Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1995-06-16
1997-11-04
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514866, A61K 3116
Patent
active
056840470
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the regulation of blood flow in human patients. More particularly, it relates to the therapeutic use of a known compound in the prevention and/or treatment of complications associated with unsatisfactory circulation, e.g. of the type that are observed in diabetics, although the treatment is also suitable for non-diabetics.
BACKGROUND OF THE INVENTION
The compound 4-guanidinobutyramide (hereinafter "4GAB"), having the formula HN.dbd.C(NH.sub.2)--NH--(CH.sub.2).sub.3 --CONH.sub.2, is a naturally-occurring compound that is known for therapeutic purposes. GB-A-1195199 and GB-A-1195200 disclose 4GAB as a hypoglycaemic agent, the latter in combination with insulin, for the treatment of diabetes. In U.S. Pat. No. 3,639,628, 4GAB is shown to reduce abnormally high levels of blood urea in diabetics. It is also stated that "improvements of retinopathy and neuropathy have been observed"; it has now been shown that 4GAB has little or no effect on retinopathy, and indeed that it is not effective at the capillary level.
Aminoguanidine is a compound having a somewhat similar structure to 4GAB, which has been proposed for the prevention of diabetic complications. Aminoguanidine may suppress advanced glycosylation end-products, and has been reported to prevent the capillary lesions of retinopathy in diabetic rats.
SUMMARY OF THE INVENTION
According to the present invention, 4GAB or a physiologically-acceptable salt thereof, is used for the purposes of arteriolar dilatation. 4GAB is therefore useful in the regulation of blood flow, and in the prevention and/or management of complications that are observed, often in diabetics, in tissues such as the kidneys, nerves, skin and Islets of Langerhans. It may also have utility in treating male impotence (in diabetic cases, perhaps in cases of senile impotence, and more generally), by facilitating penile erection.
DESCRIPTION OF THE INVENTION
Without wishing to be bound by theory, it appears that 4GAB exerts its dilatatory effect through NO release through small vessels, arterioles. 4GAB is a compound in the metabolic sequence from the brain constituent GABA to arginine which itself is a precursor of NO. The metabolism of 4GAB to arginine is controlled by enzymes that may be glucose-related.
This mechanism explains the absence of effect on retinopathy and perhaps also the effects that have previously been associated with the administration of 4GAB. The mechanism and the results presented below show that 4GAB is of particular utility in treating or preventing renal complications, neuropathy and autonomic neuropathy (possibly by affecting neuronal nutrition) and providing improved circulation, e.g. in dementias or in counteracting the reduced circulation usually observed in old age.
In both diabetic and non-diabetic patients, 4GAB may act as an anti-neuropathic and, at least in some cases, as a protrophic agent. For example, it may reverse peripheral neuropathy and also incontinence associated with lack of suppression of urination. Infants lack control through a regular cycle of release, and a similar condition can develop in adult life and particularly in old age.
The possible mechanism and effects of 4GAB have been confirmed by the injection of radioactively-labelled 4GAB into mice. Radioautographs showed that almost all the injected 4GAB was immediately taken up in the walls of blood vessels. No specific localisation in any of the body organs concerned with glucose metabolism, e.g. the liver, kidneys and muscles, could be recognised.
4GAB can be produced simply and inexpensively. It is essentially non-toxic. It can be formulated with physiologically-acceptable carriers or excipients of any conventional type, depending on the mode of administration. Formulations, modes of administration and dosages are exemplified in GB-A-1195200 and U.S. Pat. No. 3,639,628, the contents of which are herein incorporated by reference.
The following Examples illustrate the utility of 4GAB.
EXAMPLE 1
A subject who was healthy but whose peri
REFERENCES:
Tinant et al., Hormone and Metabolic Research, 1(6), pp. 258-265, 1969.
Butterfield, Lancet, 342, pp. 533-536, 1993.
Cemorc Ltd
Jordan Kimberly
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