CA2257279A1 - Compositions and method which retard the aging process and which improve age-related disease conditions - Google Patents

Compositions and method which retard the aging process and which improve age-related disease conditions Download PDF

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CA2257279A1
CA2257279A1 CA002257279A CA2257279A CA2257279A1 CA 2257279 A1 CA2257279 A1 CA 2257279A1 CA 002257279 A CA002257279 A CA 002257279A CA 2257279 A CA2257279 A CA 2257279A CA 2257279 A1 CA2257279 A1 CA 2257279A1
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magnetic field
serotonin
effective amount
pulsed magnetic
stimulant
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Reuven Sandyk
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Priority to CA002257279A priority patent/CA2257279A1/en
Priority to AU59898/96A priority patent/AU5989896A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
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    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets

Abstract

A method of retarding the aging process and improving the symptoms of agerelated disease conditions in humans which result from diminished pineal melatonin functions and reduced serotonin neurotransmission is described which comprises administering to a human in need thereof an effective amount of a composition which increases serotonin transmission to said human followed by the application to the brain of the human an effective amount of an AC pulsed magnetic field of proper intensity, frequency and waveform. Preferably the composition is supplemented by an effective amount of dietary composition rich in the amino-acid tryptophan. Optionally an effective amount of an agent which provides growth hormone release is also administered prior to the application of the AC pulsed magnetic field. A composition useful for retarding the aging process and improving the symptoms of aging in humans which result from diminished pineal melatonin functions and reduced serotonin neurotransmission when administered to a human followed by the application to the brain of the human of an effective amount of an AC pulsed magnetic field of proper intensity, frequency and waveform, is described which composition comprises an effective amount of a composition which increases serotonin transmission to said human. Optionally, the composition can also include an effective amount of an agent which promotes growth hormone release.

Description

CA 022~7279 1998-12-02 W O 97/46244 PCT/U~G/09~40 COMPOSITIONS AND METHODS WHICH
RETARD THE AGING PROCESS AND WHICE
IMPROVE AGE-RE~ATED DISEASE CONDITIONS

BACKGROUND OF THE INVENTION
The pineal gland is recognized as a neuroendocrine transaucer, whose chief function is that of synchronizing endogenous circadian rhythms via the conversion of neuronal impulses to melatonin release. Aging is characterized by disorganization of circadian rhythms caused in part by the progressive decline in the activity of the pineal gland leading ultimately to pineal failure. The pineal gland is a magnetosensor organ and its functions can be enhanced by the external application o~ pulsed magnetic fields.
In my US Patent No. 5,470,846 issued November 28, 1995, and my concurrently filed continuation-in-part thereo~ Serial No.
08/437273 ~iled May 8, 1995 (~IP-1), I described compositions and methods for treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans.
These disorders which are associated with and/or related pathogenetically to impairment of pineal melatonin functions included multiple sclerosis, Parkinson's disease, dystonia, tardive dyskinesia, epilepsy, migraine, Alzheimer's disease, depression (including seasonal affective disorder and late luteal phase dysphoric disorder), schizophrenia, Gilles de la Tourette's syndrome, Attention deficit hyperactivity syndrome, anxiety and panic disorder, obsessive compulsive disorder, narcolepsy-cataplexy, myoclonus, akathisia and restless legs syndrome and chronic pain syndromes.
For many years physiologists considered the pineal gland, lodged deep within the brain, a vestigial organ which is merely an ana~omical remnant o~ a primary sensory system. To the clinician the pineal gland, by virtue o~ its midline position and calcification, was of interest as a radiological landmark to identify intracrani-al space occupying processes. The pineal gland attracted scienti~ic attention in 1963, when its primary secretion, melatonin, was first recognized as a hormone.

CA 022~7279 1998-12-02 Wurtman and Axelrod (1965) "The pineal gland." Scientific American, 231, 50-60) termed the pineal gland a "neuroendocrine transducer," an organ which converts neural signals from the external environment such as photic, acoustic, thermic, and -magnetic cues into neuroendocrine output which acts on the nervous system largely via the secretion of its principal hormone melatonin.
The pineal gland is unique among endocrine organs for a number of reasons: (1) it is one of the few unpaired endocrine organs; (2) on a weight basis, it receives one of the richest blood supplies of any organ; (3) it lies outside the blood brain barrier, but has direct access to the cerebrospinal fluid (CSF) via the third ventricle; (4) it produces and/or contains high concentrations of a number of different 1ndoleamines and low -molecular weight peptides of probable endocrine importance; and (5) it i5 responsive to changes in magnetic field strength and to external electrical stimuli (Foley et al.(1986) "Pineal indoles: significance and measurement." Neuroscience &
Biobehavioral Reviews, 10, 273-293).
Over the past several years scientists have come to suspect that melatonin is a l'master hormone" involved in the control of circadian rhythms (biological cycles that recur at approximately 24-hour intervals), and protecting against common diseases of aging. Melatonin is now recognized to exert an important influence on a host of biological functions including synchronization of biological rhythms, stabilization of neuronal activity, regulation of sexual maturation and reproduction, immunomodulation, temperature control, sleep, mood, appetite, pain control, cognitive functions, and motor behavior (Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of NeurosuraerY, 63, 321-341;
Relkin (1966) "The pineal gland." New Enqland Journal of Medicine, 274, 944-949; Reiter (1991) "Pineal melatonin: cell biology of its synthesis and of its physiological interactions.
35 ~ Endocrine Reviews, 12, 151-180; Datta and King (1980) "Melatonin: e~fects on brain and behavior." Neuroscience &
Riobehavioral ~eviews, 4, 451-458; Anton-Tay (1974) "Melatonin:
effect on brain function." Advances in Bioçhemical Psycho~harmacoloqy, 11, 315-324; Cagnacci et al. (1994) CA 022~7279 l998-l2-02 "Melatonin-induced decrease o~ body temperature in women: a threshold event.~ Neuroendocrinoloqy, 60, 549-552; Chuang et al. (1993) "Melatonin decreases brain serotonin release, arterial pressure and heart rate in rats." Pharmacoloqy, 47, 91-97; Armstrong and Redman (1991) "Melatonin: a chronoblotic with antiaging properties?" Medical Hypotheses, 34, 300-309;
Reiter (1992) "The ageing pineal gland and its physiological consequences." BioEssavs, 14, 169-175; Trentini et al. (1991) "Pineal gland and aging." Aqinq, 3, 103-11~; Drew and Batt (1972) "A contribution to the evolutionary theory o~ dreaming:
an hypothesis on the role o~ the pineal gland in species and specimen protection." Bioloqical Psychiatxy, 4, 131-146;
Bubenik and Pang (1994) "The role o:E serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation o~ food intake, and mutual serotonin-melatonin feedback.'i Journal o~
Pineal Researc~t 16, 91-99).
In experimental animals pinealectomy (i.e., removal o~ the pineal gland) results in a syndrome of de~icits which include disruption o~ circadian rhythms and sleep phases, ~acilitation o~ a narcoleptic-type REM sleep distribution, increased susceptibility to epileptic sei~ures, ~acilitation o~ abnormal oro~acial involuntary movements, decreased tolerance to heat, impairment o~ opioid analgesia, reduction in brain neurotransmitter levels such as serotonin and GABA, delayed brain maturation, impaired electrolyte balance speci~ically sodium, calcium and phosphorus metabolism, arterial hypertension, increased plasma cortisol levels, disruption o~
adrenomedullary diurnal catecholamine synthesis, a biochemical diabetes-like state, elevation o~ blood cholesterol levels, disruption oi~ circadian rhythms o~ gonadotropins and testosterone with resultant enlargement o~ the prostate, impaired wound healing, and promotion o~ cancer growth due to disruption o~ immunomodulation and reduced ability to protect cell membranes from peroxidative damage (Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?"
Medical H~potheses, 34, 300-309; Aldegunde et al. (1985) "E~ects o~ pinealectomy on regional brain serotonin metabolism." International Journal of NeurQscience, 26, 9-13;
~unnane et al. (1979) "The pineal gland and regulation o~

CA 022~7279 1998-12-02 W O 97/46244 PCTAUS96/~9440 fibrosis: pinealectomy as a model of primary biliary ci~rhosis:
roles of melatonin and prostagl~n~,n~ in ~ibrosis and regulation of T lymphocytes." Medical Hypotheses, 5, 403-407; Kincl et al.
(1970) " Observation on the influence of changing photoperiod on spontaneous wheelrunning activity of neonatally pinealectomized rats.~ EndocrinoloaY, 87, 38-42; Banerji and Quay (1976) "Adrenal dopamine beta-hydroxylase activity: twenty four hour rhythmicity and evidence for pineal control." Experientia, 32, 253-255; Csaba and Barth (1974) "The effect o~ pinealectomy on the perifollicular cells of the rat thyroid gland." Acta Anatomica, 88, 137-146; Kinson and Peat (1971)" The influences of illumination, melatonin and pinealectomy on testicular function in the rat " Li~e Sciences,10,259-269; Shirama et al.
(1982) "Influence of pinealectomy on circadian patterns of -plasma luteinizing hormone, follicle-stimulating hormone, testosterone and dihydrotestosterone in the male rat.~ Journal of Endocrinoloqical Investiqations, 5, 397-401; Milcu et al.
(1971) "The effect of pinealectomy on plasma insulin in rats.
In G.E.W. Wolstenholme and J. Knight (Eds.), The ~ineal qland (pp. 345-360). London:Churchill Livingstone; Diaz and Blazquez (1986) "Effect of pinealectomy on plasma glucose, insulin and glucagon levels in the rat." ~ormone Metabolic Research, 18, 225-229; Zanoboni and Zanoboni-Muciaccia (1967) "Experimental hypertension in pinealectomized rats." T.; ~e Sciences, 6, 2327-Z331; Holmes and Sugden (1976) "The effect of melatonin on pinealectomy-induced hypertension in the rat." B~itish Journal o~ Pharmacoloqv, 56, 360-361; Karppanen et al. (1970) "Studies with pinealectomized rats." Pharmacoloqy, 3, 76-84; Kavaliers et al. (1983) "Ageing, opioid analgesia and the pineal gland."
Life Sciences, 32, 2279-2287; Kumar et al. (1982) "Diurnal fluctuations in methionine-enkephalin levels in the hypothalamus and preoptic area of the male rat: effects o~ pinealectomy."
Neuroendocrinoloqy, 35, 28-31; Nir et al. (1969) "Changes in the electrical activity of the brain following pinealectomy."
~:Neuroendocrinoloqy, 4, 122-127; Kamback et al. (1982) "Effect of pinealectomy on fatty acid composition of rat brain myelin."
Endocrinoloqy, 110, 907-909; Reiter et al. (1973) "Nature and time course of seizures associated with surgical removal of the pineal gland from parathyroidectomized rats.i' Ex~erimental CA 022~7279 l998-l2-02 W O 97/46244 PCT~US~v9~10 Neuroloqy/ 38, 386-397; Mouret et al. (1974) "Effet de la pinealectomie sur les etats et rythmes de sommeil du rat male.
Brain Research, 81, 97-105; Oxenkrug et al. (1984) "Effects of pinealectomy and aging on the serum corticosterone circadian ~ 5 rhythm in rats." Journal of Pineal Research, 1, 181-185; Sandyk and Fisher (1989) "Increased incidence neuroleptic-induced movement disorders in pinealectomized rats." International Journal of Neuroscience, 48, 303-308; Heldmaier and Lynch (1986) "Pineal involvement in thermoregulation and acclimatization."
Pineal Research Reviews, 4, 97-139; Pieri et al. (1994) "Melatonin:a peroxyl radical scavenger more effective than vitamin E." Life Sciences, 55, PL271-276; Lapin and Ebels (1981) "The role of the pineal gland in neuroendocrine control mechanisms of neoplastic growth." Journal of Neural Transmission, 50, 275-282; Romijn (1978) "The pineal a tranquillizing organ?" Life Sciences, 23, 2257-2274).
