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1.
Mol Pharm ; 19(5): 1515-1525, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35412842

RESUMO

Nanoparticle encapsulation is an attractive approach to improve the oral bioavailability of hydrophobic therapeutics. The high specific surface area of nanoparticle formulations, combined with the thermodynamically driven increased solubility of an amorphous drug core, promotes rapid drug dissolution. However, the physicochemical properties of the hydrophobic therapeutic can present obstacles to in vitro characterization of nanoparticle formulations. Namely, drugs with low density and high membrane binding affinity frustrate traditional analytical methods to monitor release kinetics from nanoparticles. In this work, cannabidiol (CBD) was encapsulated into nanoparticles with low polydispersity and high drug loading via Flash NanoPrecipitation (FNP), a scalable self-assembly process. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and lecithin were employed as amphiphilic particle stabilizers during the FNP process. However, the low density and high membrane binding affinity of the amorphous CBD nanoparticle core prevented the characterization of in vitro release kinetics by conventional methods. Released CBD could not be separated from intact nanoparticles by filtration or centrifugation. To address this challenge, an alternative approach is described to coencapsulate 6 nm hydrophobic Fe3O4 colloids with CBD during FNP. The Fe3O4 colloids were added at 33% by mass (approximately 20% by volume) to increase the density of the nanoparticles, resulting in particles with an average diameter of 160 nm (CBD-lecithin-Fe3O4) or 280 nm (CBD-HPMCAS-Fe3O4). This densification enabled the centrifugal separation of dissolved (released) CBD from unreleased CBD during the in vitro assay while avoiding the losses associated with a filtration step. The resulting nanoparticle formulations provided more rapid and complete in vitro dissolution kinetics than bulk CBD, representing a 6-fold improvement in dissolution compared to crystalline CBD. The coencapsulation of high-density Fe3O4 colloids to enable the separation of nanoparticles from release media is a novel approach to measuring in vitro release kinetics of nanoencapsulated low-density, hydrophobic drug molecules.


Assuntos
Canabidiol , Nanopartículas , Coloides/química , Lecitinas , Nanopartículas/química , Tamanho da Partícula , Solubilidade
2.
Integr Cancer Ther ; 21: 15347354221092706, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35481367

RESUMO

Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.


Assuntos
Canabidiol , Fotoquimioterapia , Neoplasias do Colo do Útero , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Terapia Combinada , Feminino , Humanos , Neovascularização Patológica/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico
3.
Anal Bioanal Chem ; 414(13): 3847-3862, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35380230

RESUMO

Cannabis sativa (C. sativa) is commonly chemically classified based on its Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content ratios. However, the plant contains nearly 150 additional cannabinoids, referred to as minor cannabinoids. Minor cannabinoids are gaining interest for improved plant and product characterization, e.g., for medical use, and bioanalytical questions in the medico-legal field. This study describes the development and validation of an analytical method for the elucidation of minor cannabinoid fingerprints, employing liquid chromatography coupled to high-resolution mass spectrometry. The method was used to characterize inflorescences from 18 different varieties of C. sativa, which were cultivated under the same standardized conditions. Complementing the targeted detection of 15 cannabinoids, untargeted metabolomics employing in silico assisted data analysis was used to detect additional plant ingredients with focus on cannabinoids. Principal component analysis (PCA) was used to evaluate differences between varieties. The overall purpose of this study was to examine the ability of targeted and non-targeted metabolomics using the mentioned techniques to distinguish cannabis varieties from each other by their minor cannabinoid fingerprint. Quantitative determination of targeted cannabinoids already gave valuable information on cannabinoid fingerprints as well as inter- and intra-variety variability of cannabinoid contents. The untargeted workflow led to the detection of 19 additional compounds. PCA of the targeted and untargeted datasets revealed further subgroups extending commonly applied phenotype classification systems of cannabis. This study presents an analytical method for the comprehensive characterization of C. sativa varieties.


