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1.
Neurología (Barc., Ed. impr.) ; 38(1): 49-55, enero 2023. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-JHG-251

RESUMO

Introducción: Los avances en el desarrollo de medicamentos con mecanismos de acción novedosos no han sido suficientes para modificar de manera significativa el porcentaje de pacientes con epilepsia refractaria. Esa falta de resultados clínicos satisfactorios nos ha llevado a buscar alternativas terapéuticas más eficaces y con mecanismos de acción diferentes a los convencionales.DesarrolloEl objetivo de este artículo es profundizar en los aspectos epidemiológicos relacionados con el uso de productos a base de cannabis para el tratamiento de la epilepsia, haciendo énfasis en los principales mecanismos de acción, las indicaciones de uso, la eficacia clínica y la seguridad. Para lo anterior, se realizó una revisión narrativa mediante la búsqueda de artículos en PubMed, EMBASE, Google Scholar y a través de la revisión exhaustiva de la bibliografía relevante.ConclusionesEn los últimos años ha crecido el interés relacionado con el uso de cannabis medicinal para el tratamiento de diferentes enfermedades, incluyendo la epilepsia. En la actualidad, sabemos que las plantas de cannabis contienen más de 100 compuestos terpenofenólicos que se han denominado cannabinoides. Los 2 más abundantes son el delta-9-tetrahidrocannabinol y el cannabidiol. Diferentes modelos preclínicos de epilepsia han demostrado que estos cannabinoides tienen propiedades anticonvulsivas, por ello se ha comenzado a utilizar cannabidiol purificado al 100% y extractos de cannabis enriquecidos con cannabidiol para el tratamiento de la epilepsia en humanos. La eficacia y la seguridad de estos productos han quedado demostradas en diferentes estudios abiertos y ensayos clínicos controlados y aleatorizados. (AU)


Introduction: Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting drug-resistant epilepsy. This lack of satisfactory clinical results has led to the search for more effective treatment alternatives with new mechanisms of action.DevelopmentThe aim of this study is to examine epidemiological aspects of the use of cannabis-based products for the treatment of epilepsy, with particular emphasis on the main mechanisms of action, indications for use, clinical efficacy, and safety. We conducted a narrative review of articles gathered from the PubMed, EMBASE, and Google Scholar databases and from the reference sections of relevant publications.ConclusionsIn recent years there has been growing interest in the use of cannabis-based products for the treatment of a wide range of diseases, including epilepsy. The cannabis plant is currently known to contain more than 100 terpenophenolic compounds, known as cannabinoids. The 2 most abundant are delta-9-tetrahydrocannabinol and cannabidiol. Studies of preclinical models of epilepsy have shown that these cannabinoids have anticonvulsant properties, and 100% purified cannabidiol and cannabidiol-enriched cannabis extracts are now being used to treat epilepsy in humans. Several open-label studies and randomised controlled clinical trials have demonstrated the efficacy and safety of these products. (AU)


Assuntos
Humanos , Canabinoides , Cannabis , Canabidiol , Dronabinol , Epilepsia
2.
Forensic Toxicol ; 41(1): 151-157, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36652056

RESUMO

PURPOSE: Methyl-2-(1-(4-fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (4F-MDMB-BINACA) is a newly emerging synthetic cannabinoid receptor agonists (SCRA) first described in 2018 in both Europe and the United States. Two fatal cases are reported caused by simultaneous consumption of 4F-MDMB-BINACA and ethanol. METHODS: The victims were brothers who were both found deceased after consuming 4F-MDMB-BINACA and ethanol. Post-mortem toxicological analyses of blood and urine were carried out by supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and headspace gas chromatography with flame ionization detection (HS-GC-FID). RESULTS: The concentration of 4F-MDMB-BINACA in the postmortem blood was 2.50 and 2.34 ng/mL, and blood alcohol concentration was 2.11 and 2.49 g/L, respectively. CONCLUSION: According to the reported cases and reviews of the scientific literature, concurrent ethanol consumption should amplify the toxicity of SCRAs. The threshold SCRA concentration for fatal overdose can be estimated ng/mL level (0.37-4.1 ng/mL according to the reported cases) in cases in which 1.5-2.5 g/L of ethanol is present in the blood.


