Article

Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay

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Abstract

Background: Chronic pain is a major therapeutic problem in kidney transplant patients owing to nephrotoxicity associated with nonsteroidal antiiflammatory drugs. Benefits in chronic pain treatment with cannabidiol (CBD) have been reported. This study assesses the effect, safety, and possible drug interactions in kidney transplant patients treated with CBD for chronic pain. Methods: We assessed patients who asked to receive CBD for pain treatment. Doses were increased from 50 to 150 mg twice a day for 3 weeks. Creatinine, blood count, liver function, liver enzymes, and drug levels were determined every 48 hours the first week and then once a week thereafter. Results: We assessed 7 patients with a mean age of 64.5 years (range, 58-75 years). CBD initial dose was 100 mg/d, CBD dose reduction to 50 mg/d has been done on day 4 to patient 1 for persistent nausea. Tacrolimus dose reduction in patient 3 was undertaken on days 4, 7, and 21 owing to persisting elevated levels (even before CBD) and itching, and on day 21 in patient 5. Tacrolimus levels decreased in patient 2 but were normal in the control 1 week later. Patients on cyclosporine were stable. Adverse effects were nausea, dry mouth, dizziness, drowsiness, and intermittent episodes of heat. CBD dose decrease was required in 2 patients. Two patients had total pain improvement, 4 had a partial response in the first 15 days, and in 1 there was no change. Conclusions: During this follow-up, CBD was well-tolerated, and there were no severe adverse effects. Plasma levels of tacrolimus were variable. Therefore, longer follow-up is required.

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... As CBD can interact with many targets in the CNS, animal and human studies were conducted to evaluate the therapeutic potentials of CBD in different conditions [49][50][51] (Table II). Its antiepileptic [3,52], analgesic [53,54], neuroprotective [55][56][57][58], antidepression [59,60], anxiolytic [60,61], antipsychotic [28,62], and sedative effects [63,64] were studied and might be useful in treating brain disorders. ...
... [74,75]. Daily CBD dosing, however, was shown to improve pain in an open-label study [53]. Seven kidney transplant patients with different kinds of chronic pain (fibromyalgia, osteoarticular, neuropathic) were given oral CBD for three weeks, titrating from 100 to 300 mg/day. ...
... Seven kidney transplant patients with different kinds of chronic pain (fibromyalgia, osteoarticular, neuropathic) were given oral CBD for three weeks, titrating from 100 to 300 mg/day. Partial or total pain improvements were experienced in six patients with a reduction in pain intensity and pain limitation perception [53]. Whilst there is promising evidence for the use of CBD in inflammatory pain conditions, systematic reviews have shown that oral and inhaled cannabis could only provide limited and temporary relief in chronic pain [76,77]. ...
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The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.
... Current findings have suggested CBD in the management of chronic pain. No approved pharmaceutical medicine is available containing CBD alone (Cuñetti et al., 2018;Argueta et al., 2020;Verrico et al., 2020;FDA, 2022). However, a combined product of THC/CBD in a ratio of 1:1, nabiximols, may make us think about its likelihood of action in pain control. ...
... The pain relief effect of THC and CBD with improved side effects compared to placebo was found, demonstrating their capacity to ameliorate neurogenic symptoms (Wade et al., 2003). Cuñetti et al. (2018) assessed CBD's safety, effect, and probable drug interactions for chronic pain in patients with a kidney transplant. CBD was well tolerated, with no acute side effects. ...
... Studies assessing CBD alone for pain relief are scant and two of three use methodologies with very weak strength of evidence. 51,52 The first two trials were open label single arm studies assessing pain relief from human papillomavirus (HPV) vaccine or renal transplant. While study participants had qualitatively lower pain scores over time after CBD use, researchers could not determine whether benefits seen in these trials were due to CBD, natural alleviation of symptoms over time, or placebo. ...
... A lack of intention-to-treat methodology with a high withdrawal rate may have confounded the first trial. 51,52 Similarly, the first trial used CBD-enriched hemp oil; hemp oil constituents (other than CBD) might have provided some of the benefits. 51 One randomized, double-blind, multi-group crossover trial assessed pain and spasticity. ...
Article
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After completing the activity, learners will be able to ● Discuss cannabidiol's known pharmacologic profile ● Identify FDA-approved indications for prescription cannabidiol and other indications in which research is promising ● Distinguish the FDA-approved cannabidiol from various nonprescription products in terms of quality and risk/benefit profile ● Maximize the pharmacist's role in helping patients who are good candidates for prescription cannabidiol or use nonprescription cannabidiol products either with or without other prescription drug therapies After completing the continuing education activity, pharmacy technicians will be able to ● Discuss the basic facts about cannabidiol products ● Acquire reputable sources for patients who have an interest in cannabidiol to find information ● Distinguish between nonprescription and prescription cannabidiols ● Infer when to refer patients to the pharmacist for recommendations or referral
... These findings are similar to 2 recent RCTs examining the short-term (2-hour follow-up) analgesic effects of a single dose of CBD were no significant difference between placebo was seen. 2,14 Our results contradict 2 small previous trials 13,45 investigating CBD as an analgesic therapy. However, in both studies the patients were treated with a mix of CBD and THC (up to 50%). ...
... An uncontrolled trial assessed 7 patients with kidney transplant receiving 300-mg CBD and reported an analgesic effect in 4 of 7 patients. 13 The authors did not explain how pain was quantified, and the CBD solution used had a CBD to THC ratio of 30:1 that resulted in a THC dose of 10 mg which could be intoxicating with psychotropic side effects. 27 ...
Article
Cannabidiol (CBD) is increasingly used as analgesic medication even though the recent International Association for the Study of Pain presidential task force on cannabis and cannabinoid analgesia found a lack of trials examining CBD for pain management. The present trial examines CBD as add on analgesic therapy in patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain intensity despite therapy. Using a randomized double-blind, placebo-controlled design, patients received synthetic CBD 20-30mg or placebo daily for 12 weeks. Primary outcome was pain intensity during the last 24 hours (0-100mm); safety outcomes were percentage of patients experiencing adverse events and a characterization of serious adverse events. Explorative outcomes included change in Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS) and Health Assessment Questionnaire (HAQ-DI).One hundred and thirty-six patients were randomized 129 were included in the primary analysis. Between group difference in pain intensity at 12 weeks was 0.23mm (95%CI -9.41 to 9.90; p = 0.96). 22% patients receiving CBD and 21% receiving placebo experienced a reduction in pain intensity of more than 30mm. We found neither clinically nor statistically significant effect of CBD for pain intensity in patients with hand osteoarthritis and psoriatic arthritis when compared to placebo. Additionally, no statistically significant effects were found on sleep quality, depression, anxiety, or pain catastrophizing scores.
... Russo et al. [54] who examined chronic neuropathic pain in 20 patients (10 had neuropathic pain) with MS administering nabiximol, revealed that 1 month of 800 μL/day of nabiximol successfully reduced pain rating and improved the quality of life in all 10 subjects. Cuñetti et al. [55] who examined chronic post-transplant pain in 7 subjects who received 100 mg/day of CBD revealed that 6 out of 7 patients had a positive partial response in improvement of pain control [55]. Topical cream was assessed in 3 patients with nociceptive pain by Maida and Corban [56] who revealed clinically significant analgesia (p < 0.05) associated with 1 mL of topical cannabinoid cream, which reduced opioid utilization in all 3 patients. ...
... Russo et al. [54] who examined chronic neuropathic pain in 20 patients (10 had neuropathic pain) with MS administering nabiximol, revealed that 1 month of 800 μL/day of nabiximol successfully reduced pain rating and improved the quality of life in all 10 subjects. Cuñetti et al. [55] who examined chronic post-transplant pain in 7 subjects who received 100 mg/day of CBD revealed that 6 out of 7 patients had a positive partial response in improvement of pain control [55]. Topical cream was assessed in 3 patients with nociceptive pain by Maida and Corban [56] who revealed clinically significant analgesia (p < 0.05) associated with 1 mL of topical cannabinoid cream, which reduced opioid utilization in all 3 patients. ...
Article
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Background/aims: Cannabis is increasingly used in the management of pain, though minimal research exists to support its use since approval. Reduction in stigma has led to a growing interest in pharmaceutical cannabinoids as a possible treatment for lower back pain (LBP). The objective of this review was to assess the role and efficacy of cannabis and its derivatives in the management of LBP and compile global data related to the role of cannabis in the management of LBP in an aging population. Methods: A systematic review was conducted using predetermined keywords by 3 independent researchers. Predetermined inclusion and exclusion criteria were applied, and 23 articles were selected for further analysis. Results: Studies identified both significant and insignificant impacts of cannabis on LBP. Contradicting evidence was noted on the role of cannabis in the management of anxiety and insomnia, 2 common comorbidities with LBP. The existing literature suggests that cannabis may be used in the management of LBP and comorbid symptoms. Conclusions: Further research is needed to consider cannabis as an independent management option. There is a lack of evidence pertaining to the benefits of cannabis in an aged population, and thus, additional research is warranted to support its use in the aged population.
... The review provided a coherent overview of how cannabinoids and cannabis may be used within the context of renal pathologies however it did not mention that cannabinoids may be applicable to patients who have undergone renal transplantation for endstage chronic renal failure 3,4 . Chronic pain is a frequent issue in this patient group which is often due to underlying disease or intercurrent diseases. ...
... Transplant patients are restricted in their use of nonsteroidal anti-inflammatory drugs (NSAIDS) due to their nephrotoxic side effects. Whilst evidence is limited, cannabidiol (CBD) has displayed the potential to alleviate this pain, whilst being well tolerated with calcineurin inhibitors which are the foundation of immunosuppression for renal transplant patients 3 . Despite potential pharmacokinetic advantages, activation of the endocannabinoid system has been shown to down regulate the inflammatory response of macrophages and mesenchymal stromal cells and therefore may further contribute to the immunosuppression in this patient group 5 . ...
Article
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The recently published article in the Journal of Urology titled ‘Cannabinoids in urology. Which benign conditions might they be appropriate to treat: A systematic review’, explores the broad role of cannabinoids in the treatment of benign urological diseases. Whilst the review successfully appraises a significant amount of evidence, it was unable to discuss each urological application of cannabinoids in depth due to the current evidence base suffering from a distinct lack of in-depth analysis as well as due to manuscript word-limitations. The authors of the original review would like to use this commentary as an opportunity to further expand upon key elements that were not previously discussed
... Pain control was found to be better at low doses of CBD, and in fact, worsened with increasing doses of CBD. The doses were not decreased until day 21 of the three-week study, so potentially further extension of the study may have led to more positive outcomes (76). ...
... These fluctuations in tacrolimus, however, were easily controlled within a week of dose adjustments and were unable to be linked to an interaction between CBD and calcineurin inhibitors. Cyclosporine levels in these patients were stable and remained unchanged throughout the course of the study (76). ...
Article
Chronic pain can be recurrent or constant pain that lasts for longer than three months and can result in disability, suffering, and a physical disturbance. Related to the complex nature of chronic pain, treatments have a pharmacological and non-pharmacological approach. Due to the opioid epidemic, alternative therapies have been introduced, and components of the cannabis Sativa, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have gained recent interest as a choice of treatment. The exact mechanism for cannabidiol is currently unknown, but unlike the CBD's psychoactive counterpart, THC, the side effects of CBD itself have been shown to be overall much more benign. The current pharmaceutical products for the treatment of chronic pain are known as nabiximols, and they contain a ratio of THC combined with CBD, which has been promising. This review focuses on the treatment efficacy of CBD, THC: CBD based treatments for chronic pain and adverse events with each.
... 27 The findings of this study showed that PD patients consider physical and psychological complications after kidney transplantation as important reasons for their reluctance to transplant. Side effects of immunosuppression regimes, 28 pain, 29 infection, 30 psychological distress 31 and depression 32 are among the most important complications reported after kidney transplantation. Therefore, the results of this study confirm the findings of previous studies and show that the fear of physical and psychological complications is one of the reasons for the reluctance of kidney transplantation among PD patients. ...
Article
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Background Even though kidney transplantation has better outcomes compared to dialysis therapies, some patients undergoing peritoneal dialysis (PD) refuse to consider kidney transplantation. Identification of the underlying reason for patient refusal may improve patients’ acceptance of kidney transplantation. Aim The aim of this study was to describe the reasons given by Iranian PD patients for refusing kidney transplantation. Method Eighteen patients undergoing PD participated. Data were collected using semi-structured interviews and were analysed using conventional qualitative content analysis. Results The analysis leads to the emergence of two categories and six subcategories: negative outcomes of kidney transplantation (financial burden, psychosocial problems and physical complications) and doubtful factors for kidney transplantation (negative attitudes towards kidney transplantation, long waiting time for kidney transplantation and compatibility of PD with daily life). The financial burden and long waiting time for kidney transplantation were the most important factors in the reluctance of kidney transplantation by PD patients. Implication for practice Patients undergoing PD declined kidney transplantation for several reasons, such as financial burden, fear of post-transplantation side effects, long waiting time for kidney transplantation. Reducing the time of kidney transplantation and insurance coverage of transplant costs can change the attitude of PD patients towards transplant.
... The search term "cannabis" AND "pain" was used in PubMed and results filtered for clinical trials; papers that were not relevant to pain were removed from the search. Of the 27 clinical trials described in Table 2, two-thirds of the trials reported a clear significant beneficial effect in the majority of their patients [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. Four of the trials found no significant benefit in comparison with placebo [80][81][82][83]; therefore, overall owing to a clear majority significant benefit in the use of CBPM to treat pain. ...
Article
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Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.
... However, the evidence for CBD for treating pain is limited and negative, or derived from sub-quality studies (ie, small sample sizes and lack of prospective, blinded, randomized, placebo control studies). [31][32][33][34][35] Similarly, 11% of adult Americans regularly had feelings of worry, nervousness, or anxiety. 36 Despite the frequency of marketing CBD for the treatment of depression and anxiety, the evidence for CBD treatment anxiety is also mixed. ...
Article
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Introduction: Cannabidiol (CBD) products are available nearly nationwide in the US and can coexist with medical or recreational programs. North Carolina (NC) is an example of a state with a program dedicated to integrating hemp cultivation and medicinal CBD exclusively, containing a multitude of retailers selling it as a primary product. The Food and Drug Administration (FDA) mandates that non-FDA approved CBD products cannot be marketed using medical or health-related claims and has sent warning letters to retailers violating these terms. We aim to characterize the online content of the NC CBD market by analyzing retailers' websites to determine whether hemp/CBD shops comply with FDA regulations in terms of medical claims and analyze the claimed CBD content and price of products offered online. Methods: We randomly selected three CBD retailers from the ten most populated cities of NC. We analyzed their website content: product type, medical claims, other disclaimers, price, and CBD content. Results: We found that edible, oral, inhalable, and topical products are offered in similar proportions. Word analysis of product description revealed that "pain" and "pain relief" were the most common medical claim, followed by inflammation and anxiety. Health claims were mostly related to wellbeing. Other attributes indicate that products are associated with pleasant flavors or sensations (ie, cool, lavender, delicious, honey, menthol), which resembles the strategies used for tobacco advertisement. Most products (61%) claimed to contain less than 1000 mg of CBD. The median price of products ranged from $15-30 per 300 mg. We found a positive correlation between CBD content and price. Discussion: Our data demonstrate that the NC online CBD market does not comply with FDA regulations, primarily targets patients with pain, inflammation, or anxiety, and offers products with low CBD concentration and high prices. New policies should limit the access and online promotion of non-pharmaceutical grade CBD products.
... This is a nonrandomized trial, without placebo control, and adverse effects such as nausea, dry mouth, dizziness, drowsiness, and intermittent episodes of heat were reported. 101 Recently, the efficacy of topical CBD oil in the symptomatic relief of peripheral neuropathy through the transdermal application of CBD oil has been shown to improve pain in patients with peripheral neuropathy. 102 In another clinical trial, they evaluated the effects of CBD extract and the concomitant use of opioids. ...
Article
The incidence of chronic pain is around 8% in the general population, and its impact on quality of life, mood, and sleep exceeds the burden of its causal pathology. Chronic pain is a complex and multifaceted problem with few effective and safe treatment options. It can be associated with neurological diseases, peripheral injuries or central trauma, or some maladaptation to traumatic or emotional events. In this perspective, animal models are used to assess the manifestations of neuropathy, such as allodynia and hyperalgesia, through nociceptive tests, such as von Frey, Hargreaves, hot plate, tail-flick, Randall & Selitto, and others. Cannabidiol (CBD) has been considered a promising strategy for treating chronic pain and diseases that have pain as a consequence of neuropathy. However, despite the growing body of evidence linking the efficacy of CBD on pain management in clinical and basic research, there is a lack of reviews focusing on chronic pain assessments, especially when considering pre-clinical studies, which assess chronic pain as a disease by itself or as a consequence of trauma or peripheral or central disease. Therefore, this review focused only on studies that fit our inclusion criteria: (1) used treatment with CBD extract; (2) used tests to assess mechanical or thermal nociception in at least one of the following most commonly used tests (von Frey, hot plate, acetone, Hargreaves, tail-flick, Randall & Selitto, and others); and (3) studies that assessed pain sensitivity in chronic pain induction models. The current literature points out that CBD is a well-tolerated and safe natural compound that exerts analgesic effects, decreasing hyperalgesia, and mechanical/thermal allodynia in several animal models of pain and patients. In addition, CBD presents several molecular and cellular mechanisms of action involved in its positive effects on chronic pain. In conclusion, using CBD seems to be a promising strategy to overcome the lack of efficacy of conventional treatment for chronic pain.
... Confounding effects of drug interactions with coadministered drugs cannot be excluded [71]. There have been case reports and/or series where altered tacrolimus concentrations have been observed with concurrent use of cannabidiol only or predominant products [72,73]. However, there are also case reports with tetrahydrocannabinol containing and predominant products [74,75]. ...
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Introduction: : In light of the widespread use of non-prescribed and prescribed cannabidiol, the use of cannabidiol with other medications is likely, and this may result in drug interactions. Areas covered: : We aimed to ascertain if clinical guidance could be provided on the dose range at which cannabidiol drug interactions are likely to occur with concurrently prescribed medicines. Literature searches were conducted in Embase, MEDLINE, and PubMed from database inception to January 2022 using Emtree and MeSH terms. Reference list screening yielded further studies. Using currently available data, likely drug interactions of which prescribers of cannabidiol need to be aware, at the doses likely to cause clinically significant interactions, and drug dosing changes that may be needed are highlighted. Expert opinion: : We have provided an overview of evidence-based pharmacokinetic predictions and general guidance about the dose range at which clinically relevant cannabidiol drug interactions are likely. For an individual patient, there are inherent limitations in providing clinical guidance due to gaps in specific drug dose-response data and knowledge of individual pharmacokinetic profiles, including different co-morbidities, and concurrent medicines. Clinician awareness of cannabinoid pharmacology, along with clinical and therapeutic drug monitoring are current best practice approaches to manage cannabinoid drug interactions.
... Além desses, o uso dos canabinoides por via inalatória, causaram também tosse, odinofagia e uma sensação de "gosto ruim" na boca. Foi constatado, ainda, um efeito de tolerância por parte dos receptores conforme o uso, ou seja, a mesma dose de cannabis usada de forma prolongada pode se tornar menos eficaz ao longo do tempo, sendo necessário reajustes de doses(CUÑETTI et al., 2018;VAN DE DONK et al., 2019).Como limitações do estudo podemos destacar a escassez de ensaios clínicos randomizados, com amostras pequenas e por um curto período de tempo, entretanto, apresentam uma boa recomendação, abrindo espaço para novas pesquisas na área e maiores descobertas. Devido à quantidade reduzida de ECR, e a ausência de divergências entre eles, a comparação dos resultados foi bastante restringida. ...
Article
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RESUMO: INTRODUÇÃO: A Fibromialgia é uma desordem musculoesquelética de curso insidioso e intermitente, que impacta negativamente na qualidade de vida do indivíduo tendo em vista a gama de sintomas que caracterizam o quadro clínico, levando até mesmo à incapacidade e ao desenvolvimento de transtornos psíquicos decorrentes do sofrimento vivido. Têm-se buscado diversas alternativas de tratamento para obter um controle clínico adequado, e dentre as opções propostas, a terapia com canabinoides têm surgido com um potencial relevante. OBJETIVO: Avaliar a efetividade dos canabinóides no tratamento da Fibromialgia e seus efeitos colaterais. METODOLOGIA: Consiste em uma revisão sistemática da literatura, de caráter qualitativo, composta por 04 ensaios clínicos randomizados, encontrados em bibliotecas virtuais utilizando-se dos Descritores em Ciências da Saúde (DeCS). RESULTADOS: Observou-se que os derivados medicinais da cannabis vêm demonstrando diversas vantagens em seu uso, como os variados tipos de apresentação, concentração e adaptação para o caso clínico dos mais diversos pacientes. CONCLUSÃO: Os canabinoides são efetivos no controle da doença, proporcionando melhora da qualidade de vida dos pacientes, e sendo, portanto, uma opção para associação ou substituição das drogas mais utilizadas atualmente. Além disso, apresentaram efeitos adversos leves, sendo bem tolerados pelos pacientes. PALAVRAS-CHAVE: Fibromialgia. Dor crônica. Cannabis.
... The results of this narrative systematic review generate information about cannabisdrug interactions based on the available data. Furthermore, in the cases where there was no explicit information of changes in pharmacokinetic and clinical parameters, quantitative changes were established with the information available in the relevant publication [16,17,[19][20][21][22]32,[38][39][40], allowing for an extension of the option to classify the clinical relevance of cannabis-drug interactions. ...