Assuntos
Canabidiol , Canabinoides , Cannabis , Alucinógenos , Analgésicos , Canabidiol/análise , Canabinoides/análise , Cannabis/química , Dronabinol/análise
4.
Forensic Sci Int ; 335: 111309, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35462181

RESUMO

Cannabis cultivation for medical purposes in Brazil has been increased in the last years. While cannabis crops are prohibited, hundreds patients have been granted with judicial authorizations and there is little information about the cultivation conditions, yields and chemical profiles of the plants. Cannabis plants contain hundreds of compounds, with cannabinoids and terpenes the main drivers of their toxicological and pharmacological properties. Besides the cannabinoids, terpene contents are useful for the chemotaxonomic classification of different varieties, and their role in forensic analyses should be further delineated. The present study monitored cannabis crops of fifteen participants who were granted special licenses by the Brazilian Courts in Rio de Janeiro and São Paulo. The cultivation conditions were monitored and five cannabinoids (tetrahydrocannabinol acid-THCA, tetrahydrocannabinol-THC, cannabidiolic acid-CBDA, cannabidiol-CBD and cannabinol-CBN) and nineteen terpenes were quantified in cannabis flowers. The total grow cycle of thirty-five cannabis plants ranged from 10 to 24 weeks. The dry flower yields ranged 22-90 g per plant. Most cannabis specimens were CBD-rich varieties (CBD levels from 1.6% to 16.7%, and THC levels from 0.0% to 2.6%, n = 22) used to treat epileptic patients. The THC-rich varieties contained CBD levels ranging from 0.03% to 0.8%, and THC levels from 0.7% to 20.1%, n = 11. Fewer of the samples contained THC:CBD ratios of approximately 1:1 (CBD levels of 3.3-3.8% and THC levels of 2.2-3.7%, n = 2). The most abundant terpenes in the cannabis flowers were beta-caryophyllene, alpha-humulene, guaiol and alpha-bisabolol. CBD-rich varieties showed significant higher levels of beta-caryophyllene and alpha-humulene in comparison with THC-rich varieties. Overall, the study herein provides data concerning medical cannabis crops grown in a region of Brazil that not only guide individual medical cannabis cultivation methods but also aid forensic analyses.


Assuntos
Canabidiol , Canabinoides , Cannabis , Alucinógenos , Maconha Medicinal , Analgésicos , Brasil , Canabinoides/análise , Canabinol/análise , Cannabis/química , Dronabinol/análise , Humanos , Terpenos
5.
Pharmacol Biochem Behav ; 216: 173376, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367279

RESUMO

BACKGROUND: Cocaine use disorder (CUD) is associated with various cognitive deficits that impede patients' functionality, prognosis and therapeutic outcomes. New pharmacological treatments for CUD that could improve cognition are needed. OBJECTIVE: To explore whether cannabidiol (CBD) is superior to placebo to improve cognitive functioning in individuals with CUD. METHODS: We conducted an exploratory analysis of a single site, randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in reducing craving, cocaine use and relapse in individuals with CUD. Seventy-eight individuals diagnosed with CUD were randomized to receive either CBD (800 mg) or placebo for 92 days. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess inhibition (Stop Signal Task; SST), risky decision making (Cambridge Gambling Task; CGT) and visual memory (Pattern Recognition Memory; PRM). This assessment was made on day 1, day 7 and at week 6. We controlled for sex, severity of dependence and baseline cognitive scores in our generalized estimating equation models. RESULTS: Both groups performed similarly on the PRM (correct answers: p = 0.080), SST (stop signal reaction time: p = 0.644) and CGT (quality of decision making: p = 0.994; deliberation time: p = 0.507; delay aversion: p = 0.968; risk taking: p = 0.914) tests. CONCLUSIONS: We found no evidence for 800 mg of CBD to be more efficacious than placebo for improving cognitive outcomes. Clinical trials evaluating pharmacological treatments for CUD should continue to be a research priority.