Assuntos
Canabinoides , Drogas Ilícitas , Masculino , Humanos , Estados Unidos , Canabinoides/análise , Espectrometria de Massas em Tandem , Drogas Ilícitas/análise , Cromatografia Gasosa-Espectrometria de Massas , Etanol/análise , Concentração Alcoólica no Sangue , Agonistas de Receptores de Canabinoides/análise
3.
Forensic Toxicol ; 41(1): 114-125, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36652070

RESUMO

PURPOSE: AMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA) which is primarily metabolised by hepatic enzymes producing AMB-FUBINACA carboxylic acid. The metabolising enzymes associated with this biotransformation remain unknown. This study aimed to determine if AMB-FUBINACA metabolism could be reduced in the presence of carboxylesterase (CES) inhibitors and recreational drugs commonly consumed with it. The affinity and activity of the AMB-FUBINACA acid metabolite at the cannabinoid type-1 receptor (CB1) was investigated to determine the activity of the metabolite. METHODS: The effect of CES1 and CES2 inhibitors, and delta-9-tetrahydrocannabinol (Δ9-THC) on AMB-FUBINACA metabolism were determined using both human liver microsomes (HLM) and recombinant carboxylesterases. Radioligand binding and cAMP assays comparing AMB-FUBINACA and AMB-FUBINACA acid were carried out in HEK293 cells expressing human CB1. RESULTS: AMB-FUBINACA was rapidly metabolised by HLM in the presence and absence of NADPH. Additionally, CES1 and CES2 inhibitors both significantly reduced AMB-FUBINACA metabolism. Furthermore, digitonin (100 µM) significantly inhibited CES1-mediated metabolism of AMB-FUBINACA by ~ 56%, while the effects elicited by Δ9-THC were not statistically significant. AMB-FUBINACA acid produced only 26% radioligand displacement consistent with low affinity binding. In cAMP assays, the potency of AMB-FUBINACA was ~ 3000-fold greater at CB1 as compared to the acid metabolite. CONCLUSIONS: CES1A1 was identified as the main hepatic enzyme responsible for the metabolism of AMB-FUBINACA to its less potent carboxylic acid metabolite. This biotransformation was significantly inhibited by digitonin. Since other xenobiotics may also inhibit similar SCRA metabolic pathways, understanding these interactions may elucidate why some users experience high levels of harm following SCRA use.


Assuntos
Canabinoides , Humanos , Canabinoides/farmacologia , Dronabinol , Digitonina , Células HEK293 , Agonistas de Receptores de Canabinoides/farmacologia
4.
Anesth Analg ; 136(2): 373-386, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36638515

RESUMO

BACKGROUND: Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have verified the functional interaction between opioid and cannabinoid systems in pain management, suggesting that coactivation of the opioid and cannabinoid receptors may provide synergistic analgesia with fewer adverse reactions. Herein, we developed and characterized a novel bifunctional compound containing the pharmacophores of the mu-opioid receptor agonist DALDA and the cannabinoid peptide VD-Hpα-NH2, named OCP002. METHODS: The opioid and cannabinoid agonistic activities of OCP002 were investigated in calcium mobilization and western blotting assays, respectively. Moreover, the central and peripheral antinociceptive effects of OCP002 were evaluated in mouse preclinical models of tail-flick test, carrageenan-induced inflammatory pain, and acetic acid-induced visceral pain, respectively. Furthermore, the potential opioid and cannabinoid side effects of OCP002 were systematically investigated in mice after intracerebroventricular (ICV) and subcutaneous (SC) administrations. RESULTS: OCP002 functioned as a mixed agonist toward mu-opioid, kappa-opioid, and cannabinoid CB1 receptors in vitro. ICV and SC injections of OCP002 produced dose-dependent antinociception in mouse models of nociceptive (the median effective dose [ED50] values with 95% confidence interval [CI] are 0.14 [0.12-0.15] nmol and 0.32 [0.29-0.35] µmol/kg for ICV and SC injections, respectively), inflammatory (mechanical stimulation: ED50 values [95% CI] are 0.76 [0.64-0.90] nmol and 1.23 [1.10-1.38] µmol/kg for ICV and SC injections, respectively; thermal stimulation: ED50 values [95% CI] are 0.13 [0.10-0.17] nmol and 0.23 [0.08-0.40] µmol/kg for ICV and SC injections, respectively), and visceral pain (ED50 values [95% CI] are 0.0069 [0.0050-0.0092] nmol and 1.47 [1.13-1.86] µmol/kg for ICV and SC injections, respectively) via opioid and cannabinoid receptors. Encouragingly, OCP002 cannot cross the blood-brain barrier and exerted nontolerance-forming analgesia over 6-day treatment at both supraspinal and peripheral levels. Consistent with these behavioral results, repeated OCP002 administration did not elicit microglial hypertrophy and proliferation, the typical features of opioid-induced tolerance, in the spinal cord. Furthermore, at the effective analgesic doses, SC OCP002 exhibited minimized opioid and cannabinoid side effects on motor performance, body temperature, gastric motility, physical and psychological dependence, as well as sedation in mice. CONCLUSIONS: This study demonstrates that OCP002 produces potent and nontolerance-forming antinociception in mice with reduced opioid- and cannabinoid-related side effects, which strengthen the candidacy of bifunctional drugs targeting opioid/cannabinoid receptors for translational-medical development to replace or assist the traditional opioid analgesics.