Article
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Concomitant use of cannabis with other drugs may lead to cannabis–drug interactions, mainly due to the pharmacokinetic mechanism involving the family of CYP450 isoenzymes. This narrative systematic review aimed to systematize the available information regarding clinical relevance of cannabis–drug interactions. We utilized the PubMed/Medline database for this systematic review, using the terms drug interactions and cannabis, between June 2011 and June 2021. Articles with cannabis–drug interactions in humans, in English or Spanish, with full-text access were selected. Two researchers evaluated the article’s inclusion. The level of clinical relevance was determined according to the severity and probability of the interaction. Ninety-five articles were identified and twenty-six were included. Overall, 19 pairs of drug interactions with medicinal or recreational cannabis were identified in humans. According to severity and probability, 1, 2, 12, and 4 pairs of cannabis–drug interactions were classified at levels 1 (very high risk), 2 (high risk), 3 (medium risk), and 5 (without risk), respectively. Cannabis–warfarin was classified at level 1, and cannabis–buprenorphine and tacrolimus at level 2. This review provides evidence for both the low probability of the occurrence of clinically relevant drug interactions and the lack of evidence regarding cannabis–drug interactions.
... Evidence in FMR1 knockout mice suggests CB2 receptor is necessary for protection against neuropathic pain, raising interest in targeting this receptor for treatment (77). A controlled trial examined pain in patients with multiple sclerosis, spinal cord, and other neurological conditions found pain control improved with CBD (78) in addition to two other studies that found pain relief (79,80). CBD is also being explored as an intervention in FXS (81) in an open-label trial (82) because of its benefits on sleep quality, anxiety (83), and cognitive impairment (84). ...
Article
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Individuals with the fragile X premutation report symptoms of chronic pain from multiple systems, have increased incidence of comorbid conditions where pain is a prominent feature, and pathophysiology that supports disrupted pain regulation, inflammation, and energy imbalance. Less is known about how pain manifests for the subpopulation of carriers that develop the motor and cognitive changes of fragile X-associated tremor and ataxia syndrome (FXTAS), and how pain may differ between men and women. We gathered data collected from 104 males and females with FXTAS related to chronic pain, comorbid conditions related to pain, and medications used for pain control to further explore the types of pain experienced and to better characterize how individuals with the fragile X premutation experience pain sensation across genders. We found that women experience significantly more pain symptoms than men, particularly allodynia (20 vs. 2.0%, p = 0.008), peripheral neuropathy pain (43.9 vs. 25.4%, p = 0.0488), migraine (43.9 vs. 14.5%, p = 0.0008), fibromyalgia (26.8 vs. 0%, p = 0.0071) and back pain (48.5 vs. 23.4%, p = 0.008). We found onset of peripheral neuropathy predicts the onset of ataxia (β = 0.63 ± 0.25, p = 0.019) and tremor (β = 0.56 ± 0.17, p = 0.004) across gender. Women also report significantly more anxiety (82.9 vs. 39.7%, p < 0.001), which has implications for ideal pain treatment. These pain symptoms need to be recognized in the medical history and treated appropriately, with consideration for overlapping comorbidities.
... Cannabis also acts as a substrate for P-glycoprotein, a transport protein essential for pumping drugs into the gastrointestinal tract lumen for excretion (15). There are case reports of cannabis use influencing tacrolimus metabolism in a hematopoietic stem cell transplant patient (16) as well as a kidney transplant recipient (17). A 2019 case report documented the development of PRES 5 days post-liver transplantation in a patient who had been initiated on tacrolimus in the context of a history of ingesting 2-4 medical cannabis lozenges ...
Article
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A 45-year-old female presented to hospital with confusion and visual disturbances. She had undergone a liver transplant 3 years prior for cirrhosis secondary to primary biliary cholangitis. Computed tomography and magnetic resonance imaging of the brain showed features consistent with posterior reversible encephalopathy syndrome. Her medications included tacrolimus, sirolimus, and prednisone. She reported smoking 4 grams of cannabis per day. Following cessation of tacrolimus, the patient’s encephalopathy and visual disturbances resolved. To our knowledge, this case represents the longest time elapsed from liver transplantation to the development of tacrolimus-associated posterior reversible encephalopathy syndrome in the literature. This case highlights the potential danger of cannabis use in transplant recipients who are on immunosuppressants such as tacrolimus. Clinicians should have a high index of suspicion for posterior reversible encephalopathy syndrome in post-transplant patients presenting with altered mental status, even years after liver transplantation, and be familiar with potential interactions between cannabis and immunosuppressants.
... [72] Additionally, recent human studies have reported a therapeutic signal for CBD for transplant acceptance (decreasing the development of graft vs. host disease after hematopoietic cell transplants) [73] and reducing some of the positive symptoms of schizophrenia (1000 mg/day, PO) [74]. Other recent reports have failed to demonstrate CBD efficacy to reduce symptoms of ulcerative colitis (up to 500 mg/day, PO) [75], chronic pain in kidney transplant patients (50 -300 mg/day, PO) [76], and experimentally-induced anxiety (600 mg, PO). [77] Another possible therapeutic application which has been investigated is the use of CBD to treat drug addiction. ...
Experiment Findings
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This report has been drafted under the responsibility of the WHO Secretariat, Department of Essential Medicines and Health Products,Team of Innovation, Access and Use.The report is an update and extension of the pre-review on cannabidiol, that was prepared by Prof Jason White, Adelaide, Australia, for the 39thECDD meeting in November 2017. The WHO Secretariat would like to thank the following people for their contribution in producing this review report: Dr Sharon Walsh and Dr Susanna Babalonis, Kentucky USA (update and extension search, review and drafting), and J. Rehm et al, Toronto, Canada(analysis on WHO questionnaire for the Review of Psychoactive Substances for the 40thECDD: evaluation of Cannabidiol, and report drafting).
... CBD was found to well tolerated, with no severe side effects, thus did not require discontinuation of the therapy. But a longer follow-up and more patients are required [120]. A double-blind, placebo-controlled study of coadministration of cannabis and an opioid analgesic (oxycodone) was done to check the effect of active cannabis on antinociceptive effect of opioid and to assess the interaction of cannabis with an opioid. ...
Article
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i>Cannabis sativa L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of Cannabis sativa are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research. This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of C. sativa . Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of C. sativa from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.
... COVID-19 is associated with painful symptoms, including myalgia, headache and abdominal or chest pain (Figure 2). Antinociceptive activity of CBD has been found in patients suffering from chronic pain [149], including pain in kidney transplant recipients [150] and in individuals with fibromyalgia [151], multiple sclerosis [152], diabetes and allodynia [153,154] but not in patients with advanced cancer [155]. In the latter studies, CBD was mainly administered in combination with THC as an oromucosal or sublingual spray ( Table 2). ...
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.
... The positive effects of CBD were confirmed many years ago [97][98][99], encouraging clinical trials. CBD was proven to be safe and cause only mild adverse effects in humans (e.g., ataxia, sedation, nausea, headache or decreased appetite) [100][101][102][103]. A transdermal CBD-containing gel in patients with peripheral neuropathic pain mitigated pain, as well as cold and itchy sensations [104]. ...
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Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
... Studies of Epidiolex ® have demonstrated a range of potential side effects, including behavioral changes, sleep disturbances, mild liver injury, rashes, and gastrointestinal upset [5]. Side effects reported in other studies evaluating oral cannabidiol include diarrhea, dizziness, gastrointestinal events, nausea, and sedation [14,17,32,[35][36][37]. Many studies reported side effects but not frequencies. ...
Article
The use of cannabidiol is becoming so popular that even pharmacies now carry over-the-counter (OTC) cannabidiol products in Colorado, USA. The primary goal of this study was to evaluate cannabidiol products sold in the community pharmacy setting to determine the content of cannabidiol and other active ingredients and the safety information that may be provided to individuals considering the use of these products. Documentation of cannabidiol products available for purchase in pharmacies was compiled by visiting chain and independent pharmacies within the state of Colorado. Cannabidiol products were documented for claims of use, dose, route, administration, additional ingredients, and cost. In total, 60 cannabidiol products (15 oral, 44 topical, and one transdermal) were found in 35 pharmacies. The concentrations of oral cannabidiol varied from 10 to 60 mg/mL. In total, 13 (87%) of the oral products were labeled as “full spectrum.” Six (40%) of the oral cannabidiol products listed medium-chain triglycerides, a compound with evidence of increasing oral bioavailability. The amount of cannabidiol labeled on topical products varied from 30 mg cannabidiol/15 mL to 1000 mg cannabidiol. Some products did not indicate any quantity of cannabidiol or did provide the amount of hemp extract/oil but did not specify how much cannabidiol was present. In total, 29 (66%) of the topical products contained additional active ingredients: arnica, camphor, capsaicin, menthol, peppermint oil, white willow bark (salicylic acid), tea tree oil, and trolamine salicylate. Only one type of transdermal product for cannabidiol delivery was found, which provided a dose of 20 mg cannabidiol/24 h. The findings of this study illustrate the extensive variability of cannabidiol products and the importance of communication with people considering their use. Counseling those utilizing these products may help to avoid drug–drug or drug–supplement interactions and adverse events.
... Some patients experience severe pain on their back, chest, inguinal area, the surgery area, and head after kidney transplantation surgery [9,10], and postsurgical pain is a major therapeutic problem in these patients [11]. is pain may become worse if not managed properly [12]. ...
