Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-23
2001-08-14
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06274621
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the inhibition of membrane expression of benzodiazepine receptors and in particular to the use of ginkgolides for the manufacture of medicaments for such membrane expression inhibition.
BACKGROUND OF THE INVENTION
The steroid glucocorticoid is produced by adrenal fasciculata-reticula cells in the adrenal glands, and are secreted in response to an increase in the level of plasma adrenocorticotrophic hormone (ACTH). Glucocorticoids are involved in carbohydrate, protein, and fat metabolism, have been shown to have anti-inflammatory properties, and are hypersecreted during stress. In excess, glucocorticoids have been shown to damage hippocampus, a structure in the limbic system of the brain that is critical to cognitive functions such as learning and memory. See, e.g., Sapolsky, R. M., Ann. N.Y. Acad. Sci. 746:294 (1994); and McEwen, B. S., Ann. N.Y. Acad. Sci. 746:134 (1994). Furthermore, glucocorticoid neurotoxicity and neuroendangerment has been shown to be critical in neural development and aging as well as in neurological diseases related to hippocampal damage. See, e.g., deKloet, E. R., et al., Ann. N.Y. Acad. Sci. 746:8 (1994).
Studies have been conducted to examine the beneficial effects of extract of the leaves of the gymnosphermus tree ginkgo biloba (e.g., EGb 761) on “antistress” activity by lowering corticosterine levels in stressed rat models. See, Rapin, et al., Gen. Pharmac. 25(5):1009 (1994). EGb 761 had previously been shown to have activity in the cardiovascular system (e.g., reduction of platelet adhesion and thrombi growth), central nervous system (e.g., neuroprotective activity), and neurosensory system (e.g., retinal protection). See, e.g., DeFeudis, et al., Ginkgo Biloba Extract (EGb 761): Pharmaceutical Activities and Clinical Applications (Elsevier, Paris, 1991).
It has now been found that ginkgolides are effective at inhibiting membrane expression of benzodiazepine receptors, eg. adrenal benzodiazepine receptors, and that, having this effect, they can be used to inhibit glucocorticoid release.
SUMMARY OF THE INVENTION
Thus viewed from one aspect the invention provides the use of a ginkgolide for the manufacture of a medicament for use as an inhibitor of membrane expression of a benzodiazepine receptor, eg. to inhibit glucocorticoid release in a patient. Alternatively viewed the invention provides the use of an inhibitor of membrane expression of an adrenal benzodiazepine receptor, eg. a ginkgolide, for the manufacture of a medicament for inhibiting glucocorticoid release, eg. to combat (ie. prevent or treat) conditions associated with excess glucocorticoid production.
Viewed from a further aspect the invention provides a pharmaceutical composition for use as an inhibitor of membrane expression of benzodiazepine receptors (or for combatting conditions associated with excess glucocorticoid production, etc.), said composition comprising a physiologically tolerable ginkgolide together with at least one pharmaceutically acceptable carrier or excipient.
Viewed from a yet further aspect the invention provides a pharmaceutical composition for use as an inhibitor of glucocorticoid release, said composition comprising an inhibitor of membrane expression of an adrenal benzodiazepine receptor (eg. a ginkgolide) together with at least one pharmaceutically acceptable carrier or excipient.
Viewed from a yet still further aspect the invention provides a method of inhibiting the membrane expression of a benzodiazepine receptor in a patient (eg. a human or non-human, preferably a mammal), said method comprising administering to said patient an effective amount of a ginkgolide. Viewed from a still further aspect the invention provides a method of inhibiting the release of a glucocorticoid in a patient, said method comprising administering to said patient an effective amount of a compound, eg. a ginkgolide, capable of inhibiting the membrane expression of an adrenal benzodiazepine receptor.
Reduction in excess glucocorticoid levels can, as discussed below, result in enhancement of ACTH levels with various consequent beneficial effects.
Thus viewed from a still further aspect the invention also provides the use of a ginkgolide (or other inhibitor of membrane expression of an adrenal benzodiazepine receptor) for the manufacture of a medicament for enhancing ACTH levels.
Thus one aspect of the invention involves inhibiting the membrane expression of a benzodiazepine receptor. This involves administering to a patient an effective amount of a ginkgolide. The benzodiazepine receptor may be a peripheral-type benzodiazepine receptor (PBR), e.g. found on the adrenal, intestine, kidney, brain, liver, and testis. In one embodiment, the membrane is on adrenal mitochondria. In a further embodiment, this method comprises administering an effective amount of an extract from ginkgo biloba. In another further embodiment this method comprises administering an effective amount of a pharmaceutical composition which contains a ginkgolide and a pharmaceutically acceptable carrier.
However another aspect of the invention involves inhibiting the release of a glucocorticoid (such as cortisol) in a patient. This involves the step of administering to the patient an effective amount of a compound capable of inhibiting the membrane expression of an adrenal benzodiazepine receptor. In one embodiment, this method comprises administering to said patient an effective amount of a ginkgolide. In a further embodiment, this method comprises administering an effective amount of an extract from ginkgo biloba. In another further embodiment, this method comprises the step of administering to the patient an effective amount of a pharmaceutical composition containing a ginkgolide and a pharmaceutically acceptable carrier.
An effective amount depends upon the condition being treated, the route of administration chosen, and the specific activity of the compound used, and ultimately will be decided by the attending physician or veterinarian. The compound may be administered in an amount of 0.1 to 20 mg/kg body weight of the patient (e.g., 0.5 to 4 mg/kg body weight of the patient).
The pharmaceutical composition described above contains (1) one or more of the ginkgolides to be described below, (2) one or more pharmaceutically acceptable carriers, and, optionally, (3) one or more other ingredients such as another bioactive compound or a stabilizing agent. Any extract from the ginkgo biloba tree is not considered as such a pharmaceutical composition. The carrier must be “pharmaceutically acceptable” in the sense of being compatible with the ginkgolide(s) of the composition and not deleterious to the subject to be treated.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compound(s) (e.g., ginkgolide) into association with a carrier which may contain one or more accessory ingredients. In general, the compositions for tablets (e.g., for oral administration) or powders are prepared by uniformly and intimately blending the compound(s) with finely divided solid carriers, and then, if necessary as in the case of tablets, forming the product into the desired shape and size.
Compositions suitable for parenteral administration (e.g., subcutaneous, intravenous, or intermuscular), on the other hand, conveniently comprise sterile aqueous solutions of the compound(s). Preferably, the solutions are isotonic with the blood of the subject to be treated. Such compositions may be conveniently prepared by dissolving solid compound(s) in water or saline to produce an aqueous solution, and rendering said solution sterile. The composition may be presented in unit or multi-dose containers, for example, sealed ampoules or vials.
The extracts of the ginkgo biloba tree may be prepared by standard extraction techniques. See, e.g., the book, “
Ginkgolides—Chemistry,
Biology, Pharmacology and Clinical Perspectives”, edited by P. Braquet (J. R. Prous, Science Publi
Conway John D.
Fish & Richardson
Jarvis William R. A.
Morrill Brian R.
Societe de Conseils de Recherches et d'Applications Scienti
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