AU597561B2

AU597561B2 - Method of changing the rate of oxidation of amines in vertebrates and other organisms

Info

Publication number: AU597561B2
Application number: AU41108/85A
Authority: AU
Inventors: Vernon Erk
Original assignee: Individual
Current assignee: Individual
Priority date: 1984-03-01
Filing date: 1985-03-01
Publication date: 1990-06-07
Anticipated expiration: 2005-03-01
Also published as: AU4110885A; EP0174980A4; JPS61501570A; WO1985003867A1; EP0174980A1

Description

METHOD OF CHANGING THE RATE OF OXIDATION OF AMINES IN

VERTEBRATES AND OTHER ORGANISMS

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to changing the rate of oxidation of amines in vertebrates and other organisms. It relates to the relative abundance of circulating amines. It relates to the compounds which can be used to keep the relative abundance of circulating amines within normal limits.

The invention is directed to providing preparations that will increase inhibition of the oxidation of amines and thereby permit larger concentrations of said amines in the circulation.

Additionally, the invention is directed to providing preparations for the prevention of inhibition of the oxidation of amines and thus permitting continued destruction of the amines which results in smaller concentrations of the said amines in the circulation.

2. PRIOR ART

Compounds that can be ingested and which affect the rate of oxidation of amines have been used extensively. However, these compounds do not exert their effects so directly as do the elements which occur in the mechanism of regulation. The substances presently used have side effects that interfere with the desired effects and in some cases are life-threatening or increase morbidity.

Thus, the prior art compounds used for the acceleration and deceleration of amine oxidation are not subject to the control by the same metabolic pathways existing in the body for the control of the substances occurring naturally in the body.

2. Prior Art

"Monoamine oxidase is a flavoprotein oxidase of purported CENTRAL METABOLIC IMPORTANCE CONVERTING NEUROACTIVE AMINES INTO INACTIVE ALDEHYDES.... The flavin linked monoamine oxidase is localized in the OUTER MITOCHONDRIAL MEMBRANE OF ANIMAL CELLS. Walsh pp. 402, 403.

"Actions: Monoamine oxidase is a complex enzyme system widely distributed throughout the body. Drugs that inhibit monoamine oxidase in the laboratory are associated with a number of clinical effects. Thus, it is UNKNOWN WHETHER MAO INHIBITOR PER SE, OTHER PHARMACOLOGICAL ACTIONS, OR AN INTERACTION OF BOTH IS responsible for the clinical effects observed. Therefore, the physician should become familiar with all the effects produced by drugs in this class. PDR (Physicians' Desk Reference 1983) p. 1516.

Two classifications of amine oxidases were presented in 1959. That of Blashko, et al used the response to carbonyl inhibitors to distinguish between the activities of the various amine oxidase. That of Zeller, et al, used semicarbazide inhibitors. The use of inhibitors to classify the amine oxidases reflected difficulties encountered in purifying these enzymes and studying the structure of their active sites.

"A. Occurence Monoamine oxidase (MAO) has been found in all classes of vertebrates so far examined (1970) : mammals, birds, reptiles, amphibians and teleosts (161). The enzyme occurs in many different tissues, particularly in glands, plain muscle, and the nervous system (162). In man the parotid and submaxillary glands seem to be the richest source of MAO (163). It also occurs in molluscs and plants (4)." Kapeller Adler .31.

In 1957 iproniazid was introduced for the treatment of depression. New York Times article June 4, 1981, p. B9. It has been studied extensively and is a monoamine oxidase inhibitor. However, it has a variety of effects besides the effect on depression. These have frequently posed problems. The use of these drugs has continued to be empirical. Iproniazid was removed fromthe market becaused severe liver toxicity. It is interesting to note that these drugs exert their beneficial effect in depressed patients anywhere from one to several weeks after treatment is begun. In some instances the improvement may progress to a state of euphoria, hypomania, or even mania. Central stimulatory effects are seen with these drugs in normal individuals as well as in depressed patients. Bevan. Other effects are orthostatic hypotension, allergic reactions affecting the liver dizziness and a number of anticholinergic type symptoms.