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Background and Purpose. Patients undergoing kidney transplantation surgeries suffer from postoperative pain, fatigue, and sleep disorders. Therefore, it is necessary to use different interventions in addition to modern medicine to reduce their symptoms. The present study aimed to investigate the effect of foot reflexology on pain, fatigue, and quality of sleep after kidney transplantation surgery. Materials and Methods. The study was a parallel randomized controlled trial. Patients admitted to the transplantation ward participated in the study. Fifty-three eligible patients were allocated into the foot reflexology group (n = 26) and the control group (n = 27) by using the stratified randomization method. Finally, 25 participants in each group finished the study. The intervention group received foot reflexology for 30 minutes once a day for three consecutive days, and no reflexology was applied in the control group. The intervention started on the second day after surgery. Pain, fatigue, and quality of sleep were measured on the first, second (before intervention), third, fourth, and eleventh days after surgery. Data were collected using visual analogue scale for measuring pain and fatigue and Verran and Snyder-Halpern sleep scale for measuring quality of sleep. Results. In each group, 25 patients finished the study. The mean pain score in the foot reflexology and control groups decreased from 9.44 ± 0.96 and 9.36 ± 0.91 on the day of surgery to 1.32 ± 0.94 and 4.32 ± 1.68 on the eleventh day after surgery, respectively. The mean fatigue score in the reflexology and control groups decreased from 8.76 ± 1.27 and 8.6 ± 1.26 on the day of surgery to 1.24 ± 1.2 and 3.92 ± 1.63 on the eleventh day after surgery, respectively. The mean sleep score in the foot reflexology and control groups increased from 33.38 ± 11.22 and 39.59 ± 12.8 on the day of surgery to 69.43 ± 12.8 and 56.27 ± 8.03 on the eleventh day after surgery, respectively. While pain, fatigue, and sleep quality scores improved in both groups, those in the intervention group showed significantly greater improvement compared with the control group (). No significant difference was found between the two groups in the use of acetaminophen on the first, second, third, fourth, and eleventh days after surgery (). Conclusion. Foot reflexology may reduce pain and fatigue and improve sleep quality of patients after kidney transplantation. 1. Introduction Kidney transplantation is the most effective treatment for end-stage kidney disease worldwide [1]. According to the statistics from the Global Observatory on Donation and Transplantation, the cases of kidney transplantation were 90,306 worldwide in 2017 [2]. In Iran, 48.8% of kidney failure patients are undergoing kidney transplantation [3]. Evidence suggests that successful kidney transplantation can improve quality of life, life expectancy, and reduce health costs [4]. However, patients may experience different physical difficulties such as cardiovascular and neurologic complications [5], sexual dissatisfaction [6], or mental disorders such as anxiety, depression, or stress [7]. Patients may also experience postoperative pain, fatigue, and sleep disorders [8]. Some patients experience severe pain on their back, chest, inguinal area, the surgery area, and head after kidney transplantation surgery [9, 10], and postsurgical pain is a major therapeutic problem in these patients [11]. This pain may become worse if not managed properly [12]. An inverse association is available between pain and blood pressure, and uncontrolled postoperative pain leads to hypotension and other postoperative disorders [13]. Fatigue and lack of energy are other common postoperative symptoms [14]. Few studies have shown that patients under kidney transplantation experience more fatigue than healthy subjects [15]. The prevalence of postoperative fatigue was 48.3% in one study, which was 41.5% three months later and 38.1% six months later [16]. Fatigue can affect quality of sleep of kidney transplant recipients. On the other hand, sleep deprivation in these patients can cause fatigue, depression, pain, and stress [17, 18]. Different complementary and alternative medicine (CAM) methods such as foot reflexology are used for managing symptoms among some patients after kidney transplantation [19]. Foot reflexology is a special form of massage that accompanies with the pressure of the fingers, especially the thumbs on the reflex areas usually in the feet. These areas are believed to associate with all parts of the body, and applying pressure on them can affect the physiological responses of the body. They are thought to improve recovery and return homeostasis [20]. Foot reflexology can regulate blood circulation and hemodynamic variables [21]. The underlying mechanisms of reflexology are not well understood. Reflexology is assumed to facilitate relaxation, release endorphins, and modulate pain-impulse transmission and pain perception [22]. Subsequently, relaxation can effect quality of sleep and fatigue [23–25]. In addition, touch and massage of reflex points in the foot may reduce patients’ pain. Diseases are caused by the blockage of energy in the body, and stimulation of reflex points may eliminate these obstructions and release energy in the body [26]. Several studies have examined the effects of foot reflexology on symptoms such as pain, fatigue, and quality of sleep of patients [19, 27–30]. Other studies showed a positive effect of foot reflexology on pain and anxiety of patients after general and spinal surgery [29, 30] and during chemotherapy and after breast cancer surgery [31, 32]. Different studies showed the positive effects of reflexology on alleviating fatigue in patients [33, 34]. Asltoghiri et al. showed the improvement of sleep disorders using reflexology [35]. Lee considered foot reflexology as a useful intervention to decrease fatigue and promote quality of sleep [36]. Moreover, the results of a systematic review showed that reflexology was safe and effective for insomnia, but further studies with greater accuracy and power are needed [37]. The complementary and alternative therapies have been increasingly used in recent decades, and nurses prefer to use noninvasive methods with minimal side effects [36]. Since reflexology does not have major side effects [37], nurses can use it to improve the quality of nursing care. However, decisions are still being made with caution due to insufficient research studies. No study has investigated the effect of reflexology on pain, fatigue, and quality of sleep after kidney transplantation; therefore, the current study tested the hypothesis that the mean scores of pain, fatigue, and quality of sleep in patients after kidney transplantation surgery were different between the foot reflexology and control groups after the intervention and one week later. 2. Materials and Methods 2.1. Study Type and Setting This study was a parallel randomized controlled trial. Patients taken to the transplantation department of Afzalipour Hospital, Kerman, Iran, were studied from April 2018 to May 2019. 2.2. Sample Size and Sampling According to a pilot study (5 samples in each group) (on the fourth day after surgery, the mean and standard deviation in the pilot reflexology group were 3.2 ± 2.17 and the mean and standard deviation in the pilot control group were 5.2 ± 1.3), the sample size was estimated to be 21 individuals for each group with a confidence coefficient of 95% and type II error of 10%. Due to the probability of dropout, 25 samples were selected in each group. It is noteworthy that the pilot samples were included in the final analysis. Furthermore, power analysis calculated with Power software indicates that (power = 90%, ) 46 participants would be needed (23 per group) to detect an effect size of 0.2. Inclusion criteria were the minimum age of 15 years old, the first turn of the kidney transplantation, no ulcers or injuries in feet, especially the sole, complete postoperative consciousness, no history of using foot reflexology, no addiction to drug use or alcohol, and no mental disorder. Exclusion criteria were the patient’s return to the operating room during the study, the patient’s need to a sedative, and any symptoms indicative of transplant rejection (with the doctor’s diagnosis). Sixty patients were examined for the inclusion criteria, of whom seven were not eligible due to different reasons such as a second transplant, no age fulfillment, and mental disorder. In addition, there were three dropouts due to returning to the operating room and rejection of the transplant. Finally, 25 samples in each group completed the study, and their data were analyzed (Figure 1). Eligible patients were selected by convenience sampling and allocated to the intervention and control groups with the stratified randomization method using gender and age (±2) as strata. In other words, the first sample was randomly allocated either to the intervention or control groups (using the lottery), and the subsequent samples were randomly allocated to both groups according to the matching variables. The first author assessed the participants according to the inclusion criteria and allocated them into the groups.
... Although none of the four phytocannabinoids quantified in the current study are known to behave as CB 2 agonists individually, phytocannabinoid synergy at the CB 2 receptor may result in CB 2 agonism and, in turn, the subsequent anti-nociceptive effects observed clinically. This may explain the anti-nociceptive effects observed in cannabis plant extracts [31][32][33], as well as CBD-containing cannabinoid mixtures, such as nabiximols, unlike CBD alone [34]. ...
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Cannabis is widely used as a therapeutic drug, especially by patients suffering from psychiatric and neurodegenerative diseases. However, the complex interplay between phytocannabinoids and their targets in the human receptome remains largely a mystery, and there have been few investigations into the relationship between the chemical composition of medical cannabis and the corresponding biological activity. In this study, we investigated 59 cannabis samples used by patients for medical reasons. The samples were subjected to extraction (microwave and supercritical carbon dioxide) and chemical analyses, and the resulting extracts were assayed in vitro using the CB1 and CB2 receptors. Using a partial least squares regression analysis, the chemical compositions of the extracts were then correlated to their corresponding cannabinoid receptor activities, thus generating predictive models that describe the receptor potency as a function of major phytocannabinoid content. Using the current dataset, meaningful models for CB1 and CB2 receptor agonism were obtained, and these reveal the insignificant relationships between the major phytocannabinoid content and receptor affinity for CB1 but good correlations between the two at CB2 receptors. These results also explain the anomalies between the receptor activities of pure phytocannabinoids and cannabis extracts. Furthermore, the models for CB1 and CB2 agonism in cannabis extracts predict the cannabinoid receptor activities of individual phytocannabinoids with reasonable accuracy. Here for the first time, we disclose a method to predict the relationship between the chemical composition, including phytocannabinoids, of cannabis extracts and cannabinoid receptor responses.
... Daily CBD dosing regimens have reduced pain in clinical populations in several small, single-arm open-label studies. In an open-label study of kidney transplant patients who requested CBD to treat their chronic pain, CBD (50 mg increased to 150 mg, twice daily) qualitatively reduced self-reported pain (either partially or completely) in 6/7 patients after 3 weeks; of note, the cause of chronic pain varied across these individuals (e.g., fibromyalgia, osteoarticular, neuropathic) [24]. In a second open-label study of 12 female participants with severe somatoform and dysautonomic syndrome following HPV vaccination, administration of sublingual CBD-rich hemp oil (titrated up to 150 mg/mL CBD per day over 3 months) improved physical component scores, vitality, and social role functioning on the short-form health survey questionnaire [25]. ...
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Purpose of Review Global policy changes have increased access to products containing cannabidiol (CBD), a primary constituent of hemp and cannabis. The CBD product industry has experienced tremendous growth, in part, because CBD is widely touted as an effective therapeutic for myriad health conditions. However, only 1 CBD product (Epidiolex®) has been approved by the US Food and Drug Administration (FDA) to date. There is substantial interest among consumers and the medical and scientific communities regarding the therapeutic potential of CBD, including for indications that are not recognized by the FDA. The purpose of this review was to synthesize available evidence from clinical research regarding the efficacy of CBD as a therapeutic. Recent Findings Human laboratory studies and clinical trials (e.g., randomized controlled trials and single-arm, open-label trials) evaluating the efficacy of CBD as a therapeutic were identified for various medical conditions, including epilepsy, anxiety, pain/inflammation, schizophrenia, various substance use disorders, post-traumatic stress disorder, and others. There is clear evidence supporting the utility of CBD to treat epilepsy. For other health conditions reviewed, evidence was often mixed and/or there was a general lack of well-powered randomized, placebo-controlled studies to draw definitive conclusions. Summary Rigorous, controlled evidence for the therapeutic efficacy of CBD is lacking for many health conditions. Possible concerns with the use of CBD as a therapeutic include the potential for adverse effects (e.g., liver toxicity), drug-drug interactions, and lack of sufficient regulatory oversight of retail CBD products.
... The efficacy of CBD as a prophylactic treatment for GVHD was also demonstrated in a phase II clinical trial [127]. Cuñetti et al. showed pain improvement in six out of seven kidney transplant patients receiving CBD, but they did not examine the effect on organ rejection [128]. Greenan et al. did not find any significant effect from the Cannabis recreational use on kidney allograft outcomes at one-year after renal transplantation. ...
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The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.
... Cunetti et al. [43] 2018 Observational: prospective study 7 adults CBD for chronic pain Capano et al. [44] 2020 Prospective cohort study 131 adults (97 completed) Chronic pain Poli et al. [45] 2018 [63]. Some research points to possible membrane stabilization with cannabidiols [64] and anecdotal, usually last ditch, trials with cannabidiols have been reported as effective in the literature for reducing seizure frequency [65]. ...
