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Non-neurotoxic plasminogen activating factors for treating of strokeRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain StructureNon-neurotoxic plasminogen activating factors for treating of stroke description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060142195, Non-neurotoxic plasminogen activating factors for treating of stroke. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION [0001] This is a continuation of application Ser. No. 10/184,01 filed Jun. 28, 2002, which claims the benefit of priority to German Patent Application No. 101 53 601.1, filed on Nov. 2, 2001, and European Patent Application No. 01 130 006.8 filed on Dec. 17, 2001, all of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention pertains to the therapeutic use of non-neurotoxic plasminogen activators especially from the saliva of Desmodus rotundus (DSPA) preferentially for the treatment of stroke. BACKGROUND OF THE INVENTION [0003] The term "stroke" is a general term that covers conditions having different clinical symptoms. For example, a stroke may be caused by an ischaemic or haemorrhagic insult. [0004] Ischaemic insults (ischaemia) are characterized in a reduction or interruption of the blood circulation in the brain due to a lack of arterial blood supply. Often this is caused by thrombosis of an arteriosclerotic stenosed vessel or by arterio arterial, or cardial embolisms. [0005] Haemorrhagic insults are based inter alia on the perforation of brain supplying arterias damaged by arterial hypertonia. However, only approximately 20% of all cerebral insults are caused by haemorrhagic insults. Thus, stroke due to thrombosis is much more prevalent. [0006] In comparison to other tissue ischaemias, the ischaemia of the neuronal tissue is widely accompanied by necrosis of the effected cells. The higher incidence of necrosis in neuronal tissue can be explained with the new understanding of the phenomenon "excitotoxicity," which is a complex cascade comprising a plurality of reaction steps. The cascade is initiated by ischaemic neurons affected by a lack of oxygen, which then lose ATP instantaneously and depolarize. This results in an increased postsynaptic release of the neurotransmitter glutamate, which activates membrane bound glutamate receptors regulating cation channels. However, due to the increased glutamate release glutamate receptors become over activated. [0007] Glutamate receptors regulate voltage dependent cation channels, which are opened by a binding of glutamate to the receptor. This results in a Na.sup.+ and Ca.sup.2+ influx into the cell massively disturbing the Ca.sup.2+ dependent cellular metabolism. Especially the activation of the Ca.sup.2+ dependent catabolic enzymes result in subsequent cell death (Lee, Jin-Mo et al., "The changing landscape of ischaemic brain injury mechanisms"; Dennis W. Zhol "Glutamate neurotoxicity and diseases of the nervous system"). [0008] Although the mechanism of glutamate mediated neurotoxicity is not yet entirely understood, it is agreed upon that it contributes in a large extent to neuronal cell death following cerebral ischaemia (Jin-Mo Lee, et al.). [0009] The re-opening of a closed vessel has priority in the therapy of acute cerebral ischaemia, in addition to safeguarding vital functions and stabilizing physiological parameters. The re-opening can be performed by different means. The mere mechanical re-opening, as e.g., the PTCA after heart attack, so far has not yet led to satisfying results. Only with a successful fibrinolysis can an acceptable improvement of the physical condition of patients be achieved. This can be accomplished by a local application using a catheter (PROCAT, a study with pro-urokinase). However, despite initial positive results, this method has not yet been officially approved as a pharmaceutical treatment. [0010] Naturally occurring fibrinolysis is based on the proteolytic activity of the serine protease plasmin, which originates from its inactive precursor by catalysis (activation). The natural activation of plasminogen is catalyzed by the plasminogen activators u-PA (urokinase type plasminogen activator) and t-PA (tissue plasminogen activator) occurring naturally in the body. In contrast to u-PA, t-PA forms a so-called activator complex together with fibrin and plasminogen. Thus, the catalytic activity of t-PA is fibrin dependent and is enhanced in its presence approximately 550-fold. Besides fibrin, fibrinogen can also stimulate t-PA mediated catalysis of plasminogen to plasmin, though to a lesser extent. In the presence of fibrinogen, the t-PA activity only increases 25-fold. Also the cleavage products of fibrin (fibrin degradation products (FDP)) can stimulate t-PA. [0011] Early attempts of thrombolytic treatment of acute stroke go back to the 1950s. Extensive clinical trials with streptokinase, a fibrinolytic agent from beta-haemolysing streptococci, started in 1995. Streptokinase forms a complex with plasminogen that catalyzes other plasminogen molecules into plasmin. [0012] Streptokinase therapy has severe disadvantages since streptokinase is a bacterial protease and therefore can provoke allergic reactions in the body. Furthermore, if a patient had a previous streptococci infection that resulted in a production of antibodies, the patient may exhibit streptokinase resistance, making the therapy more difficult. Besides this, clinical trials in Europe (Multicenter Acute Stroke Trial of Europe (MAST-E), Multicenter Acute Stroke Trial of Italy (MAST-I)) and Australia (Australian Streptokinase Trial (AST)) indicated an increased mortality risk and a higher risk of intracerebral bleeding (intracerebral haemorrhage, ICH) after treating patients with streptokinase. These trials had to be terminated early. [0013] Alternatively, urokinase--also a classical fibrinolytic agent--can be used. In contrast to streptokinase, it does not exhibit antigenic characteristics since it is an enzyme naturally occurring in various body tissues. It is an activator of plasminogen and independent of a co-factor. Urokinase is produced in kidney cell cultures. [0014] Another therapeutic thrombolysis agent tested was a recombinant tissue type plasminogen activator, rt-PA (see EP 0 093 619, U.S. Pat. No. 4,766,075), produced in recombinant hamster cells. In the 1990s several clinical trials were performed world-wide using t-PA with acute myocardial infarction as the main indication, leading to only partially understood and contradictory results. In the European Acute Stroke Trial (ECASS) patients were treated within a time frame of 6 hours after the onset of the symptoms of a stroke intravenously with rt-PA. After 90 days the mortality rate as well as the Barthel-Index were examined as an Index for the disability or the independent viability of patients. No significant improvement of the viability was reported but an increase of mortality was seen. Thus, a thrombolytic treatment with rt-PA of patients being individually selected according to their respective case history immediately after the beginning of the stroke could possibly be advantageous. However, a general use of rt-PA within the time frame of 6 hours after the onset of stroke was not recommended since an application during this time increased the risk of intracerebal haemorrhage (ICH) (C. Lewandowski C and Wiliam Barsan, 2001: Treatment of Acute Stroke; in: Annals of Emergency Medicine 37:2; S. 202 ff.). [0015] The thrombolytic treatment of stroke was also subject of a clinical trial conducted by the National Institute of Neurologic Disorder and Stroke (so called NINDS rtPA Stroke Trial) in the USA. This trial concentrated on the effect of intravenous rt-PA treatment within only three hours after the onset of the symptoms. Patients were examined three months after the treatment. Due to the observed positive effects of this treatment on the viability of patients; rt-PA treatment within the limited time frame of three hours was recommended, although the authors found a higher risk for ICH. [0016] Two further studies (ECASS II Trial: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke (ATLANTIS)) examined whether the positive effects of rt-PA treatment within three hours after the onset of stroke could be repeated instead with a treatment within six hours time. However, the results indicated that there was no improvement in the clinical symptoms, nor was there any decrease in mortality. Further, the higher risk for ICH remained. [0017] These partially contradictory results led to a high caution in the use of rt-PA. A 1996 publication of the American Heart Association pointed out the strong skepticism among doctors with respect to thrombolytic treatment of stroke; in contrast, there is no such skepticism with respect to fibrinolytica in the therapy of myocardical infarct (van Gijn J, MD, FRCP, 1996--Circulation 1996, 93: 1616-1617). [0018] A rationale behind this skepticism was first given in a summary of all stroke trials published 1997 (updated in March 2001). According to this review all thrombolytica treatments (urokinase, streptokinase, rt-PA or recombinant urokinase) resulted in a significant higher mortality within the first 10 days after a stroke, while the total number of either dead or disabled patients was reduced when the thrombolytica were applied within six hours after stroke onset. This effect was mainly due to ICH. Such results gave reason to some to make the sarcastic statement that stroke patients had the choice to either die or to survive disabled (SCRIP 1997: 2265, 26). The broad use of thrombolytica for the treatment of stroke was therefore not recommended. [0019] Nevertheless, the therapy with rt-PA currently is the only treatment of acute cerebral ischaemia approved by the Food and Drug Administration (FDA) in the USA. However, it is restricted to administration within three hours after the onset of stroke. [0020] The approval of rt-PA was reached in 1996. In 1995, first announcements about negative side effects of t-PA became known, which provide an explanatory basis for its dramatic effects when applied in stroke treatment outside the three hour time frame. Microglia cells and neuronal cells of the hippocampus produce t-PA, which contributes to the glutamate mediated excitotoxicity. This was concluded from a comparative study on t-PA deficient and wild type mice where glutamate agonists were injected in their hippocampuses. The t-PA deficient mice showed a significant higher resistance against external (inthrathecal) applicated glutamate (Tsirka S E et al., Nature, Vol. 377, 1995, "Excitoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator"). These results were confirmed in 1998, when Wang et al. demonstrated a nearly double quantity of necrotic neuronal tissue in t-PA deficient mice when t-PA was injected intravenously. This negative effect of external t-PA on wild type mice was only approximately 33% (Wang et al., 1998, Nature, "Tissue plasminogen activator (t-PA) increases neuronal damage after focal cerebral ischaemia in wild type and t-PA deficient mice".) [0021] Further results on the stimulation of excitotoxicity by t-PA were published by Nicole et al. in the beginning of 2001 (Nicole O., Docagne F Ali C; Margaill I; Carmeliet P; MacKenzie E T, Vivien D and Buisson A, 2001: The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling; in: Nat Med 7, 59-64). They showed that t-PA being released by depolarized cortical neurons could interact with the NR1 sub-unit of the glutamate receptor of the NMDA type, leading to a cleavage of NR1. This increased the receptor's activity, resulting in greater tissue damage after glutamate agonist NMDA was applied. The NMDA agonist induced excitotoxicity. Thus, t-PA exhibits a neurotoxic effect by activating the glutamate receptor of the NMDA type. Continue reading about Non-neurotoxic plasminogen activating factors for treating of stroke... 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Moreover, the mixture may ... 20090281023 - Mixtures of calcitonin drug-oligomer conjugates and methods of use in pain treatment - A mixture of conjugates in which each conjugate in the mixture comprises a calcitonin drug coupled to an oligomer that includes a polyalkylene glycol moiety is disclosed. The mixture may lower serum calcium levels in a subject by 10, 15 or even 20 percent or more. Moreover, the mixture may ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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