Astrazeneca stroke renovis cerovive
Peter H. Proctor, PhD, MD
The spin trap and spin label homepage covers the biological and therapeutic aspects of nitrone and nitroxide spin labels and spin traps. One example is Cerovive, Astrazenca's new stroke drug.
Briefly, nitroxides and nitrones are stabilized forms of the biological messenger nitric oxide. They also have some unique properties. e.g. unlike other antioxidants, they generally neither act as proxidants, nor do they propagate free radical chain reactions.
Likewise, these agents inhibit the reaction of superoxide and nitric oxide to produce peroxinitrite. Recent evidence suggests that this reaction may play a crucial role in a wide range of degenerative diseases. These include Parkinsonism, stroke, ischaemic injury, heart attack, and age-related dementias.
Similarly, free radicals are also important, often extracellular, "redox" signaling messengers and this is likely responsible for much "cellular dysfunction" . Thus, many of the actions of the archetype spin trap, PBN or its disulfonic acid derivative ( AstraZeneca's "Cerovive" ), are likely explicable in terms of redox-signaling-mediated processes. One example is the effect of such compounds on cytokines such as TNF alpha. This may acount for the effect of REN-1654, Renovis' drug for neuropathic pain. Similarly, the redox-modulated ion channel TRPM7 may play a key role in neuronal death in stroke.
Because they inhibit fundamental pathogenic mechanisms, these drugs are extremely promising for the treatment of inflammatory and degenerative diseases such as the senile dementias, parkinsonism, cancer, stroke, etc. The archetype nitrone drug, PBN, uniquely extends maximum lifespan in experimental animals. For a summary of such diseases and pathogenic processes, read my review article " Free Radicals and Human Disease ",
A Patent Dispute with Centaur
Look here for my patents, etc. on nitrone and nitroxide drugs. While nominally for topical use, these patents also grant general utility for "ameliorating a cellular dysfunction of a tissue". This includes "parenteral" use. Thus, the patents incorporate claims for the treatment of diseases which I had previously listed in review articles.
E.g., US patent 5,732,502 (covering use of PBN and other nitrones as drugs) claims " other free radical diseases as outlined in Proctor et al., "Free Radicals and Disease in Man," Physiological Chemistry and Physics and Medical NMR, volume 16, pp. 175-195 (1984) which is hereby incorporated herein by reference; and the like." Click Free radicals and Disease for a copy of this review article.
Similarly, the '502 patent claims treatment of "ischemic reperfusion injury secondary to myocardial infarction, stroke (emphasis-added) and surgical procedures". Because of their early priority date ( about 1985, 4-5 years before anything similar ) these are the primary patents for the use of such compounds as drugs. But their late date of issue means they still have many years to run.
However, while my patents were pending, reseachers with Centaur Pharmaceuticals applied for similar ones. These applications were after the European publication of my claims. Go to Centaur for their statement concerning this patent dispute.
Infringement only begins when a drug company applies for FDA approval--- here, not before 2006. Thus, Centaur temporized on this patent issue. Unfortunately, VC investors are a nervous lot who read the patent literature. My IP aside, this did not exactly correspond to Centaur's assertions. For an example, go to ANDA.
Patent problems can kill a company. By 2002, Centaur had a potential blockbuster drug (Cerovive) going into phase-3 trials. Moreover, at this point all further costs were assumed by AstraZeneca, along with a $4,500,000 milestone payment to Centaur. Not to mention other promising nitrone drugs were in the pipeline.
However, Centaur could not raise a last round of funding and liquidated. Apparently findng few other bidders, Centaur then sold its assets at a fraction of their former book value to Renovis , another drug development firm. This was a good deal for Renovis stockholders, if Renovis can resolve the multiple patent problems that apparently caused Centaur to fail. This is not certain.
Renovis then did an IPO primarily based upon Centaur's problematic intellectual property. See Renovis IPO for their prospectus. Renovis' statement on my part of this patent issue.**
Stroke ---Decades ago, Demopolous et al reported a role for free radicals etc. in stroke and and ischaemic injury. For a good general review, see " Mechanisms of Action of Neuroprotectants in Stroke ". The disulfonyl derivative of PBN ( phenybutylnitrone ), NXY059 or "Cerovive" (TM) is now in phase-3 clinical trials for stroke at Astrazeneca. For a review (needs signup for full access), see Cerovive.
Peter H. Proctor, PhD, MD
4126 SW Freeway, Suite 1616
Houston, TX 77027
Phone: +1 713 960 1616
FAX: +1 713 960 1616
stroke astrazeneca renovis cerovive.
Cerovive, is the registered trademark of AstraZeneca for NXY-059, the disulfonyl derivative of phenylbutylnitrone (PBN).
** Naturally, if someone from Renovis wishes to enlarge upon, correct or dispute any of this, I will be happy to post their comments.
Keywords antioxidant free radical organic semiconductors trpm7 alzheimers multiinfarct dementia superoxide ros reperfusion injury reperfusion injury peroxide catalase sod dismutase astrazenica (sp) signaling thiolactone cancer treatment redox vascular musculoskeletal disorder arthritis inflammation renovis endothelium no inos cnos signaling messenger active oxygen deafness nkbeta inner ear cis platinum stria microvasculature vascularis adriamycin bleomycin pbn nxy-059 astrazenica electron transfer hydroxyl radical catalase peroxidase anticancer high conductivity alcaptonuria phenothiazine dopa uric acid radioprotection radiation treatment melanin lesch-nyhan manganese hemochromatosis iron copper porphyria cancer radiotherapy nkbeta apoptosis.