CHEMICAL EFFECTS OF MONOAMINE OXIDASE

"SPECIFICITY

"The enzyme isolated from a number of sources exhibits low specificity. In general, primary, secondary, and tertiary amines, tryptamine derivatives and catecholamines are oxidized (1,5). The enzyme isolated from human placenta, however, will only attack primary amines and with simple alkyl amines increase in chain length results in increased affinity (7)." Barman p. 180.

"Inhibition of MAO leads to a very pronounced increase in the levels of norepinephrine in the sympathetic nervous system and of the monoamines serotonin, norepinephrine, and dopamine in the monoamine-containing neurones of the CNS....Large amounts of amine now accumulate in the cytoplasm. The storage sites rapidly become filled to capacity with the transmitter. This enhanced accumulation of neuroamines within the neurones is presumed to be the basis for the antidepressant action of the MAO inhibitors....It should be added that the presence in the urine of large amounts of unmetabolized serotonin and 3-0-methylated catedholamines is characteristic of patients on MAO inhibitor antidepressants." Bevan pp. 183, 184.

These urinary compounds indicate clearance of the above amines from the blood and is consistent with an increased turnover rate of increased amounts of each amine.

"The flavoprotein responsible for the oxidative deamination of the cateeholamine (monoamine oxidase) is found in a wide variety of tissues and is located primarily in the-outer membrane of mitochondria." Frisell p. 628. CHEMICAL EFFECTS ON MONOAMINE OXIDASE

Halogenated compounds enter the body frequently from the environment. The anaesthetics halothane and methoxyflurane are cases in point.

"Incubation of the volatile general anaesthetics halothane or methoxyflurane (labelled with ¹⁶Cl) with hepatic microsomes, NADPH, and oxygen is accompanied by extensive

DECHLORINATION.

"Similarly thyroxine and triiodothyronine undergo deiodination by hepatic microsomal enzymes (8)." Bacq p. 577.

"Dimino and Hoch (1972) found a considerable enrichment of iodine in liver mitochondria of rats injected with T₄. These mitochondria were more dense than those of untreated animals and appeared to contain iodine TIGHTLY BOUND TO THEIR INNER MEMBRANES (9). ...Direct effects of T₄ on isolated mitochondria have been known for some time, but they occur only at HIGH, UNPHYSIOLOGICAL CONCENTRATIONS and their significance is doubtful. (9)." Lash p. 332.

"The actual biochemical mechanism of thyroid hormone action on neural tissue is poorly understood."

"It is evident that a single regulatory reaction has not been found to explain the multiple effects of thyroid hormones.

"Although the activities of more than 100 enzymes have been shown to be affected by thyroxine administration it appears that all are not influenced to the same degree. (10) ." Frisell p. 608. MANGANESE METABOLISM

"The early studies of Greenberg (65) with radiomanganese indicated only 3-4% of an orally administered dose is absorbed in rats. The absorbed manganese quickly appeared in the bile and was excreted in the feces. Experiments since that time with several species including man indicate that manganese is almost totally excreted via the intestinal wall by several routes. These routes are interdependent and combine to provide the body with an efficient homeostatic mechanism regulating the manganese levels in the tissues (16,90,129). The relative stability of manganese concentrations in the tissues to which earlier reference was made is due to such controlled excretion rather than to regulated absorption. (27)." Underwood p. 184.

It is important to realize that each of these tissues in the intestinal tract are actually using the same system to take in and to dispose of manganese. Whis is being described above is the flow of manganese into mitochondria and out again. It is a reflection of the mitochondrial pool, which is a very labile pool. Manganese is carried in the plasma bound to protein. Very little of it is cleared by the kidneys.

"Injected radiomanganese disappears rapidly from the bloodstream (23,90). Borg and Cotzias (28) have resolved this clearance into three phases. The first and fastest of these is identical to the CLEARANCE RATE OF OTHER SMALL IONS, SUGGESTING THE NORMAL TRANSCAPILLARY MOVEMENT, the second can be identified with the ENTRANCE diet. It appears, therefore, that calcium can influence manganese metabolism by affecting retention of absorbed manganese as well as by affecting manganese absorption. Variations in dietary phosphorus had no comparable effects on the excretion of intraperitoneally administered ⁵⁴Mn, BUT THE ABSORPTION OF ORALLY ADMINISTERED ⁵⁴Mn WAS IMPAIRED. Underwood. p. 186.