Assuntos
Canabidiol , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Transtornos Relacionados ao Uso de Substâncias , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cognição , Fissura , Método Duplo-Cego , Humanos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
6.
Phytother Res ; 36(5): 2246-2263, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35393641

RESUMO

Cannabis sativa L. is increasingly emerging for its protective role in modulating neuroinflammation, a complex process orchestrated among others by microglia, the resident immune cells of the central nervous system. Phytocannabinoids, especially cannabidiol (CBD), terpenes, and other constituents trigger several upstream and downstream microglial intracellular pathways. Here, we investigated the molecular mechanisms of a CBD- and terpenes-enriched C. sativa extract (CSE) in an in vitro model of neuroinflammation. We evaluated the effect of CSE on the inflammatory response induced by exposure to lipopolysaccharide (LPS) in BV-2 microglial cells, compared with CBD and ß-caryophyllene (CAR), CB2 receptors (CB2r) inverse and full agonist, respectively. The LPS-induced upregulation of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α was significantly attenuated by CSE and only partially by CBD, whereas CAR was ineffective. In BV-2 cells, these anti-inflammatory effects exerted by CSE phytocomplex were only partially dependent on CB2r modulation and they were mediated by the regulation of enzymes responsible for the endocannabinoids metabolism, by the inhibition of reactive oxygen species release and the modulation of JNK/p38 cascade with consequent NF-κB p65 nuclear translocation suppression. Our data suggest that C. sativa phytocomplex and its multitarget mechanism could represent a novel therapeutic strategy for neuroinflammatory-related diseases.


Assuntos
Canabidiol , Cannabis , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Citocinas/metabolismo , Endocanabinoides/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia , NF-kappa B/metabolismo , Receptor CB2 de Canabinoide/metabolismo
7.
Eur J Pharm Biopharm ; 174: 29-34, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35364254

RESUMO

Efficient delivery of highly lipophilic drugs or prodrugs to the mesenteric lymph nodes (MLN) can be achieved following oral administration with lipids. However, it remains unclear which specific MLN can be targeted and to what extent. Moreover, the efficiency of drug delivery to the retroperitoneal lymph nodes (RPLN) has not been assessed. The aim of this study was to assess the distribution of a highly lipophilic model drug cannabidiol (CBD), known to undergo intestinal lymphatic transport following administration with lipids, into specific MLN and RPLN in rats at various time-points post dosing. In vivo studies showed that at 2 h following administration, significantly higher concentrations of CBD were present in the region second from the apex of the MLN chain. From 3 h following administration, concentrations in all MLN were similar. CBD was also found at substantial levels in RPLN. This study demonstrates that drug concentrations in specific MLN are different, at least at the peak of the absorption process. Moreover, in addition to the MLN, the RPLN may also be targeted by oral route of administration, which may have further implications for treatment of a range of diseases.


Assuntos
Canabidiol , Pró-Fármacos , Administração Oral , Animais , Excipientes , Lipídeos , Linfonodos , Ratos
8.
J Chromatogr A ; 1671: 463020, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35405405

RESUMO

The knowledge of compounds stability in the process of sample preparation for analysis and during analysis itself helps assess the accuracy and precision of estimating their concentration in tested samples. The present paper shows that a significant amount of CBD present in the blood/plasma sample analyzed by means of GC transforms in the hot GC injector not only to 9α-hydroxyhexahydrocannabinol, 8-hydroxy-iso-hexahydrocannabinol, delta-9-tetrahydrocannabinol, Δ8-tetrahydrocannabinol, and cannabinol but also to the trifluoroacetic esters of Δ9-THC and Δ8-THC, when trifuoroacetic acid is used as protein precipitation agent. The amount of those newly revealed CBD transformation products depends on the GC injector temperature and on the extrahent type when extracts of the supernatants centrifuged from human plasma samples are analyzed after their preliminary protein precipitation by trifuoroacetic acid. Although trifuoroacetic acid as a protein precipitating agent has many disadvantages, it is quite often used for this purpose due to its very high protein precipitation efficiency. The results presented in the study demonstrate why the use of trifuoroacetic acid for plasma samples deproteinization should be avoided when CBD is determined by GC.


Assuntos
Canabidiol , Artefatos , Canabidiol/análise , Canabinol/análise , Canabinol/química , Dronabinol/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos
9.
J Org Chem ; 87(9): 6075-6086, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35476908

RESUMO

Despite centuries-long use of Cannabis in human culture and the now ubiquitous claims of its medicinal value, only a small handful of phytocannabinoids have been rigorously evaluated for pharmacological properties. While more than 100 distinct minor cannabinoids have been documented to date, a paucity of studies on their biological activities have been conducted due to a lack of routine access to sufficient quantities for testing. Herein, we report a strategy to prepare several structurally diverse minor cannabinoids deriving synthetically from readily available cannabidiol. Furthermore, we examined their ability to polarize activated microglia toward an anti-inflammatory phenotype using LPS-stimulated BV2 microglial cells. The minor cannabinoids studied, especially cannabielsoin, dehydrocannabielsoin, cannabimovone, and 3'-epicannabimovone, inhibited the production of prototypical pro-inflammatory biomarkers. This study represents the beginning of a systematic mapping of the roles minor cannabinoids may play in the medicinal properties of cannabis used for the treatment of pain and inflammation.