Article
Regulatory approvals for Epidiolex (purified cannabidiol) in the treatment of childhood drug resistant epilepsy have set a precedent for the use of cannabinoids as a prescribed medicine. Two common reasons cited for the use and prescription of cannabis-based products are pain and insomnia. Unlike drug resistant epilepsy, the level of evidence of efficacy in pain is poorly developed. The lowest quality trials with the greatest methodological shortcomings suggest some benefit, a level of evidence that is inconsistent with widespread prescribing. The evidence in insomnia is scant. Ongoing trial development and critical review of the literature should not be overshadowed by increasing permissiveness towards cannabis use and anecdotal reports of efficacy.
... However, these studies were often limited by small cohorts, and the varied disease states indicated that the beneficial effects of CBD are context dependent, which was illustrated in a study where treatment did not improve outcomes in patients suffering from Crohn's disease (Naftali et al., 2014). CBD was also seemingly effective in treatment of chronic pain associated with kidney transplantation and when given topically to patients suffering from peripheral neuropathy of their lower extremities (Cuñetti et al., 2018;Xu et al., 2019). As well, in patients with fibromyalgia, CBD treatment decreased pain by more than 30% in significantly more patients than placebo (Van De Donk et al., 2019). ...
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Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life. CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations. In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.
... Several case reports demonstrate increased tacrolimus levels associated with CBD in a patient with interstitial nephritis and in non-kidney transplant recipients [127 & ,128,129], whereas one small case series of low dose CBD for chronic pain among kidney transplant recipients did not reveal any change in tacrolimus levels [130]. Inaccurate product labeling and batch to batch variability of CBD products [68] may lead to unpredictable CNI levels, potential toxicity, or underdosing, especially with intermittent use of different cannabinoid products. ...
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Purpose of review: Cannabis (marijuana, weed, pot, ganja, Mary Jane) is the most commonly used federally illicit drug in the United States. The present review provides an overview of cannabis and cannabinoids with relevance to the practice of nephrology so that clinicians can best take care of patients. Recent findings: Cannabis may have medicinal benefits for treating symptoms of advanced chronic kidney disease (CKD) and end-stage renal disease including as a pain adjuvant potentially reducing the need for opioids. Cannabis does not seem to affect kidney function in healthy individuals. However, renal function should be closely monitored in those with CKD, the lowest effective dose should be used, and smoking should be avoided. Cannabis use may delay transplant candidate listing or contribute to ineligibility. Cannabidiol (CBD) has recently exploded in popularity. Although generally well tolerated, safe without significant side effects, and effective for a variety of neurological and psychiatric conditions, consumers have easy access to a wide range of unregulated CBD products, some with inaccurate labeling and false health claims. Importantly, CBD may raise tacrolimus levels. Summary: Patients and healthcare professionals have little guidance or evidence regarding the impact of cannabis use on people with kidney disease. This knowledge gap will remain as long as federal regulations remain prohibitively restrictive towards prospective research.
... 21,72 In a recent small trial (n=7), CBD also reduced pain following kidney transplant. 22 Therefore, cannabinoid and administration preferences may predict differences in cannabinoid effectiveness for chronic pain management. ...
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Cannabis is widely used for chronic pain. However, there is some evidence of an inverse dose-response relationship between cannabis effects and pain relief which may negatively affect analgesic outcomes. In this cross-sectional survey, we examined whether daily cannabis use frequency was associated with pain severity and interference, quality of life measures relevant to pain (e.g., anxiety and depressive symptoms), and cannabis use preferences (administration routes, cannabinoid ratio). Our analysis included 989 adults who used cannabis every day for chronic pain. Participant use was designated as light, moderate, and heavy (1-2, 3-4, and 5 or more cannabis uses per day, respectively). The sample was also sub-grouped by self-reported medical only use (designated MED, n=531, 54%) vs. medical use concomitant with a past-year history of recreational use (designated MEDREC, n=458, 46%). In the whole sample, increased frequency of use was significantly associated with worse pain intensity and interference, and worse negative affect, although high frequency users also reported improved positive affect. Subgroup analyses showed that these effects were driven by MED participants. Heavy MED participant consumption patterns showed greater preference for smoking, vaporizing, and high THC products. In contrast, light MED participants had greater preference for tinctures and high CBD products. Selection bias, our focus on chronic pain, and our cross-sectional design likely limit the generalizability our results. Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as lower risk cannabis use behaviors among MED participants. Future longitudinal studies are needed to examine how high frequency of cannabis use interacts with potential therapeutic benefits. PERSPECTIVE: Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as safer use behaviors (e.g., preference for CBD and non-inhalation administration routes). These trends highlight the need for developing cannabis use guidelines for clinicians to better protect patients using cannabis.
... Only one patient experienced an increase in Scr attributed to the elevated trough level. 20 Comparatively, our subject received a significantly higher dose of CBD (up to 25 mg/kg/day). As mentioned, a limitation of this report is the lack of CBD pharmacokinetic data. ...
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Cannabidiol (CBD), a major purified non‐psychoactive component of cannabis with anticonvulsant properties, was approved by the Food and Drug Administration in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by CYP3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug‐drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3‐fold increase in dose normalized tacrolimus concentrations while receiving 2000‐2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of a FDA approved CBD product. Larger studies are needed to better understand the impact of this drug‐drug interaction in solid organ transplant recipients. This article is protected by copyright. All rights reserved.
... However, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) recommended the acceptable daily intake of Tween-20 without any side effects to be 25 mg/kg body weight. Since the effective CBD dose used to treat chronic pain in humans is 100 mg/day [34], the dose of Tween-20 contained in the prepared CBD-NE (70% ratio for Tween-20) can be calculated to be 20. mg/kg/day for a 70-kg human, which is less than the abovementioned acceptable daily intake value (25 mg Tween-20/ kg), assuming that the bioavailability of CBD was increased by the NE formulation by 65%. ...
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Background: Cannabidiol (CBD) is highly lipophilic, and its oral bioavailability is known to be very low in humans. In this study, we developed a novel nanoemulsion preparation of CBD (CBD-NE) to improve the poor solubility and absorption of CBD. The pharmacokinetic profiles of CBD in rats were evaluated after oral administrations of CBD oil and CBD-NE, and the effect of bile secretion on CBD absorption was also evaluated. Methods: The CBD-NE formulation developed in this study consisted of vitamin E acetate, ethanol, Tween-20, and distilled water (1.7/3.8/70/24.5, w/w%). A CBD oil formulation (CBD oil, control) 100 mg/kg or CBD-NE 50 mg/kg was orally administered to rats, and the blood samples were collected over time. Moreover, the CBD oil or CBD-NE was orally administered to bile-fistulated rats, and the pharmacokinetic profiles of CBD were also evaluated. CBD concentrations in plasma were measured using LC-MS/MS. Results: The particle size of CBD-NE was 35.3 ± 11.8 nm. Mean Tmax of CBD-NE was shortened significantly by the factor of 3 (from 8.00 to 2.40 h, p < 0.001) and AUC0-∞/dose increased by 65% (from 0.272 ± 0.045 to 0.448 ± 0.087 h L/kg) compared with CBD oil. AUC0-∞/dose and Cmax/dose after oral administration of CBD oil were significantly reduced by the factor of 27 and 23 (p < 0.05 and p < 0.01), respectively, in bile-fistulated rats compared with the untreated rats. In contrast, all pharmacokinetic parameters after oral administration of CBD-NE were not significantly different between the untreated and bile-fistulated rats. Therefore, these results demonstrated that conventional CBD oil formulation but not CBD-NE requires bile-mediated micelle formation. Conclusions: The novel NE formulation developed in this study successfully improved the absorption of CBD regardless of bile secretion. The newly developed oral CBD-NE preparation could be useful to achieve a more stable and quicker onset of action by CBD.
... Importantly, in June 2018, the US Food and Drug Administration has approved CBD for treating seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged 2 years or older, and the European Medicines Agency is also evaluating this possibility [88]. These decisions confirm the safety of CBD and its therapeutic potential and will open new possibilities for exploring other therapeutic properties of CBD. ...
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Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options. Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD. In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD. We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia). We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD. We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.
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Introduction: Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an adjunctive treatment in managing the opioid withdrawal syndrome. Materials and Methods: A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. Results: CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Conclusions: Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.
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Background: Preclinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis, has a wide range of reported pharmacological effects such as analgesic and anxiolytic actions; however, the exact mechanisms of action for these effects have not been examined in chronic osteoarthritis (OA). Similar to other chronic pain syndromes, OA pain can have a significant affective component characterized by mood changes. Serotonin (5-HT) is a neurotransmitter implicated in pain, depression, and anxiety. Pain is often in comorbidity with mood and anxiety disorders in patients with OA. Since primary actions of CBD are analgesic and anxiolytic, in this first in vivo positron emission tomography (PET) imaging study, we investigate the interaction of CBD with serotonin 5-HT1A receptor via a combination of in vivo neuroimaging and behavioral studies in a well-validated OA animal model. Methods: The first aim of this study was to evaluate the target involvement, including the evaluation of modulation by acute administration of CBD, or a specific target antagonist/agonist intervention, in control animals. The brain 5-HT1A activity/availability was assessed via in vivo dynamic PET imaging (up to 60 min) using a selective 5-HT1A radioligand ([18F]MeFWAY). Tracer bindings of 17 ROIs were evaluated based on averaged SUVR values over the last 10 min using CB as the reference region. We subsequently examined the neurochemical and behavioral alterations in OA animals (induction with monosodium iodoacetate (MIA) injection), as compared to control animals, via neuroimaging and behavioral assessment. Further, we examined the effects of repeated low-dose CBD treatment on mechanical allodynia (von Frey tests) and anxiety-like (light/dark box tests, L/D), depressive-like (forced swim tests, FST) behaviors in OA animals, as compared to after vehicle treatment. Results: The tracer binding was significantly reduced in control animals after an acute dose of CBD administered intravenously (1.0 mg/kg, i.v.), as compared to that for baseline. This binding specificity to 5-HT1A was further confirmed by a similar reduction of tracer binding when a specific 5-HT1A antagonist WAY1006235 was used (0.3 mg/kg, i.v.). Mice subjected to the MIA-induced OA for 13-20 days showed a decreased 5-HT1A tracer binding (25% to 41%), consistent with the notion that 5-HT1A plays a role in the modulation of pain in OA. Repeated treatment with CBD administered subcutaneously (5 mg/kg/day, s.c., for 16 days after OA induction) increased 5-HT1A tracer binding, while no significant improvement was observed after vehicle. A trend of increased anxiety or depressive-like behavior in the light/dark box or forced swim tests after OA induction, and a decrease in those behaviors after repeated low-dose CBD treatment, are consistent with the anxiolytic action of CBD through 5HT1A receptor activation. There appeared to be a sex difference: females seem to be less responsive at the baseline towards pain stimuli, while being more sensitive to CBD treatment. Conclusion: This first in vivo PET imaging study in an OA animal model has provided evidence for the interaction of CBD with the serotonin 5-HT1A receptor. Behavioral studies with more pharmacological interventions to support the target involvement are needed to further confirm these critical findings.
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Background: Cannabidiol (CBD) is purported to work for a variety of therapeutic indications. Interest in CBD products has significantly increased as patients with cancer seek ways to improve symptom control and quality of life. Objectives: The purpose of this study was to explore patients' knowledge of and experience with CBD. Methods: A panel of oncology nurse practitioners, an oncologist, and oncology pharmacy specialists developed a survey to capture information about patient knowledge and use of CBD. The initial survey was pilot tested and further refined, resulting in the final item survey. The final survey was administered to 100 participants undergoing or having completed cancer treatment and being followed in a supportive oncology care clinic at a large academic medical center. Findings: Most patients learned about CBD through a family member or friend. The majority of patients had never tried CBD. The most common reported indications were pain, anxiety, and nausea. Of those who had not tried CBD, the most common reasons included lack of knowledge about CBD and providers not recommending CBD.
Article
Background and objective: Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years. Methods: A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD). Results: Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23-253.56; IR: 84.76, 95% CI 0.13-326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24-495.93; treatment related, IR: 1.76, 95% CI 4.63-23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35-42.52; IR: 7.83, 95% CI 3.26-14.38, respectively). The THC:CBD treatment had a low risk of all-cause and treatment-related adverse events (IR: 100.72, 95% CI 0.25-383.00; IR: 55.38, 95% CI 8.61-142.80, respectively), but reported a risk of all-cause and treatment-related serious adverse events (IR: 21.32, 95% CI 0.18-93.26; IR: 3.71, 95% CI 0.21-11.56, respectively), and all-cause and treatment-related withdrawals (IR: 78.63, 95% CI 17.43-183.90; IR: 34.31, 95% CI 6.09-85.52, respectively). Significant heterogeneity (I2 >55%) was present in most analyses. Conclusions: Although cannabinoid-based medications were generally safe and acceptable to adults aged over 50 years, these estimates are limited by the lack of a control condition and considerable heterogeneity. Nevertheless, they complement and are consistent with comparable evidence from randomised controlled trials.
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Background With millions of people using cannabinoids to treat a host of medical conditions, clinicians want guidance on how to utilize cannabinoids as pharmacotherapy in their practices. The Delphi method is a systematic, interactive forecasting method that aims to develop consensus best practices where guidelines are not available. Body A multidisciplinary group of global cannabinoid experts utilized a modified Delphi process to develop three protocols for the dosing and administration of cannabinoids to treat chronic pain. Two protocols recommend cannabidiol (CBD), for which there is limited evidence as an analgesic, starting well below doses required for other indications. Guidance on prescribing CBD for pain may demonstrate consensus recommendations based upon suboptimal evidence. Conclusion Consensus processes like the Delphi method are well-meaning, but they are not a substitute for rigorous RCTs with large sample sizes, adequate duration, and standardized outcome measures.
Article
Legalization of cannabidiol (CBD) products has ignited interest in clinical practice and research. One desired indication includes possible pain-relieving effects of CBD. The purposes of the current article are to (1) clarify terminology relevant to cannabinoids; (2) explain and understand the pharmacotherapeutics of CBD; (3) examine research of the current use of CBD by older adults for treating pain; (4) discuss safety considerations with using CBD products; and (5) provide best practice recommendations for clinicians as they advise their older adult patients. A review of the literature demonstrated mixed results on the efficacy of CBD in relieving pain in older adults. There is inconsistency in the labeling of over-the-counter CBD products that can result in safety issues and will require more federal quality control. Likewise, gaps in knowledge regarding safety and efficacy of CBD use in older adults are vast and require further research. [Journal of Gerontological Nursing, 47(7), 6-15.].
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This in-depth review discusses cannabis as it relates to heart transplantation and the growing dilemma of legalization around the world creating disparities in transplant candidacy. One will learn about two of the most common cannabinoids: Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids are metabolized by cytochrome P-450 and P glycoprotein, which are essential for the metabolism of drugs for transplantation, such as calcineurin inhibitors. Addiction, withdrawal, and cannabis use disorder will be reviewed as well as hyperemesis syndrome. Maintaining adequate immunosuppression will depend on a variety of factors, including drug-drug interactions, pharmacokinetics of cannabinoids and chronicity of cannabis usage. These drug interactions are further confounded by varying concentrations of cannabis products available at medical dispensaries. One will also learn about the outcomes of transplant recipients using cannabis such as graft failure and the risk of infections. Although more research is needed to establish transplant guidelines, the available data is concerning and fairness in organ distribution should not vary by transplant program or institution.
Article
The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on ‘Cannabinoids’.
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The medicolegal landscape of cannabis continues to change, and with ever increasing access there has been a concurrent proliferation of research seeking to understand the utility of cannabinoids in treating innumerable conditions with pain at the forefront. This article seeks to summarize clinically relevant findings in cannabinoid research to better prepare clinicians in the utility of cannabis in the treatment of pain.
Chapter
The sleep-wake cycle is a complex composition of specific physiological and behavioral characteristics. In addition, neuroanatomical, neurochemical and molecular systems exerts influences in the modulation of the sleep-wake cycle. Moreover, homeostatic and circadian mechanisms interact to control the waking or sleeping states. As many other behaviors, sleep also develops pathological features that include several signs and symptoms corresponding to medical conditions known as sleep disorders.In addition to the neurobiological mechanisms modulating sleep, external elements also influence the sleep-wake cycle, including the use of Cannabis sativa (C. sativa). In this regard, and over the last decades, the interest of studying the pharmacology of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of C. sativa, has been addressed. Moreover, in recent years, the focus of scientific interest has moved on to studying the second plant constituent with non-psychotropic pharmacological properties: Cannabidiol (CBD).The pharmacological and pharmaceutical interest of CBD has been focus of attention due to the accumulating body of evidence regarding the positive outcomes of using CBD for the treatment of several health issues, such as psychiatric and neurodegenerative disorders, epilepsy, etc. Since the most prominent sleep disruptions include excessive daytime sleepiness (EDS), current treatments include the use of drugs such as stimulants of antidepressants. Notwithstanding, side effects are commonly reported among the patients under prescription of these compounds. Thus, the search of novelty therapeutical approaches aimed to treat ESD may consider the use of cannabinoid-derived compounds, such as CBD. In this chapter, we will show experimental evidence regarding the potential role of CBD as a wake-inducing compound aimed to manage EDS.
Chapter
Cannabidiol (CBD), a naturally occurring constituent compound isolated from cannabis and hemp, has been the subject of basic science research since 1940. Over the past 5 years, CBD has entered the everyday lexicon of health advocates for nutraceutical products, federal regulators, and legislative authorities. While CBD nutraceutical food products have grown rapidly in North American markets to meet demand with safe supply chain distribution and finished products, acceptance of CBD globally by foreign governments has been slower due to increased scrutiny over safety. Some countries have recently opined on safe levels permitted for use in foods, removing regulatory barriers that once prevented their lawful entry. While the safety of CBD has been established to a degree that permits its endorsement by the WHO and marketing as a prescription drug, there remain significant gaps in the understanding of its toxicity in the context of use in conventional food, dietary supplements, and health and wellness products. Assessing the safety of CBD as a nutraceutical ingredient, this chapter provides an analysis of the available literature from genotoxicity to human clinical trials, with a focus on utilizing appropriate preclinical models and interpreting safety data to establish safe exposure levels.
Chapter
This chapter will cover some key aspects of how the psychoactive constituents of cannabis interact with our brains to produce the characteristic experiences associated with the drug's “high.” It also explores the body's complex and naturally occurring neurochemical internal cannabinoid signaling system that interacts with plant-produced chemicals found inside the cannabis flower. This chapter summarizes the discovery of the ECS, our realization of its growing medical and behavioral importance, and our changing view of its many functions. This whole area of cannabinoid-related research is of intense interest not only to scientists of various stripes, but also pharmaceutical companies, who glimpse the possibilities of designing drugs to manipulate the system in order to help treat a wide variety of illnesses.
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Cannabis, or marijuana, is comprised of many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and anti-inflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis and 14 recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned and systematic approach to cannabis. The results of our national survey unfortunately found little consensus amongst institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use.
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Editor's Note: For those whose response to COVID-19 includes exploring beyond vaccines, conventional pharmaceuticals, and the watchful or healthy waiting until such tools might arrive, interest in cannabinoids has been high - and controversial. It has already stimulated one journal, the Liebert Cannabis and Cannabinoid Research, to issue a call for papers on COVID-19. The unique place of cannabis in the culture seems to always mark the herb with an exponential asterisk whenever basketed with the other natural health strategies that are both widely used, and as broadly derided. In this invited commentary, JACM Editorial Board member Michelle Sexton, ND starts by describing the multiple immune modulating effects associated with the herb. The University of California San Diego Assistant Adjunct Professor in Anesthesiology then asks: "Given these effects, can phytocannabinoids be either helpful, or harmful for immune competency, in the context of the current COVID-19 pandemic?" A skilled edge-walker, Sexton lets the research fall where it may in wending a path through this evidentiary maze. -John Weeks, Editor-in-Chief, JACM.
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Kidney pain is one of the clinically significant features of renal dysfunction. Mild to severe pain is seen in the lower back area. Painkillers are mostly recommended in these cases to relieve the symptom. Yet, several analgesics are associated with side effects that can worsen the state of the disease. This review is based on the studies conducted in these aspects analgesics used to treat kidney pain and their effectiveness, renal consequences of postoperative analgesia, and pharmacogenetics of these palliatives are briefly summarized in this paper. Kidney pain is one of the clinically significant features of renal dysfunction. Painkillers are mostly recommended in these cases to relieve the symptom. Analgesics used to treat kidney pain and their effectiveness, renal consequences of postoperative analgesia, and pharmacogenetics of these palliatives are briefly summarized in this paper.
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Cannabidiol (CBD) is a highly touted product for many different disorders among the lay press. Numerous CBD products are available, ranging from a US Food and Drug Administration (FDA)‐approved product called Epidiolex to products created for medical marijuana dispensaries and products sold in smoke shops, convenience stores, and over the Internet. The legal status of the non–FDA‐approved products differs depending on the source of the CBD and the state, while the consistency and quality of the non–FDA‐approved products vary markedly. Without independent laboratory verification, it is impossible to know whether the labeled CBD dosage in non–FDA‐approved CBD products is correct, that the delta‐9‐tetrahydrocannabinol content is <0.3%, and that it is free of adulteration and contamination. On the Internet, CBD has been touted for many ailments for which it has not been studied, and in those diseases with evaluable human data, it generally has weak or very weak evidence. The control of refractory seizures is a clear exception, with strong evidence of CBD's benefit. Acute CBD dosing before anxiety‐provoking events like public speaking and the chronic use of CBD in schizophrenia are promising but not proven. CBD is not risk free, with adverse events (primarily somnolence and gastrointestinal in nature) and drug interactions. CBD has been shown to increase liver function tests and needs further study to assess its impact on suicidal ideation.
