Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-08-28
1988-12-20
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
047925647
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method for the prevention and treatment of cerebral vasospasm, especially the vasospasm which usually follows subarachnoid hemorrhage (SAH).
BACKGROUND ART
Cerebral vasospasms are the leading cause of death and morbidity in cases of subarachnoid hemorrhage. Attempts to define the substance or substances responsible for the cerebral vasospasms which usually follow SAH have not to date been successful.
Many agents including calcium blockers have been used with some success to prevent the formation of such secondary vasospasms. Unfortunately, however, to date, no substances have been available to reverse the cerebral vasospasm once it has occurred. Obviously, the availability of such a product could be a valuable life-saving tool especially where the vasospasms follow SAH caused by trauma.
In the Nagano, et al., U.S. Pat. No. 4,200,640, the compound N-(2-hydroxy ethyl) nicotinamide (nicorandil) is described as being useful in treating circulatory diseases. More specifically, the compound is described as having peripheral vasodilator properties including the properties of a cerebral vasodilator and a renal vasodilator. However, there is no disclosure in the patent that would lead one skilled in the art to believe the compound might be useful for treatment and reversal of cerebral vasospasm.
It is the primary object of the present invention to disclose a method for the treatment of cerebral vasospasms.
It is a further object to disclose a method for preventing the occurrence of cerebral vasospasm.
The method of the present invention comprises administering intravenously to a patient a safe and effective amount of nicorandil to either prevent or to treat the cerebral vasospasm that follows subarachnoid hemorrhage.
The method was discovered using a model that involved the cisternal injection of autologous blood into animals, such as cats and dogs, to produce spasms of basilar and anterior spinal arteries (ASA).
Using this model in cats we found in basilar arteries in spasm significant membrane depolarization resulting from an apparent reduction in K.sup.+ conductance (g.sub.k). We then set out to determine if there was muscle membrane depolarization in basilar and ASA from dogs using the double injection (of autologous blood) model of SAH and to determine the role of g.sub.k in this regard.
We found that in basilar arteries from double injected dogs 4-7 days post ictus the muscle cell membrane was markedly depolarized. Further electrophysiological analysis suggested that the arterial muscle depolarization resulted from reduction of g.sub.k similar to that found in cat cerebral arteries following SAH.
We then discovered that the use of a drug which specifically increases g.sub.k in a variety of tissues, namely nicorandil (N-(2-hydroxyethyl) nicotinamide), repolarized the arterial muscle cells after exposure to subarachnoid blood. Our data demonstrated that not only does nicorandil repolarize basilar arteries exposed to subarachnoid blood by increasing g.sub.k, but that it also reverses the secondary vasospasm in dogs 4-7 days post ictus as evidenced via angiogram and evoked potentials in intact animals. Thus, by using the model to understand the ionic mechanisms of cerebral vasospasm we have been able to develop the method of the present invention which employs a drug which is specific for reversal of that mechanism and reverses the disease state.
MATERIALS AND METHODS
Mongrel dogs 12-18 kg were used. Two days prior to the initial cisternal injection of autologous blood, cortical recording electrodes for evoked potentials were implanted via a small cranial window which was subsequently sealed with the excised bone flap. The dogs were fully anesthetized with 60 mg/kg Na-pentobarbital during the procedure which was done under sterile conditions.
Just prior to the initial injection of arterial blood into the cisternal space, control evoked potentials (somatosensory) and angiograms were obtained. Angiograms were performed by threading a 5 Fr. catheter into the
REFERENCES:
patent: 4200640 (1980-04-01), Nagano et al.
Chemical Abstracts vol. 100; 1984, Columbus, Ohio USA (Sakai et al. 414W).
Chemical Abstracts, vol. 96; 1982, Columbus, Ohio, USA (Aono et al. 28411R).
Gross John G.
Harder David R.
Robinson Allen J.
The Medical College of Wisconsin Inc.
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