During 1970 a rash of books drew attention to energized translocation or transport and to the changes in conformation of the membranes of the mitochondria. There were extensive correlations devised with the mitochondrial oxidative phosphorylations. By 1975 some of this was discounted by claims that many solutes crossed the mitochondrial membrane without active transport. A number of postulates evolved including proton, phosphate and other mechanisms for these transfers.

In muscle and nervous tissue there are differences of sixty millivolts or more between the inner and outer surfaces of cell membranes. A Ca/Mg pump explains a wide variety of data. There seemed initially to be good data for high resonant phosphate compounds activating the cation pumps of mitochondria. Such a pump is affected by changes in concentration of calcium and it is also modulated by magnesium. Mn goes in and out of mitochondria readily. It dose so by active translocation and in the company of alkaline earth metal cations. Other metals participate but to a lesser degree. A Ca/Mg pump operating in tandem with Na/K ATPase pumps not only fits the cell membrane, but it also would have a place in the mitochondrial scheme of things. It has long been suggested that mitochondria represent primitive bacteria originally ingested when cells developed phagocytic functions. The effective oxidation processes of the ingested cells are cited as the cause of the symbiosis developing. The corollary of that suggestion is the need that developed to correlate flow of high resonant compounds between the original cell and the mitochondria. This theory suggests that metabolic disease might well occur at the site of such a complex metabolic adjustment between the metabolism of two different cells. This mechanism of regulation is consistent with that theory.

The added point must be made that the high efficiency ascribed to mitochondria as sources of high resonant bonds highlights the need for a central control mechanism. Such a mechanism must collate the energy production of the mitochondria with the energy metabolism of the cells, organs, and indeed the entire organism.. Calcium would seem a logical choice as the modulator of a system interactive between eukaryotic cells and mitochondria. This is consistent with the present presentation.

This mechanism or system of control has been called a mechanism of regulation. Listing the sequence of components described includes cation, ATPase pump, Mn, deiodinase, thyroid hormones, monoamine oxidase and amines. ALL ARE FOUND IN CLOSE PROXIMITY IN THE MITOCHONDRIA. SUPPLEMENTARY PRIOR ART STATEMENT

"MANIA,..., is undoubtedly one of the most dramatic of all psychiatric illnesses. Within days or weeks a reasonably well-balanced individual may develop uncontrollable enthusiasm. In HYPOMANIA, the mildest form of the illness, it is not always easy to decide whether the patient is mentally sick or merely acting peculiarly because of some change in the circumstances of his work or family life; often some unusual event may appear to have affected him unduly. First, it may be noted that the patient is attracting more attention than ordinarily. The routine of daily living is suddenly broken. Facial expression is more gay and animated; dress is less restrained or eccentric in some way. All actions and reactions are more brisk...."

"ACUTE MANIA is a more severe degree of hypomania. At this stage the abnormality of the patient's behavior is abnormal beyond question...."

"In HYPERACUTE MANIA or DELIRIOUS MANIA the patient is completely uncontrollable. He paces the floor and, if restrained struggles constantly and tosses about. Speech is completely incoherent and his utterances make no sense

This is the classic mania. The patient is the classic maniac. The patient is manic-depressive, psychotic. The disease is also called dipolar psychosis because of the tendency for such patients to have both mania and depression. Depression is said to be ten times as common as mania. At one extreme patients drift in and out of depression. At the other, patients have intermittent bouts of mania. In between are those that swing back and forth from one pole to the other.

Other diseases have mania, providing combinations of mental and muscle hyperactivity, disorganization, disorientation, delirium and sometimes death. Many a patient has died on the table before the surgeon could get the thyroid out IN 'THYROID CRISIS' or 'THYROID STORM' . Severe thyrotoxicosis is the diagnosis of the patient.

Among the miners in Chile, men develop running. If they were only alcoholics, it would be called a 'running jag'. They do not know why they run or pursue some other muscular hyperactive .pattern. Mines have had to be closed because of the high incidence of mania in manganese mines. Cotzias has studied the disease and found that the miners that have less Mn in their bodies are at risk. This seems to represent a metabolism that is not able to turn over the manganese as rapidly as the miners who have larger amounts but do not develop the mania.

All three of these manias have in common the alterations in the 'CMTA sequence' explained in the FORMULATION, Section VII, which precedes this supplement to the prior art.

Eventually the activities of the manganese miners that are affected abate after cellular exhaustion leaves them with residual neurological defects that are not as severe as might have been anticipated. These miners have both a respiratory and an oral intake of manganese in their work. The formulation section has discussed the presence of excessive levels of entire spectra of amines when monoamine oxidase is inhibited, especially the catecholamines. In hyperthyroidism the increased concentrations of catecholamines was also documented and the increased amounts of T₄and T₃ that result from the inhibition of deiodinase by Mn have highlighted the participation of manganese in certain types of thyroid disease. In these three manias, the great rush of catecholamines, serotonin and other amines has created immense feeling of power, immense activity, immense confusion in the affected subject. It has created the MANIAC. IT HAS CREATED CLASSICAL MADNESS.

Ray Adams in his discussion in Harrisnon's Principles of Internal Medicine 1970 6th edition pp. 1871 to 1874 reviewed briefly the CAUSE AND MECHANISM of the disease, i.e., manic-depressive psychosis. The role of genetics, the correlation with body types, the psychological structure of the personality, with obsessive compulsive traits, overdevelopment of the ego (Freud) and other attributes thought to correlate.

"The medium by which the gene alters function has been sought in an endocrine disorder without success. Recently, however, the discovery that iproniazid, an antidepressant agent, increases the quantity of epinephrine in the brain by inhibiting monoamine oxidase, and imipramine (another antidepressant) has a similar effect by another mechanism has given new stimulus to chemical theories. This is in line with another earlier observation that reserpine can produce depression, an effect that can be counteracted by dopamine, a precursor of catecholamine. From these studies, one can conclude, as does Kety, that this evidence supports "the concept that certain biogenic amines, especially the catecholamines, in particular areas of the brain play important roles in mediating normal and abnormal affective states." Therapeutic agents such as drugs and electroshock are capable of increasing the synthesis, release, or otherwise enhancing the effective concentration of norepinephrine and possibly other amines."

The CMTA sequence explains these observations and more importantly explains the normal mechanisms for controlling the amounts of the substances making up the mechanism of regulation of all of this.

Electroshock is a terror-producing experience. It

disorganizes structure and function. Memory defects gradually disappear. Many weeks or months may be required. Their disappearance, however, indicates that protein structures in the central nervous system remain intact. The neurotransmitter stores are disturbed.

Lithium salts gradually slow down the manic phase. Alterations in affect and activity and attention span correlate with serum lithium levels, "The toxic levels for lithium are close to therapeutic levels." PDR, 1983 37th edition p. 1904. One to three weeks are required to gain control of the acute manic phase. Renal disease may contribute to excessive levels and toxicity. "No specific antidote for lithium poisoning is known." Ibid. The use of lithium salts has long been employed for the treatment of manic-depressive psychosis. It was revived three decades or so ago by an Australian physician and was popularized in psychiatry. The original use of it was probably in ancient Greece or earlier. In Greece, springs and spas were associated with the oracles. As in Europe today, certain springs probably became associated with certain diseases.

The use of lithium has a number of explanations provided for it. For the most part these do not hold together well when examined in terms of the biochemistry involved. The probable explanation is in the size of the radius of the lithium. The element is below hydrogen in the first column. Its atomic number is three. Its atomic weight is about seven. The single bond covalent radium is listed as 1.23; the metallic as 1.55, For sodium and potassium the values are:1.54 and 1.90 and

2.03 and 2.38 respecitively in Demitras, et al., Inorganic Chemistry Table 2.1 p. 34. 1972.

The sodium/potassium ATPase membrane pump is responsible for maintaining the difference in charge between the inside of the muscle cell or the nerve cell and the outside of each of these cell-types. The sodium is pumped out, the potassium is said to fall in. The pumping is of the monovalent ions. The monovalent ion of lithium is of the competitive size range with the sodium. The ionic radii are not given for the hydrated forms of these which may match more closely. Lithium would have a slowing effect upon the pump. SUMMARY OF THE INVENTION Manganese-containing pharmaceutical preparations for the deceleration of the rate of oxidation of amines with the resulting increased levels of amines cause higher levels of physiological activity as shown by the basal metabolic rate (BMR) and changes in emotional tone.

Divalent cationic compositions of Group IIA calcium-, magnesium- and strontium-containing compounds; Group IIB zinc-containing compounds; Group 13 copper-containing compounds; and Group VIII3 iron-containing compounds for the acceleration of the rate of oxidation of amines and the resulting decreased levels of amines cause lower levels of physiological activity as shown by the BMR and changes in emotional tone

DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring now to the invention, there is provided elemental compounds adapted for use in the system of oxidation of amines in mammalian and plant life. It is the overall concept of the subject invention to provide these elemental compounds to control the rates of amine oxidation.

In particular, the compositions of the subject Patent Application deal with the alkaline earth metals and transition metals found in Groups IIA, VIIB, VIIIB and

113. Still further the compositions utilize the elements in the ratios compatible with those in vertebrates and other organisms.

Thus, Group IIA utilizes calcium, magnesium and strontium.

Group VIIB utilizes manganese.

Group VIIIB may utilize iron if it is well-tolerated.

Group IB may utilize copper.

Group IIB utilizes zinc.

Thus, calcium, magnesium, strontium, manganese, iron, copper and zinc are utilized in ratios compatible with those in vertebrates and other organisms.

The amounts of trace elements found in mammals generally and in human beings in particular reflect environmental and genetic factors. In order that the invention may be more easily understood, the following examples will now be given, though by way of illustration only, to show details of the formulation of the invention and the clinical test results obtainable using such formulations.

No patients with mania were seen.

The numbers of patients taking the manganese-containing pharmaceutical preparation included a wide range of common diseases. The compound commonly used was manganese gluconate. The emphasis was upon the use of pure substances. In each case the amount of the manganese gluconate used was determined at the time of use in terms of the amount required.

Manganese has been included in mixtures of trace minerals and other nutrients dispensed or sold to patients for many years. What was noticeable from such preparations was that different patients had different dominant effects and some would have more of the effects than noted in others and vice versa- A preparation containing three trace minerals and two amino acids highlighted these incongruities. It became apparent that valid conclusions could not be derived from using that preparation. It was necessary for the trace metal to be studied separately in each case. Study was initiated of one of the other transition metals. This required a very considerable period in order to sort out its effects. When these were sufficiently understood, study of manganese was begun. It proved to be surprising from the beginning. Example 1

Patient A.H.

Period of chronic muscle strain in Type II diabetes mellitus and essential hypertension.

Treatment Periods: daily to one to three week intervals. Treatment: Fasting blood sugar drawn periodically

(70 % of time). Hypoglycemic agents given 80% of time when seen Antihypertensive agents given 70% of time. Manganese gluconate given 30% of time when seen in doses ranging from 2 to 6 milligrams

Blood glucose: varied from(90-100) to (170-180) mg/100ml, usually from(100)to(150).

Blood pressure: varied from 130/82 to 184/80 mm. of mercury.

Systolic pressure: varied from 130 to 184.

Diastolic pressure: varied from 70 to 90.

Pulse: varied from 68 to 92.

Pulse pressure: (= systolic pressure - diastolic pressure) varied from 48 to 106 mm. of mercury.

Medication ratios: As between hypoglycemic agents varied from

2.5/1 to 30/1 All dosages in milligrams. Dosages of hypoglycemic agents varied from 50 to 1500.

The hypoglycemic agent with the lowest ratio to manganese ranged from 17/1 to 100/1 when given concurently.

The hypoglycemic agent with the highest ratio to manganese ranged from 167/1 to 750/1.

Treatment intervals for Mn varied from daily to 2 weeks or more.

Clinical response: gradually improving muscle strain. Higher glucose levels occurred in association with episodes of pain and associated loss of sleep.

Eighty per cent of fasting blood glucose values fell between 100 and 150 mg/100 ml. Example 2

Patient E.G. Late middle-age

Period of stress in late-onset (Type II) diabetes mellitus NIDDM

Treatment Periods: daily to every 4 to 5 days.

Treatment: Blood sugar drawn fasting and hypoglycemic agents given each morning seen with manganese gluconate 6-25 mg/treatment.

Blood sugar: varied from 175 mg% to 120 mg% over six week interval.

Objective of treatment: to restore blood sugar to normal range with 110 to 140 mg% acceptable.

Clinical response: feeling well despite levels of blood sugar. patient essentially symptom-free ? occult infection.

Example 4

Patient B.E. midlife

History of recurrent attacks of depression. Periods of stress have contributed to recurrent episodes at a rather long spacing of intervals.

Treatment periods: Circumstances prevented daily visits during depression on one occasion. On another daily medication possible.

Treatment: Evaluation of emotional status. Dietary management for stabilization of blood sugar.

Placed on antidepressant and manganese gluconate about 4 mg to 8 mg after initial therapy with 3 to 4 mg. (doses calculated by manganese content in mg in the gluconate)

Treatment Period Interval: Initially daily to every two- three days. This continued for ten to fourteen days, then, every three to four days for a week or two more, then quickly to once a week, once every ten to fourteen days and then every three to four weeks. Dietary program became sufficient with intervals at one to two months.

Objective of treatment: To restore emotional tone to normal range.

Clinical Response: Normal affect and emotional pattern with full work schedule within to to three weeks, but with normal pattern of response delayed to six to eight weeks. Supportive treatment at intervals.

Second episode: Very little time for treatment. Followed as above about one week with same degree of improvement. Then, given 8 to 12 mg manganese as gluconate and large dosage of antidepressant at weekly or longer intervals. Rapid improvement. Continued full schedule of work.

Range of medication: About eight mg manganese most needed at any one time. This was quickly spaced out and reduced. Once pattern of response known, program could be accelerated. The examples demonstrate that the same ratios of manganese and the other medications used cannot be expected in the various disease states.

In mania no manganese is given. The objective is to establish a negative manganese balance.

During the depression, patients are given manganese in 5 to 10 mg/75 kg.

During hypertension, they may vary from 5. to 12.5 mg/75 kg or more up to 25 to 50 mg/ 75 kg initiallly, i.e., at the top level arrived at early in treatment. The amounts then become smaller and smaller and more and more infrequent.

Diabetest mellitus is characterized by doses ranging from 3 to 5 mg/50 kg up to 12.5 to 25 mg/50 kg or even more.

In hypoglycemia 5 mg/50 kg or more may be needed during the initial phase of treatment.

At the same time that the manganese intake is varying, the intake of antimaniacal, anitdepressant, antihypertensive, antidiabetic and antihypoglycemic agents is also varying. As a result the therapeutic ratios may be characterized by constant fluctuations. Calculated recommended amounts of manganese as the gluconate

(values given in mg manganese) can be listed as follows:

Mania zero or negative (balance) amounts.

Depression 1 mg = 1000 ng (nanograms) 76 to 133 ng/kg body weight.

Hypertension 67/kg to 333 ng/kg

Diabetes 100 to 500 ng/kg (or in mg 0.1 to 0.5 mg/kg)

Hypoglycemia 0.1 mg/kg or more may be used in the early stages.

The general nature of the effect of manganese is illustrated by the fact that it is being given for syndromes that are the opposites of one another, e.g., hypoglycemia and the hyperglycemia of diabetes. Variations of the gastrointestinal excretion of the element develop when large amounts are given.

This is best avoided in order to enable the clinician to more easily predict the effect of a given dosage of manganese.

Such adjustments are, of course, ecessary when dose levels change in a 'cumulative' treatment program.

The disease states treated result from interactions between the underlying metabolic cycles being no longer able to sustain life and vitality free of at least some degree of morbidity. There is no clear overlay of symptoms on the one hand and the metabolic cycle on the other. Thus, as an individual ages, there develop accumulations of complaints, such as aches and pains and stiffness, e.g., the stiffness apparent when one watches an old dog get up.

Claims

1. A method of changing the rate of oxidation of amines in vertebrates and other organisms comprising orally administering to the subject in an amine-oxidation-rate-alteringly effective ratio an effective nonlethal amount therefor of at least one of

(a) comprising compounds of calcium, magnesium, strontium and zinc and an effective nonlethal amount therefor of

(b) a preparation consisting essentially of a. manganese compound.

2. A method of changing the rate of oxidation of amines in mania comprising administering to the affected subject in an amine-oxidation-rate-alteringly effective ratio an effective norlethal amount therefor of at least one of

(a) comprisirg compounds of calcium, magnesium, strontium and zinc and an effective nonlethal amount therefor of

(b) a preparation consisting essentially of a manganese compound.