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The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprised of CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential towards treating various pathologies while avoiding the adverse psychotropic effects, which can accompany CB1 receptor-based therapies. With the appreciation that CB2 selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research both from a mechanistic as well as therapeutic perspective. In this review we will summarize our present knowledge of CB2 receptor signaling, localization and regulation. We will discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data using CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
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To compare mortality in chronic kidney disease (CKD) stages 4 and 5 (estimated glomerular filtration rate <30 mL/min/1.73 m(2)), peritoneal dialysis, haemodialysis and transplanted patients. Population-based cohort study. Swedish national healthcare system. Swedish adult patients with CKD stages 4 and 5 (n=3040; mean age 66 years), peritoneal dialysis (n=725; 60 years), haemodialysis (n=1791; 62 years) and renal transplantation (n=606; 48 years) were identified in Stockholm County clinical quality registers for renal disease between 1999 and 2010. Five general population controls were matched to each patient by age, sex and index year. CKD status (stage 4 or 5/peritoneal dialysis/haemodialysis/transplanted). All-cause mortality was ascertained from the Swedish Causes of Death Register. Mortality HRs were estimated using Cox regression conditioned on age, sex, diabetes status, education level and index year. During 6553 person-years, 766 patients with CKD stages 4 and 5 died (deaths/100 person-years 12, 95% CI 11 to 13) compared with 186 deaths during 1113 person-years in peritoneal dialysis (17, 95% CI 15 to 19), 924 deaths during 3680 person-years in haemodialysis (25, 95% CI 23 to 27) and 53 deaths during 2935 person-years in transplanted patients (1.8, 95% CI 1.4 to 2.4). Against matched general population controls, the mortality HR was 3.6 (95% CI 3.2 to 4.0) for CKD, 5.6 (95% CI 3.5 to 8.9) for transplanted patients, 9.2 (95% CI 6.6 to 12.7) for peritoneal dialysis and 12.6 (95% CI 10.8 to 14.6) for haemodialysis. In direct comparison versus CKD, the mortality HR was 1.7 (95% CI 1.4 to 2.1) for peritoneal dialysis, 2.6 (95% CI 2.3 to 2.9) for haemodialysis and 0.5 (95% CI 0.3 to 0.7) for transplanted patients. We did not find support for mortality in CKD to be similar to dialysis mortality. The patients with CKD stages 4 and 5 had considerably lower mortality risk than dialysis patients, and considerably higher risk than transplanted patients and matched general population controls.
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Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'.
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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.
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Δ(9)-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC(50) = 4.01-24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent K(i) values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC(50) = 7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC(50) = 6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC(50) = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles.
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FK506 (Prograf) is a new immunosuppressive agent, recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection, even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection, 75% of patients were still alive at 3 years following FK506 conversion, and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials, freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due, in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression, FK506 was shown to be effective, as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation, as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects, many of which are similar, and some of which are peculiar to a given organ transplant.
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The extent to which renal allotransplantation - as compared with long-term dialysis - improves survival among patients with end-stage renal disease is controversial, because those selected for transplantation may have a lower base-line risk of death. In an attempt to distinguish the effects of patient selection from those of transplantation itself, we conducted a longitudinal study of mortality in 228,552 patients who were receiving long-term dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a waiting list for transplantation, 23,275 of whom received a first cadaveric transplant between 1991 and 1997. The relative risk of death and survival were assessed with time-dependent nonproportional-hazards analysis, with adjustment for age, race, sex, cause of end-stage renal disease, geographic region, time from first treatment for end-stage renal disease to placement on the waiting list, and year of initial placement on the list. Among the various subgroups, the standardized mortality ratio for the patients on dialysis who were awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to 58 percent lower than that for all patients on dialysis (annual death rate, 16.1 per 100 patient-years). The relative risk of death during the first 2 weeks after transplantation was 2.8 times as high as that for patients on dialysis who had equal lengths of follow-up since placement on the waiting list, but at 18 months the risk was much lower (relative risk, 0.32; 95 percent confidence interval, 0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups within 5 to 673 days after transplantation in all the subgroups of patients we examined. The long-term mortality rate was 48 to 82 percent lower among transplant recipients (annual death rate, 3.8 per 100 patient-years) than patients on the waiting list, with relatively larger benefits among patients who were 20 to 39 years old, white patients, and younger patients with diabetes. Among patients with end-stage renal disease, healthier patients are placed on the waiting list for transplantation, and long-term survival is better among those on the waiting list who eventually undergo transplantation.
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Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
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Impressive renal allograft survival improvement between 1988 and 1995 has been described using projections of half-lives based on limited actual follow up. We aimed, now with sufficient follow up available to calculate real half-lives. Real half-lives calculated from Kaplan-Meier curves for the overall population as well as subsets of repeat transplants and African Americans recipients were examined. Real half-lives were substantially shorter than projected half-lives. As a whole, half-lives have improved by about 2 years between 1988 and 1995 as compared to the earlier projected 6 years of improvement. The improvement seems to be driven primarily by the improvement in graft survival of re-transplants. First transplants showed a cumulative increase in graft survival of less than 6 months. Projected half-lives are a risky estimation of long-term survival especially when based on short actual follow up. First transplant survival has only marginally improved during the early years of post transplant follow up while no significant improvement in long-term survival could be detected between 1988 and 1995. Redirection of attention from early endpoints towards the process of long-term graft loss may be necessary to sustain early gains in the long term.
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Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug’s pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics that hinder the separation of drugs of interest from biological matrices—and from each other—and lower drug recovery due to adsorption of compounds of interest to multiple surfaces. Δ 9-Tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, and its metabolites 11-hydroxy-Δ 9-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol are the focus of this chapter, although cannabidiol and cannabinol, two other cannabinoids with an interesting array of activities, will also be reviewed. Additional material will be presented on the interpretation of cannabinoid concentrations in human biological tissues and fluids following controlled drug administration.
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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+ HLADR+ T cells, combined with a sustained enhancement of CD4+ CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+ CD25(+high) T cells, which showed donor-Ag specificity. FOXP3+ CD4+ CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.
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Unlabelled: Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity. Case: A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred to our facility two days after initial presentation for liver transplant evaluation. At that time, her APAP level was 2.0 mg/L. Oral NAC therapy was continued after transfer. The patient's liver function subsequently improved and she ultimately did not require transplantation. She did develop acute renal failure during the course of her hospitalization, with a creatinine of 2.3 mg/dL on transfer, which increased to 8.1 mg/dL nine days later (approximately 11-13 days post-ingestion). Medical toxicology was consulted by the intensive care unit team to address whether this was acetaminophen-induced renal failure and if there was a role for NAC in this setting.
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Monitoring for alloreactive memory T cells after organ transplantation may allow individualization of immunosuppression. Two pathways of T cell allorecognition have been implicated in chronic graft dysfunction: Direct (recipient T cells respond to donor peptides presented by donor antigen-presenting cells) and indirect (donor peptides are processed and presented by recipient antigen-presenting cells). Previous studies have assessed these alloresponses only during the first 2 yr after kidney transplantation,so this study correlated the presence of circulating donor-reactive memory/effector T cells, primed by both pathways, in 34 longstanding living-donor renal transplant recipients using the highly sensitive IFN-gamma Elispot assay. Remarkably, 59% of patients had directly primed donor-reactive T cells, and their presence correlated directly with serum creatinine (P = 0.001) and inversely with estimated GFR (P = 0.042). Multivariate analysis revealed that hyporesponsiveness of direct, donor-specific T cells was the only variable that significantly correlated with graft function and that antidonor indirect alloreactivity was the only variable that significantly correlated with proteinuria. Interestingly, when both allorecognition pathways were considered together, patients with undetectable direct alloreactivity had better longterm graft function, independent of allosensitization by the indirect pathway. In conclusion, circulating donor-specific alloreactive T cells primed by both pathways are detectable long after transplantation and are associated with graft injury. Assessment of alloreactive memory/effector T cells might be helpful to tailor individual immunosuppression regimens for transplant recipients in the future.
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Preparations of the Cannabis sativa plant have been used to analgesic effect for millenia, but only in recent decades has the endogenous system responsible for these effects been described. The endocannabinoid (EC) system is now known to be one of the key endogenous systems regulating pain sensation, with modulatory actions at all stages of pain processing pathways. The EC system is composed of two main cannabinoid receptors (CB1 and CB2) and two main classes of endogenous ligands or endocannabinoids (ECs). The receptors have distinct expression profiles, with CB1 receptors found at presynaptic sites throughout the peripheral and central nervous systems (PNS and CNS, respectively), whilst CB2 receptor is found principally (but not exclusively) on immune cells. The endocannabinoid ligands are lipid neurotransmitters belonging to either the N-acyl ethanolamine (NAEs) class, e.g. anandamide (AEA), or the monoacylglycerol class, e.g. 2-arachidonoyl glycerol (2-AG). Both classes are short-acting transmitter substances, being synthesised on demand and with signalling rapidly terminated by specific enzymes. ECs acting at CB1 negatively regulate neurotransmission throughout the nervous system, whilst those acting at CB2 regulate the activity of CNS immune cells. Signalling through both of these receptor subtypes has a role in normal nociceptive processing and also in the development resolution of acute pain states. In this chapter, we describe the general features of the EC system as related to pain and nociception and discuss the wealth of preclinical and clinical data involving targeting the EC system with focus on two areas of particular promise: modulation of 2-AG signalling via specific enzyme inhibitors and the role of spinal CB2 in chronic pain states.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are principal pharmacologic agents for symptom relief in patients with arthritis and other inflammatory conditions. Cardiovascular risk is associated with all NSAIDs, excluding aspirin. Selective inhibition of cyclo-oxygenase-2 (COX)-2 could produce a relative reduction in endothelial production of prostacyclin, while leaving the platelet production of thromboxane A2 (TXA2 ) intact. It has been speculated that this imbalance of homeostatic prostanoids might increase the risk for thrombotic events. The goal of this review is to provide physicians guidelines to mitigate cardiovascular and nephrotoxicity of NSAIDs. We conducted a systematic literature review to determine what information is available to guide treatment decisions in this patient population. Selective inhibition of COX-2 could produce a relative reduction in endothelial production of prostacyclin, while leaving the platelet production of TXA2 intact. Increasing degrees of selectivity for COX-2 are associated with augmented cardiovascular risk, whereas increasing degrees of selectivity for cyclo-oxygenase-2 (COX-1) are associated with augmented gastrointestinal risk. Some NSAIDs (such as ibuprofen) can interfere with the cardioprotective effects of aspirin by competitively binding to COX-1 enzyme, resulting in increased TXA2 production Naproxen may differ from other NSAIDs in sustaining functionally important degrees of inhibition of platelet cyclooxygenase-1 activity throughout the dosing interval. It is of paramount importance to consider individual health factors when choosing therapy with NSAIDs.