Assuntos
Analgésicos , Agonistas de Receptores de Canabinoides , Canabinoides , Receptores Opioides , Dor Visceral , Animais , Camundongos , Analgésicos/farmacologia , Analgésicos Opioides , Relação Dose-Resposta a Droga , Receptores de Canabinoides , Receptores Opioides/agonistas , Dor Visceral/induzido quimicamente , Dor Visceral/tratamento farmacológico , Agonistas de Receptores de Canabinoides/farmacologia
5.
Forensic Toxicol ; 41(1): 47-58, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36652054

RESUMO

PURPOSE: Methyl (S)-2-(1-7 (5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-MDMA-PICA) intoxication in 1.5-year-old child was presented, together with diagnostic parameters discussion and 5F-MDMB-PICA determination in biological material. Furthermore, 5F-MDMB-PICA metabolites were identified in a urine sample as markers of exposure in situation when a parent compound is not present in specimens. METHODS: Drugs and metabolites were extracted from serum and urine with ethyl acetate both under alkaline (pH 9) and acidic (pH 3) conditions. Hair, after decontamination and pulverization, were incubated with methanol (16 h, 60 °C). The analysis was carried out using ultra-high-performance liquid chromatography-tandem mass spectrometry. For the identification of 5F-MDMB-PICA metabolites, an urine sample was precipitated with cold acetonitrile. Analysis was performed using ultra-high-performance liquid chromatograph with quadrupole time-of-flight mass spectrometer. RESULTS: 5F-MDMB-PICA was determined only in serum sample at concentration of 298 ng/mL. After 1 year, when analysis was repeated, concentration of synthetic cannabinoid in the same sample was only 17.6 ng/mL which revealed high instability of 5F-MDMB-PICA in serum sample. Eight 5F-MDMB-PICA metabolites were identified in urine sample, including two potentially new ones with m/z 391.18964 and m/z 275.14016. CONCLUSIONS: Toxicological analysis confirmed a 1.5-year-old boy intoxication with 5F-MDMB-PICA. Besides the parent drug, metabolites of 5F-MDMB-PICA were identified, including two potentially new ones, together with possible metabolic reactions which they resulted from. Metabolites determination could serve as a marker of 5F-MDMB-PICA exposure when no parent drug is present in biological material.


