Each year, 750,000 strokes occur in the US and resultant deaths account for stroke being one of the top three causes of mortality as well as a major economic burden on healthcare systems (see Acute Stroke - Symptom Awareness Will Reduce Headache). Most strokes are ischemic however 20% are hemorrhagic; irrespective of the subtype treatments are limited. One candidate molecular target for stroke is 20-HETE, an ecosanoid that has been suggested to contribute to the development of vasospasm. Taisho Pharmaceutical have developed a potent and selective 20-HETE synthesis inhibitor, TS-011 which has been reported to display efficacy in models of both hemorrhagic and ischemic stroke. The latest available new from Taisho is that TS-011 entered phase I development in the US in 2003.

Each year, 750,000 strokes occur in the US and resultant deaths account for stroke being one of the top three causes of mortality. Incidence is expected to increase in the next ten years. Long term disability caused by stroke is a major economic burden on healthcare systems, current treatment options are limited and general awareness of stroke is poor. Therefore the opportunity for new drugs is huge and lucrative for companies willing to invest in increasing awareness (see Acute Stroke - Symptom Awareness Will Reduce Headache).

Of all strokes approximately 20% are hemorrhagic. Following an initial period of cerebral ischemia lasting several hours during which acute vasospasm is observed, hemorrhagic stroke is associated with delayed vasospasm in about half the surviving patients. Mortality in the first month is around 50% with the majority of deaths occurring during the first 2 days mirroring ischemic brain injury. Current treatments for hemorrhagic stroke focuses on the repair of aneurysms and reducing intracranial pressure. The remaining 80% of stroke patients suffer ischemic stroke; long term damage be minimized if blood flow is restored within 2 hrs after the onset of the stroke or if the metabolic demand of the tissue is reduced. Thus thrombolytic therapy represent the only approved treatment of acute ischemic stroke although the narrow time frame over which this approach is effective excludes its use in almost all patients.

One candidate molecular target for stroke is 20-HETE, an ecosanoid that has been suggested to contribute to the development of vasospasm following subarachnoid hemorrhage. This concept is supported by data showing that 20-HETE is a potent constrictor of cerebral arteries and its levels increase in CSF following subarachnoid hemorrhage. On the other hand, inhibition of the synthesis of 20-HETE or blockade of its vasoconstrictor actions prevents the acute fall in cerebral blood flow following subarachnoid hemorrhage. There is also evidence that blockade of the synthesis of 20-HETE may also reverse delayed vasospasm.

The JPET study highlighted here characterizes the effects of Taisho Pharmaceutical's 20-HETE synthesis inhibitor, TS-011. The IC50 for TS-011 was found to be 8 and 9nM in human and rat microsomes respectively and thus considerably more potent than other 20-HETE synthesis inhibitors described to date. TS-011 inhibited CYP4F2, CYP4F3A, 4F3B and 4FA11, albeit with 4-10-fold higher IC50 values. The inhibition of these CYP isoforms (that are known to produce of 20-HETE in man) was selective compared to other CYP isoforms (that play a major role in hepatic drug metabolism); little effect was observed against a panel of other receptors and enzymes investigated.

The efficacy of TS-011 was then evaluated in a model of decreased cerebral blood flow following subarachnoid hemorrhage. The model was based on the injection of blood into the CSF which caused a decrease in cerebral blood flow and an increase in intra-cerebral pressure. These responses were biphasic consisting of an initial phase lasting about 10 minutes followed by a sustained but less extreme phase of reduced cerebral blood flow and increased pressure. Pretreatment with TS-011 prevented the sustained fall in cerebral blood flow and sped recovery to normal cerebral pressure but had no effect on baseline parameters. TS-011 was also effective when given therapeutically (45 minutes after the injection of blood) with cerebral blood flow returning to control values within about 60 minutes, contrasting with controls which remained unchanged over this period.

Having demonstrated the ability of TS-011 to reverse changes in cerebral blood flow and pressure the Taisho group then investigated its effect on infarct size in another model of intracerebral hemorrhage involving the administration of collagenase into the brain. This procedure caused cerebral infarction and severe motor neurological deficits. TS-011 dose-dependently reduced infarct size up to 30% and reduced the degree of motor deficit. Likewise in a model of ischemic stroke, total and cortical infarcts resulting from transient occlusion of the MCA were reduced by 35% following administration of TS-011 60 minutes after occlusion and just prior to reperfussion. In this model TS-011 is at least as effective as NMDA, endothelin, leukotriene, PAF or Ca channel blockers in reducing infarct size.

This study therefore establishes TS-011 as a candidate for further development as a treatment of both hemorrhagic and ischemic stroke. The latest available new from Taisho is that TS-011 entered phase I development in the US in 2003.

Entry date Thursday, June 02, 2005

J Clin Invest. 2005 May 2;115(5):1275-1280. Epub 2005 Apr 7

LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report.

This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider.