Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.

 Biochemical Pharmacology “The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis.

Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases.

In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration.

Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects.

Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS.

Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder.

Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/30121249

https://www.sciencedirect.com/science/article/abs/pii/S000629521830337X

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Reprint of: Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Complementary and alternative medicine (CAM) therapies may be used as a non-pharmacological approach to chronic pain management.

Inhaled cannabis, graded motor imagery, and Compound Kushen injection (a form of Chinese medicine) were found the most efficient and tolerable for chronic pain relief.”

https://www.ncbi.nlm.nih.gov/pubmed/30107944

https://www.sciencedirect.com/science/article/pii/S027858461830602X?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Current natural therapies in the treatment against glioblastoma.

Phytotherapy Research banner

“Glioblastoma (GBM) is the most common and aggressive brain tumor, which causes the highest number of deaths worldwide. It is a highly vascularized tumor, infiltrative, and its tumorigenic capacity is exacerbated. All these hallmarks are therapeutic targets in GBM treatment, including surgical removal followed by radiotherapy and chemotherapy.

Current therapies have not been sufficient for the effective patient’s management, so the classic therapies have had to expand and incorporate new alternative treatments, including natural compounds.

This review summarizes natural products and their physiological effects in in vitro and in vivo models of GBM, specifically by modulating signaling pathways involved in angiogenesis, cell migration/invasion, cell viability, apoptosis, and chemoresistance. The most important aspects of natural products and their derivatives were described in relation to its antitumoral effects.

As a final result, it can be obtained that within the compounds with more evidence that supports or suggests its clinical use are the cannabinoids, terpenes, and curcumin, because many have been shown to have a significant effect in decreasing the progress of GBM through known mechanisms, such as chemo-sensitization or decrease migration and cell invasion.

Natural compounds emerge as promising therapies to attack the progress of GBM.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

Image result for Br J Pharmacol.

“Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy leads to the accumulation of damaged intracellular organelles that greatly contribute to the aggravation of muscle damage.

We explored the possibility of using non-euphoric compounds present in Cannabis sativa, including cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV) to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.

We found that CBD and CBDV promote the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+ ]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. CBD and CBDV also promoted the differentiation of myoblasts from DMD donors. In primary cultures prepared from satellite cells isolated from healthy donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case mostly via TRPA1 activation. In mdx mice, CBD (60 mg Kg-1), CBDV (60 mg Kg-1 ) prevented the loss of locomotor activity at two distinct ages (from 5 to 7 and 32 to 34 weeks of age). This effect was associated with a reduction in tissue and plasma pro-inflammatory markers, together with the restoration of autophagy.

CONCLUSION AND IMPLICATIONS:

We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co-adjuvant therapies to prevent muscle degeneration in DMD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30074247

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Emerging strategies targeting cb2 cannabinoid receptor: biased agonism and allosterism.

Biochemical Pharmacology

“During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB2 receptor.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

VCE-004.3, A CANNABIDIOL AMINOQUINONE DERIVATIVE, PREVENTS BLEOMYCIN-INDUCED SKIN FIBROSIS AND INFLAMMATION TROUGH PPARγ- AND CB2 -DEPENDENT PATHWAYS.

Publication cover image

“The endocannabinoid system (ECS) as well as PPARγ are relevant targets for the development of novel compounds against fibrotic diseases such as Systemic Sclerosis (SSc), also called Scleroderma.

The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and to study it anti-inflammatory and anti-fibrotic activities.

CONCLUSION AND IMPLICATIONS:

VCE-004.3 is a novel semi-synthetic cannabidiol derivative behaving as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of Scleroderma.”

https://www.ncbi.nlm.nih.gov/pubmed/30033591

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14450

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Interferon- α-mediated Activation of T Cells from Healthy and HIV-infected Individuals is Suppressed by Δ 9 -Tetrahydrocannabinol

Journal of Pharmacology and Experimental Therapeutics

“HIV patients routinely use medicinal cannabinoids to treat neuropathic pain, anxiety, and HIV-associated wasting. However, Δ 9 -Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, suppresses T cell function and secretion of interferons, both critically important in the anti-viral immune response.

Interferon- α (IFN α), a key cytokine in T cell activation and peripheral control of HIV infection, can potentiate responsiveness to IL-7, a crucial homeostatic cytokine for peripheral T cell maintenance. . The objective of this investigation was to compare the response of T cells to stimulation by IFNα and IL-7 in T cells from healthy and HIV+ donors in the absence and presence of THC.

T cells from healthy and HIV+ donors were stimulated in vitrowith IFN α and IL-7 in the absence and presence of THC followed by measurements of signaling events through IFNAR, IFN α-induced expression of IL-7Rα, cognate signaling through IL-7R, and on IL-7-mediated T cell proliferation by flow cytometry and RT-qPCR. CD8+ T cells from HIV+ donors showed a diminished response to IFN α-induced pSTAT1 compared to CD8+ T cells from healthy donors while CD4+ T cells from HIV+ donors and healthy donors were comparable. Treatment with IFN α promoted IL-7R expression and potentiated IL-7-induced STAT5 phosphorylation to augment IL-7-mediated proliferation by T cells from healthy and HIV+ donors. Finally, HIV+ donors exhibited reduced sensitivity to THC-mediated suppression by IFN α and IL-7-mediated stimulation compared to healthy donors.

These results further support THC as immune suppressive while identifying putatively beneficial aspects of cannabinoid-based therapies in HIV+ patients.

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

Image result for bmc pediatrics

“Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies.

With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available.

The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.

DISCUSSION:

This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/29981580

“Children with epileptic encephalopathies resistant to standard therapy are at considerable risk for long-term neurocognitive impairment and poor quality of life. CBD-enriched Cannabis based therapies have been shown in several studies to provide a reduction in seizure frequencies and improvements in sleep patterns, mood, and alertness.”  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1191-y

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabis: A Prehistoric Remedy for the Deficits of Existing and Emerging Anticancer Therapies

“Cannabis has been used medicinally for centuries and numerous species of this genus are undoubtedly amongst the primeval plant remedies known to humans.

Cannabis sativa in particular is the most reported species, due to its substantial therapeutic implications that are owed to the presence of chemically and pharmacologically diverse cannabinoids.

These compounds have long been used for the palliative treatment of cancer.

Recent advancements in receptor pharmacology research have led to the identification of cannabinoids as effective antitumor agents.

This property is accredited for their ability to induce apoptosis, suppress proliferative cell signalling pathways and promote cell growth inhibition.

Evolving lines of evidence suggest that cannabinoid analogues, as well as their receptor agonists, may offer a novel strategy to treat various forms of cancer.

This review summarizes the historical perspective of C. sativa, its potential mechanism of action, and pharmacokinetic and pharmacodynamic aspects of cannabinoids, with special emphasis on their anticancer potentials.”

http://www.xiahepublishing.com/ArticleFullText.aspx?sid=2&jid=3&id=10.14218%2FJERP.2017.00012

Cannabis products.

“Cannabis products. First row, left to right: Indian, Lebanese, Turkish and Pakistani hashish. Second row, left to right: Swiss hashish, Zairean marijuana, Swiss marijuana, Moroccan hash oil.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.

Image result for Biochem Pharmacol.

“Breast cancer is the second leading cause of death among women. Although early diagnosis and development of new treatments have improved their prognosis, many patients present innate or acquired resistance to current therapies. New therapeutic approaches are therefore warranted for the management of this disease.

Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. Most of these studies have been conducted with pure compounds, mainly Δ9-tetrahydrocannabinol (THC).

The cannabis plant, however, produces hundreds of other compounds with their own therapeutic potential and the capability to induce synergic responses when combined, the so-called “entourage effect”.

Here, we compared the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP). The BDP was more potent than pure THC in producing antitumor responses in cell culture and animal models of ER+/PR+, HER2+ and triple-negative breast cancer. This increased potency was not due to the presence of the 5 most abundant terpenes in the preparation.

While pure THC acted by activating cannabinoid CB2 receptors and generating reactive oxygen species, the BDP modulated different targets and mechanisms of action. The combination of cannabinoids with estrogen receptor- or HER2-targeted therapies (tamoxifen and lapatinib, respectively) or with cisplatin, produced additive antiproliferative responses in cell cultures. Combinations of these treatments in vivo showed no interactions, either positive or negative.

Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous