US3565560A - Pharmaceutical preparation containing hydrofuramide and method of using it - Google Patents

Abstract

HYDROFURAMIDE CAUSES, ON ORAL ADMINISTRATION, AN INCREASE IN THE CHOLINESTERASE BLOOD LEVEL, AN INCREASE IN THE ALBUMEN LEVEL IN THE SERUM, A LOWERING OF THE BLOOD VISCOSITY, AND AN INCREASE OF THE SPEED OF THE CIRCULATING BLOOD AND THUS HAS PROVED TO BE OF VALUE IN THE THERAPY OF ALL DISORDERS AND DISEASES WHICH ARE ACCOMPANIED BY DECREASED CHOLINESTERASE BLOOD LEVEL, ALBUMEN LEVEL IN SERUM, AND SPEED OF BLOOD FLOW AND INCREASED BLOOD VISCOSITY. DAILY DOSES BETWEEN 0.45 G. AND 1.35 G. AND SINGLE DOSES BETWEEN 0.1 G. AND 1.0 G. AND PREFERABLY BETWEEN 0.3 G. AND 0.45 G. HAVE PROVED TO BE THERAPEUTICALLY EFFECTIVE, FOR INSTANCE, IN ALCOHOLISM, CIRRHOSIS OF THE LIVER, ANGINA PECTORIS, HYPOTHYREOSIS, POLYCYTHEMIA, ARTERIOSCLEROSIS, AND OTHERS.

Description

United States Patent 3,565,560 PHARMACEUTICAL PREPARATION CONTAINING HYDROFURAMIDE AND METHOD OF USING IT Frederick W. Proewig, 3359 Demott Place, Wantagh, N.Y. 11793 No Drawing. Filed July 16, 1968, Ser. No. 745,109 Int. Cl. A61k 27/00 US. Cl. 424-285 6 Claims ABSTRACT OF THE DISCLOSURE Hydrofuramide causes, on oral administration, an increase in the cholinesterase blood leevl, an increase in the albumen leevl in the serum, a lowering of the blood viscosity, and an increase of the speed of the circulating blood and thus has proved to be of value in the therapy of all disorders and diseases which are accompanied by decreased cholinesterase blood level, albumen level in serum, and speed of blood flow and increased blood viscosity. Daily doses between 0.45 g. and 1.35 g. and single doses between 0.1 g. and 1.0 g. and preferably between 0.3 g. and 0.45 g. have proved to be therapeutically effective, for instance, in alcoholism, cirrhosis of the liver, angina pectoris, hypothyreosis, polycythemia, arteriosclerosis, and others.

BACKGROUND OF THE INVENTION (1) Field of the invention The present invention relates to pharmaceutical compositions and more particularly to pharmaceutical compositions containing hydrofuramide, and to a method of using such compositions in therapy.

(2) Description of the prior art Nachmansohn stated Without cholinesterase there is no life. cholinesterase is unique among all the enzymes as being ubliquitous and of multipurpose action. Cholinesterase is found in all blood-cells as well as in the blood serum, in the membranes of every cell, at the junction (synapse) of nerve cells. Margaret Greig and coworkers published scientific data of their investigations showing that the permeability of cells and more particularly their membranes, i.e. the exchange between blood and body cells is based upon the acetylcholine-cholinesterase balance and that the functioning of this balance is responsible for the cation separation between body fluid and cell interior and for the fact that the sodium: potassium equilibrium of the serum is reversed within the cells of the body. (Greig et al. Arch. Biochem. vol. 23, page 370 (1949); Brit. J. Pharmacol. vol. 5, page 461 (1950); J. Pharmacol. and exp. Therap. vol. 102, No. 1, page 19 (1951); Am. J. Physiol, vol. 170, page 339 (1952); Arch Biochem. vol. 26, page 151 (1951).) g

It is now clinically well established that the cholinesterase level of the blood is constant and that 75 to 80 units are normal for healthy individuals. It was found through testing that chronic debilitating diseases (cirrhosis of the liver, chronic nephritis) tend to regulate the cholinesterase level downward. The lowest levels, around 40 units or slightly lower, are found in cancer victims. On the other Patented Feb. 23, 1971 have it fixed at a high level. The higher the level, the better is the exchange of metabolites between blood serum and body cells and nerve action, the easier is the oxygen transport across the bloodzcell barrier. This increased supply and cellular exchange of substances for metabolic and anabolic purposse, for cellular repair and for respiration is of importance for the well being especially of elderly persons. Therefore, it is of great clinical importance to provide the medical profession with a preparation which causes a substantial increase in the cholinesterase blood level.

SUMMARY OF THE INVENTION Now it is one object of the present invention to provide a highly effective pharmaceutical composition which increases the cholinesterase blood level considerably more than heretofore possible.

Another object of the present invention is to provide a method of therapeutically increasing the cholinesterase blood level and thus to favorably affect these disorders and dieases in which the acetylcholine-cholinesterase equilibrium is reduced.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle the compositions according to the present invention contain, as the cholinesterase blood level increasing agent, hydrofuramide, i.e. N,N-di-2-furfurylidene-Z-furfurylidene diamine of the formula This compound has a melting point of 117 C. It is obtained by reaction of furfural with aqueous ammonia. It is relatively stable and is decomposed into furfural and ammonia only by boiling in water.

It was found that oral administration of hydrofuramide results in a substantial increase in the cholinesterase level in the blood. As a result thereof the albumen level in serum is also increased. This is of clinical value, for instance, in the treatment of liver cirrhosis in which the serum albumen is low.

Furthermore, the viscosity of the blood is lowered, a reaction of hydrofuramide. No other drug is known at present to have such action with the exception of the thyroid hormone. Lowering of blood viscosity leads to better circulation demonstrated by a decrease of the Decholin time. This test is used for measuring blood viscosity. About 11 seconds is the time in normal persons within which the intravenously administered drug Decholin is felt as bitter taste on the tongue. This time increases to 30 seconds or more with an increase in viscosity. The viscosity itself can be tested by means of viscosimeters such as the one designed by Hess. Normal values for the blood vicosity are 3.5 to 3.7. The viscosity may be increased to 5.5 or higher, i.e. to values at which a cardiac thrombosis is threatened. The increase of viscosity goes hand, patients with compensated heart condltlons and having mild polycythemia tend to be higher than normal in their cholinesterase levels.

Various clinical investigators all over the world have tried to induce a rise in cholinesterase levels through drugs, enzymes, hormones, radiation etc. The maximum thus achieved was an elevation of 5 units. The acetyl choline-cholinesterase equilibrium acts in an analogous manner as, for instance, metabolism. It is desirable to hand In hand with an increase of red blood cell counts and globulin in the serum. For instance, a hemoglobin value of 17.5 g. percent instead of the normal content of 14.5 g. percent is accompanied by an increase in viscosity to 5.5. When orally administering hydrofuramide in small doses of 0.4 g. to 0.7 g. daily, the high viscosity value of 5.5 will be lowered to 3.7 within three Weeks. This has proved of value in the treatment of angina pectoris, for instance.

Lowering of the viscosity by administration of hydrofuramide causes also an increase in the speed of circulation of the blood, i.e. a decrease of the circulation time. Thus when through lowering of the blood viscosity the initially determined circulation time of 22 seconds is lowered to 11 seconds, it is evident that twice the amount of oxygen within the same period of time is offered to all body cells.

As a result of the increase of the blood chlolinesterase level and the accelerated blood flow, the exchange of metabolites will be improved and the blood supply to starving organs will be restored almost to normalcy. The increased cholinesterase content of the blood facilitates the exchange from blood to cell and the decreased blood viscosity about doubles the blood supply to the body cells. Thus hydrofuramide administration surpasses in its effectiveness upon angina pectoris even the effect of nitro compounds. Patients, after being put on hydrofuramide, have discontinued using either long acting or immediately acting nitro compounds. Fading memory and disorientation in elderly persons becomes normal. Symptoms secondary in diabetes are eliminated. Intermittent claudicatio, Menieres disease, paresthesias, pruritus, irrespectively whether these symptoms are caused by diabetes or arteriosclerosis, are markedly improved.

The same beneficial effect of hydrofuramicle with respect to circulation observed in cases of angina pectoris were also observed in other cardiac conditions such as tachycardia or extrasystoles. Hydrofuramide given in amounts of 0.4 g. to 0.7 g. daily eliminates extrasystoles even after three years duration, whereas textbooks on cardiology state that extrasystoles persisting longer than one and half years cannot be influenced therapeutically any more.