Assuntos
Canabidiol , Canabinoides , Cannabis , Anti-Inflamatórios/farmacologia , Canabidiol/farmacologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico
10.
ACS Chem Neurosci ; 13(8): 1165-1177, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35385645

RESUMO

Cannabidiol is a nonpsychoactive phytocannabinoid produced by the Cannabis sativa plant and possesses a wide range of pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective activities. Cannabidiol functions in a neuroprotective manner, in part through the activation of cellular antioxidant pathways. The glyoxalase pathway detoxifies methylglyoxal, a highly reactive metabolic byproduct that can accumulate in the brain, and contributes to the severity of neurodegenerative diseases, including Alzheimer's disease. While cannabidiol's antioxidant properties have been investigated, it is currently unknown how it may modulate the glyoxalase pathway. In this research paper, we examine the effects of Cannabidiol on cerebellar neurons and in several Caenorhabditis elegans strains. We determined that a limited amount of Cannabidiol can prevent methylglyoxal-mediated cellular damage through enhancement of the neural glyoxalase pathway and extend the lifespan and survival of C. elegans, including a transgenic C. elegans strain modeling Alzheimer's disease.


Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Canabidiol , Lactoilglutationa Liase , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/farmacologia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/farmacologia , Canabidiol/farmacologia , Lactoilglutationa Liase/metabolismo , Longevidade , Aldeído Pirúvico/metabolismo
11.
Drug Deliv ; 29(1): 1272-1281, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35467472

RESUMO

One of the most common complications of cancer chemotherapy is oral mucositis (OM), a serious kind of oral ulceration, but its effective treatment remains a serious challenge. In this study, we used deoxycholic acid and fucoidan to prepare inflammation-targeting nanomicelles (FD), because fucoidan can target inflammation due to its high binding affinity for P-selectin. The hydrophobic anti-inflammatory drug cannabidiol (CBD) was then loaded into the hydrophobic core of FD. The resulting CBD-loaded FD micelles (CBD/FD) had uniform particle size and morphology, as well as favorable serum stability. Moreover, administration of the FD micelles via intravenous injection or in situ dripping in an OM mouse model enhanced the accumulation and retention of CBD. CBD/FD also showed a better anti-inflammatory effect compared to free CBD after local or systemic administration in vivo, while they accelerated OM healing and inhibited Ly6G inflammatory cell infiltration and NF-κB nuclear transcription. Our results show that CBD/FD nanomicelles are a promising agent for OM treatment.


Assuntos
Canabidiol , Estomatite , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Canabidiol/farmacologia , Inflamação/tratamento farmacológico , Camundongos , Micelas , Estomatite/induzido quimicamente , Estomatite/tratamento farmacológico
12.
Sci Rep ; 12(1): 6454, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440801

RESUMO

This study aimed to assess the ultrapure cannabidiol (CBD) antibacterial activity and to investigate the antibacterial activity of the combination CBD + polymyxin B (PB) against Gram-negative (GN) bacteria, including PB-resistant Gram-negative bacilli (GNB). We used the standard broth microdilution method, checkerboard assay, and time-kill assay. CBD exhibited antibacterial activity against Gram-positive bacteria, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis), and Mycobacterium tuberculosis, but not against GNB. For most of the GNB studied, our results showed that low concentrations of PB (≤ 2 µg/mL) allow CBD (≤ 4 µg/mL) to exert antibacterial activity against GNB (e.g., Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii), including PB-resistant GNB. CBD + PB also showed additive and/or synergistic effect against LOS-expressing GND. Time-kill assays results showed that the combination CBD + PB leads to a greater reduction in the number of colony forming units per milliliter compared to CBD and PB alone, at the same concentration used in combination, and the combination CBD + PB was synergistic for all four PB-resistant K. pneumoniae isolates evaluated. Our results show that CBD has translational potential and should be further explored as a repurposed antibacterial agent in clinical trials. The antibacterial efficacy of the combination CBD + PB against multidrug-resistant and extensively drug-resistant GNB, especially PB-resistant K. pneumoniae, is particularly promising.


