Tag Archives: treatment

Effective treatment of spasticity using dronabinol in pediatric palliative care.

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“Cannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far.

We conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care.

Sixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored.

RESULTS:

Drops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (n = 12). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0 mg/kg/d with a median of 0.33 mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each).

No serious and enduring side effects occurred even in young children and/or over a longer period of time.

CONCLUSIONS:

In the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity.”

http://www.ncbi.nlm.nih.gov/pubmed/27506815

Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting.

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“Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic.

If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea-a conditioned response to the contextual cues associated with illness-inducing chemotherapy-can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options.

One of the first documented medicinal uses of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV.

Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.”

http://www.ncbi.nlm.nih.gov/pubmed/27507945

A new antipsychotic mechanism of action for cannabidiol

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Totally dope! – A new antipsychotic mechanism of action for cannabidiol, by Anand Gururajan

“The pharmacological strategy for the treatment of schizophrenia has not changed in the six decades since chlorpromazine was introduced in 1952. Although several newer agents have recently gained approval, the mechanism of action of antipsychotics is still largely based on normalising dopaminergic neurotransmission which does not adequately address the symptomatology of a very complex disorder. Moreover, they cause side effects such as extrapyramidal motor symptoms and metabolic syndrome which can worsen the patient condition.

In this regard, preclinical and clinical studies since the ’90s have demonstrated the antipsychotic potential of cannabidiol (CBD), a derivative of the cannabis sativa plant which does not have the adverse psychoactive properties of tetrahydrocannabinol.

In particular, CBD has been shown to be effective in attenuating the positive symptoms of schizophrenia with a negligible side-effect profile.

Accumulating evidence implicates dysfunction of the mammalian target of rapamycin (mTOR) signaling cascade in the pathophysiology of schizophrenia. Thus, in a recent paper, Renard et al. (2016) used the amphetamine (AMPH)-sensitisation protocol in rats to investigate whether the antipsychotic effects of CBD were mediated by its effects on the mTOR cascade. Specifically, they focused on the nucleus accumbens shell (NASh) which has been implicated as a therapeutically relevant ‘hot-spot’ for antipsychotic action and is one of the brain regions targeted by CBD.

Thus, together with the fact that CBD alone had no behavioural effects, the behavioural findings reinforce the potential utility of this cannabinoid as an antipsychotic for the treatment of the positive symptoms of schizophrenia.”

http://medicalxpress.com/news/2016-08-antipsychotic-mechanism-action-cannabidiol.html

Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids.

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“We have investigated the effects of cannabinoid agonists and antagonists on tumour necrosis factor-alpha (TNF-alpha)-induced secretion of interleukin-8 from the colonic epithelial cell line, HT-29.

The cannabinoid receptor agonists [(-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol] (CP55,940); Delta-9-tetrahydrocannabinol; [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate] (WIN55,212-2) and 1-propyl-2-methyl-3-naphthoyl-indole (JWH 015) inhibited TNF-alpha induced release of interleukin-8 in a concentration-dependent manner.

We conclude that in HT-29 cells, TNF-alpha-induced interleukin-8 release is inhibited by cannabinoids through activation of cannabinoid CB(2) receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/12498928

“Essential involvement of interleukin-8 (IL-8) in acute inflammation.”  http://www.ncbi.nlm.nih.gov/pubmed/7964163

“Interleukin-8 (IL-8) is known to possess tumorigenic and proangiogenic properties. Overexpression of IL-8 has been detected in many human tumors, including colorectal cancer (CRC). IL-8 promotes tumor growth, metastasis, chemoresistance and angiogenesis, implying IL-8 to be an important therapeutic target in CRC.”  http://www.ncbi.nlm.nih.gov/pubmed/20648559

Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids.

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“This study has implications for developing new therapeutics for the treatment of cancer, pain, and metabolic disorders.

GPR55 is activated by l-α-lysophosphatidylinositol (LPI) but also by certain cannabinoids.

