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Expert Opinion on Emerging Drugs Mar 2024Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million.... (Review)
Review
INTRODUCTION
Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.
AREAS COVERED
After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.
EXPERT OPINION
Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.
Topics: Child; Humans; Risperidone; Antipsychotic Agents; Autism Spectrum Disorder; Aripiprazole; Riluzole
PubMed: 38296815
DOI: 10.1080/14728214.2024.2313650 -
Pharmaceuticals (Basel, Switzerland) Dec 2023We reviewed gastric ulcer healing by dopamine considering several distinctive duodenal key points. Selye and Szabo describe the cysteamine-induced duodenal ulcer in rats... (Review)
Review
We reviewed gastric ulcer healing by dopamine considering several distinctive duodenal key points. Selye and Szabo describe the cysteamine-induced duodenal ulcer in rats as a duodenal stress ulcer in patients. Szabo's cysteamine duodenal ulcer as the dopamine duodenal healing and cysteamine as a dopamine antagonist signifies the dopamine agonists anti-ulcer effect and dopamine antagonists ulcerogenic effect. From these viewpoints, we focused on dopamine and gastric ulcer healing. We mentioned antecedent studies on the dopamine presence in the stomach and gastric juice. Then we reviewed, in the timeline, therapy significance arising from the anti-ulcer potency of the various dopamine agonists, which is highly prevailing over the quite persistent beneficial evidence arising from the various dopamine antagonists. Meanwhile, the beneficial effects of several peptides (i.e., amylin, cholecystokinin, leptin, and stable gastric pentadecapeptide BPC 157, suggested as an acting mediator of the dopamine brain-gut axis) were included in the dopamine gastric ulcer story. We attempt to resolve dopamine agonists/antagonists issue with the dopamine significance in the stress (cysteamine as a prototype of the duodenal stress ulcer), and cytoprotection (cysteamine in small dose as a prototype of the cytoprotective agents; cysteamine duodenal ulcer in gastrectomized rats). Thereby, along with dopamine agonists' beneficial effects, in special circumstances, dopamine antagonists having their own ulcerogenic effect may act as "mild stress (or)" or "small irritant" counteracting subsequent strong alcohol or stress procedure-induced severe lesions in this particular tissue. Finally, in the conclusion, as a new improvement in further therapy, we emphasized the advantages of the dopamine agents' application in lower gastrointestinal tract therapy.
PubMed: 38139825
DOI: 10.3390/ph16121699 -
Vertex (Buenos Aires, Argentina) Apr 2024La esquizofrenia es una patología crónica y grave que se caracteriza por la presencia de delirios, alucinaciones, síntomas negativos, desorganización del pensamiento...
La esquizofrenia es una patología crónica y grave que se caracteriza por la presencia de delirios, alucinaciones, síntomas negativos, desorganización del pensamiento y del comportamiento. Si bien su prevalencia en menores de 13 años es muy baja, aumenta sustancialmente durante la adolescencia. Cuando se desarrolla antes de los 18 años se denomina esquizofrenia de inicio precoz y representa del 12 al 33 % del total de los individuos con este trastorno. Existen fármacos como el haloperidol, risperidona, paliperidona, aripiprazol, olanzapina, quetiapina, brexpiprazol y lurasidona aprobados por la Food and Drug Administration (FDA) para el tratamiento de la esquizofrenia en adolescentes. Sin embargo, a excepción del haloperidol, todas las indicaciones farmacológicas que se realizan para tratar este trastorno en menores de 13 años resultan "off label" (fuera de las indicaciones de la ficha técnica). Si bien esta práctica no se encuentra prohibida, conlleva riesgos adicionales. En el siguiente trabajo se revisará la evidencia disponible acerca del uso de los antipsicóticos para el tratamiento de la esquizofrenia en la población infantojuvenil, con el objetivo de realizar una síntesis de la información con aplicabilidad clínica.
Topics: Child; Humans; Adolescent; Schizophrenia; Haloperidol; Retrospective Studies
PubMed: 38619996
DOI: 10.53680/vertex.v35i163.527 -
The Primary Care Companion For CNS... Mar 2024
Topics: Humans; Risperidone; Antipsychotic Agents; Drug-Related Side Effects and Adverse Reactions; Chemical and Drug Induced Liver Injury
PubMed: 38579255
DOI: 10.4088/PCC.23cr03658 -
Science Advances Oct 2023Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed...