Assuntos
Canabidiol , Polimixina B , Antibacterianos/farmacologia , Canabidiol/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Bactérias Gram-Negativas , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Polimixina B/farmacologia
13.
J Pharm Biomed Anal ; 214: 114750, 2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35398615

RESUMO

A cannabidiol (CBD) oral solution (Epidiolex®) has been approved by the United States Food and Drug Administration to treat seizure conditions. However, the biomedical and pharmaceutical applications of CBD are hindered partially due to a limited understanding of CBD's pharmacokinetic behaviors, such as its interactions with plasma proteins. Herein, we investigated the molecular interactions between CBD and two plasma proteins, namely, human serum albumin (HSA) and γ-globulin, using biophysical techniques including surface plasmon resonance (SPR), isothermal titration calorimetry, and differential scanning calorimetry, as well as molecular docking. CBD bound to HSA and γ-globulin in an exothermic manner (enthalpy: -9.3 ×104 and -3.7 ×104 kcal/mol, respectively) with a binding affinity of 1.8 × 10-5 and 1.3 × 10-5 M, respectively. The binding ratio between CBD and HSA or γ-globulin was approximately 1:1 and 3:1, respectively. Furthermore, computational modeling suggested that CBD and warfarin may bind to HSA independently, supported by data from a competitive SPR binding assay. Findings from the current study elucidate CBD's plasma protein binding characteristics and shed light on their impact on CBD's pharmacokinetic property.


Assuntos
Canabidiol , Calorimetria/métodos , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica/química , Albumina Sérica Humana/química , Ressonância de Plasmônio de Superfície , gama-Globulinas/metabolismo
14.
Front Immunol ; 13: 870787, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401543

RESUMO

Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/ß-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/ß-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.


Assuntos
COVID-19 , Canabidiol , Enzima de Conversão de Angiotensina 2 , COVID-19/tratamento farmacológico , Células CACO-2 , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Humanos , PPAR gama , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , beta Catenina
15.
Int J Mol Sci ; 23(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35409142

RESUMO

Despite numerous studies conducted over the past decade, the exact role of the cannabinoid system in cancer development remains unclear. Though research has focused on two cannabinoid receptors (CB1, CB2) activated by most cannabinoids, CB2 holds greater attention due to its expression in cells of the immune system. In particular, cytokine-induced killer cells (CIKs), which are pivotal cytotoxic immunological effector cells, express a high-level of CB2 receptors. Herein, we sought to investigate whether inducing CIK cells with cannabidiol can enhance their cytotoxicity and if there are any possible counter effects in its downstream cascade of phosphorylated p38 and CREB using a pancreatic ductal adenocarcinoma cell line (PANC-1). Our results showed that IL-2 modulates primarily the expression of the CB2 receptor on CIK cells used during ex vivo CIK expansion. The autophagosomal-associated scaffold protein p62 was found to co-localize with CB2 receptors in CIK cells and the PANC-1 cell line. CIK cells showed a low level of intracellular phospho-p38 and, when stimulated with cannabidiol (CBD), a donor specific variability in phospho-CREB. CBD significantly decreases the viability of PANC-1 cells presumably by increasing the cytotoxicity of CIK cells. Taken together, in our preclinical in vitro study, we propose that a low effective dose of CBD is sufficient to stimulate the cytotoxic function of CIK without exerting any associated mediator. Thus, the combinatorial approach of non-psychoactive CBD and CIK cells appears to be safe and can be considered for a clinical perspective in pancreatic cancer.