In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant®, CB2 receptor agonists, and Cannabis sativa constituents.

Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands.

Here, we report that the little investigated cannabis constituents CBDV, CBGA, and CBGV are potent inhibitors of LPI-induced GPR55 signaling.

The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI.

Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV.

These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/

“Lysophosphatidylinositol (LPI) is a bioactive lipid generated by phospholipase A2 which is believed to play an important role in several diseases.”  http://www.ncbi.nlm.nih.gov/pubmed/22285325

 “The putative cannabinoid receptor GPR55 promotes cancer cell proliferation.  In this issue of Oncogene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressiveness-related manner, suggesting a novel cancer biomarker and a potential therapeutic target.” http://www.ncbi.nlm.nih.gov/pubmed/21057532
“The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. These findings reveal the importance of GPR55 in human cancer, and suggest that it could constitute a new biomarker and therapeutic target in oncology.” http://www.ncbi.nlm.nih.gov/pubmed/20818416
“The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. These findings may have important implications for LPI as a novel cancer biomarker and for its receptor GPR55 as a potential therapeutic target.”  http://www.ncbi.nlm.nih.gov/pubmed/20838378
“L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Evidence points to a role of L-α-lysophosphatidylinositol (LPI) in cancer.”  http://www.ncbi.nlm.nih.gov/pubmed/21367464

Peripherally selective cannabinoid 1 receptor (CB1R) agonists for the treatment of neuropathic pain

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 Journal of Medicinal Chemistry

“Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ~0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene’s anti-allodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain.”

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00516

Endocannabinoids: new targets for drug development.

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“The possible therapeutic use of marijuana s active principles, the cannabinoids, is currently being debated.

It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB1 and CB2 cannabinoid receptor subtypes.

This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential.

The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids.

Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer.

These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.”

http://www.ncbi.nlm.nih.gov/pubmed/10903398

Preparation and characterization of Δ(9)-tetrahydrocannabinol-loaded biodegradable polymeric microparticles and their antitumoral efficacy on cancer cell lines.

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“Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer, AIDS and multiple sclerosis), analgesics, and in the treatment of multiple sclerosis and cancer, among other conditions.

However, despite their high clinical potential, only few dosage forms are available to date.

In this paper, the development of Δ(9)-tetrahydrocannabinol (THC) biodegradable microspheres as an alternative delivery system for cannabinoid parenteral administration is proposed.

As THC has shown therapeutic potential as anticancer drug, the efficacy of the microspheres was tested on different cancer cell lines.

Interestingly, the microspheres were able to inhibit cancer cell proliferation during the nine-day study period.

All the above results suggest that the use of biodegradable microspheres would be a suitable alternative delivery system for THC administration.”

http://www.ncbi.nlm.nih.gov/pubmed/23773072

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.

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Psychopharmacology

“Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders.

Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing.

Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG).

RESULTS:

All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.

CONCLUSIONS:

These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/21796370

Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent mechanism.

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“Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain-barrier and a strong inflammation in the brain.

We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM).

Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2-/-) mice inoculated with Plasmodium berghei ANKA-erythrocytes exhibited enhanced survival and a diminished blood-brain-barrier disruption.

Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice.

Hematopoietic-derived immune cells were responsible for the enhanced protection in bone-marrow-chimeric (BM)-Cnr2-/- mice. Mixed BM-chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b+ cell population, containing macrophages and neutrophils, expanded in the Cnr2-/- spleen after infection and expressed macrophage mannose receptors, arginase-1 activity and IL-10.

Also in the Cnr2-/-brain CD11b+ cells that expressed selected anti-inflammatory markers accumulated and expression of inflammatory mediators IFN-γ and TNF-α was reduced.

Finally, the M2-macrophage chemokine CCL17 was identified as essential factor for enhanced survival in the absence of CB2, since CCL17 x Cnr2 double-deficient mice were fully susceptible to ECM.

Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.”

http://www.ncbi.nlm.nih.gov/pubmed/27474745