THERAPEUTIC USE OF ACETAZOLAMIDE FOR THE TREATMENT OF CEREBRAL EDEMA
INTRODUCTION This invention relates to the medical treatment of victims of cerebral edema, and especially to the relief of cerebral inflammation as a result of ischemic attacks especially, but also to inflammation due to tumors, surgeries, or brain traumas, whose inflammation normally results in a severe disability and often the death of the patient. More particularly, this invention relates to the therapeutic use of acetazolamide as a medicament for alleviating such cerebral inflammation or edema. Acetazolamide is a commonly prescribed diuretic, distributed under the tradenames of SEQUELS® prolonged-release capsules of DIAMOX® acetazolamide, DIAMOX® acetazolamide tablets, and DIAMOX® parenteral sterile acetazolamide sodium (supplied as a sodium salt).
DIAMOX® and SEQUELS® are registered trademarks of Lederle Laboratories Division of American Cyanamid Company. Ischemic attacks are the result of a sudden compromise of the blood supply to the brain, which often causes inflammation of brain cells, abnormal electrical discharges of the brain, and brain death. Since the causative factor in the compromise of the blood supply to the brain can be transient, like small emboli that obstruct a vessel and then pass, allowing the blood flow to be restored. It is unknown how often such transient ischemic attacks result in a complete attack (ie, no progress or immediate regression of symptoms). Some patients with such crises develop attacks; in others, the symptoms disappear without sequelae. Even transient ischemic attacks can cause inflammation of brain cells, a symptom that contains a potential death threat. PREVIOUS TECHNIQUE The current management of an attack involves several steps that are taken as the need becomes apparent: a. Duct support for air and ventilatory support is given to patients with decreased levels of consciousness; Complementary oxygen is used for hypoxic patients. b. Caution is advised in the use of any antihypertensive agent. c. The American Heart Association's Attack Council disapproves of the use of corticosteroids for cerebral edema and increasing intracranial pressure after the attack, noting that conventional and large doses of corticosteroids in clinical trials showed no improvement. d. Osmotherapy and hyperventilation are recommended for patients whose condition deteriorates as a side effect of increased intracranial pressure. and. The Council of Attacks emphasizes that the data about the safety and efficacy of heparin in ischemic attacks were insufficient and incompatible, potentially dangerous, observing the frequency of parenchymal hemorrhage. f. The panel also refused to recommend the use of nimodipine, barbiturates, naloxono, swallowing antagonists, or amphetamines. U.S. Patent No. 5,389,630 was issued on February 14, 1995 to Sato et al., Claiming an arrangement of certain diamine compounds and their use to treat disorders of cerebral function or to prevent the progression of such disorders, including cerebral hemorrhage, infarction. cerebral, subarachnoid hemorrhage, transient ischemic attack, cerebrovascular disorders, and the like. The Sato et al patent illustrates the efficacy by means of animal tests.
According to the foregoing, cerebral protective drugs are desired which promise an excellent clinical effect and which are readily available and useful for oral or intravenous administration. The applicant believes that the present invention meets that need. DETAILED DESCRIPTION OF THE INVENTION It is believed that at least part of the damage done during cerebral edema from an ischemic attack and other trauma is due to the formation of bicarbonates in the cells, whose reaction is accelerated by the presence of carbonic anhydrase. Carbonic anhydrase inhibitors are known: acetazolamide and dichlorophenamide are among them. The first is a commonly prescribed diuretic, especially useful for short-term use, since its effectiveness is reduced after 2 or 3 days. It is labeled under the trade name DIAMOX® by Lederle Laboratories Division of American Cyanamid Company. The simplified chemical formula for acetazolamide is C4H6N403S2 and the chemical name that is believed to be respected by the rules of reference of the International Union of Chemistry is: N- (5-sulfamoyl-1,3-thiadiazol-2-yl) - acetamide Acetazolamide, as an enzyme inhibitor, acts specifically on carbonic anhydrase, the enzyme that catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid: H20 + C02 = H + + HC03 Equation 1
Affecting this reaction is said to be the source of the diuretic effect in the kidney. The result is renal loss of bicarbonate ion (ie, HC03), which contains sodium, water and potassium. In addition, there are reports of evidence that seem to indicate that acetazolamide has utility as an adjuvant in the treatment of certain dysfunctions of the central nervous system (for example, epilepsy). The inhibition of carbonic anhydrase in this area seems to slow the excessive, paroxysmal, abnormal discharge of the neurons of the central nervous system. No prior art is known to suggest the use of these carbonic anhydrase inhibitors specifically for the treatment of stroke victims, or victims of other inflammations or brain traumas. Nothing indicates that acetazolamide is a brain protective drug of value in the treatment of such victims. The efficacy of this therapeutic treatment could probably be considered by medical researchers as anecdotal, not being part of a clinically designed, double-checked clinical trial, but the success rate in the use of acetazolamide as a last resort on patients who would otherwise be would think terminals, has led this researcher to seek patent protection for the treatment method. The results of twelve patients who have various brain disorders, who were treated, as a last resort, with intravenous injections of a solution containing 500 mg of acetazolamide in 5 ml of sterile water. Initially, the dose administered was 2.5 ml of this solution; eventually, the complete injection of 5 ml was used. The injections continued daily for 2-3 days. This treatment was used with hyperventilation of the lung (still using supplemental oxygen), to reduce by this the content of carbon dioxide (C02) and raise the content of oxygen (02) in the blood and therefore in the brain - whether or not the patient has been hypoxic - and diuresis to remove excess water (an additional effect of acetazolamide, although other diuretics may be used). The objective was to conduct the reversible reaction of Equation 1 to the left, thereby reducing the amount of bicarbonate ions formed and further decreasing the formation of bicarbonate. The twelve cases cited included: six cerebral infarcts, one of which exhibited acute hydrocephalus; two intracranial hemorrhages, a malignant meningioma; another tumor that involved a cerebral hematoma; an anoxic encephalopathic coma; and a case of thyroid coma with brain inflammation. Those cases involving tumors that were removed included post-surgical edema. All the patients survived the crisis that suggested the treatment of last resort with acetazolamide. It was believed that all were in terminal stages of their respective crisis situations, allowing emergency measures in an attempt to prolong life. None of the patients treated by this method during this period of examination failed to show improvements and a final recovery from the respective crisis conditions. Based on the limited experience cited above, the method for the treatment of ischemic attacks sought to be protected comprises the initial administration of acetazolamide by intravenous injection and additional doses of acetazolamide which are either administered orally (i.e., by ingestion). ) or are injected intravenously. In the preferred mode, the use of acetazolamide is combined with continuous hyperventilation of the lungs. Diuresis is recommended, using a diuretic different from a carbonic anhydrase inhibitor. The recommended dose of acetazolamide may vary depending on the perceived severity of the ischemic attack as well as the patient's body weight, but it is believed that an initial dose of between 250 and 500 mg with complementary doses of between 250 and 500 mg per day, administered orally (ie, by ingestion) or by injection are effective. Having described this invention, including the citation of specific functional examples thereof, the applicant wishes to include within the scope of his invention those improvements that would be immediately obvious to those skilled in the art, whose improvements of some, but not all of which may have been referred to in the present. The applicant wishes that the extension of his invention be limited only by the scope of the claims appended thereto.