Current natural therapies in the treatment against glioblastoma.

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“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.”

Personal experience and attitudes of pain medicine specialists in Israel regarding the medical use of cannabis for chronic pain.

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“The scientific study of the role of cannabis in pain medicine still lags far behind the growing use driven by public approval. Accumulated clinical experience is therefore an important source of knowledge. However, no study to date has targeted physicians who actually use cannabis in their daily practice.

RESULTS:

Sixty-four percent of all practicing pain specialists in Israel responded. Almost all prescribe cannabis. Among them, 63% find cannabis moderately to highly effective, 56% have encountered mild or no side effects, and only 5% perceive it as significantly harmful. Common indications are neuropathic pain (65%), oncological pain (50%), arthralgias (25%), and any intractable pain (29%). Leading contraindications are schizophrenia (76%), pregnancy/breastfeeding (65%), and age <18 years (59%). Only 12% rated cannabis as more hazardous than opiates. On a personal note, 45% prefer cannabis for themselves or a family member. Lastly, 54% would like to see cannabis legalized in Israel.

CONCLUSION:

In this survey, pain clinicians experienced in prescribing cannabis over prolonged periods view it as an effective and relatively safe treatment for chronic pain, based on their own experience. Their responses suggest a possible change of paradigm from using cannabis as the last resort.”

The Role of Cannabis within an Emerging Perspective on Schizophrenia.

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“Approximately 0.5% of the population is diagnosed with some form of schizophrenia, under the prevailing view that the pathology is best treated using pharmaceutical medications that act on monoamine receptors.

We briefly review evidence on the impact of environmental forces, particularly the effect of autoimmune activity, in the expression of schizophrenic profiles and the role of Cannabis therapy for regulating immunological functioning.

A review of the literature shows that phytocannabinoid consumption may be a safe and effective treatment option for schizophrenia as a primary or adjunctive therapy.

Conclusions: Emerging research suggests that Cannabis can be used as a treatment for schizophrenia within a broader etiological perspective that focuses on environmental, autoimmune, and neuroinflammatory causes of the disorder, offering a fresh start and newfound hope for those suffering from this debilitating and poorly understood disease.”

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

“The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30100226

https://www.epilepsybehavior.com/article/S1525-5050(18)30473-6/fulltext

Treatment of Periodontal Ligament Stem Cells with MOR and CBD Promotes Cell Survival and Neuronal Differentiation via the PI3K/Akt/mTOR Pathway.

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“Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order to understand if treatment could improve their survival and their in vitro differentiation capacity. Stem cells survival is fundamental to achieve a successful therapy outcome in the re-implanted tissue of patients. Through NGS transcriptome analysis, we found that combined treatment increased hPDLSCs survival, by inhibition of apoptosis as demonstrated by enhanced expression of anti-apoptotic genes and reduction of pro-apoptotic ones. Moreover, we investigated the possible involvement of PI3K/Akt/mTOR pathway, emphasizing a differential gene expression between treated and untreated cells. Furthermore, hPDLSCs were cultured for 48 h in the presence or absence of CBD and MOR and, after confirming the cellular viability through MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) assay, we examined the presence of neuronal markers, through immunofluorescence analysis. We found an increased expression of Nestin and GAP43 (growth associated protein 43) in treated cells. In conclusion, hPDLSCs treated with Moringin and Cannabidiol showed an improved survival capacity and neuronal differentiation potential.”

https://www.ncbi.nlm.nih.gov/pubmed/30096889

http://www.mdpi.com/1422-0067/19/8/2341

Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

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“To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.

The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.

Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile.”

Glial Endocannabinoid System in Pain Modulation.

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“Pain is affecting the human for centuries and there still is no satisfactory strategy for patients suffering pain particularly chronic pain although intensive studies about its mechanism have been performed in order to improve the treatment of pain.

Cannabinoid is a group of chemicals extracted from plants and has a long history in treating pain through the endogenous cannabinoid receptor in the body, however, its application in pain treatment is limited due to its inverse effects.

Recent studies have indicated that glial cells play critical role in mediating pain processing through multiple pathway, including excitatory and inhibitory neurotransmission in different levels of the nervous system.

Furthermore, the glial cells are found to express cannabinoid receptors.

This review summarized the recent studies about the cannabinoid system in glial cells, which may provide some insight for the studying of pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30084280

https://www.tandfonline.com/doi/abs/10.1080/00207454.2018.1503178

Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials.

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“Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects.

Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system.

These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well.

Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD.

The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30087591

https://www.frontiersin.org/articles/10.3389/fnins.2018.00502/full

Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs.

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“The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).

Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01).

Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.”

https://www.ncbi.nlm.nih.gov/pubmed/30083539

https://www.frontiersin.org/articles/10.3389/fvets.2018.00165/full

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine

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“The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed.

Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression.

Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival.

Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone.

Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice.

Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p.

Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients’ outcome.”

https://www.nature.com/articles/s41388-018-0390-1

“Cannabinoid improves survival rates of mice with pancreatic cancer”  https://medicalxpress.com/news/2018-07-cannabinoid-survival-mice-pancreatic-cancer.html

“Study: CBD From Marijuana Plus Chemotherapy Tripled Cancer Survival Rates In Mice” https://www.forbes.com/sites/daviddisalvo/2018/07/31/study-cbd-from-marijuana-plus-chemotherapy-triples-cancer-survival-rates-in-mice/#491942d44630

“Cannabis drug may help pancreatic-cancer patients live almost THREE TIMES longer, study finds” http://www.dailymail.co.uk/health/article-6007275/Cannabis-drug-help-pancreatic-cancer-patients-live-THREE-TIMES-longer-study-finds.html

“Substance in cannabis ‘could boost pancreatic cancer treatments’. Scientists say cannabidiol could extend patients’ lives by a matter of years”  https://www.theguardian.com/science/2018/jul/30/substance-in-cannabis-could-boost-pancreatic-cancer-treatments

“Cannabinoid mice trial holds hope for pancreatic cancer patients”  https://www.smh.com.au/national/cannabinoid-mice-trial-holds-hope-for-pancreatic-cancer-patients-20180731-p4zuls.html

“Medical cannabis extract could help pancreatic cancer patients live longer, early study suggests” https://www.independent.co.uk/news/health/pancreatic-cancer-medical-cannabis-cbd-oil-cannabidiol-chemotherapy-a8470406.html

“Cancer ‘remarkable’ treatment – cannabis CBD could improve survival rate by THREE times. CANCER symptoms could be prevented with a “remarkable” new treatment, which includes cannabis CBD, scientists have revealed. Pancreatic cancer survival rates could be improved by three times, by adding CBD into chemotherapy treatments, they said.” https://www.express.co.uk/life-style/health/996657/cancer-treatment-pancreatic-symptoms-cannabis-cbd

“Compound in cannabis could help pancreatic cancer patients live significantly longer” https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/310718/compound-in-cannabis-could-help-pancreatic-cancer-patients-live-signif.html