المؤلفون: Diego del Río, Laura

المساهمون: University/Department: Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut

مرشدي الرسالة: Ortún Rubio, Vicente

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Drug information service, Pharmaceutical policy, New drug assessment, Opioid antagonists, Opioid-induced bowel dysfunction, Methylnaltrexone, Alvimopan, Naloxone, Centro de información de medicamentos, Avaluación de nuevos medicamentos, Política farmacéutica, Antagonistas opioides, Disfunción intestinal inducida por opioides, Metilnaltrexona, Naloxona

الوصف: On the 50th anniversary of the creation of the first medicines information center, the core of this PhD Thesis offers an insider perspective and provides several examples of independent drug information, with a focus on new drugs. On the one hand, it provides an overview of the origins and challenges current medicines information centers within public healthcare organizations are experiencing. Several strategic lines aiming for information centers continue to meet drug information needs in the actual healthcare and economic context are presented. Additionally, various examples of independent drug information as a tool for medicines management are as well provided. First, the evaluation of the place in therapy of methylnaltrexone, the first peripherally acting mu-opioid receptor antagonist, licensed for opioid-induced constipation in patients with advanced illness. Second, the role of three novel opioid antagonists (methylnaltrexone, alvimopan and modified release naloxone) and four other agents (NKTR-118, TD-1211, ADL-7445 and ADL-5945), which are currently under different stages of clinical development, in the management of opioid-induced bowel dysfunction is discussed. The annexes compile two editorials, one on new drugs’ policies and a second on how should the pharmaceutical benefit scheme be reviewed in order to maximize its economic impact without compromising healthcare quality. For illustrative purposes, several drug information bulletins are enclosed, reviewing the place in therapy of other newly marketed drugs.

الوصف (مترجم): En el contexto del 50 aniversario de la creación del primer centro de información de medicamentos, esta tesis ofrece una perspectiva interna y varios ejemplos de actividades de información independiente, centrándose especialmente en los nuevos medicamentos. Por un lado, revisa los orígenes y retos a los que se enfrentan los centros de información de medicamentos de la sanidad pública hoy en día. En este sentido, se proponen varias líneas estratégicas para garantizar que éstos centros continúen respondiendo a las necesidades de información en el actual contexto económico y sanitario. Adicionalmente, se presentan varias actividades de información independiente que sirven de herramienta para la gestión del medicamento. En primer lugar, la evaluación del lugar en terapéutica de la metilnaltrexona, el primer antagonista periférico del receptor mu-opioide, indicado para el tratamiento del estreñimiento inducido por opioideis en pacientes con enfermedad avanzada. En segundo lugar, se revisa el papel de los nuevos antagonistas opioides (metilnaltrexona, alvimopan y naloxona de liberación prolongada) y de otros cuatro agentes (NKTR-118, TD-1211, ADL-7445 y ADL-5945), actualmente en diferentes fases de desarrollo clínico, en el manejo de la disfunción intestinal inducida por opioides. Los anexos compilan dos editoriales, una primera sobre las políticas de nuevos medicamentos y la segunda sobre cómo maximizar el impacto en la reducción de la oferta de medicamentos públicamente financiados sin comprometer la calidad asistencial. A modo ilustrativo, se incluyen varios boletines de información de medicamentos en los que se revisa el lugar en la terapéutica de otros nuevos medicamentos recientemente comercializados.
Programa de doctorat en Biomedicina

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/129850Test

المؤلفون: Celine M. Laffont, Prasad Purohit, Nash Delcamp, Ignacio Gonzalez-Garcia, Phil Skolnick

المصدر: Frontiers in Psychiatry, Vol 15 (2024)

مصطلحات موضوعية: synthetic opioids, fentanyl, carfentanil, cardiac arrest, translational model, opioid antagonists, Psychiatry, RC435-571

الوصف: IntroductionUsing a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the μ-opioid receptor antagonists naloxone and nalmefene.MethodsThis translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment.ResultsFollowing simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene.ConclusionSimulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fpsyt.2024.1399803/fullTest; https://doaj.org/toc/1664-0640Test

الوصول الحر: https://doaj.org/article/6680e0efae9f45fa90e216c8d4945fcfTest

المؤلفون: S. Andrea Laguado, PharmD, BCPS, BCPP, Stephen R. Saklad, PharmD, BCPP

المصدر: Mental Health Clinician, Vol 12, Iss 4, Pp 254-262 (2023)

مصطلحات موضوعية: olanzapine, weight gain, body mass index, opioid antagonists, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Pharmacy and materia medica, RS1-441

الوصف: Introduction: Olanzapine (OLZ) is a second generation antipsychotic that is approved for the treatment of schizophrenia, bipolar disorder type 1 as monotherapy (acute manic or mixed episodes, maintenance), or as an add-on to lithium or valproate (manic or mixed episodes). It is one of the most effective antipsychotics for the treatment of schizophrenia, but concerns remain due to its significant metabolic adverse effects. Notably, OLZ has one of the highest rates of weight gain among all antipsychotic drugs. Previous studies report on potential mitigation of weight gain with opioid antagonists. A systematic review was conducted to summarize the impact of these agents on weight and BMI when used as adjuncts to OLZ. Methods: A systematic review of randomized controlled trials was conducted with 3 searches between March 2, 2021 and March 27, 2022. Results: Six studies met inclusion criteria, 5 of which assessed OLZ and samidorphan (SAM) and 1 of which assessed OLZ and naltrexone compared with OLZ monotherapy. A total of 1752 patients were included with 952 receiving SAM and 14 receiving naltrexone as an adjunct to OLZ. SAM was shown to mitigate OLZ-induced weight gain by 1.0 kg. Only 1 study assessed naltrexone with no statistically significant results for weight gain. Discussion: SAM is effective at reducing OLZ-induced weight gain. Naltrexone did not reduce OLZ-induced increases in weight or BMI. However, there is a paucity of data on other opioid antagonists as adjuncts to OLZ treatment to prevent increases in weight or BMI.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2168-9709Test

الوصول الحر: https://doaj.org/article/338e1f1e2e444690aef4c7208fd0d9ebTest

المؤلفون: Juan Carlos Prieto, Viviana Noriega, Hugo F Miranda

مصطلحات موضوعية: Rosuvastatin, Analgesia, Opioid antagonists, RisperidoneL-NAME

الوصف: Statins are widely used in cardiovascular disease as cholesterol lowering drugs. However, they also have other actions (pleiotropic effects) including antiproliferative, antithrombotic, neuroprotective, immunomodulatory, anti-inflammatory and antinociceptive activity. The aim of this study was to determine the antinociception properties of rosuvastatin in two murine models of pain and the involvement of opioid antagonists (naltrexone, naltrindole, norbinaltorphimine), risperidone, and L-NAME (L-NG-nitro arginine methyl ester) in this effect. Rosuvastatin was chosen among available statins because it is commonly prescribed and has high potency, efficacy, and an acceptable safety profile. Rosuvastatin antinociception was evaluated in the acetic acid writhing test and the formalin hind paw test by dose-response curves, before and after the i.p. administration of opioid antagonists, risperidone, and L-NAME. This work demonstrates that the assayed drugs modulate the antinociceptive effect of rosuvastatin in both ...

العلاقة: https://dx.doi.org/10.5281/zenodo.11217570Test

الإتاحة: https://doi.org/10.5281/zenodo.1121757110.5281/zenodo.11217570Test

المؤلفون: Irene Escamilla, Nerea Juan, Celeste Peñalva, Marta Sánchez-Llorens, Jorge Renau, Ana Benito, Gonzalo Haro

المصدر: European Journal of Psychotraumatology, Vol 14, Iss 2 (2023)

مصطلحات موضوعية: Dissociation, naloxone, naltrexone, opioid antagonists, meta-analysis, Disociación, Psychiatry, RC435-571