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Abstract Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.
Article
After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ(9)-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s. Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the "endocannabinoid signaling system," its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity. The way researchers look at this system has thus rapidly evolved towards the idea of the "endocannabinoidome," that is, a complex system including also several endocannabinoid-like mediators and their often redundant metabolic enzymes and "promiscuous" molecular targets. These peculiar complications of endocannabinoid signaling have not discouraged efforts aiming at its pharmacological manipulation, which, nevertheless, now seems to require the development of multitarget drugs, or the re-visitation of naturally occurring compounds with more than one mechanism of action. In fact, these molecules, as compared to "magic bullets," seem to offer the advantage of modulating the "endocannabinoidome" in a safer and more therapeutically efficacious way. This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation.
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The concept that the immune system can communicate with peripheral sensory neurons to modulate pain is based mostly on documented interactions between opioid ligands and receptors. Such findings may have broad implications for the development of safer pain medication. Innovative strategies take into account that analgesics should be particularly active in pathological states rather than producing a general suppression of the central nervous system, as with conventional morphine- or cannabinoid-like drugs. Inflammation of peripheral tissue leads to increased functionality of opioid receptors on peripheral sensory neurons and to local production of endogenous opioid peptides. In addition, endocannabinoids were detected in leukocytes, but their role in pain modulation has yet to be addressed. Future aims include the development of peripherally restricted opioid agonists, selective targeting of opioid-containing immune cells to sites of painful injury, and the augmentation of peripheral ligand and receptor synthesis (e.g., by gene therapy). Similar approaches may be pursued for cannabinoids. The ultimate goal is to avoid detrimental side effects of currently available analgesics such as respiratory depression, cognitive impairment, addiction, gastrointestinal bleeding, and thromboembolic complications.
Article
Presence of subclinical rejection (SCR) with IF/TA in protocol biopsies of renal allografts has been shown to be an independent predictor factor of graft loss. Also, intragraft Foxp3+ T(reg) cells in patients with SCR has been suggested to differentiate harmful from potentially protective infiltrates. Nonetheless, whether presence of Foxp3 T(reg) cells in patients with SCR and IF/TA may potentially protect from a deleterious graft outcome has not yet been evaluated. This is a case-control study in which 37 patients with the diagnosis of SCR and 68 control patients with no cellular infiltrates at 6-month protocol biopsies matched for age and time of transplantation were evaluated. We first confirmed that numbers of intragraft Foxp3-expressing T cells in patients with SCR positively correlates with Foxp3 demethylation at the T(reg) -specific demethylation region. Patients with SCR without Foxp3+ T(reg) cells within graft infiltrates showed significantly worse 5-year graft function evolution than patients with SCR and Foxp3+ T(reg) cells and those without SCR. When presence of SCR and IF/TA were assessed together, presence of Foxp3+ T(reg) could discriminate a subgroup of patients showing the same graft outcome as patients with a normal biopsy. Thus, presence of Foxp3+ T(reg) cells in patients with SCR even with IF/TA is associated with a favorable long-term allograft outcome.
Article
Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations. Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry. CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1″-OH-, 2″-OH-, 3″-OH-, 4″-OH-, and 5″-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4″-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4″-hydroxylations of CBD in HLMs.
Article
Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9)-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research.
Article
The cannabinoid field is currently an active research area. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most characterized endogenous cannabinoids (also known as endocannabinoids). These neuromodulators have been implicated in various physiologically relevant phenomena, including mood (Witkin et al., 2005), the immune response (Ashton, 2007), appetite (Kirkham and Tucci, 2006), reproduction (Wang et al., 2006), spasticity (Pertwee, 2002), and pain (Hohmann and Suplita, 2006). Pharmacological manipulation of AEA and 2-AG signaling should prove to have significant therapeutic applications in disorders linked to endocannabinoid signaling. One way to alter endocannabinoid signaling is to regulate the events responsible for termination of the endocannabinoid signal-cellular uptake and metabolism. However, to pharmacologically exploit AEA and/or 2-AG signaling in this way, we must first gain a better understanding of the proteins and mechanisms governing these processes. This review serves as an introduction to the endocannabinoid system with an emphasis on the proteins and events responsible for the termination of AEA and 2-AG signaling.
Article
The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.
Article
Neurologic complications are common after solid organ transplantation and are associated with significant morbidity. Approximately one-third of transplant recipients experiences neurologic alterations with incidence ranging from 10% to 59%. The complications can be divided into such of those common to all types of transplant and others of those specific to transplanted organ. The most common complication seen with all types of transplanted organ is neurotoxicity attributable to immunosuppressive drugs, followed by seizures, opportunistic central nervous system (CNS) infections, cardiovascular events, encephalopathy and de novo CNS neoplasms. Amongst immunosuppressants, calcineurin inhibitors are the main drugs involved in neurotoxicity, leading to complications which ranges from mild symptoms, such as tremors and paresthesia to severe symptoms, such as disabling pain syndrome and leukoencephalopathy. Neurologic complications of liver transplantation are more common than that of other solid organ transplants (13-47%); encephalopathy is the most common CNS complication, followed by seizures; however, central pontine myelinolysis can appear in 1-8% of the patients leading to permanent disabilities or death. In kidney transplanted patients, stroke is the most common neurologic complication, whereas cerebral infarction and bleeding are more typical after heart transplantation. Metabolic, electrolyte and infectious anomalies represent common risk factors; however, identification of specific causes and early diagnosis are still difficult, because of patient's poor clinical status and concomitant systemic and metabolic disorders, which may obscure symptoms.
Article
These results demonstrate that FK-506 can inhibit humoral and cellular immunity and alloantigen-driven cell proliferation across strong histocompatibility barriers. The results lead to the conclusion that FK-506 has profound immunosuppressive properties in vitro and in vivo. FK-506 is not only a unique potential prototype for suppression of transplant rejection but is also an attractive probe for studying the lymphocyte activation cascade.
The pharmacokinetics of Δ 9-tetrahydrocannabinol (THC) administered intravenously was evaluated in four subjects after oral administration of placebo and 1500 mg of cannabidiol (CBD) according to a crossover design. The cannabidiol pretreatment had no apparent effect on THC pharmacokinetics, yet there may have been minimal effect on the formation and excretion of metabolites. The total (metabolic) blood clearance of THC averaged 17.4 ml/min/kg without CBD and 20.9 ml/min/kg with CBD, and was probably hepatic blood flow limited. The apparent steady-state volume of distribution averaged 9.86 (with CBD, 10.54) liters/kg. Irrespective of CBD pretreatment, the renal clearance of THC metabolites ranged from 17 ml/min after approximately 1 hr to 1.13 ml/min 3.5days after dosing with THC. The apparent terminal half life for metabolites averaged 8.2 days.
Article
FK506 (Prograf) is a new immunosuppressive agent? recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection, even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection, 75% of patients were still alive at 3 years following FK506 conversion, and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials, freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due, in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression, FK506 was shown to be effective, as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation, as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects, many of which are similar, and some of which are peculiar to a given organ transplant.
Article
Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other’s blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).
Article
The immunosuppressive benefits of cyclosporine and tacrolimus in short-term and medium-term renal allograft survival are well documented. It is becoming increasingly clear that the basis of this immunosuppression, the inhibition of calcineurin, may be linked with nephrotoxicity, hypertension, hyperlipidemia, and new-onset diabetes mellitus, side effects that may lead to CRAD, death due to CVD, and late renal allograft loss. This clinical picture presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection while simultaneously reducing the side effects associated with CNI-related therapies. Sirolimus combined with cyclosporine and tacrolimus has demonstrated an ability to reduce incidences of early acute rejection and, used as base therapy, has provided protection against acute rejection equivalent to that of cyclosporine, without the consequent nephrotoxicity associated with CNIs. In preliminary results from an ongoing clinical trial, sirolimus has been used to eliminate cyclosporine during maintenance immunosuppression, with subsequent improvements in measures of blood pressure and renal function. In addition, the antiproliferative properties of sirolimus and its ability to prevent graft vascular disease in animal studies make sirolimus a promising agent to decrease incidences of CRAD and improve long-term renal allograft survival. These findings point to a clear need to further explore both the efficacy of sirolimus immunotherapy and its long-term effects.
Article
Medications cause renal failure through a variety of mechanisms. Hemodynamic renal failure may result from drugs that reduce renal prostaglandins and hence renal blood flow and glomerular filtration rate. A relatively new group of drugs with this potential is the cyclooxygenase-2 selective inhibitors. Direct renal tubular toxicity has also been described with a number of new medications with unique effects on the epithelial cells of the kidney. These include the antiviral agents cidofovir, adefovir, and tenofovir as well as the bisphosphonate pamidronate. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including the antiparasitic drug sulfadiazine, the antiviral agent acyclovir, and the protease inhibitor indinavir. Finally, an unusual form of renal failure characterized by swollen, vacuolated proximal tubular cells can develop from hyperosmolar substances. Agents recently described to induce an "osmotic nephrosis" include intravenous immunoglobulin and the plasma expander hydroxyethyl starch.
Article
Subclinical rejection (SCR) of renal allografts refers to histologic patterns of acute rejection despite stable renal function. The clinical approach to SCR is controversial; it would be helpful to identify biomarkers that could determine whether the identified cellular infiltrates were detrimental. For investigation of whether the presence of FoxP3+ regulatory T cells (Treg) could help determine the functional importance of tubulointerstitial infiltrates observed in 6-mo protocol biopsies, 37 cases of SCR were evaluated. The presence of FoxP3+ Treg discriminated harmless from injurious infiltrates, evidenced by independently predicting better graft function 2 and 3 yr after transplantation. Furthermore, the FoxP3+ Treg/CD3+ T cell ratio positively correlated with graft function at 2 yr after transplantation, suggesting that an increasing proportion of Treg within the global T cell infiltrate may facilitate renal engraftment; therefore, immunostaining for FoxP3+ Treg in patients with SCR on protocol biopsies may ultimately be useful to identify patients who may require alterations in their immunosuppressive regimens.
Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy
  • I Ujvaíry
  • H Lumír
Ujvaíry I, Lumír H. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis and Cannabinoid Research 2016;1:1.
Influence of interactions between immunosuppressive drugs on therapeutic drug monitoring
  • A Gronewold
  • G Skopp
Gronewold A, Skopp G. A preliminary investigation on the distribution of cannabinoids in man. Forensic Sci Int 2011;210:e7e11. [31] Kuypers DR. Influence of interactions between immunosuppressive drugs on therapeutic drug monitoring. Ann Transplant 2008;13(3):11e8.