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Caracterización de la actividad inmunomoduladora de diferentes quimiotipos de Cannabis sativa L enriquecidos en terpenos
Abstract
Resumen: Las enfermedades autoinmunes agrupan alrededor de 80 patologías que, en conjunto, generan un alto impacto en salud pública en el mundo y así mismo en Colombia. Esto se debe directamente a la alta prevalencia de estas, la incapacidad física y los costos que genera para el paciente y el sistema de salud (1, 2). Un ejemplo de estas enfermedades es la Artritis Reumatoide (AR), en la cual las células del sistema inmune como monocitos y macrófagos, entre otros, pierden la capacidad de reconocer las células propias del individuo y las ataca por error; generando una respuesta inmune crónica y un ambiente inflamatorio exacerbado, que conlleva a la destrucción continua de las articulaciones (3). En la búsqueda de nuevas fuentes de medicamentos que puedan utilizarse en el manejo de este tipo de padecimientos, aquellos provenientes de plantas han venido cobrando gran importancia. Este es el caso de Cannabis sativa, en la que se ha encontrado un gran potencial fitoterapéutico complementario y/o alternativo, para el manejo de diferentes enfermedades entre las que se encuentran las inflamatorias (4). En este contexto, en este trabajo se caracterizó la actividad inmunomoduladora de diferentes quimiotipos del Cannabis, sobre células proliferantes mononucleares humanas a fin de comprender su efecto en procesos inflamatorios, extrapolables a la AR. Los resultados obtenidos, revelan como la composición química de diferentes quimiotipos de la planta, afecta de diferente forma la proliferación in vitro de las células. El extracto con mayor actividad anti proliferativa fue el denominado M1, quien tiene además de los Cannabinoides tradicionales THC:CBD (1:3), una mezcla única y diferencial de terpenos como el α-Terpineol, el α-Guaiene, el Agarospirol y el Caryophyllen de los que se sabe, tienen actividad anti inflamatoria que podría explicar la mayor actividad de este extracto (5). Los análisis de viabilidad también mostraron que el extracto M1, protege a las células de la muerte por apoptosis o necrosis. Lo cual propone que el mecanismo de control de la proliferación que ejerce el extracto podría estar enfocado en la liberación de mediadores inflamatorios o en la inactivación directa de las células inmunes proliferantes.
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To estimate the global burden of rheumatoid arthritis (RA), as part of the Global Burden of Disease 2010 study of 291 conditions and how the burden of RA compares with other conditions.
The optimum case definition of RA for the study was the American College of Rheumatology 1987 criteria. A series of systematic reviews were conducted to gather age-sex-specific epidemiological data for RA prevalence, incidence and mortality. Cause-specific mortality data were also included. Data were entered into DisMod-MR, a tool to pool available data, making use of study-level covariates to adjust for country, region and super-region random effects to estimate prevalence for every country and over time. The epidemiological data, in addition to disability weights, were used to calculate years of life lived with disability (YLDs). YLDs were added to the years of life lost due to premature mortality to estimate the overall burden (disability-adjusted life years (DALYs)) for RA for the years 1990, 2005 and 2010.
The global prevalence of RA was 0.24% (95% CI 0.23% to 0.25%), with no discernible change from 1990 to 2010. DALYs increased from 3.3 million (M) (95% CI 2.6 M to 4.1 M) in 1990 to 4.8 M (95% CI 3.7 M to 6.1 M) in 2010. This increase was due to a growth in population and increase in aging. Globally, of the 291 conditions studied, RA was ranked as the 42nd highest contributor to global disability, just below malaria and just above iodine deficiency (measured in YLDs).
RA continues to cause modest global disability, with severe consequences in the individuals affected.
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
Effective treatment of active rheumatoid arthritis (RA) requires early diagnosis and early disease modifying antirheumatic drug (DMARD) treatment to have an impact on long term morbidity and mortality. Clinical criteria would facilitate early referral of the patient with suspected RA to a rheumatologist for definitive diagnosis and initiation of DMARD treatment at that point in the disease most likely to have an impact on the long term outcome.
To develop a referral recommendation that may serve as a clinical guide for primary care doctors, enabling them to identify patients with suspected RA during the early inflammatory stages.
Key points of the referral criteria were formed based on a thorough literature review targeting early RA, early arthritis clinics, DMARD treatment for early RA, prognostic factors of disease progression, early RA clinical trials, and quality of life. Evidence was graded using the methods defined by Shekelle et al. A draft version of the criterion was circulated among the authors for critical evaluation. A consensus integrated these comments.
Clinical evidence strongly supports the observations that structural damage occurs early in active RA and that early DMARD treatment improves the long term outcome of the disease. The observations indicate that rapid referral to a rheumatologist is advised when RA is suspected. This may be supported by the presence of any of the following: >or=3 swollen joints, metatarsophalangeal/metacarpophalangeal involvement, and morning stiffness of >or=30 minutes.
The proposed early referral recommendation is a viable tool for primary care doctors to identify potential patients with active RA early in the disease. Early referral to a rheumatologist for definitive diagnosis and early DMARD treatment should improve the long term outcome of RA.
Previous studies have estimated a prevalence of a broad grouping of autoimmune diseases of 3.2%, based on literature review of studies published between 1965 and 1995, and 5.3%, based on national hospitalization registry data in Denmark. We examine more recent studies pertaining to the prevalence of 29 autoimmune diseases, and use these data to correct for the underascertainment of some diseases in the hospitalization registry data. This analysis results in an estimated prevalence of 7.6-9.4%, depending on the size of the correction factor used. The rates for most diseases for which data are available from many geographic regions span overlapping ranges. We also review studies of the co-occurrence of diseases within individuals and within families, focusing on specific pairs of diseases to better distinguish patterns that may result in insights pertaining to shared etiological pathways. Overall, data support a tendency for autoimmune diseases to co-occur at greater than expected rates within proband patients and their families, but this does not appear to be a uniform phenomenon across all diseases. Multiple sclerosis and rheumatoid arthritis is one disease pair that appears to have a decreased chance of coexistence.
Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood and can be broadly categorized into four pathways: apoptosis, inhibition of proliferation, suppression of cytokine and chemokine production and induction of T regulatory cells (T regs). Studies from our laboratory have focused on mechanisms of apoptosis induction by natural and synthetic cannabinoids through activation of CB2 receptors. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.
Facultad de Medicina y a la asociación Colombiana de Reumatología (ASOREUMA), por la financiación de esta iniciativa de investigación
- A La Fundación Universitaria Juan
- N Corpas
A la Fundación Universitaria Juan N. Corpas, Facultad de Medicina y a la asociación Colombiana de
Reumatología (ASOREUMA), por la financiación de esta iniciativa de investigación.
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