Assuntos
Canabinoides , Drogas Ilícitas , Masculino , Humanos , Pré-Escolar , Lactente , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodos , Drogas Ilícitas/metabolismo , Canabinoides/análise , Indóis
7.
Clin Ter ; 174(1): 53-60, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36655645

RESUMO

Objectives: Ten million new cases of dementia are recorded annually worldwide, with agitation and idiopathic weight loss being the most common symptoms. Several pharmacological therapies have emerged in recent years, but the clinical use of cannabis extracts in older patients with AD is constantly growing. This retrospective, analytical, observational, spontaneous trial aimed to enhance the clinical action of THC: CBD cannabis extract administration in AD patients with severe symptoms such as agitation, weight loss, cognitive impairment, and sleep disturbance. Methods: Thirty patients (9 men and 21 women) diagnosed with mild, moderate, or severe AD, aged 65-90 years, appealing to our Second Opinion Medical Consultation (Modena, Italy), were enrolled and required to use oil-diluted cannabis extract, Bedrocan® (22% THC, 0.5% CBD, Olive Oil 50 ml), twice a day for 12 weeks. The efficacy of cannabinoid therapy was evaluated at baseline and 12 weeks after therapy, employing three self-administered questionnaires completed by the parents of the enrolled patients: NPI-Q, CMAI, and MMSE. Key findings: The NPI-Q demonstrated a reduction (p<0.0001) in agitation, apathy, irritability, sleep disturbances, and eating disturbances, consequently improving caregiver distress. Levels of physically and verbally aggressive behaviours, measured using the CMAI questionnaire, were lower (p<0.0001) in all patients. The MMSSE questionnaire confirmed a significant decrease (p<0.0001) in cognitive impairment in 45% of the patients. Conclusion: Our anecdotical, spontaneous, and observational study demonstrated the efficacy and safety of oil-diluted cannabis extract in patients with AD. The limitations of our study are: 1) small patient cohort, 2) absence of control group, 3) self-administered questionnaires that are the most practical but not objective instruments to assess the neurologic functions of AD patients.


Assuntos
Doença de Alzheimer , Canabinoides , Cannabis , Masculino , Humanos , Feminino , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Estudos Retrospectivos , Extratos Vegetais/uso terapêutico
8.
J Mol Model ; 29(2): 46, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36656418

RESUMO

INTRODUCTION: The use of the Cannabis sativa plant by man has been common for centuries due to its numerous therapeutic properties resulting from the compounds present in it, called cannabinoids. However, the use of these compounds as drugs is still limited due to the psychotropic effects caused by them. The proteins that act as receptors of cannabinoid compounds were identified and characterized, being called CB1 and CB2 receptors. There is a series of 50 cannabinoid compounds that was studied through quantum and chemometric methods in order to obtain a mathematical model that could relate the structure of these compounds to their psychotropic activity. That model proved to be effective by predicting the psychoactivity of the 50 compounds from the series and elucidating relevant characteristics that imply in psychoactivity. However, most of these 50 compounds do not have experimental data of biological activity with CB1 and CB2 receptors. OBJECTIVES: This study aims to generate QSAR models in order to predict the biological activity of the 50 cannabinoid compounds and then relate the predicted biological activity values to the already known psychoactivity. METHODS: Another series of cannabinoid compounds was selected to generate and validate QSAR models, aiming to predict the biological activity of the 50 cannabinoid compounds with both CB1 and CB2 receptors. RESULTS: The PLS-CB1 and PLS-CB2 QSAR models were generated and validated in this work, proving to be highly predictive, and the biological activities (pK ) of the 50 cannabinoid compounds were predicted by them. It is important to highlight compounds Ic14, Ic18, and Ic19 (psychotropic inactive) which presented higher predicted pK values than the main cannabinoid compounds (Δ9-THC and Δ8-THC). Also, compound Ic21 stood out as the highest value of the predicted biological activities in the interaction with the CB2 receptor. CONCLUSION: The generated PLS models and the predicted pKi values of the 50 cannabinoid compounds can provide valuable information in the drug design of new cannabinoid compounds that can interact with CB1 and CB2 receptors in a therapeutic way with no psychotropic effects.


Assuntos
Canabinoides , Humanos , Masculino , Canabinoides/farmacologia , Canabinoides/uso terapêutico
9.
Anal Methods ; 15(3): 333-342, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36594640

RESUMO

The global market for new psychoactive substances (NPSs) continues to expand, and the range of drugs available on the market has probably never been wider. Synthetic cannabinoids (SCRAs) constitute the largest family of NPSs, and they go unnoticed during illicit drug market control and during routine toxicological-forensic analysis. Membrane-assisted solvent extraction (MASE) has been a novelty proposed for the simultaneous extraction of SCRAs, and urine has been selected as a model forensic-clinical sample. Isolated SCRAs were further determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). An optimised sample pre-treatment procedure consists of using 400 µL of n-hexane as an extraction phase placed inside a polypropylene (PP) membrane, adjusting the donor phase (urine) at a pH value of 5.9. Extraction was assisted by mechanical (orbital-horizontal) stirring in a temperature-controlled chamber at room temperature for 20 min. n-Hexane extracts were evaporated to dryness and re-suspended in 100 µL of mobile phase, which leads to a pre-concentration factor of 50. Method validation showed analytical recoveries higher than 80% for most SCRAs and repeatability (inter-day and intra-day assays) with RSD values lower than 20%. The proposed method was found to be selective and sensitive and limits of quantification (LOQs) between 0.10 and 1.0 µg L-1 were achieved.


Assuntos
Agonistas de Receptores de Canabinoides , Canabinoides , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Canabinoides/urina , Solventes
10.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614303

RESUMO

Melanoma is deadly, physically impairing, and has ongoing treatment deficiencies. Current treatment regimens include surgery, targeted kinase inhibitors, immunotherapy, and combined approaches. Each of these treatments face pitfalls, with diminutive five-year survival in patients with advanced metastatic invasion of lymph and secondary organ tissues. Polyphenolic compounds, including cannabinoids, terpenoids, and flavonoids; both natural and synthetic, have emerging evidence of nutraceutical, cosmetic and pharmacological potential, including specific anti-cancer, anti-inflammatory, and palliative utility. Cannabis sativa is a wellspring of medicinal compounds whose direct and adjunctive application may offer considerable relief for melanoma suffers worldwide. This review aims to address the diverse applications of C. sativa's biocompounds in the scope of melanoma and suggest it as a strong candidate for ongoing pharmacological evaluation.


Assuntos
Canabinoides , Cannabis , Melanoma , Humanos , Cannabis/química , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Canabinoides/química , Terpenos/farmacologia , Melanoma/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
11.
Reg Anesth Pain Med ; 48(3): 97-117, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596580

RESUMO

BACKGROUND: The past two decades have seen an increase in cannabis use due to both regulatory changes and an interest in potential therapeutic effects of the substance, yet many aspects of the substance and their health implications remain controversial or unclear. METHODS: In November 2020, the American Society of Regional Anesthesia and Pain Medicine charged the Cannabis Working Group to develop guidelines for the perioperative use of cannabis. The Perioperative Use of Cannabis and Cannabinoids Guidelines Committee was charged with drafting responses to the nine key questions using a modified Delphi method with the overall goal of producing a document focused on the safe management of surgical patients using cannabinoids. A consensus recommendation required ≥75% agreement. RESULTS: Nine questions were selected, with 100% consensus achieved on third-round voting. Topics addressed included perioperative screening, postponement of elective surgery, concomitant use of opioid and cannabis perioperatively, implications for parturients, adjustment in anesthetic and analgesics intraoperatively, postoperative monitoring, cannabis use disorder, and postoperative concerns. Surgical patients using cannabinoids are at potential increased risk for negative perioperative outcomes. CONCLUSIONS: Specific clinical recommendations for perioperative management of cannabis and cannabinoids were successfully created.


Assuntos
Canabinoides , Cannabis , Humanos , Canabinoides/efeitos adversos , Manejo da Dor/efeitos adversos , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Agonistas de Receptores de Canabinoides
13.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675144

RESUMO

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus; EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018; 0.3-3-6 mg/kg) and Δ9-tetrahydrocannabinol (Δ9-THC; 0.3-3-6 mg/kg), administered in awake CD-1 male mice. The results showed that higher doses of JWH-018 (3-6 mg/kg) induced deep and long-lasting bradycardia, alternated with bradyarrhythmia, spaced out by sudden episodes of tachyarrhythmias (6 mg/kg), and characterized by ECG electrical parameters changes, sustained bradypnea, and systolic and transient diastolic hypertension. Otherwise, Δ9-THC provoked delayed bradycardia (minor intensity tachyarrhythmias episodes) and bradypnea, also causing a transient and mild hypertensive effect at the tested dose range. These effects were prevented by both treatment with selective CB1 (AM 251, 6 mg/kg) and CB2 (AM 630, 6 mg/kg) receptor antagonists and with the mixture of the antagonists AM 251 and AM 630, even if in a different manner. Cardio-respiratory and vascular symptoms could be induced by peripheral and central CB1 and CB2 receptors stimulation, which could lead to both sympathetic and parasympathetic systems activation. These findings may represent a starting point for necessary future studies aimed at exploring the proper antidotal therapy to be used in SCs-intoxicated patient management.


Assuntos
Canabinoides , Dronabinol , Hipertensão , Animais , Masculino , Camundongos , Bradicardia/induzido quimicamente , Canabinoides/farmacologia , Dronabinol/farmacologia , Receptor CB1 de Canabinoide
14.
Curr Treat Options Oncol ; 24(1): 30-44, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36633803

RESUMO

OPINION STATEMENT: The potential medicinal properties of Cannabis continue to garner attention, especially in the brain tumor domain. This attention is centered on quality of life and symptom management; however, it is amplified by a significant lack of therapeutic choices for this specific patient population. While the literature on this matter is young, published and anecdotal evidence imply that cannabis could be useful in treating chemotherapy-induced nausea and vomiting, stimulating appetite, reducing pain, and managing seizures. It may also decrease inflammation and cancer cell proliferation and survival, resulting in a benefit in overall patient survival. Current literature poses the challenge that it does not provide standardized guidance on dosing for the above potential indications and cannabis use is dominated by recreational purposes. Furthermore, integrated and longitudinal studies are needed but these are a challenge due to arcane laws surrounding the legality of such substances. The increasing need for evidence-based arguments about potential harms and benefits of cannabis, not only in cancer patients but for other medical use and recreational purposes, is desperately needed.


Assuntos
Neoplasias Encefálicas , Canabidiol , Canabinoides , Cannabis , Humanos , Canabinoides/efeitos adversos , Qualidade de Vida , Canabidiol/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico
15.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674826

RESUMO

In this study, we have investigated a possible mechanism that enables CB1/M3 receptor cross-talk, using SH-SY5Y cells as a model system. Our results show that M3 receptor activation initiates signaling that rapidly upregulates the CNR1 gene, resulting in a greatly potentiated CB1 receptor response to agonists. Calcium homeostasis plays an essential intermediary role in this functional CB1/M3 receptor cross-talk. We show that M3 receptor-triggered calcium release greatly increases CB1 receptor expression via both transcriptional and translational activity, by enhancing CNR1 promoter activity. The co-expression of M3 and CB1 receptors in brain areas such as the nucleus accumbens and amygdala support the hypothesis that the altered synaptic plasticity observed after exposure to cannabinoids involves cross-talk with the M3 receptor subtype. In this context, M3 receptors and their interaction with the cannabinoid system at the transcriptional level represent a potential pharmacogenomic target not only for the develop of new drugs for addressing addiction and tolerance. but also to understand the mechanisms underpinning response stratification to cannabinoids.


Assuntos
Canabinoides , Neuroblastoma , Humanos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Cálcio/metabolismo , Canabinoides/farmacologia , Canabinoides/metabolismo , Sinalização do Cálcio
16.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674774

RESUMO

We report enzymes from the berberine bridge enzyme (BBE) superfamily that catalyze the oxidative cyclization of the monoterpene moiety in cannabigerolic acid (CBGA) to form cannabielsoin (CBE). The enzymes are from a variety of organisms and are previously uncharacterized. Out of 232 homologues chosen from the enzyme superfamily, four orthologues were shown to accept CBGA as a substrate and catalyze the biosynthesis of CBE. The four enzymes discovered in this study were recombinantly expressed and purified in Pichia pastoris. These enzymes are the first report of heterologous expression of BBEs that did not originate from the Cannabis plant that catalyze the production of cannabinoids using CBGA as substrate. This study details a new avenue for discovering and producing natural and unnatural cannabinoids.


Assuntos
Canabinoides , Cannabis , Canabinoides/metabolismo , Cannabis/genética , Cannabis/química , Oxirredução , Catálise , Óxido Nítrico Sintase/metabolismo
17.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674832

RESUMO

The development of Cannabis sativa strains with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) content is a growing field of research, both for medical and recreational use. However, the mechanisms behind clinical actions of cannabinoids are still under investigation, although there is growing evidence that mitochondria play an important role in many of them. Numerous studies have described that cannabinoids modulate mitochondrial activity both through activation of mitochondrial cannabinoid receptors and through direct action on other proteins such as mitochondrial complexes involved in cellular respiration. Thus, the aim of this study was to determine the actions of a panel of extracts, isolated from high-CBD varieties of Cannabis sativa, on the activity of the mitochondrial electron transport chain complex IV, cytochrome c oxidase (CCO), in order to select those with a safer profile. After demonstrating that Cannabis sativa strains could be identified by cannabinoids content, concentration-response curves were performed with a collection of extracts from strains with high-CBD and low-THC content using bovine CCO. The CCO rate was clearly modified by specific extracts of Cannabis sativa plants compared to others. Half maximal inhibitory concentrations (IC50) of extracts and the inhibitory effects evoked at 1 × 10-4 g/mL displayed a significant correlation with the THC. Therefore, the screening of extracts based on CCO activity provides a powerful and rapid methodology to identify those plants with higher mitochondrial toxicity or even mito-protective actions.


Assuntos
Canabidiol , Canabinoides , Cannabis , Animais , Bovinos , Dronabinol/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons , Extratos Vegetais/farmacologia , Canabinoides/farmacologia , Canabidiol/farmacologia , Biomarcadores , Mitocôndrias
18.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674936

RESUMO

There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1-30 µM) and exposure times (24-48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.


Assuntos
Astrócitos , Canabinoides , Humanos , Astrócitos/metabolismo , Canabinoides/toxicidade , Canabinoides/química , Naftalenos/toxicidade , Naftalenos/metabolismo , Neurônios/metabolismo
19.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675254

RESUMO

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors' expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.


Assuntos
Canabinoides , Exossomos , Hepatopatia Gordurosa não Alcoólica , Humanos , Receptores de Canabinoides , Receptor CB1 de Canabinoide/genética
20.
Molecules ; 28(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36677696

RESUMO

Cannabinoids, terpenophenolic chemicals found only in cannabis, are primarily responsible for cannabis pharmacologic effects; nearly 150 distinct cannabinoids have been identified thus far. Among these, the main psychoactive molecule, tetrahydrocannabinol (THC), and the non-psychoactive counterpart, cannabidiol (CBD) are distinguishable. In the past decade, a CBD-containing pharmaceutical preparation was approved by Food and Drug Administration (FDA) for the treatment of drug-resistant epileptic seizures in children, and research trials for a variety of additional medical conditions for which CBD has been suggested as a therapy are being conducted. Additionally, the number of "CBD-containing" dietary supplements, largely available online, is increasing rapidly. Consequently, the necessity for the development of qualitative and quantitative methodologies for the analysis of the bioactive components of Cannabis is rising because of the increase in the production of therapeutic cannabis products. One of the analytical methods with good potential in cannabinoids analysis is capillary electrophoresis (CE). It has advantages related to high separation efficiency, relatively short analysis time, and the small consumption of analytes and reagents which generates relatively lower operational costs than other methods. This review focuses on the use of CE techniques to examine biological matrices and plant materials for the presence of cannabinoids and other bioactive compounds found in cannabis. The advantages, drawbacks, and applicability of the various electromigration approaches are also assessed. The article provides an overview of the "state of the art" and the latest trends in CE-based methods for the determination of cannabinoids.


Assuntos
Canabidiol , Canabinoides , Cannabis , Alucinógenos , Criança , Humanos , Canabinoides/uso terapêutico , Canabinoides/análise , Canabidiol/farmacologia , Dronabinol/farmacologia , Cannabis/química , Agonistas de Receptores de Canabinoides , Eletroforese Capilar
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