Assuntos
Canabidiol , Canabinoides , Células Matadoras Induzidas por Citocinas , Neoplasias Pancreáticas , Canabidiol/metabolismo , Canabidiol/farmacologia , Canabinoides/farmacologia , Humanos , Neoplasias Pancreáticas/terapia , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide
16.
Can Vet J ; 63(4): 423-426, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35368394

RESUMO

Objective: We aimed to examine the effects of cannabidiol (CBD)-containing hemp oil without delta-9-tetrahydrocannabinol (THC) as a supplemental treatment for canine atopic dermatitis (CAD), as well as its adverse effects, and effects on concurrent drug use in dogs. Animal: In this retrospective case series, 8 dogs with CAD were diagnosed by veterinary dermatologists certified by the Japanese Society of Veterinary Dermatology. Procedure: The medical records of dogs supplemented with CBD-containing hemp oil were evaluated with respect to signalment, physical examination, plasma C-reactive protein concentrations, pharmacologic management, the CAD Extent and Severity Index (4th iteration), and the Pruritus Visual Analog Scale. Results: Overall, CBD, used as a supplement in combination with other drugs, was well-tolerated over a wide dose range and decreased the occurrence of pruritus in dogs with CAD when ingested twice a day. Conclusion: This study provides the first report of supplementation with CBD without THC that was effective in controlling pruritic behavior in dogs with CAD. Clinical relevance: Further controlled studies are required to investigate the dose range, efficacy, and safety.


Effets du cannabidiol sans delta-9-tétrahydrocannabinol sur la dermatite atopique canine : évaluation rétrospective de huit cas. Objectif: Nous avons cherché à examiner les effets de l'huile de chanvre contenant du cannabidiol (CBD) sans delta-9-tétrahydrocannabinol (THC) en tant que traitement complémentaire de la dermatite atopique canine (CAD), ainsi que ses effets indésirables et ses effets sur les médicaments concomitants utilisés chez le chien. Animal: Dans cette étude rétrospective de cas, huit chiens atteints de CAD ont été diagnostiqués par des dermatologues vétérinaires certifiés par la Société japonaise de dermatologie vétérinaire. Procédure: Les dossiers médicaux des chiens supplémentés avec de l'huile de chanvre contenant du CBD ont été évalués en ce qui concerne le signalement, l'examen physique, les concentrations plasmatiques de protéine C-réactive, la gestion pharmacologique, l'indice CAD Extent and Severity Index (4ème itération) et le Pruritus Visual Analog Scale. Résultats: Dans l'ensemble, le CBD, utilisé comme supplément en association avec d'autres médicaments, a été bien toléré sur une large gamme de doses et a diminué l'apparition de prurit chez les chiens atteints de CAD lorsqu'il est ingéré deux fois par jour. Conclusion: Cette étude fournit le premier rapport de supplémentation en CBD sans THC efficace pour contrôler le comportement prurigineux chez les chiens atteints de CAD. Pertinence clinique: D'autres études contrôlées sont nécessaires pour étudier la gamme de doses, l'efficacité et l'innocuité.(Traduit par Dr Serge Messier).


Assuntos
Canabidiol , Dermatite Atópica , Doenças do Cão , Animais , Canabidiol/uso terapêutico , Cannabis , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/veterinária , Doenças do Cão/tratamento farmacológico , Cães , Dronabinol/uso terapêutico , Extratos Vegetais , Estudos Retrospectivos
18.
J Vet Pharmacol Ther ; 45(3): 245-254, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35246858

RESUMO

The use of cannabinoids in veterinary medicine has been increasing exponentially recently and there is little information regarding the pharmacokinetics of cannabinoids except for cannabidiol (CBD) and tetrahydrocannabinol (THC), with even more sparse information related to their native acid forms found in cannabis. Cannabigerol (CBG) is the precursor molecule to cannabinoid formation in the cannabis plant which may have medicinal properties as well, yet there are no publications related to CBG or the native cannabigerolic acid (CBGA) in companion animal species. The aim of this study was to investigate similar dosing of CBG and CBGA from hemp plants that have been used for cannabidiol pharmacokinetic studies. Administration in the fed and fasted state was performed to better understand absorption and retention of these unique hemp-derived cannabinoids in dogs. Results suggest that when providing a hemp-derived CBG/CBGA formulation in equal quantities, CBGA is absorbed approximately 40-fold better than CBG regardless of being given to fed or fasted dogs. After twice daily dosing for two weeks at 2 mg/kg in the fasted and then fed state, no differences in the mean serum CBG (5 ng/ml) or CBGA (250 ng/ml) serum concentrations were observed between states. Importantly, physical examination, complete blood counts, and serum chemistry evaluations over the two weeks suggest no adverse events during this short-term dosing trial.


