Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-12-10
2001-08-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S489000, C424S408000
Reexamination Certificate
active
06277393
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the area of the treatment and/or preventing of cerebrovascular diseases, traumas and damages of the nervous system (“neural injuries”), and includes local (topical) or systemic application of an effective amount of tetracycline, tetracycline derivative or a mixture of tetracycline and/or tetracycline derivative(s) (“active agent(s)”), optionally in a pharmaceutically-acceptable diluent, carrier or tetracycline release system (“active composition”).
BACKGROUND OF THE INVENTION
Degeneration, traumas and injuries of the nervous system, comprising brain, spinal cord and peripheral nerves, are characteristic of certain diseases and common consequences of accidents. Cerebrovascular accident (CVA) is a clinical definition used to describe symptoms of an acute neurological disorder caused by disturbance of the cerebral blood supply. Intracerebral and subarachnoid hemorrhages account for approx 20% of CVAs and 80% are of ischemic type. Stroke defines all conditions in which the duration of the CVA symptoms exceeds 24 h. Hemorrhagic strokes may be situated intra- or extracerebrally. Intracerebral hemorrhage can be caused by artery aneurysm rupture, and a subdural hemorrhage by cranial trauma. See, Ter Horst G J and Postigo A., In: Ter Horst G J and Korf J (eds.), ClinicalPharmacology of Cerebral Ischemia, Humana Press, Totowa, N.J., 1-30, 1997, the entire disclosure of which is incorporated herein by reference.
The causes of ischemic stroke are numerous and include large artery atherosclerosis, small vessel occlusion, embolisms, and thrombosis. Focal (regional) ischemia is clinically more common than global (forebrain) ischemia A focal insult usually occurs after thrombosis or embolus in the middle cerebral artery, whereas global ischemia results from transient cardiac arrest. See, Ter Horst G J and Postigo A., In: Ter Horst G J and Korf J (eds.), Clinical Pharmacology of Cerebral Ischemia, Humana Press, Totowa, N.J., 1-30, 1997.
If such damages, traumas or injuries as described above are not treated in a proper way they can lead to extensive death of nerve cells leading further to several permanent symptoms, including paralysis and other motor dysfunctions, sense disorders, mental disorders or even death of the patient.
The need to control cerebrovascular accidents and spinal cord injuries has led to a search for therapeutic agents and treatment methods that are both safe and effective. Animal studies and clinical trials have shown that amino acid transmitters (especially glutamate), oxidative stress and inflammatory reactions contribute strongly to cell death in brain diseases and damages. There are available some pharmacological methods to prevent cell deaths in the above cases. However, these methods have severe limitations and/or side-effects so that in practice there is no effective medical method for the treatment of cerebral stroke and spinal cord injuries. For example, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate, dizocilpine maleate) and CNS 1102 block another type of glutamate receptor and are neuroprotective in several rodent models of brain ischemia. See, Muir K W, Grosset D G and Lees K R (1995). Ann. NY Acad. Sci. 765:279-289; Muir K W, Lees K R (1995). Stroke 26:503-513; Kornhuber J, Weller M (1997). Biol. Psych. 41:135-144; Marshall L F, Marshall S B (1995). New Horiz. 3:573-580; Bullock R (1995). Ann. NY Acad. Sci 765:272-278; the entire disclosures of which are each incorporated herein by way of this reference. However, these compounds lead to hallucinations and cause vacuolization and death of certain cortical neurons. See Olney J W (1994). Psychopharmacol. Bull. 30:533-540, the entire disclosure of which is incorporated herein by this reference. NBQX (6-nitro-7-sulphamoylbenzo (f) quinoxaline-2,3dione (disodium)) acts as an antagonist of glutamate receptors, but it causes interstitial tubular nephrite and hallusinations. See, Muir K W, Lees K R (1995). Stroke 26:503-513;Marshall L F, Marshall S B (1995). New Horiz. 3:573-580; and Buchan A M, Lesiuk H, Bames K A, Li H, Huang Z-G, Smith K E, Xue D (1993). Stroke 24:I148-I151, Suppl. I, the entire disclosures of which are incorporated herein by way of this reference. Oxidative stress can be prevented with antioxidative enzymes, which unfortunately have very short half-life, typically only minutes or hours, in vivo. e.g. Cu,Zn-superoxidedismutase (Cu, Zn-SOD) protects cells agains oxidative stress but its half-life in vivo is, in free form, 6 min and, as conjugated, 38 hours. See Liu T H, Beckman J S, Freeman B A, Hogan E L and Hsu Y (1989). Am. J. Physiol. 256:H589-H593, the entire disclosure of which is incorporated herein by this reference. In addition, even though antioxidative compounds and anti-inflammatory drugs cross the blood-brain barrier, cerebral concentration high enough for neuronal protection is not usually achieved. See Chan P H, Longar S, Fishman R A (1987). Ann. Neurol. 21:540-547.;Insel P A: Chapter 26, 638-681 in: Goodman and Gilman (eds) the Pharmacological Basis of Therapeutics. Eight edition, Pergamon Press, New York, 1990; and Grilli M, Pizzi M, Memo M, Spano P (1996). Science 274:1383-1385; the entire disclosures of which are incorporated herein by way of this reference.
As a result, there is a significant and very long-standing need to identify new methods and/or new agents with favourable benefit to risk ratios that can be applied topically (locally) or given systemically to prevent or suppress (i.e. “treat”) neuronal death after damages, traumas and diseases of the brain and spinal cord, and the associated symptoms of paralysis, cardiac complications, psychosis and agitation. Optimally, such agents should be effective when administered topically (locally) or systemically and systemic absorption should not result in blood levels high enough to cause significant systemic toxicity or other adverse side effects.
It is therefore an object of the present invention to provide methods for treating brain stroke (brain ischemias and hemorrhages) and spinal cord injuries.
It is another object of the present invention to provide methods for systemic treatment of brain stroke (brain ischemias and hemorrhages) and spinal cord injuries.
It is yet another object of the present invention to provide methods for topical/local treatment of brain ischemias (brain stroke) and spinal cord injuries.
SUMMARY OF THE INVENTION
A method for treating brain stroke (ischemia, hemorrhage) and/or spinal cord injuries in a human or other mammal is disclosed that involves the administration of an effective amount of tetracycline and/or tetracycline derivative or a mixture of tetracycline and/or tetracycline derivatives (“active agent(s)”), optionally in a pharmacutically-acceptable diluent, carrier or release matrix (“active composition”). The treatment can be used for brain stroke and/or spinal cord injury occuring in any area of the brain or spinal cord. Additionally, patients with brain stroke and/or spinal cord injuries may have a tendency to develop cerebral edema, cardiac complications, dysfunction of the autonomic nervous system, psychosis and agitation. These related conditions can also be prevented and/or treated with active agents(s) and/or active composition according to the method of the invention. In a preferred embodiment for the treatment of brain ischemia and/or spinal cord injury, active agent(s) and/or active composition is administered intravenously or intra-arterially and the administration is continued orally. In another preferred embodiment for the treatment of brain ischemia and/or spinal cord injury, active agent(s) and/or active composition is administered locally on or into brain or spinal cord by means of a diluent, a carrier or drug releasing system.
The active agent and/or active composition can be administered in any dosage that achieves the desired result. Systemic dosages of between 10 and 180 mg/kg/day are typically useful for the above indications. The dosages can be given at any appropriate interva
Kaikkonen Auvo
Keinänen Riitta
Koistinaho Jari
Miettinen Susanna
Törmäl{umlaut over (a )} Pertti
Bioabsorbable Concepts, Inc.
Fubara Blessing
Kenyon & Kenyon
Page Thurman K.
LandOfFree
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