WO1985003874A1

WO1985003874A1 - Method of treating depression in vertebrates

Info

Publication number: WO1985003874A1
Application number: PCT/US1985/000331
Authority: WO
Inventors: Vernon Erk
Original assignee: Vernon Erk
Priority date: 1984-03-01
Filing date: 1985-03-01
Publication date: 1985-09-12
Also published as: EP0174981B1; DE3587988D1; AU598722B2; AU4066685A; EP0174981A1; EP0174981A4; JPS61501568A

Abstract

Method of treatment for depression in vertebrates and other organisms comprising administration of manganese-containing pharmaceutical preparations in appropriate ratios with phenylalanine and tyrosine to return the emotional state of the affected individual to within appropriate limits; all of these to be given in cumulative amounts appropriate to the individual subject in a schedule of treatment which varies in amount, frequency and said ratios, reflecting the changing emotional tone of the affected individual as adjustment is made to within normal limits.

Description

METHOD OF TREATING DEPRESSION

IN VERTEBRATES

BACKGROUND OP THE INVENTION 1. Field of the invention This invention relates to changing the emotional tone of vertebrates and other organisms. It relates to changing the relative abundance of circulating amines. It relates to restoring the emotional tone from one of depression to one within normal limits. It relates to the compounds which can be used to keep emotional tone within normal limits.

The invention is directed to providing preparations that will relieve anxiety and depression in affected individuals.

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 PHARMACOLOC-ICAL 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 semi-carbazide 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 p. 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 from the market because of 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-O-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 catecholamine (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. THE VALENCE ELECTRONS

The valence electrons are the ones in the outer orbitals. At each level, the effort is to achieve a filled group of orbitals. Thus, the chloride atom is likely to add an electron its outer set of orbitals and carry an extra electron when it is structured as an ion. Thus, it mimics the electron cloud of argon.

The calcium atom has a filled 4s² grouping but tries to get rid of those two electrons to form Ca⁺⁺ ion which then mimics the argon electron cloud. The electron clouds of group VIII A belong to the inert gases and thus are all filled.

Group VII B is between the alkaline earths and thehalogens. At the fourth row, the smallest of this group lies between calcium which is next to the left end of that row and bromide which is next to the right end of that row.

It is the fifth transition metal to the right of calcium and the tenth metal to the left of bromide. Bromide has two of the s electrons in the fourth series and five of the p electrons in the fourth level. Iodide has the same distribution of s and p at the fifth level. In addition, it has a full ten of the d electrons in the fourth level.

Since there is a special overlapping of the orbitals of the two levels, it illustrates the opportunities for similarities in the electron clouds that surround the nuclei of atoms when elements are larger with a larger number of orbitals. These considerations of structure relate the first element of the VIIB group to calcium on the left end of its row and to iodine on the other end of the next row, i.e., in size. In other words it has strong similarities to calcium and to iodine. When viewed at the atomic level of size it would appear similar to calcium and it would appear similar to iodine. Three is the quantum for its d electrons. A quantum number is the numerically defined symbol designed to indicate the 'energy' of the electron. Energy in reality is the total movement of the electron. The quantum numbers of the electrons indicate their movement and on occasion we shall refer to this as 'resonance'. Resonance infers the amount of movement one attributes to an electron in its orbital.

Electrons, then, are defined by their positions relative to the position of the nucleus of an atom or in the case of molecules relative to the position of the nuclei of the atoms around which an orbital extends. We may indicate position by P and the change in position by delta P. Defining the position by P and the change in position by delta P enables us to measure the pathway of the electron from some arbitrarily selected site and thus comparing its movement with that of the other entities in its atomic environment.

At the atomic level, manganese looks like a calcium ion when both of lose their outer electrons and conform to the inert gas Argon. Iodine looks like manganese. Both are solids at room temperature and both have outer electrons of a group of two electrons and a group of five electrons. Except for the halogens, THIS OUTER CONFIGURATION IS FOUND ONLY IN MANGANESE. Except for some considerations of spin, the atoms of iodine and manganese should have very pronounced similarities. These are reflected in the SCB radii, and manganese is the element that would be expected to most closely approximate the specificity requirements of the deiodinase enzyme located at the inner membrane of the mitochondria.

The salts of manganese are found nearby inside the mitochondria. These salts occur there along with the salts of calcium, strontium and magnesium. Active translocation of manganese into the mitochondrial matrix by high resonant ATP conforms well to the calcium in the active translocation of divalent cations. Manganese also conforms well to the active site of the inner membrane enzyme which selectively removes the iodine atoms from the 3 and 5 position of the distal phenyl rings of thyronine in the thyroid hormones T₄ and T₃.

WHEN MANGANESE OCCUPIES THE ACTIVE SITE OF THE DEIODINASE THE ENZYME IS PREVENTED FROM REMOVING IODINE FROM THE THYROID HORMONES AND THE MOLECULES OF THE THYROID HORMONES INCREASE IN CONCENTRATION. Thus, when the manganese enters the nonpolar pocket of the active site it inhibits the deiodinase. 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 OF THE MANGANESE INTO THE MITOCHONDRIA OF THE TISSUES, AND

THE THIRD AND SLOWEST COMPONENT COULD INDICATE THE RATE OF

NUCLEAR ACCUMULATION OF THE ELEMENT ....The kinetic patterns for blood clearnace and for liver uptake of manganese are almost identical indicating that the two manganese pools- BLOOD MANGANESE AND LIVER MITOCHONDRIAL MANGANESE - RAPIDLY

ENTER EQUILIBRIUM. A high proportion of body manganese must, therefore, be in a dynamic mobile state. Underwood p. 185.

"The turnover of parenterally administered ⁵⁴Mn has been directly related to the level of stable manganese in the diet of mice over a wide range (27). A linear relationship between the rate of excretion of the tracer and the level of manganese in the diet was observed and the concentration of ⁵⁴Mn in the tissues was directly related to the level of the stable manganese in the diet. THIS PROVIDES FURTHER SUPPORT FOR THE CONTENTION THAT VARIABLE EXCRETION RATHER THAN VARIABLE ABSORPTION REGULATES THE CONCENTRATION OF THE METAL IN TISSUES." Underwood p. 185.

"Little is known of the mechanism of absorption of manganese from the gastrointestinal tract, or of the means by which excess dietary calcium and phosphorus reduce manganese availability....The effect of variations in dietary calcium and phosphorus on the metabolism of ⁵⁴Mn in rats has been studied further by Lassiter and associates (100). These workers found that the fecal excretion of parenterally administered ⁵⁴Mn was much higher and the liver retention lower on a 1.0% calcium diet than on a 0.64 calcium diet. " Ibid. 186. lt 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. SUMMARY OF THE INVENTION

Manganese-containing pharmaceutical preparations decelerate the rate of oxidation of biogenic amines. The increased levels of amines resulting therefrom cause higher levels of physiological activity as shown by the basal metabolic rate (BMR) and changes in emotional tone. This is accompanied by an elevation of emotional tone. Depressed individuals become progressively less depressed and anxious.

The effect is further enhanced by providing precursor substances of the catecholamines.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring now to the invention, there are manganese-containing compounds provided adapted for use in the system of oxidation of amines in biological systems. It is the overall concept of the subject invention to provide these compounds to control the rates of amine oxidation.

In order that the invention may be more easily understood, the following example 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.

Depression is best evaluated by the clinician personally whenever any treatment is undertaken initially. This is dictated by the changes in dosage that sometimes occur very quickly. The patient should be taken off all drugs when beginning treatment. It is necessary that the clinician have an accurate picture of the true state of the patient no masked by drug effects. Blood pressure levels are low in depression. Many medications confuse these readings.

Because of the cumulative nature of the medication, treatment should be begun with small amounts and worked up to maxim dose« Then, almost as quickly, over a period of days, it may be necessary to decrease the dosage again. The manganese may be considered to modulate the phenylalanine or other antidepressant listed here in its action as a precursor for the catecholamines. Example 1

Patient B .E . midlife

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

Treatment periods: Circumstances prevented daily visits during one episode of depression. Another episode medication could be provided daily.

Treatment: Evaluation of emotional status. Dietary management for stabilization of blood sugar. Placed on combination of phenylalanine and manganese (doses calculated in mg of manganese in manganese gluconate). Initial therapy with 3 to 4 mg of manganese. Phenylalanine begun with about ten to twenty mg. These were increased to about 4 to 8 mg of manganese and then decreased when this amount was no longer needed. The phenylalanine was increased to 25 to 50 mg. Its dosage was then given at less frequent intervals and in decreasing amounts.

Treatment Period Interval: Initially it varied from daily to every two or three days. After ten to fourteen days, every three or four days for a week or two more. This changed quickly to once a week, then 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 two to three weeks. Full normal pattern of response delayed to about 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 about 8 to 12 mg of manganese as gluconate and 50 mg or more mg of phenylalanine at weekly or longer intervals. Rapid improvement. Continued full schedule of work.

Ratios of medication: B.W. 75 kg. Mn ranged from 0.040 mg to 0.106 mg per kg; phenylalanine from 0.133 to 0.667 mg/kg

Phenylalanine was given on an average of three to five times as often as manganese.

Claims

- C LAIMS -

1. A method of treating depression in vertebrates and other organisms which comprises administering to an affected subject in an antidepressantly effective ratio an effective amount therefor of at least one of (a) comprising L-phenylalanine, D-phenylalanine, L-tyrosine, D-tyrosine and their alpha-keto and alpha-hydroxy analogs and acetyl-L-phenylalanine, acetyl-D-phenylalanine, acetyl-L-tyrosine, and acetyl-D-tyrosine and dipeptides and tripeptides of the aminoacids or a pharmaceutically acceptable acid addition salt thereof and an effective nonlethal amount therefor of (b) a preparation consisting essentially of a manganese compound.

1. A method of treating depression in vertebrates and other organisms which comprises administering to an affected subject in an antidepressantly effective ratio an effective amount therefor of at least one of (a) comprising L-phenylalanine, D-phenylalanine, L-tyrosine, D-tyroisine and their alpha-keto and alpha-hydroxy analogs and acetyl-L-phenylalanine, acetyl-D-phenylalanine, acetyl-L-tyrosine, and acetyl-D-tyrosine and dipeptides and tripeptides of the said aminoacids or a pharmaceutically acceptable acid addition salt thereof and an effective nonlethal, physiologically-tolerable, pharmacokinetically-appropriate, pharmaceutically-acceptable amount therefor of (b) a preparation consisting essentially of a manganese compound.