الوصف: ABSTRACTBackground: The clinical guidelines for the treatment of dissociation focus primarily on psychotherapy. However, different psychoactive drugs are used in clinical practice. The use of opioid antagonists has been proposed as a therapeutic option based on the theory that dissociation might be a phenomenon mediated by dysregulation of the endogenous opioid system.Objective: To review and meta-analyse the available evidence on the efficacy of the opioid antagonists naltrexone, naloxone, and nalmefene as treatments for dissociative symptoms and disorders.Method: The PRISMA guidelines were followed, and this review was registered in Prospero with reference number CRD42021280976. The search was performed in the PubMed, Scopus, Web of Science, EMBASE, PsycINFO, and PubPsych databases.Results: 1,798 citations were obtained. After removing duplicates and applying inclusion and exclusion criteria, we included 5 comparative studies with 9 dissociation measures that had included a total of 154 participants, of whom 134 had been treated with an opioid antagonist. The results of the meta-analysis showed a treatment effect for dissociation when using opioid antagonists [pooled d = 1.46 (95% CI: 0.62–2.31)]. However, the studies we included were very heterogeneous [Q = 66.89 (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2000-8066Test

الوصول الحر: https://doaj.org/article/a1296cd5db8447ccbe5d68e2109e64a1Test

المؤلفون: Nariman Essmat, Dávid Árpád Karádi, Ferenc Zádor, Kornél Király, Susanna Fürst, Mahmoud Al-Khrasani

المصدر: Molecules, Vol 28, Iss 23, p 7766 (2023)

مصطلحات موضوعية: OIC, opioid antagonists, PAMORAs, gut-selective MOR antagonists, OID, Organic chemistry, QD241-441

الوصف: Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1420-3049/28/23/7766Test; https://doaj.org/toc/1420-3049Test

الوصول الحر: https://doaj.org/article/96c59c3c6c4c4ed79c68127a836304a5Test

المؤلفون: Stephanos Schafer-Kavvadias

مصطلحات موضوعية: Extended-release, naltrexone, opioid antagonists, opioid-dependence treatment

الوصف: Numerous health and social relationship problems, namely an increased risk of contracting HIV, mortality, crime, unemployment and impaired interpersonal relationships, are related to drug dependence, with opioids at the helm. For this reason, opioid addiction is considered a major public health problem [1] and is characterized as a ‘chronic relapsing disease’ and is a major concern for public health, as are drug and alcohol addictions [1, 2]. In addition to social support and psychotherapy, treatment of opioid dependence relies on medication intake. The three main opioid-dependence treatment categories include opioid agonists, opioid antagonists, and non-opioid medications. Naltrexone hydrochloride (API), one of the most commonly used medications relies on an opioid antagonist. It reduces opioid cravings, it can be administered outside the hospital setting and cannot be abused [3]. However, during treatment several patients often forget to take a dose, doubling the next dose to compensate. In some cases, this finding in the therapeutic levels not being reached, while in other cases undesired (side) effects appear. For this reason, especially in the case of long-term treatments of numerous diseases, an extended dosing interval is recommended, so that the patient receives the drug, only once a day, instead of two or three times a day.

العلاقة: https://zenodo.org/record/7771314Test; https://doi.org/10.5281/zenodo.7771314Test; oai:zenodo.org:7771314

الإتاحة: https://doi.org/10.5281/zenodo.7771314Test
https://doi.org/10.5281/zenodo.7771313Test
https://zenodo.org/record/7771314Test

المؤلفون: Renan Fernandes do Espírito-Santo, Dourivaldo Silva Santos, Pedro Santana Sales Lauria, Alyne Almeida de Lima, Lucas Silva Abreu, Josean Fechine Tavares, Marcelo Santos Castilho, Milena Botelho Pereira Soares, Cristiane Flora Villarreal

مصطلحات موضوعية: Biochemistry, Genetics, Molecular Biology, Neuroscience, Physiology, Pharmacology, Ecology, Immunology, Science Policy, Mental Health, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, significant chemical similarity, complete freund ’, cold plate tests, alter paw edema, stillingia loranthacea <, cold plate test, >, measuring preproenkephalin, tonantzitlolone b modulates, opioid antagonists naloxone, ex vivo <, kg ), naltrindole, indicating, endogenous opioid system, b promotes antinociception, mice tonantzitlolone b, vivo <

