The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Precise cannabis treatment dosing remains a major challenge, leading to physicians' reluctance to prescribe medical cannabis. OBJECTIVE: To test the pharmacokinetics, analgesic effect, cognitive performance and safety effects of an innovative medical device that enables the delivery of inhaled therapeutic doses of Δ9 -Tetrahydrocannabinol (THC) in patients with chronic pain. METHODS: In a randomized, three-arms, double-blinded, placebo-controlled, cross-over trial, 27 patients received a single inhalation of Δ9 -THC: 0.5mg, 1mg, or a placebo. Δ9 -THC plasma levels were measured at baseline and up to 150-min post-inhalation. Pain intensity and safety parameters were recorded on a 10-cm visual analogue scale (VAS) at pre-defined time points. The cognitive performance was evaluated using the selective sub-tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Following inhalation of 0.5 mg or 1mg, Δ9 -THC plasma Cmax  ± SD were 14.3 ± 7.7 and 33.8 ± 25.7 ng/ml. Tmax  ± SD were 3.7 ± 1.4 and 4.4 ± 2.1 min, and AUC0  â†’ infinity ±SD were 300 ± 144 and 769 ± 331 ng*min/ml, respectively. Both doses, but not the placebo, demonstrated a significant reduction in pain intensity compared with baseline and remained stable for 150-min. The 1-mg dose showed a significant pain decrease compared to the placebo. Adverse events were mostly mild and resolved spontaneously. There was no evidence of consistent impairments in cognitive performance. CONCLUSION: This feasibility trial demonstrated that a metered-dose cannabis inhaler delivered precise and low THC doses, produced a dose-dependent and safe analgesic effect in patients with neuropathic pain/ complex-regional pain syndrome (CRPS). Thus, it enables individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically by accepted pharmaceutical models. SIGNIFICANCE: Evidence suggests that cannabis-based medicines are an effective treatment for chronic pain in adults. The pharmacokinetics of THC varies as a function of its route of administration. Pulmonary assimilation of inhaled THC causes rapid onset of analgesia. However, currently used routes of cannabinoids delivery provide unknown doses, making it impossible to implement a pharmaceutical standard treatment plan. A novel selective-dose cannabis inhaler delivers significantly low and precise doses of THC, thus allowing the administration of inhaled cannabis-based medicines according to high pharmaceutical standards. These low doses of THC can produce safe and effective analgesia in patients with chronic pain.

Platelet lysates stimulate angiogenesis, neurogenesis and neuroprotection after stroke.

Platelets contain chemo-attractants and mitogens that have a major role in tissue repair. Therefore we hypothesised that tissue regeneration secondary to activation of endogenous neural stem cells (eNSC) can be enhanced by delivering platelets to the ischaemic brain. To examine these potential therapeutic effects we injected platelet-poor plasma (PPP), fibroblast growth factor (FGF2) and platelet lysate (PLT) to the lateral ventricles after permanent middle cerebral artery occlusion (PMCAO) in rats. The animals were tested with the neurological severity score, and infarct volumes were measured at 90 days post-PMCAO. Immunohistochemistry was used to determine the fate of newborn cells and to count blood vessels in the ischaemic brain. Platelets significantly increased eNSC proliferation and angiogenesis in the subventricular zone (SVZ) and in the peri-lesion cortex. Functional outcome was significantly improved and injury size was significantly reduced in rats treated with PLT suggesting additional neuroprotective effects. In conclusion, local delivery of PLT to the lateral ventricles induces angiogenesis, neurogenesis and neuroprotection and reduces behavioural deficits after brain ischaemia.

The role of platelets and their microparticles in rehabilitation of ischemic brain tissue.

Stroke is a leading cause of mortality and chronic disability. Therapies aimed at reducing stroke related morbidity are currently limited. Therefore it is very important to develop effective treatments that will maximize rehabilitation after stroke. Current efforts in the field of cellular therapy focus on stem cell transplantations. This approach involves biological and ethical complications and therefore, the use of endogenous neural stem cells (eNSC) for repairing damage in various neurological disorders has been suggested. eNSCs reside in specialized vascular niches in defined regions, such as the subventricular zone (SVZ) of the lateral ventricle. These cells have an unlimited potential to create newborn cells. Interrelations between newborn neural and endothelial cells have an important role in eNSC survival, maturation, migration and differentiation and neurogenesis occurs in close spatio-temporal association with vessel growth in these niches. Previous studies have shown that application of external factors can boost long-term endogenous repair mechanisms in the cerebral cortex. Activated platelets and their microparticles contain a variety of growth and trophic factors essential to angiogenesis and neurogenesis and may therefore serve as novel therapeutic agents for brain injury. Specifically, factors from platelets and their microparticles may promote neurogenesis by stimulating eNSC proliferation, migration and differentiation, and by stimulating niche angiogenesis and the release of neurogenic signals from endothelial cells and astrocytes. In this review we will show that combined augmentation of angiogenesis, neurogenesis and neuroprotection using platelets and their microparticles is feasible and results in improved functional gain after stroke.

Involvement of platelet derived microparticles in tumor metastasis and tissue regeneration.

Platelets play a major role in hemostasis, but are also involved in vascular biology processes such as angiogenesis and tumor metastasis. Activated platelets release many proteins favoring wound healing and promoting angiogenesis. Microparticles (MP) are small plasma membrane vesicles shed from cells upon their activation or apoptosis. Platelet-derived microparticles (PMP) constitute the majority of the pool of MP circulating in the blood. PMP express and may transfer functional receptors, stimulate the release of cytokines, activate intracellular signaling pathways, promote angiogenesis, and are involved in tissue regeneration and cancer metastasis. We investigated the effect of PMP on cancer cells metastasis and their potential beneficial effect in an ischemic stroke model.

Platelet microparticles induce angiogenesis and neurogenesis after cerebral ischemia.

Activated platelets shed microparticles, which contain a variety of growth factors central to angiogenesis and neurogenesis. The aim of this study was to explore whether platelet derived microparticles (PMP) can boost endogenous neural stem cells dependent repair mechanisms following stroke in a rat model. To examine the effects of PMP therapy in-vivo, we delivered PMP or vehicle via a biodegradable polymer to the brain surface after permanent middle cerebral artery occlusion (PMCAO) in rats. Rats were tested with the neurological severity score and infarct volumes were measured at 90 days post-ischemia. Immunohistochemistry was used to determine the fate of newborn cells and to count blood vessels in the ischemic brain. The results show that PMP led to a dose dependent increase in cell proliferation, neurogenesis and angiogenesis at the infarct boundary zone and significantly improved behavioral deficits.

Platelet microparticles promote neural stem cell proliferation, survival and differentiation.

Platelet microparticles (PMP) are small subcellular fragments, shed upon platelet activation. PMP host a variety of cytokines and growth factor that were previously shown to affect angiogenesis and postischemic tissue regeneration. This study attempted to explore the effect of PMP on neural stem cell (NSC) proliferation, survival and differentiation. Cells were grown as neurospheres and treated with PMP, or relevant growth factors, sphere size and cell fates were evaluated. PMP treatment led to larger neurospheres with increased cell survival. PMP treatment was comparable with the effect of acceptable single growth factors such as fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). PMP treatment also increased the differentiation potential of NSC to glia and neurons. Specific growth factor inhibitors only partly blocked these effects, which were associated with increments in ERK and Akt phosphorylation. In this study, we show that various growth factors contained within the PMP promote neuronal cell proliferation, survival and differentiation. The results suggest a role for platelet microparticles in augmenting endogenous neural progenitor and stem cells angiogenesis and neurogenesis that might be utilized for treatment following brain injury.