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Topics: Humans; Glioblastoma; Trifluoperazine; Brain Neoplasms; Temozolomide; Chemoradiotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37878712
DOI: 10.1126/sciadv.adf1332 -
Schizophrenia Bulletin Jan 2024Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. (Meta-Analysis)
Meta-Analysis
Long-Acting Injectable Second-Generation Antipsychotics vs Placebo and Their Oral Formulations in Acute Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled-Trials.
BACKGROUND AND HYPOTHESIS
Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia.
STUDY DESIGN
We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1.
STUDY RESULTS
Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations.
CONCLUSIONS
SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.
Topics: Humans; Antipsychotic Agents; Paliperidone Palmitate; Aripiprazole; Olanzapine; Risperidone; Delayed-Action Preparations; Schizophrenia
PubMed: 37350486
DOI: 10.1093/schbul/sbad089 -
Journal of Pain & Palliative Care... Mar 2024Symptoms of nausea and vomiting are common in palliative care and hospice patients. One of the many classes of medications used for the treatment of nausea and vomiting... (Review)
Review
Symptoms of nausea and vomiting are common in palliative care and hospice patients. One of the many classes of medications used for the treatment of nausea and vomiting is dopamine receptor antagonists which are particularly helpful for treating nausea mediated by the chemoreceptor trigger zone (CTZ) and impaired gastrointestinal function. While dopamine antagonists can be very effective treatments for nausea they should be used with caution as they carry the risk of QTc prolongation, have a FDA black box warning for tardive dyskinesia (TD), and increased risk of precipitating psychosis and death in patients with dementia. This review will cover haloperidol, olanzapine, prochlorperazine, and metoclopramide for treatment of nausea and vomiting including evidence of efficacy, pharmacokinetics, and pharmacodynamics to improve safe and effective utilization in clinical practice. This includes medication receptor site affinities at histaminic, muscarinic, serotonergic, and alpha-adrenergic receptors which can help providers anticipate potential adverse effects and risk of extrapyramidal symptoms (EPS), TD, and QTc prolongation. This review also includes considerations for dose adjustments based on renal function, hepatic function, and age. Understanding the pharmacology of dopamine antagonists can help providers choose the best treatment for control of nausea and vomiting and subsequently improve patients' quality of life.
Topics: Humans; Dopamine Antagonists; Palliative Care; Quality of Life; Vomiting; Nausea; Long QT Syndrome
PubMed: 37843383
DOI: 10.1080/15360288.2023.2268065 -
Trends in Pharmacological Sciences Aug 2023It is generally assumed that the rewarding effects of cannabinoids are mediated by cannabinoid CB receptors (CBRs) the activation of which disinhibits dopaminergic... (Review)
Review
It is generally assumed that the rewarding effects of cannabinoids are mediated by cannabinoid CB receptors (CBRs) the activation of which disinhibits dopaminergic neurons in the ventral tegmental area (VTA). However, this mechanism cannot fully explain novel results indicating that dopaminergic neurons also mediate the aversive effects of cannabinoids in rodents, and previous results showing that preferentially presynaptic adenosine A receptor (AR) antagonists counteract self-administration of Δ-9-tetrahydrocannabinol (THC) in nonhuman primates (NHPs). Based on recent experiments in rodents and imaging studies in humans, we propose that the activation of frontal corticostriatal glutamatergic transmission constitutes an additional and necessary mechanism. Here, we review evidence supporting the involvement of cortical astrocytic CBRs in the activation of corticostriatal neurons and that AR receptor heteromers localized in striatal glutamatergic terminals mediate the counteracting effects of the presynaptic AR antagonists, constituting potential targets for the treatment of cannabinoid use disorder (CUD).
Topics: Humans; Animals; Cannabinoids; Receptors, Cannabinoid; Reward; Dopaminergic Neurons; Receptor, Cannabinoid, CB1
PubMed: 37331914
DOI: 10.1016/j.tips.2023.05.003 -
Journal of Basic and Clinical... Jan 2024Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the... (Review)
Review
Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.
Topics: Humans; Alzheimer Disease; Thiethylperazine
PubMed: 38491747
DOI: 10.1515/jbcpp-2023-0264 -
International Journal of Psychiatry in... Sep 2023Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other... (Review)
Review
Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics.
Topics: Humans; Antipsychotic Agents; Dopamine Agonists; Dopamine; Aripiprazole; Receptors, Dopamine D2
PubMed: 36495086
DOI: 10.1080/13651501.2022.2151473