CA1277908C - Method of treating depression - Google Patents

Abstract

ABSTRACT

The invention relates to a method of treatment for depression in vertebrates and other organisms com-prising administration of manganese-containing pharmaceutical preparations in appropriate ratios with phenylalanine and tyrosine to return the emo-tional 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

1.;~77~()8 INTRODUCTION

This is a method for changing the rates of oxidation of neuroactive amines and other biogenic amines by monoamine oxidase. Increasing activity of the enzyme results in lower levels of these amines. Decreased activity results in higher levels of these amines. Many of the affected amines fulfill the specificity requirements of receptor sites on the membranes of cells. When such a receptor site is occupied the activity of a membrane pump changes in many cases. Production of "second messenger~ molecules such as cAMP and cGMP at the inner surface of the membrane occurs in most cases. These cyclic compounds commonly activate protein kinases. The protein kinases are enzymes possessing phosphorylase activity.
When protein kinases are activated in the nucleus of the cell production of RNA becomes possible and eventually protein synthesis. When protein kinases are activated in the cytosol such actions as glycogenolysis become possible.
The effect is determined by how the cell is built when differentiated. The structure of the cell determines what specialized function it will serve when protein kinases are activated.
So many of the amines oxidized by monoamine oxidase affect these various cells that most of the major functions of the body are affected. This may result in profound alterations in the vital functions of vertebrates and other organisms. Imbalance between vital functions are defined as diseases if morbidity or risk to life occurs.

-~ sd/ml -2-~Z779Q8 I-lealthy individuals have both optimum levels of these amines and appropriate ratios between these amines. Many metabolic diseases in the human are associated with changes in the levels and ratios of these amines. The rates of oxidative deamination of these amines by monoamine oxidase constitutes part of a 'MECHANISM OF REGULATION' imbalance of which produces many of the diseases of vertebrates.
The following abbreviations and definitions are in the approximate order in which the words are introduced.

Neuroactive Capable of affecting nerve cell function.
Biogenic amine An amine originating in a biological system.
The term is generally applied to an amine associated with some physiological action.
Specificity The exactness with which a molecule must be structured in order to occupy a receptor site of a protein or peptide.
Receptor site A molecule, usually a protein, which has an active site in it. Occupation of the active site may, for instance, activate or inactive an enzyme.
Active site Region of enzyme surface which interacts with the substrate molecule. (Lehninger) X sd/jc -3-1~!'77gQB

Second messenger A compound formed on the inside of the cell membrane, e.g., cAMP, cGMP., when the first messenger occupies a receptor site.
First messenger A compound which occupies a receptor site on the outer surface of a cell membrane, e.g., adrenalin.
Membrane pump Any of many protein complexes incorporated into the membranes of cells by which smaller molecules, ions, or atoms are pumped in and out of cells or their compartments by activity of enzymes in the protein complex.
Cytosol The fluid suspension within cells exclusive of organelles such as the nucleus and mitochondria.
Glycogenolysis The breakdown of glycogen.
RNA Ribonucleic acid cAMP Adenosine monophosphate cGMP Guanosine monophosphate Glycogen A starch like compound occurring in the cells of vertebrates and other organisms.
0 Differentiation The formation of a new cell type from a simpler cell type and the preparation of the new cell structurally to carry out a new function.
Vital Pertaining to life.

sd/Jc -4-lZ7~9~B
Disease A definite morbid process having a characteristic train of symptoms. It may affect the ~hole body or any of its parts. Dorland 23rd edition p.
393.
As here used, an imbalance in vital processes sufficient to interfere with maintenance of life support systems and to reduce vitality and to produce risk to life.
Morbid L. morbidus; sick Pertaining to disease or affected with disease. Dorland 23rd edition p. 856.
Mechanism of Regulation As here used, a system of interacting enzymes whose combined actions serve to regulate the levels of molecules involved in maintaining life supporting functions.
Vertebrate An organism possessing a spinal column.

sd/jc -5_ `` 1277~8 2~ Prior Art "Monoamine oxidase is a flavoprotein oxidase of pur-ported CENrRAL M~TA30LIC IMPORTA~CE CONVERTI~G NEUROACTIV~

AMINES INTO INACTIvE ALDEHYDES The flavin linked mono-amine oxidase is localized in the OUTER MITOCHONDRIAL MEM-8RANE OF ANIMAL CELLS Walsh pp 402, 403 ~ Action~ Monoamine oxidase is a complex enzyme sys-tem widely distributed throughout the body Drugs that in-hibit monoamine oxidase in the laboratory are associated with a numbor Or clinical er~ect~ Thus, it i~ UNKNOWN
WHETHER MAO INHIBITOR PER SE, OTHER PHARMACOLOGICAL ACTIONS, OR AN INTERACTlON OP ~OTH IS responsible ror th- clinical ct- ob8erved Therefore, the phy~ician should b-com ~a~illar wlth all the ffects produced by drugs in this cl~--, PDR (Physicianc' D-sk Reference 1983) p. 1516 Two classirications Or amin- oxidases were presented in 1959 That of Blashko, et al used the response to carbo-nyl inhibitor~ to di~tinguish between the activities of the various amine oxitase That of Zeller, et al, used semi-carbazide inhibitors The use Or inhibitors to classify the amine oxidases reflected difficulties encountered in puriryin~ these enzymes and studying the structure of their acti~e ~ites "A Occurence Monoamine oxidase (MAO) has been found in all classes of vertebrates so far examined (1970) ~ammals, birds, reptiles, amphibians and teleosts (161) ne enzyme occurs in many different tissues, particularly nds, plain muscle, and the nervous system (162) ~. .

12Y~7~8 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 ~evere liver toxicity. It i8 intere6ting to note that these drugs exert their beneficial effect in depressed patient~ anywhere from one to several weeks after treat-ment is begun. "In some instances the improvement may progres~ to a state Or 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.

~2?79~8 MAO Monoamine oxidase. MAOI Monoamine oxidase inhibitor.

Inhibitor A compound or atom which when it occupies the active site of an enzyme prevents the usual chemical reaction(s) from taking place there.
Mitochondria Membrane surrounded organelles in the cytoplasm of aerobic cells which contain respiratory en~yme systems. (Lehninger) The 'powerhouse' of the cell. An organelle engaged in the production of high resonant compounds by oxidation of compounds from all the major foods.
Depression (L. depressio: de down + premere to press) Dorland 23rd edition p. 366. 3. A lowering or decrease of functional activity. 4. Absence of cheerfulness or hope; emotional dejection.
Euphoria (Gr. The power of bearing easily) Ibid p. 480.
In psychiatry an abnormal or exaggerated sense of well being.
Hypomania (hypo. + Gr. mania madness) Mania of a moderate type. Ibid p. 651.
Mania (Gr. madness) Ibid p. 795. 1. A phase of mental disorder characterized by an expansive emotional state, elation, hyperirritability, overtalkativeness or flight of ideas, and increased motor activity;
specifically, the mania of manic depressive psychosis.
Orthostatic hypotension Lowered blood pressure when the person changes from a supine sd/ml -8-to an erect position. Ibid p. 654 Anticholinergic Blocking the passage of impulses through the parasympathetic nerves; parasympatholytic.
Ibid p. 99.

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 8ites 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.

sd/ml _9_ These urinary compounds indicate clear~nce 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.

sdtml -9A-1 ~277908 - - ~ The following ab~reviations and definitions are ln the approximate order in which th~ words are introduced.

Affinity Attraction.
Antidepressant Tending to overcomet a feeling of depression.
Flavoproteln An enzyme having a riboflavin (82) compound as a coenzy~e.
Sympathetic nervous system A dlvision o~ the autonomic nervous system.
Catechola~ines nne group of neuroactiva amines, e.g., dopa~ine, noreplnephrin , anæ epinephrin .

.-... ,,~ -. ..

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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 l6Cl) 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.

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12779~

ADVANTAGES OVER THE PRIOR ART

Leyden Webb maintains that a NORMAL STATE of a biological system should be regarded as a perfect balance of complex chemical and functional activities, the possibilities depending on a precise coordination of the rates of these various processes. The incorporation of an inhibitor into a biological system leads to an alteration of the rates of some of these processes and thus to a disturbance of the perfect balance.
-lo Usually only the results of the imbalance induced by the inhibitor can be determined. Thus, if the inhibitor upsets the balance to the detriment of the organism, it is generally termed a poison. On the other hand, when the change of balance favors the survival of the total system, the inhibitor may be regarded as a drug. Expeller Adler p. S0.

1. The invention provides for the use of the natural components of the 'mechanism of regulation' of which monoamine oxidase is a component part. This makes zo it possible to distinguish between clinical effects due to MONOAMINE OXIDASE INHIBITION per se and OTHER PHARMACOLOGIC
ACTIONS.
In fact, it provides a control against which other drugs can be tested, such as those presently in use as monoamine oxidase inhibitors.

sd -12-~2'7790~3 2. The invention provides a method of knowing what substance is producing what effect.

3. When natural substances are administered in the use of this method they have cumulative effects.
This dictates a sequential decrease in the frequency with which these substances are to be given.
Eventually treatment may, in fact, be required only very infrequently if at all.
Cumulative (L. cumulus, heap), Increasing by successive additions, the total being greater than the expected sum of its parts. Dorland 23rd Edition p. 337.
Bouvier Vol.l 1914. Rawle's revi6ion p. 737 gives the meaning in legal terms similarly, with the sense of heaping up, building a mound, as of cumulative evidence which is that which goes to prove what has already been established by other evidence. Both of these, the medical and the legal, are wide of the mark intended here.
As used here it is in the sense of filling in a depression or trench not in the sense of building a mound.
DESCRIPTION OF THE NOVELTY OF THE INVENTION

The MTA sequence is a central mechanism of regulation which maintains vital functions within the commonly encountered parameters of normal individuals. It is present in vertebrates sdIml -13-. . - ~

' ' ~Z~79~

and other organisms. The complexity of the MTA sequence varies as the complexity of the organism. Thus, some active amines present in man are not found in lower organisms.

Imbalance of active amines in the MTA sequence results in changes in vital functions. Balance is restored by restoring the structures of the MTA sequence. This comprises administering effective amounts of at least one of the precursors of active amines decreased in the MTA sequence, and comprises administering effective amounts of the deiodinase inhibitor.
The substances administered are cumulative as structures of the MTA sequence are restored. The amounts of these natural substances are administered:
a. with decreasing frequency and b. in decreasing amounts.
Considerable intervals may elapse before administration of effective amounts of these substances require repeating.

, sd/ml -14-DESGRIPTION OF ~HE PROCE ~ 7r79~ 3 The administration o~ manganese compounds results in inhibition of deiodinase enzyme iand an increase in the concentration of T4 and T3.
The increased concentrations of T4 and T3 increase the inhibition of monoamine oxidase and glutamate dehydro-genase.
The levels of dopamine and norepinephrineiand sero-tonin and other biogenic amines increase ias well as those Or amino acids.
Cells with receptor sites for these trani~mitters and ~ther active amines have an increased probability of hiaving those receptor sites occupied.
A OEeat many cell types in the body are activated.
Activation of a cell type is accompanied by more metabolic activity and protein synthesis.
In carrying out the process for which the cell type has been differentiated and programmed there is an increase in oxidation.
This increase in the use of oxygen can be measured indirectly by determining the basal metabolic rate (BMR).

1.2779~

"Many investigations have been carried O11t with the goal of identifying some specific enzyme catalyzed reaction in oxidative metabolism that is controlled by the thyroid hormone. In early investigations it was found that thyroxine stimulates respiration and uncouples oxidative phosphorylation when added to isolated mitochondria. Moreover, thyroxine also promotes the respiration-dependent swelling of mitochondria.
However such effects REQ~IRE EXCESSIVELY HIGH CONCENTRATIONS
OF THYROXINE and it is now doubtful whether they represent true endocrine effects of the hormone.... The molecular basis for the mode of action of thyroxine is still a challenging puzzle." Lehninger p. 413.

To understand Lehninger's statement about thyroxine stimulating respiration and uncoupling of oxidative phosphorylation when added to isolated mitochondria it is necessary to provide the following sequence of definitions, many of which are his.

Mitochondria Membrane-surrounded organelles in the cytoplasm of aerobic cells which contain respiratory enzyme systems. (Lehninger) Oxidation The loss of electrons from a compound; an oxidizing agent is an electron acceptor. Ibid.

ADP Adenosine diphosphate ATP Adenosine triphosphate Oxidative phosphorylation The enzymatic phosphorylation of ADP to ATP which is coupled sd/ml -16-~gQ~ .

to electron transport-along the respiratory chain to oxygen (in mitochondria). Ibid.
Energy Movement.
Coupled reactions Two chemical reactions which have a common intermediate and therefore a means by which energy can be transferred from one reaction to the other. (Lehninger) We can now substitute movement of electrons for energy in the above definition.
Common intermediate A chemical compound`that is common to two chemical reactions, as either a reactant or a product. Chemical energy may be transferred from one reaction to another via such a common intermediate. (Lehninger) Similarly we can now substitute electron movement for chemical energy in the above definition.
Uncoupling agent A substance (example 2,4-dinitrophenol) which can uncouple phosphorylation of ADP from electron transport; the energy is then released as heat. (Lehninger) Chemistry The exchange and/or sharing of electrons between the outer orbitals of atoms.
Heat The movement of molecules and atoms. It is calibrated in terms of the rate of movement. At room temperature the skin sensors registers no change, for instance.

sd/ml -17--`` l.Z7790~3 When the rate of movement of molecules and atoms in the skin increases, an increased number'of impulses are transmitted to the brain where a feeling of hotness is experienced referable to the original site.
When the rate of movement decreases, the brain interprets a feeling of coldness in the site of origin of the impulses.
Electron dynamics The study of the movement of electrons.
It may be restated as a study of the energy of electrons. A more specific presentation permits the total movement of an electron to be defined as the energy of that electron. However, reversing the statement, the energy of the electron is the total movement of the electron. This, in effect, renders the word 'energy' redundant whenever movement and change in movement i5 stated for the electron in a system.
Respiration The oxidative breakdown and release of energy from fuel molecules by reaction with oxygen in aerobic cells. (Lehninger) Electron transport The movement of electrons from subs,trates to oxygen catalyzed by the respiratory chain during respiration. (Lehninger) Looking at respiration, that definition can be restated as the release of sd/ml -18-1277gQ~ ' movement of electrons from mhlecules reacting with oxygen in aerobic cells.
Electron carriers Enzymes such as flavoproteins and cytochromes which can gain and lose electrons reversibly;
the respiratory chain consists of a series of electron carriers. (Lehninger) In order to follow the specific movements of electrons it is necessary now to address the other terms used by Lehninger with regard to energy. Thus:
-lo Free energy That component of the total energy of a system which can do work under conditions of constant temperature and pressure. (Lehninger).
We may substitute total movement for total energy.
Work When a force acts against resistance to produce motion in a body the force is said to do work.
WEAST 49th edition 1968-1969. When we analyze this we find work being defined in terms of the displacement, i.e., change in position, delta P of a body. Work is being défined in terms of movement of a body.
We can then state that free energy becomes that component of total movement which is available to move another body. In other words, for work to be done, there must be movement from an area of high rate of movement to be applied to an area of low rate of movement.
We may derive from the definition of free energy the sense that a compound with electrons having -,~

sd/ml -19-~77~Q~3 high rates of movement can transfer some o,f that movement to electrons in compounds where the electrons have lower rates of movement.
Hydrolysis The cleavage of a molecule into two or more smaller molecules by the addition of a water molecule. (Lehninger) Excited state That energy-rich state of an atom or molecule existing after an electron has been moved from its normal stable orbital to an outer orbital having a higher energy level, as the result of the absorption of light energy (Lehninger). We may substitute resonance rich for energy-rich indicating the type of movement of an electron in an orbital, i.e., curvilinear.
Similarly we may use the term higher resonance level for higher energy level, again indicating the movement of the electron. Finally we may use the term light photon movement for light energy absorbed during the photoelectric effect. In each instance we are able to define the term energy as a kind of movement of the electron.
Low-energy phosphate compound A phosphorylated compound having a relatively low standard free energy of hydrolysis. (Lehninger) High-energy phosphate compound A phosphorylated compound sd/nl -20-~r~

lz7~a~
having a highly negative standard free ene,rgy of hydrolysis. Ibid.
We may state this as a relatively small amount of total movement available and the second as a relatively large amount of total movement available to move another electron or electrons.
High energy bond A bond that yields a large (at least 5Kcal/mole) decrease in free energy upon hydrolysis under standard conditions.
(Lehninger) This can be restated to say that a large amount of resonant movement (at least 5Kcal/mole) becomes available on hydrolysis under standard conditions to move electrons or other bodie~. It is important to recall that heat is the movement of molecules and atoms and that movements of electrons can be transferred to other entities within the molecule and thus change the movement of the nucleus or nuclei.
The high resonance phosphates, then, are ideal for producing changes in the movements of compounds with which they interact by transferring the movements sd/ml -21-~2779~3 of their electrons to those of the interacting compound.
"It has been demonstrated that thyroxine stimulates the synthesis of protein by microsomes and that this stimulation is SECONDARY TO AN EFFECT ON THE MITOCHONDRIA (Sokoloff et al, JBC, 238, 1432. 1963)." U.S. Dispensatory p. 1186 26th edition 1967.
"It is evident that a single regulatory reaction has not been found to explain the multiple effects of thyroid 10 hormonesThe question of the "primary" site of action of the hormone remains unanswered." Duncan (Bondy ed.) p. 769 1969.
"In hyperthyroidism the elevated metabolic rate is reflected in increased glycogenolysis, a hyperglycemia, and glucosuria. The clinical syndrome for this condition is called TOXIC DIFFUSE GOITER, or EXOPHTHALMIC GOITER, OR Grave's DISEASE." Frisell p. 609. "The basal metabolic rate (BMR) measures oxygen consumption in the basal state and is expressed as percentage of values found in normal individuals of the same age, sex, and body surface area (13.)" Harrison p. 449. The correlation between the catecholamine effect and monoamine oxidase activity is clear. Similarly the correlation between thyroid effect and catecholamine effect is clear. In essence Exophthalmic goiter Goiter accompanied by bulging eyes due to mucoprotein accumulation behind the eyes.

sd/ml -22-- l~nso~

Toxic diffuse goiter Goiter in which there are ~iffuse changes throughout the enlarged gland.

Phosphate bond energy A term used to denote the decline in free energy as one mole of a phosphorylated compound undergoes hydrolysis to equilibrium at pH
7.0 and 25, in a 1.0 M solution.
W~ may state this as a decline in the electron movement during hydrolysis, movement presumably transferred to water.
The same effect is being discussed when thyroid and monoamine oxidase effects upon neurotransmitter amines are being discusséd.

Thus far the control of transmitter amine levels by monoamine oxidase oxidative deamination has been traced to the availability of thyroid hormones T4 and T3. The next step is the inhibition of deiodination in order to have a high enough concentration of these thyroid hormones to effectively inhibit the monoamine oxidase in the outer membrane of the mitochondria. We have noted that large amounts of T4 and T3 have been demonstrated tightly bound to the inner membrane of the mitochondria. These were studies conducted outside the body. The concentrations required for the activities to be demonstrated were said sdtml -23-~2779~

to be too high, to be nonphysiological. The enz~yme that occurs in the mitochondria is a dehalogenase similar to that in the endoplasmic reticulum. The specificity of these enzymes include bromide chloride, and iodide, but with fluoride there is less activity. When we consult the periodic table, these comments are of interest. The four halogens named are nonmetals. The remaining one astatine is a metal by this classification.

METALLIC RADII
The metallic radium may be defined as one half the distance between the atoms of a metal in the metallic close packed crystal lattice (in which the metal exhibits a coordination number of 12). Metallic radii are generally some 10 to 15% larger than the single bond covalent radii (see Table 2.1) but at the same time are considerably smaller than the nonbinding van der Waals radii. The metallic bond (see Chapter ,) that governs the proximity of metal atoms to one another in the metallic crystal is NOT locali~ed between any two pairs of atoms as is the covalent bond. This results in the two metal atoms not being drawn quite as close to each other in the metallic crystal as they are in forming a covalent bond. At the same time, however, the bonding forces are appreciable in governing interatomic distances as evidenced by the comparatively much larger van der Waals radii for the same atom. METALLIC RADII ARE QUITE OFI'EN REFERRED to as ATOMIC RADII in reference tables." Demitras, et al sd/ml -24-12779~

pp. 37,38. Iodine is classified as the largest ~onmetal element, the one with the greatest mass.
The fifth postulate of Dalton's atomic theory has been stated as "The combining proportions mentioned in the laws of definite and multiple proportions are related to the relative mass of atoms." Blumberg & Stanley p.
49. The periodic law used by Mendeleev to construct the Periodic Table in a form that was finally quickly accepted can be stated thus "The properties of the elements vary in a periodic way with an increase in atomic number."
Ibid. p. 206. Thus, both properties of mass and the number assigned to an element are related to the properties of the element.
PERIODIC TRENDS IN ATOMIC RADII
"Whether one considers the covalent radii, metallic radii, or van der Waals radii, significant trends appear as one traverses a period of the periodic table or compares the~e properties in a group. THE IMPORTANCE OF THE RADII
LIES IN THE FACT THAT THE SIZE OF THE ATOM as much as any other single property of the atom determines its PHYSICAL
AND CHEMICAL PROPERTIES. The chemical reactivity of an atom is a function of the ability of the atom to lose, gain, or share electrons, and this ability is very largely controlled by the electrostatic attractive force exerted by the nucleus on the valence electrons. In turn, the attractive force is governed largely by the distance of the valence electrons from the nucleus, i.e., the radius.
At the same time many physical properties such as density are dependent on the radii of the atom." Demitras, et sd/ml -25-12 7790~

al, pp. 38, 40.
VALUES OF RADII
In table 2.1 of Demitras et al, the radii of the elements in group VIIA read as follows:
Halogens: Single bond covalent radii (SBC R).
F 0.64 Cl 0.99 Br 1.14 I 1.33 At 1.45 These are nonmetals except for the last so that no metallic radii are given.
In table 2.4 van der Waals radii are listed ]o as follows;
F 1.35 Cl 1.60 Br 1.95 I 2.15 Group VIIB
The radii of these transition metals are listed as follows:
SBC RAdius 1st 1.17 2nd 1.27 3rd 1.28 Metallic radius 1.27 1.35 1.37 respectively for the same elements in order of increasing size.

ss/ml -25A-T Æ VALENCE ELECTRONS ~-¦

The valence electrons are the ones in the outer orbitals At each level, the e~rort is to achieve a ~illed group of orbitals. Thus, the chloride atom i8 likely to add an electron it8 outer set of orbitals and carry an extra electron when it is structured as an ion Thus, it mi~ics the electron cloud Or argon The calciua atoa has a rilled 482 grouping but tries to get rid Or those two electrons to rOra Ca~ ion which then ~i~ics the argon lectron cloud. The electron clouds Or group ~III A belong to the inert gases and thus are all rill.d.
Croup ~ b-t~een the al~alin earths and the halog n- ~t th rourth ro~, the s~allest Or this group li-- b t~e-n c lciu ~hlch 18 no~t to th- l-rt end Or that ro~ and bro~id~ ~hich ~- n ~t to th- right end o~ that row It i- the ritth tran~itlon ~ tal to th- right o~ calcium and the tenth n tal to th- lert Or bromide. Bromide has t~o Or th- 8 electrons in the rourth series and ri~e Or the p electrono in the rourth level Iodide has the same distribution Or 8 and p at the rirth level In addition, it has a rull ten Or th- d electrons in the rourth level Since there is a special overlapping Or the orbitals Or the two levels, it illustrates the opportunities ror similarities in the electron clouds that surround the nuclei Or atoms when elements are larger with a larger number Or orbitals ~6 Those considerations of structure relate the rirst element of the VIIB group to calcium on the loft end o~
its row and to iodine on the other end Or the next row, l o , in size In other words it has strong similarities to calcium and to iodino When riowed at the atomic le~el Or size it would appear s~milar to calcium and it would appear ~imilar to iodine Three i8 tho quantu ror its d olectrons A quantum number ~8 the numerically derined s~mbol dosigned to lndicate the 'energy' of the electron En-rgy in roality i8 the tot~ movemont of the electron Tho qusntum numbors Or the electrons lndlcate their move-ment and on occasion w shall ro~or to thi~ a- 'r~-onanc-' Rosonanco int~rs th- amount of vem-nt on ~ttribut-- to n l-ctron in lt- orbital.
El-ctron , th-n r- d-rin d by th-ir po-ition-r-lati~ to th- po-ition Or th- nucl-u Or an atom or in th- c--- Or mol-cul-- r-lativ~ to th- po-ition Or th-nucl-i Or th- ato~s round ~hich an orbital xt-nd- W
~ay lndicat- po-ltlon by P an~ th- chang ln po-ition by d-lta P Derining th- position by P and th- ch nge in position by delta P enables U8 to m-asur- th~ pathway Or the electron rrom 80mo arbitrarily seloctod sito and thus comparing its movement with that Or the other ontitios in its atomic environment At tho atomic level, manganese 100~8 like a calcium ion when both o~ lose their outer electrons and con~orm to the inert gas Argon a 7 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 ~or the halogens, THIS WTER CONFI W RATION IS FOUND ONLY
IN MANGAMESE Except for some considerations of spin, the atoms Or iodin¢ and manganese should ha~e very pro-nounced similarities These are reflected in the SCB
radii, and manganese is the ¢lement that would be expect-ed to most closely approximate the speci~icity require-~ent- ot th- t-iodina~- enzyme located at the inner ~e~-br n o~ th- ~to¢hondrla.
Th salts Or ~anganese are round nearby inside the ~ltochondrla. The~- salts occur there along with the ~alt- ot c~lclu , strontiu~ and magnesium. Acti~e trans-location ot ~ neanes- into th- mitochondrial matrlx by high re-onant ATP con~or~s well to the calclum in the acti~ translocation Or di~alent cations Manganese also conror~s well to the acti~e site Or the inner membrane enzy~e which selecti~ely removes the iodine atoms from the 3 and 5 position Or the distal phenyl rings Or thy-ronine in the thyroid hormones T4 and T3 ~--WHEN ~ANCANESE OCCUPIES THE ACTIVE SITE OF THED~IODIN~SE THE ENZY~E IS PREVENTED PROM RE~OVING IODINE
PROM THE THYROID HOR~ONES AND THE MOLECULES OF THE THYROID
HORMONES INCRE~SE IN CONCENTRATION Thus, when the man-ganes- enters the nonpolar pocket Or the acti~e site it inhibits the deiodinase.

