ligand, but their structural shape will dramatically changes upon illumination (photoisomerization). Therefore, the two possible isomers will have distinct binding modes to the target protein and will lead to different protein activities under different light conditions, which is known as photoswitching. Metabotropic Glutamate Receptors (mGluRs) belong to the class C/Glutamate family of G Protein-Coupled Receptors and control many neuronal and glial functions. mGlu receptors are endogenously activated by glutamate, which is the major excitatory neurotransmitter in the central nervous system (CNS), but they can also be activated or inactivated by allosteric modulators. They are usually considered better drug candidates than the orthosteric ligands because usually highly specific for a receptor and able to modulate the activity of a given receptor without blocking endogenous ligand binding. First of all, we designed and synthesized three families of compounds, using an azo-replacement strategy, to obtain photoswitchable allosteric modulators with possible NAM activity in mGlu5 in the cis isomers, while in the trans form they are inactive. This behavior is easily controlled by illuminating with different wavelengths and it is reversible in vitro. All the three families were inactive as NAMs, but some results suggest that the compounds could act as mGlu5 PAMs in trans form. Studies are continuing in this direction (Chapter 1). Next, we carry out the design and synthesis of compounds to improve PAM activity at the mGlu4 receptor and increase selectivity over the other group III mGluRs of at least one azo benzene candidate with a structure similar to Optogluram, the first photoswitchable positive allosteric modulator for the mGlu4 receptor. We obtained Optogluram-2 with good pharmacological potency and improved the photoisomerization properties. Under 380 nm light, the potency of Optogluram-2 is significantly reduced. The change in photoinduced potency observed is greater in Optogluram-2 than in Optogluram. Optogluram-2 has similar potency to Optogluram but is more selective for mGlu4 both on the receptors of the same group III as on the other mGluRs. All this indicates that Optogluram-2 can induce an improved activated/deactivated profile change as well as have an optimal selectivity for more complex assays, such as in vivo assays (Chapter 2). Additionally, we synthesized two series of compounds to find the first photoswitchable compound to selectively enable optical control of the endogenous mGlu1 receptor. Photoglurax-1 arose as a PAM of mGlu1 with micromolar potency in the trans isomer. Under 380nm light, the potency is significantly reduced. Photoglurax-1 turned out to be an equipotent mGlu4 PAM and therefore its general profile is not suitable for in vivo translation as a possible mGlu1 PAM tool compound. However, a dual mGlu1/mGlu4 PAM activity could be intriguing for an antipsychotic agent, since mGlu4 PAM activity can alleviate catalepsy, a major adverse event with standard antipsychotic drug treatment. In contrast, Photoglurax-2 acts as a mGlu1 PAM and does not show any observable allosteric effect on mGlu4 or activity on mGlu5, and therefore Photoglurax-2 represents a potential in vivo photoswitchable PAM mGlu1 tool compound. Reversible monitoring of mGlu1 activity obtained with light can be very advantageous in studying the pharmacological and physiological implications of mGlu1 in many diseases with unprecedented precision (Chapter 3). Finally, we designed and synthesized a family of novel photoswitchable azoheteroarenes as mGlu1 NAMs with an active trans isomer and an inactive cis isomer to reversibly inactivate the function of the mGlu1 receptor. The potencies of the trans configurations of some compounds of the family are in the micromolar range . Unfortunately, after 400 nm illumination the results were inconclusive due to artifacts that could originate from a possible toxicity of cis azo compounds. More experiments should be done with cells that do not express mGlu1 and also changing the light system to corroborate eventual toxicity (Chapter 4). Likewise, we use some of these compounds in their trans form, therefore without applying light, as tools to expand the knowledge about the nature of the intermediate states induced by mGlu receptor agonists in studies of fluorescence conformational dynamics. Analysis of the effect of mGlu1 NAMs on receptor conformational changes is reported in Chapter 4.[spa] Los receptores metabotrópicos de glutamato (mGlu) son GPCRs distribuidos a través del CNS y se consideran dianas farmacológicas para trastornos neurológicos, tales como el dolor neuropático y la enfermedad de Parkison, entre otras. En primar lugar, diseñamos y sintetizamos tres familias de compuestos, utilizando una estrategia de azo- reemplazo, para obtener moduladores alostéricos de GPCR fotoconmutable con posible actividad NAM en mGlu5 en los isomeros cis, mientras que en la disposición trans son inactivos. Este comportamiento se controla fácilmente con iluminación con diferentes longitudes de onda y es reversible in vitro. Ninguna familia resultò activa como NAMs, pero algunos resultados sugieren que los compuestos podrían actuar como PAMs mGlu5 en forma trans. La investigación continúa siguiendo esta dirección (Capítulo 1). Seguidamente, realizamos el diseño y sintesis de compuestos para mejorar la actividad de PAM en el receptor mGlu4 y aumentar la selectividad sobre los otros mGluR del grupo III de al menos un candidato a azobenceno con estructura similar a Optogluram, el primer modulador alostérico positivo fotoconmutable para el receptor mGlu4. Obtuvimos Optogluram-2 con buena potencia farmacologica y mejoramos las propriedades de fotoisomerizacion. Bajo una luz de 380 nm, la potencia de Optogluram-2 se reduce significativamente. El cambio de potencia fotoinducido observado es mayor en Optogluram-2 que en Optogluram.Optogluram-2 tiene potencia parecida a Optogluram pero es màs selectivo para mGlu4 tanto sobre los receptores del mismo grupo III como sobre los demas. Todo esto indica que Optogluram-2 puede inducir un cambio de perfil activado/desactivado mejorado asì como tener una selectividad optimal para ensayos más complejos, como los ensayos in vivo (Capítulo 2). Sintetizamos dos series para encontrar el primer compuesto fotoconmutable para habilitar selectivamente el control óptico del receptor mGlu1 endógeno. Photoglurax-1 surgió como un PAM de mGlu1 con potencia micromolar en el isómero trans. Bajo una luz de 380 nm, la potencia se reduce significativamente. Photoglurax- 1 resultó ser un mGlu4 PAM equipotente y por eso su perfil general no es apropiado para una traducción in vivo como una posible herramienta molecular mGlu1 PAM. Sin embargo, una actividad dual mGlu1/mGlu4 PAM podría ser intrigante para un agente antipsicótico,ya que la actividad mGlu4 PAM puede aliviar la catalepsia, un evento adverso importante con el tratamiento estándar con fármacos antipsicóticos. En cambio, Photoglurax-2 actúa como un PAM mGlu1 y no muestra ningún efecto alostérico observable en mGlu4 ni actividad en mGlu5 y por lo tanto Photoglurax-2 representa una potencial herramienta molecular PAM mGlu1 fotoconmutable in vivo. El control reversible de la actividad de mGlu1 obtenido con luz puede ser muy ventajoso para estudiar las implicaciones farmacológicas y fisiológicas de mGlu1 en muchas enfermedades con una precisión sin precedentes (Capítulo 3). Finalmente, intentamos diseñar y sintetizar una familia de novedosos azoheteroarenos fotoconmutables como NAMs de mGlu1 con un isomero trans activo y un isomero cis inactivo para inactivar reversiblemente la función del receptor mGlu1. Las potencias de las configuraciones trans de algunos compuestos de la familia estan en el rango de micromolaridad. Desafortunadamente, tras una iluminación de 400 nm los resultados fueron no concluyentes debido a artefactos que podrían originarse a partir de una posible toxicidad de los compuestos cis azo. Se deben realizar más experimentos con células que no expresen mGlu1 y cambiando tambien el sistema de luz para comprobar si se trata de toxicidad (Capítulo 4). Asimismo, utilizamos algunos de estos compuestos en su forma trans, por lo tanto sin aplicar luz, como herramientas para ampliar el conocimiento sobre la naturaleza de los estados intermedios inducidos por agonistas de los receptores mGlu en estudios de dinámica conformacional de fluorescencia. El análisis del efecto de los NAMs de mGlu1 sobre los cambios conformacionales del receptor están reportados en el Capítulo 4. En resumen, encontramos como obtener un interruptor molecular entre varias actividades farmacologicas. Ademàs, demostramos que la fotofarmacologia presenta ventajas respecto a la farmacologia convencional, ya que permite ajustar la activacion del receptor con luz