The fiow of blood accelerated by administration of hydrofuramide and the increased exchange of oxygen favorably affects even severe cases of emphysema. Although results observed here are less dramatic than those observed in heart ailments, the patients felt better when taking hydrofuramide and stated that breathing is made easier.

The beneficial effect of cellular respiration and increase in metabolism is seen more particularly in cases of alcoholism. When alcoholics abstain from drinking, the well known Withdrawal symptoms occur for one to two weeks, i.e. extreme nervousness, irritation, tremors, and psychosis. These withdrawal symptoms are never seen when 0.7 g. of hydrofuramide are given daily. Since under hydrofuramide the switch from dipsomania to abstinence is not felt at all, it is not necessary to give such patients sedatives, tranquilizers, or massive doses of vitamins. The treatment can even be ambulatory. Hospitalization is not required.

Since it has been reported that the ability to learn is greater, the higher the concentration of cholinesterase in the brain, administration of hydrofuramide has also a favorable effect on learning children.

Summarizing the effect of administration of hydrofuramide, it has proved effective (a) in the treatment of alcoholism and cirrhosis of the liver because the cholinesterase level as well as the albumin level in the blood are increased;

(b) in the treatment of angina pectoris, multiple sclerosis, hypothyreosis, polycythemia, and diabetes because the high blood viscosity in these diseases is lowered thus causing at least a marked improvement;

for preventing intoxicating side effects such as radiation hangover encountered on X-ray and radiocative cobalt irradiation and for increasing the tolerated dose of such irradiation;

(d) as highly effective agent for stimulating appetite and for relieving Parkinsons symptoms whereby it has a similar effect as furfural but is much better tolerated than the latter.

The daily dose of hydrofuramide to be administered is between about 0.3 g. and about 2.0 g., the preferred daily dose is between about 0.45 g. and about 1.35 g., the single dose is between about 0.1 g. and about 1.0 g. and the preferred single dose is between about 0.30 g. and about 0.45 g.

The preparation is orally administered, preferably in the form of tablets, or dragees. Capsules may also be given.

DESCRIPTION OF THE PREFERRED EMBODIMENTS As stated above, hydrofuramide is preferably administered orally in the form of tablets, dragees, pills, lozenges, and the like shaped preparations. Hydrofuramide may also be administered in powder form, preferably enclosed in gelatin or the like capsules. Oral administration in liquid form, such as in the form of emulsions, suspensions, and the like are also possible. Aqueous preparations, however, cannot be stored over a prolonged period of time but suspensions, for instance, in edible oils and the like can be used.

Such solid and liquid preparations are produced in a manner known per se of compounding and processing pharmaceutical products whereby the conventional diluting, binding, and/ or expanding agents, lubricants, and/ or other excipients, such as lactose, cane sugar, dextrins, starch, talc, kaolin, magnesium carbonate, pectin, gelatin, agar, bentonite, magnesium stearate, and others may be employed.

The following examples serve to illustrate the present invention without, however, limiting the same thereto.

Example 1 50 kg. of hydrofuramide are intimately mixed with 73.5 kg. of lactose, 10 kg. of corn starch, and 1.5 kg. of magnesium stearate and the mixture is compressed to tab lets weighing about 405 mg. Each tablet contains about 150 mg. of hydrofuramide.

Example 2 200 g. of hydrofuramide are mixed with g. of corn starch, moistened with a 5% gelatin solution, and granulated by pressing through a sieve #20. The granulate is dried. g. of potato starch and 30 g. of purified talc are thoroughly admixed thereto and the mixture is compressed to 1000 tablets, each weighing 400 mg. and containing 200 mg. of hydrofuramide.

Example 3 The mixture of hydrofuramide, lactose, corn starch, and magnesium stearate is compressed to bi-convex dragee cores of 405 mg. These cores are sugar-coated by rotating in a coating pan with sugar sirup. Each dragee contains about mg. of hydrofuramide.

Example 4 Before sugar-coating, the dragee cores obtained according to Example 3 are shellac-coated by means of an alcoholic shellac solution. The finally sugar-coated dragees do not dissolve in the gastric juices but only in the intestines. The therapeutic effect, however, is about the same.

Example 5 Hard gelatin capsules are filled each with 300 mg. of hydrofuramide.

Compositions as described in the examples have been administered to patients in the treatment of various disorders and diseases. Thus 17 alcoholics received three times daily 2 to 3 tablets of hydrofuramide, each tablet containing 150 mg. of the active compound. After three days no alcohol was given. There were no withdrawal symptoms, such as tremor, anorexia, headache, convulsions, and the appetite of the patient was good. No additional administration of vitamins, tranquilizers, or sedatives was required.

A case of liver cirrhosis was treated with hydrofuramide. The patient, a 53 year old male, was hospitalized because of severe hemorrhages from varicose veins of the esophagus. This is usually the last stage in this disease. The extremely swollen liver prevents the return of venous blood from the lower end of the esophagus. Varicosities result and these will rupture when sufficiently large. Haemoptoe from the mouth is considerable, most patients with esophageal varices bleed to death in this way. The patients hemoglobin was down to 5.5 g. (normal is 14.5 g); icteric index 45 units (normal 4 to 6 units); albumen 2.0 g. (normal 4.5 to 5.5 g.); severely icteric skin, sclerea deep yellow; liver in size increased down to level of navel; considerable ascites, and swelling of lower legs and ankles. After 6 months of treatment with hydrofuramide (0.6 g. daily), the patients icteric index was down to 14 units, which is considered subicteric. His skin and sclerea were only faintly yellow; his albumen was up to 3.9 g., the hemoglobin 10.5 g. His ascites was completely gone together with the swelling of the legs. The patient has never experienced any bleeding from the esophagus or throat since his first episode. The liver is down in size to normal below the right lower rib margin, "but is still increased to he left over the stomach and slightly tender there. Patient is well and working.

A 65 year old male patient has been suffering from angina pectoris for the past 9 years. He has been treated with long acting tetranitrate compounds, digitalis, and sedation. This well nourished man had to retire from business about 18 months ago after he had gone through an anterior wall infarction. He was given hydrofuramide (0.9 g. daily). After two weeks the patient noticed improvement of the retrosternal pain. The angina attacks occurred less often and the pain was considerably less. After four weeks of treatment the patient was free from symptoms. His blood pressure remained the same systolic, 160 mm. Hg, his diastolic pressure, however, was markedly decreased: from 120 mm. Hg at the beginning of the treatment it was down to 95 mm. during the fifth week. Patients yellowish complexion had changed to healthy pinkinsh flush, indicating improved circulation due to widening of the arterioles. After six weeks of hydrofuramide medication all other drugs, nitrates, sedatives, digitalis were discontinued. Patient resumed his regular work. His. friends remarked that he was looking so much better. He has been working for two years now and has never noticed anginal pain when working, carrying loads, ascendmg stairs. Patient is now on a maintenance dose of 0.3 g. of hydrofuramide daily.

Other patients suffering from angina pectorls with a decholin time over 20 seconds who received hydrofuramide showed a decrease of the decholin tlme to near normal (11 seconds), thus indicating an almost doubling of the rate of blood flow with a corresponding lowering of blood viscosity.

Another patient was treated for hypothyreos1s and polycythemia. Both conditions have in common: Red blood cell count about 25% above normal, high viscosity of blood as measured by the viscosimeter after Hess, made by Hellige. Normal values are 3.5 to 3.6- compared with water. This patient, a 25-year-old male, showed viscosity values of 5.5 and higher. He complained about fatigue, frequent headaches, and nosebleeds. Heart and blood pressure were normal. His blood count ranged from 5.4 to 5.7 million red cells, his hemoglobin was elevated from 115 to 122%. He was observed for 2 years while being treated with occasional phlebotomies. After the patient was given hydrofuramide (0.15 g. three times daily) patients subjective symptoms got gradually better. His blood count remained high. It was not affected by the therapy. The viscosity, however, was reduced to 4.0 to 3.4, an average drop of 1.8 standard values, or an average of about one third. As a result thereof, the speed of blood flow was increased and the patient feels less tired. After treatment was begun, patients cholinesterase level increased from 88 units to units, further aiding supply and metabolism of body cells.