الوصف: Tonantzitlolone B (TZL-B) is a diterpene isolated from the roots of Stillingia loranthacea . Its antinociceptive effects were investigated in male Swiss mice using the following models of pain: formalin test, inflammation induced by Complete Freund’s Adjuvant (CFA), tail flick test, and cold plate test. The influence of TZL-B on the opioid system was assessed in vivo , using opioid antagonists; in silico , investigating the chemical similarity among TZL-B and opioid agonists; and ex vivo , measuring preproenkephalin (PENK) gene expression in the spinal cord by RT-qPCR. TZL-B (10–1000 μg/kg) promoted antinociception in the four experimental models without impairing mice’s motor function. TZL-B did not alter paw edema during CFA-induced inflammation. The antinociceptive effects of TZL-B in the tail flick and cold plate tests were diminished by the opioid antagonists naloxone (5 mg/kg), NOR-BNI (0.5 mg/kg), naltrindole (3 mg/kg), and CTOP (1 mg/kg), indicating the involvement of κ-, δ-, and μ-opioid receptors. TZL-B showed no significant chemical similarity to opioid agonists, but the treatment with TZL-B (1000 μg/kg) increased PENK gene expression in the spinal cord of mice. These data suggest that TZL-B promotes antinociception by enhancing the transcription of PENK, hence modulating the endogenous opioid system.

العلاقة: https://figshare.com/articles/journal_contribution/Tonantzitlolone_B_Modulates_the_Endogenous_Opioid_System_to_Promote_Antinociception_in_Mice/24545056Test

الإتاحة: https://doi.org/10.1021/acs.jnatprod.3c00731.s001Test
https://figshare.com/articles/journal_contribution/Tonantzitlolone_B_Modulates_the_Endogenous_Opioid_System_to_Promote_Antinociception_in_Mice/24545056Test

المؤلفون: Cecilie Siggaard Knoph, Mathias Ellgaard Cook, Camilla Ann Fjelsted, Srdan Novovic, Michael Bau Mortensen, Liv Bjerre Juul Nielsen, Mark Berner Hansen, Jens Brøndum Frøkjær, Søren Schou Olesen, Asbjørn Mohr Drewes

المصدر: Trials, Vol 22, Iss 1, Pp 1-12 (2021)

مصطلحات موضوعية: Methylnaltrexone, Opioid antagonists, Drug antagonism, Acute pancreatitis, Treatment, Randomised controlled trial, Medicine (General), R5-920

الوصف: Abstract Background Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. Methods PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer’s lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. Discussion This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. Trial registration ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1745-6215Test

الوصول الحر: https://doaj.org/article/ee3a1ab8f3784561a534a0e55c46a957Test

المؤلفون: Citrome L, Graham C, Simmons A, Jiang Y, Todtenkopf MS, Silverman B, DiPetrillo L, Cummings H, Sun L, McDonnell D

المصدر: Neuropsychiatric Disease and Treatment, Vol Volume 17, Pp 2885-2904 (2021)

مصطلحات موضوعية: antipsychotic agents, clinical efficacy, olanzapine, opioid antagonists, safety, weight gain, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429

الوصف: Leslie Citrome,1 Christine Graham,2 Adam Simmons,2 Ying Jiang,2 Mark S Todtenkopf,2 Bernard Silverman,2 Lauren DiPetrillo,2 Hannah Cummings,2 Lei Sun,2 David McDonnell3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Alkermes, Inc., Waltham, MA, USA; 3Alkermes Pharma Ireland Limited, Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1-845-362-2081Email citrome@cnsconsultant.comAbstract: Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥ 5 cm by half, compared with olanzapine at week 24. Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.Keywords: antipsychotic agents, clinical efficacy, olanzapine, opioid antagonists, safety, weight gain

وصف الملف: electronic resource

العلاقة: https://www.dovepress.com/an-evidence-based-review-of-olzsam-for-treatment-of-adults-with-schizo-peer-reviewed-fulltext-article-NDTTest; https://doaj.org/toc/1178-2021Test

الوصول الحر: https://doaj.org/article/a8c9473278d14e10b367a12fc711ddf4Test