Photoswitchable allosteric modulators for metabotropic glutamate receptors

Metabotropic glutamate receptors (mGlu) are a family of class C G protein-coupled receptors (GPCRs) with important biological functions and widespread expression. The mechanisms of mGlu activation and the development of allosteric modulators for these dimeric proteins have attracted singular attention including the use of light regulated ligands. Photopharmacology involves the integration of a photoactive moiety into the ligand structure that following specific illumination undergoes a structural rearrangement and changes its biological activity. The use of light-regulated allosteric ligands offers the opportunity to manipulate mGlu signalling with spatiotemporal precision, unattainable with classical pharmacological approaches. In this review, we will discuss some of the innovations that have been made in the allosteric photopharmacology of mGlu receptors to date. We discuss the prospects of these molecular tools in the control of mGluRs and the new perspectives in understanding mGlu mechanisms, pharmacology and (patho)physiology that can ultimately result in innovative drug discovery concepts.The project on which these results are based has received funding from Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación 10.13039/501100011033 and ERDF A way of making Europe (projects I+D+i CTQ2017-89222-R, PCI2018-093047 and PID2020-120499RB-I00), the Neuron-ERANET program (MAGNOLIA project), by the Catalan government (2017 SGR 1604) to AL and XR, and the European Union's Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 801342 (Tecniospring INDUSTRY, TECSPR19-1-0062) and the Government of Catalonia's Agency for Business Competitiveness (ACCIÓ) to XG-S.Peer reviewe

Photopharmacology of G -Protein-Coupled Receptors

G-protein-coupled receptors (GPCRs) are a super-family of membrane proteins and major targets for drug development. However, many GPCRs drug candidates suffer from a lack of selectivity. Photopharmacology gives the possibility of modulating GPCR activity with an unprecedented local and temporal precision with the use of light. In this review, we compile and classify the different strategies in photopharmacology for GPCRs, we revise the different methods of analysis and characterization of light-regulated molecules used for GPCRs, and we give perspective of the impact of photopharmacology in research applications and in the development of new drugs.Peer reviewe

Preliminary molecular evidence of feasting in the Inca site of Fuerte Quemado-Intihuatana, Catamarca, Argentina

Feasting was an important aspect of the domination strategy designed by the Inca Empire in the provinces. Hospitality banquets were the setting for negotiations between Cuzco and the annexed populations. Consumption of food and drink played a fundamental role in these feasts. In this paper we present the first study of organic residues recovered from ceramic vessels from the archaeological site of Fuerte Quemado-Intihuatana (Catamarca, Argentina), an important settlement of the Collasuyu province. Earlier functional studies proposed that these vessels were used to store and serve food and drink in commensal contexts. Results from this preliminary molecular study support this hypothesis because all the containers yielded organic residues. Chemical and isotopic studies suggest that food and different kinds of beers were held in these containers during festive events.Fil: Lantos, Irene Johanna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Orgaz, Martín Alfonso. Universidad Nacional de Catamarca. Escuela de Arqueología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Panarello, Hector Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geocronología y Geología Isotópica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geocronología y Geología Isotópica; ArgentinaFil: Maier, Marta Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentin