Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-11
1999-10-26
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3133
Patent
active
059729244
DESCRIPTION:
BRIEF SUMMARY
Central nervous tissue & to a lesser extent, peripheral nervous tissue, has poor reparative abilities. Thus damage to nervous tissue causes significant permanent disability & is a frequent cause of death. Damage to nervous tissue occurs in many ways, including ischemia in cerebrovascular accidents, cerebral circulatory disturbances, episodes of absolute & relative hypoxia, from metabolic disturbances, & from various forms of trauma. In areas of focal ischemia or damage, there is a core of more profound damage, surrounded by a perifocal penumbra of lesser damage. The neurons in the penumbra can for a time maintain homeostasis, & are potentially more salvageable by pharmacological agents.
Current treatment of nervous damage is limited. Supportive measures are taken in hospital during the period after nervous insult, such as stroke or trauma. Several medications have met with differing but incomplete success as agents to protect nervous function from insult. Nimodipine, a calcium channel blocker, is used clinically to treat vasospasm after subararchnoid hemorrhage. Methyaprednisolone, a steroid, in very high doses is helpful in spinal cord compression. Tirilazad, a 21-aminosteroid linked to a free radical scavenger, is undergoing clinical trials to decrease the damage caused by stroke. The high rate of disability from nervous insult, & current lack of a truely effective neuroprotective agent demonstrates the need for such a discovery.
It has now been discovered that the treatment medication known as cyclosporin A having the formula: ##STR1## is a useful & effective neuroprotective agent.
It is already known that cyclosporin A is an immunosuppressive drug. The above mentioned treatment medication has already been described, in U.S. Pat. No. 4,117,118 & numerous patents since, which relate to its production, formulation & immunosuppressive properties.
Cyclosporin A is a product of the fungus Tolypocladium Inflatum Gams. It is a cyclic poly-amino acid molecule, consisting of 11 amino acids. One of the amino acids is unique for cyclosporin A, a .beta.-hydroxyamino acid called butenyl-methyl-threonin (MeBmt). The molecular weight is 1202.6 & the chemical composition is C.sub.62 H.sub.111 N.sub.11 O.sub.12.
The molecule is highly lipophilic, & virtually insoluble in water. The bioavailability after an oral dose varies between 8 & 60% depending in part on the bile flow. The drug is absorbed mainly in the small intestine. The drug is transported in the blood within red blood cells to about 58%, & the remaining approximately 10-20% in leukocytes, & 33% bound to plasma proteins. In the plasma cyclosporin A is bound to high-density lipoproteins & low-density lipoproteins & very-low density lipoproteins, & a small fraction to albumin. A very small fraction is free in the plasma.
The drug undergoes extensive metabolism, mainly in the liver by the cytochrome P450 system. There are at least 30 known metabolites of cyclosporin A, with various chemical modifications, such as hydroxylation, demethylation, oxidation & epoxide formations. There are a number of variants of cyclosporin A, differing for example in one amino acid, which have similar pharmacological properties.
There is an enterohepatic circulation, & gut bacteria can metabolize the drug, with a further uptake of the metabolites in patients. 95% of a single dose given orally can be found in the feces within 95 hrs. The remaining fraction is excreted via the kidneys. Under normal conditions cyclosporin A & its metabolites do not pass the blood-brain barrier.
This entire family of cyclosporins, all derivatives, variants, amino acid variants, metabolites, including variations of mono-, di- & trihydroxylates, N-demethylates, aldehydes, carboxylates, conjugates, sulfates, glucuronides, intramolecular cyclizations & those without a cyclic structure as well as shorter peptides & amino acids & their derivatives & salts will hereinafter be referred to as cyclosporins. Pharmacologically acceptable forms of cyclosporins will hereinafter be referred to as treatment medication or
REFERENCES:
patent: 4117118 (1978-09-01), Harri et al.
Shiga et al., Chemical Abstracts (118: 93972) Cyclosporin A protects against ischemia-reperfusion injury in the brain.
Elmer Eskil Mats
Keep Marcus Floyd
Kokaia Merab
Kokaia Zaal
Uchino Hiroyuki
Maas BiolAB, LLC
Weddington Kevin E.
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