12779~

MANGANESE METABOLISM
"The early studies of Greenberg (6S) with radio-manganese 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 manganes~ 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. What 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

sd/ml -29-~Z779~8 OF THE MANGANESE INTO THE MITOCHONDRIA OF THE TI~SUES, AND THE THIRD AND Sl.OWEST COMPONENT COULD INDICATE THE
RATE OF NUCLEAR ACCUMULATION OF THE ELEMENT....The kinetic patterns for blood clearance and for liver uptake of manganese are almost identical indicating that the two manganese pools-BLOOD MANGANESE AND I.IVER 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.
THlS 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). Thase workers found that the fecal excretion of parenterally administered 54Mn was much higher and the sd/ml -30-1.~77908 liver retention lower on a 1.0% calcium diet th~n on a 0.64 calcium 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 ~4Mn 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 does 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 sd/ml -31-12779Q~

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 in~gested 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 beween the metabolism of two different cell6. This mechanism of regulation is consistent witl 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 mechani6m mu6t 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 sdlml -32-1277sn~

amines. ALL ARE FOUND IN CLOSE PROXIMITY IN THE MITOCHONDRIA.
Of these seven components we may concentrate on the small molecules; the enzymes would be PD0 for phosphorylase deiodinase and oxidase. The small molecules give MTA
for manganese, thyroid hormone, and amine. If calcium were added at the beginning when cation pumps are discussed as part of the mechanism of regulation, then the letters might be CMTA. The word 'sequence' affords a description of event.
Here we will use the designation 'MTA sequence', and if there is reason to emphasize calcium or divalent cations other than that of manganese 'CMTA sequence' can also be referred to in the textual material.
The formulation here discussed as 'MTA sequence' has been provided in keeping with the suggestions presented in the article by Marcus in the J. of the PØ Soc. September, 1969, Vol. 52, No. 9 on page 559. It is an attempt to insure that one skilled in the art will be able to reproduce the results described in a disclosure or advanced in a constructive reduction to practice. It has been felt that treatments are greatly facilitated by insight into this complex biochemical mechanism.

~; sd/ml -33-," .. . . ..

--' 1~9Q8 ~ UMMARY OF THE INVENTION
Mànganese-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 i8 further enhanced by providing precursor eubstance~ of the oatecholamin ~.

3~

. . -'-- ' 1.2779~

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 under-stood, 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 obtsinable using such rormulations.
Depression is best evaluated by the clinician personally whenever any treatment is undertaken initially. This i8 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 pic-ture Or the true state of the patient no masked by drug effects. Blood pressure levels are low in depression.
Many medications confuse these readings.
Because Or the cumulative nature Or 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 modu-late the phenylalanine or other antidepressant listed here in its action as a precursor for the catechola-mines.

, . . .

lZ~9Q8 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: Circumætances prevented daily visits during one episode of depression. Another epi-sode 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 le~s frequent intervals and in decreasing amounts.
Treatment Period Intervalt Initially it varied from daily to every two or three days. After ten to fourteen day8, 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 be-came 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. Fol-lowed 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 o.667 mg/kg Phenylalanine was given on an average of three to five times as often as manganese.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition for treating depression, comprising:
(a) a compound selected from L-phenylalanine, D-phenyl-alanine, L-tyrosine, D-tyrosine, an alpha-keto analog, an alpha-hydroxy analog, a dipeptide and a tripeptide of said amino-acids, acetyl-L-phenylalanine, acetyl-D-phenylalanine, acetyl-L-tyrosine, acetyl-D-tyrosine, a pharmaceutically acceptable acid addition salt of said amino-acids, analogs, peptides and acetyls, and a mixture thereof; and (b) a nonlethal, pharmaceutically acceptable, physiologically tolerable, pharmacokinetically appropriate amount of an Mn compound;
wherein components (a) and (b) are present in effective amounts and a ratio to render the composition antidepressantly active.