Assuntos
Canabidiol , Canabinoides , Cannabis , Administração Oral , Animais , Benzoatos , Gluconato de Cálcio , Canabinoides/química , Cannabis/química , Cães , Extratos Vegetais/química
19.
Int Immunopharmacol ; 107: 108693, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35303507

RESUMO

The purpose of this study was to evaluate if phytocannabinoids, synthetic cannabidiol (CBD), and tetrahydrocannabivarin (THCV), and their combination, could protect mice from Paclitaxel-induced peripheral neuropathy (PIPN). Six groups of C57BL/6J mice (n = 6) were used in this study. The mice were given paclitaxel (PTX) (8 mg/kg/day, i.p.) on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for behavioral parameters, and dorsal root ganglions (DRG) were collected from the animals and subjected to RNA sequencing and westernblot analysis at the end of the study. On cultured DRGs derived from adult male rats, immunocytochemistry and mitochondrial functional assays were also performed. When compared to individual treatments, the combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by twofold. Targets for CBD and THCV therapy were identified by KEGG (RNA sequencing). PTX reduced the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase while increasing the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-ß, NLRP3 inflammasome, and caspase 3 in DRG homogenates of mice. Combination therapy outperformed monotherapy in reversing these protein expressions. The addition of CBD and THCV to DRG primary cultures reduced mitochondrial superoxides while increasing mitochondrial membrane potentials. WAY100135 and rimonabant altered the neuroprotective effects of CBD and THCV respectively by blocking 5-HT1A and CB1 receptors in mice and DRG primary cultures. The entourage effect of CBD and THCV against PIPN appears to protect neurons in mice via 5HT1A and CB1 receptors respectively.


Assuntos
Canabidiol , Canabinoides , Neuralgia , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Canabinoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Paclitaxel/efeitos adversos , Ratos , Roedores
20.
Drug Alcohol Depend ; 234: 109388, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35316689

RESUMO

BACKGROUND: Mood, sleep and pain problems are common comorbidities among treatment-seeking cannabis-dependent patients. There is limited evidence suggesting treatment for cannabis dependence is associated with their improvement. This study explored the impact of cannabis dependence treatment on these comorbidities. METHODS: This is a secondary analysis from a 12-week double-blind placebo-controlled trial testing the efficacy of a cannabis agonist (nabiximols) against placebo in reducing illicit cannabis use in 128 cannabis-dependent participants. Outcome measurements including DASS-21 (Depression, Anxiety, and Stress subscales); Insomnia Severity Index (ISI); and Brief Pain Inventory (BPI), were performed at weeks 0, 4, 8, 12 and 24. Each was analysed as continuous outcomes and as binary cases based on validated clinical cut-offs. RESULTS: Among those whose DASS and ISI scores were in the moderate to severe range at baseline, after controlling for cannabis use, there was a gradual decrease in severity of symptoms over the course of the trial. BPI decreased significantly until week 12 and then rose again in the post-treatment period during weeks 12-24. Neither pharmacotherapy type (nabiximols vs placebo) nor number of counselling sessions contributed significant explanatory power to any of the models and were excluded from the final analyses for both continuous and categorical outcomes. CONCLUSIONS: Participants in this trial who qualified as cases at baseline had elevated comorbidity symptoms. There was no evidence that nabiximols treatment is a barrier to achieving reductions in the comorbid symptoms examined. Cannabis dependence treatment reduced illicit cannabis use and improved comorbidity symptoms, even when complete abstinence was not achieved.


Assuntos
Cannabis , Alucinógenos , Abuso de Maconha , Maconha Medicinal , Analgésicos/uso terapêutico , Canabidiol , Agonistas de Receptores de Canabinoides/uso terapêutico , Comorbidade , Método Duplo-Cego , Dronabinol , Combinação de Medicamentos , Alucinógenos/uso terapêutico , Humanos , Abuso de Maconha/terapia , Maconha Medicinal/uso terapêutico , Dor/tratamento farmacológico , Sono , Resultado do Tratamento
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