A 62-year-old male was retired from his job as petroleum engineer because of disorientation due to arteriosclerosis. He was unable to work because of mental dissociation, slowness of comprehending, and forgetfulness. He had lost weight steadily and exhibited shallow complexion. At home he was disturbed to the effect that he got out of bed at 3 am. pretending that it was breakfast time. He could not select a telephone number from the book or dial the telephone. He received two tablets of hydrofuramide twice daily, i.e., 0.6 g. per day. Improvement began soon after initiation of therapy. After three months he again was able to attend meetings, he could drive his car, he made no mistakes dialing the telephone. His mind became absolutely clear, he gained weight (35 lbs. in about six months). He has a healthy complexion and his friends repeatedly made the statement that he never looked and acted so well in all his life. The increase of cholinesterase in the blood accounts for his improvement. The blood-brain barrier is lowered.

Another patient, a 60-year-old male, has been suffering from diabetes for the past ten years. He received the standard treatment, i.e., insulin and later Orinase. But he complained of secondary symptoms which were not alleviated through diet and medication. He always felt weak, especially in the legs. He noticed cramps in the calves when walking. He had tingling in the extremities, occasional itching of the skin. When given hydrofuramide (0.45 g. daily) tiredness and all other symptoms disappeared during the fourth week of treatment. Patient noticed specifically that he could walk faster and did not tire anymore. Fasting blood sugar and sugar tolerance, however, were unaffected by the drug. But hydrofuramide evidently eliminates completely the secondary effects of diabetes mellitus, namely circulatory disturbances, neuritis and tiredness which usually are unaffected by standard medication.

Another patient, a 66-year-old male, was hospitalized because of multiple kidney stones causing anuria. The anuria subsided after 36 hours following treatment. Patient was discharged three days later with the advice to be scheduled for later operation for removal of kidney stones. He was given 0.3 g. of hydrofuramide three times daily. During the second week of the treatment patient passed repeatedly numerous stones (calcium. oxalate). Control X-rays two weeks later showed no residual stones present.

With respect to radiation the following effects of the hydrofuramide therapy were observed.

(a) The ionization hangover never occurs in patients treated with large doses of cobalt for malignancy.

(b) Healthy tissue is better protected against radiation damage as can be demonstrated by the increased tolerance of mice against lethal doses of radioactive cobalt.

(c) Hydrofuramide evidently interferes with the pathological metabolism of cancer tissue by temporarily inhibiting, or partially inhibiting, the reductive amidation which is specific for cancer tissue. As a result thereof a lowering of the pH-value in cancer tissue only renders the malignant growth more sensitive to therapeutic radiation.

Thus a female patient suffering from a gynecological cancer, inoperable grade 4, received cobalt treatment and was given hydrofuramide before and during treatment. She never experienced X-ray sickness and felt well throughout. On re-examination it was found that the tumor had receded more than is usual with radiation and laparotomy. It was found at operation that high up the abdominal aorta some lymphnodes were left enlarged due to metastases. This area was not reached by the first series of radiation with cobalt. So after discharge from the hospital the patient received a second series of cobalt treatment also while taking hydrofuramide. As a result of this treatment, the patient has gained weight, feels well, performs all her duties as housewife, etc. These and other case histories show that hydrofuramide has a noteworthy effect on all disorders and diseases which are due to, or are accompanied, by a reduced cholinesterase blood level and/ or an increased viscosity of the blood.

I claim:

1. A method of treating disorders and diseases of human patients in Whom the acetylcholine-cholinesterase equilibrium is reduced and of increasing the cholinesterase level in the blood of such patients, said method comprising orally administering to such patients between about 0.3 g. and about 2.0 g. of hydrofuramide daily given in single doses is between about 0.1 g. and about 1.0 g.

2. The method of claim 1, wherein the daily dose is between about 0.45 g. and about 1.35 g. and the single dose is between about 0.3 g. and about 0.45 g.

3. The method as defined in claim 1, wherein hydrofurarnide is administered in tablet form.

4. The method as defined in claim 1, wherein hydrofuramide is administered in capsule form.

5. The method as defined in claim 2, wherein hydrofuramide is administered in tablet form.

6. The method as defined in claim 2, wherein hydrofuramide is administered in capsule form.

References Cited Chem. Albst. (l), 63, 1l935e (1965). Chem. Abst. 2 63, 18968a (1965).

STANLEY J. FRIEDMAN, Primary Examiner