Wednesday, May 31, 2006

Cannabinoids, opioids and approaches to neurodegeneration

DailyUpdates 31st May: Today's edition of DailyUpdates focuses on a controversial area of neurotransmission: opioids, cannabinoids and their overlap. Our featured press release is from Allon Therapeutics and announces further progress on their novel approach to neurodegenerative disorders. Read on for an overview or visit today's edition of DailyUpdates here

Cannabinoids and opioids - their intereaction in the modulation of pain:
Cannabinoid therapeutics have the potential to be used in multiple indications and therefore have blockbuster possibilites (see Cannabinoids - A potential blockbuster market), The activity of the endogenous cannabinoid, arachidonylethanolamide (anandamide) is mediated through its binding to the cannabinoid receptors, CB1 and CB2. The signal subsequent to receptor activation is switched off through its transport into various cells by a specific transporter and then the degradation by the fatty acid amide hydrolase (FAAH). Multiple strategies are currently being investigated in an attempt to modulate cannabinoid activity including receptor ligands; agents that bind to the transporter protein; and inhibitors of FAAH. The latter represent an attractive approach to the treatment of chronic pain condition through the prolongation of the analgesic activity of cannabinoid receptor activation by endogenous cannabinoids. The neuropathic pain market has traditionally been a poorly defined area, with widely varying drug classes prescribed. Gabapentin remains the gold standard treatment to beat in the 5 EU and US neuropathic pain markets, which are estimated at a combined total of $2,543m in 2005, reaching $4,118m in 2007. More recently Lyrica (pregabalin) and Cymbalta (duloxetine) have entered the market as alternatives to gabapentin in the treatment of pain (see Pipeline Insight: Neuropathic Pain - Pipeline Drugs Fail to Nail Neuropathic Pain). Today’s featured report, published by researchers at Johnson & Johnson represents an in depth study of the pharmacology of the FAAH inhibitor, OL135 in pain models and suggests that a major component of its analgesic effect results from the activation of CB2 receptors and opioid pathways.

Allon's broad potential neuroprotective agent passes through phase 1b studies Market analysis shows that products currently used that have a neuroprotective effect had a market value of 5.1 billion in 2005. With the approval of new products and takeover of markets for obsolete symptomatic therapies, the neuroprotection market value will rise $11.5 billion by the year 2010 when it will constitute a major and important component of the CNS market and further to $24 billion (see our two features World Neurodegeneratives Disease Markets, 2005-2009 and Neuroprotection - Drugs, Markets and Companies). Allon is one company actively involved in the develop,ment of neuroprotectives. The company's platform originated from studies on vasoactive intestinal peptide (VIP) which has been shown to be a broadly acting neuroprotectant. VIP was shown to exert its neuroprotective effects by causing neuroprotective proteins to be secreted from glial cells. Activity-dependent neuroprotective protein (ADNP) and activity-dependent neurotrophic factor (ADNF) were identified as the proteins secreted by glial cells that provide neuroprotection in response to VIP. For ADNP, in addition to its neuroprotective efficacy, it was shown to be critical for brain development. Further research showed that an eight amino acid peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAP), and a nine amino acid peptide, Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (also termed ADNF-9), from ADNP and ADNF respectively, are necessary and sufficient to reconstitute neuroprotective activities. AL-208 is an intravenous formulated eight amino acid neuroprotective peptide based on NAP. AL-208 protects neurons against numerous toxins and cellular stresses including Alzheimer’s disease neurotoxin (B-amyloid peptide), excitotoxicity (N-methyl-D-aspartate), the toxic envelope protein of HIV (gp120), electrical blockade (tetrodotoxin), oxidative stress (hydrogen peroxide), dopamine toxicity, decreased glutathione, and tumor necrosis factor (TNFα)-associated toxicity. AL-208 has neuroprotective activity in a variety of animal models including the learning deficient apolipoprotein E knock-out mice (a model related to AD), mouse paradigms of traumatic head injury (a risk factor for AD), fetal alcohol syndrome (severe oxidative stress), as well as rat models of cholinotoxicity(with cholinergic loss being a whole mark of AD) and stroke (associated with vascular dementia). It is active at unprecedented low concentrations (femtomolar). AL-208 is thought to prevent neuronal cell death by binding to neuron-specific tubulin, subsequently repairing the microtubular network as well as potentially restoring both axonal transport within nerve cells and chemical transmission between them. Allon’s compounds also promote neurite growth, which is dependent on microtubule formation. Today's featured press release from Allon announces data from a phase 1b study of AL-208 demonstrating safety and tolerability.


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