Many of the disease conditions associated with aging such as sleep and cognitive disorders, mental depression, disruption of the circadian rhythms of pituitary hormone secretion, obesity, hypertension, atherosclerosis, osteoporosis, hyper-cholesterolemia, glucose intolerance, ionic imbalance, endocrine changes (i.e., decrease plasma gonadotropin and growth hormone levels) and gastrointestinal disorders (i.e., bowel constipation), are thought to be related to or associated with the gradual decline in the secretory activity of the pineal gland with aging with resultant disorganization of circadian rhythms (Brown et al. (1979)"Melatonin in human cerebrospinal fluid in daytime; its origin and variation with age." Life Sciences, 25, 929-936; Iguchi et al. (1982)" Age-dependent reduction in serum melatonin concentrations in healthy human subjects." Journal o~ Clinical EndocrinolQqY and Metabolism, 55, 27-29; Nair et al. (1986) "Plasma melatonin - an index of brain aging in humans?" Bioloqical PsvchiatrY, 21, 141-150; Sack et al. (1986) "Human melatonin production decreases with age.~
Journal of Pineal Research, 3, 379-388; Sandyk et al. (1992) "Is ~ Postmenopausal osteoporosis related to pineal gland ~unctions?"
International Journal o~ Neuroscience, 62, 215-225; Birau (1981) "Melatonin in human serum: progress in screening investigation and clinic." In Birau N. and Shloot W. (Eds.), CA 022~7279 1998-12-02 W O 97/46244 PCTrUS96/09440 Melatonin:current status and perspectives (pp. 297-326).Oxford:Pergamon Press; Barnes et al. (1974! "Insulin resistance, skin changes, and virilization: a recessively inherl~ed syndrome possibly due to pineal gland dysfunction.~
~Diabetoloqia, 10, 285-289." Tasca et al. (1974) "Disappearance of aortic lesions in the rabbits with experimental atheromatosis after pineal extraction administration." Revue Roumanian d'Endocrinoloqie, 11, 209-213; Ostroumova and Vasiljeve (1976) Effect of polypeptide pineal extract on fat-carbohydrate metabolism." Problems in Endocrinoloqy, 22, 66-6g; Muller-Wieland et al. (1994) "Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes.'~ Biochemical and Bio~hysical Research Communications, 203, 416-421; Trentini et al. (1991) "Pineal 15 ~gland and aging." Aqing, 3 103-116; Grad and Rozencwaig (1993) "The role of melatonin and serotonin in aging:update."
Psychoneuroendocrinolqy, 18, 283-295; Armstrong and Redman (1991) "Melatonin:a chronobiotic with antiaging properties?"
Medical Hvpotheses, 34, 300-309; Reuss et al. (1986) "Electrophysiological and endocrinological aspects of aging in the rat pineal gland." Neuroendocrinoloqy, 43, 466-470; Thomas and Miles (1989) "Melatonin secretion and age." Bioloqical Psychiatrv, 25, 365-367; Wetterberg (1983) "The relationship between the pineal gland and the pituitary-adrenal axis in health, endocrine and psychiatric conditions."
PsvchoneuroendocrinoloqY, 8, 75-80; Touitou et al. (1984) "Patterns of plasma melatonin with ageing and mental condition:
stability of nyctohemeral rhythms and differences in seasonal vatriatons.~ Acta Endocrinolo~ica, 106, 145-151; Copinschi and Van Cauter (1994) 'IPituitary hormone secretion in aging: roles of circadian rhythmicity and sleep.~ EuroPean Journal of Endocrinoloqy, 131, 441-442).
In fact, in recent years, melatonin has been considered an anti-aging hormone and the hypothesis has been put forward that aging is secondary to pineal ~ailure (Walker et al. (1978) '~Pineal gland structure and respiration as reflected by age and diet.~ ExPerimental Gerontoloqy, 13, 91-99; Rozenchwaig et al.
(1987) "The role of melatonin and serotonin in aging." Medical Hy~otheses, 23, 337-352; Sandyk (1990) "Possible role of pineal CA 022~7279 1998-12-02 WO 97t46244 PCT/US96/09440 melatonin in the mechanisms of aging." International Journal o~
Neuroscience, 52, 85-92; Grad and Rozencwaig (1993) "The role of melatonin and serotonin in aging:update.PsvchoneuroendocrirloloqY, 18, 283-295; Pierpaoli et al. (l990) "Aging-postponing effects of circadian melatonin:
experimental evidence, significance and possible mechanisms.~
International ~ournal of Neuroscience, 51, 339-340; Pierpaoli (l99l) "The pineal gland:a circadian or seasonal aging clock?"
Aqing, 3, 99-101; Lesnikov and Pierpaoli (1994) "Pineal cross transplantation (old-to-young and vice versa~ as evidence for an endogenous "aging clock." Annals of l~he New York Academv of Sciencgs, 719, 456-460; Sharma et al. (1989) "Circadian rhythms of melatonin and cortisol in aging." Bioloqical Psychiatrv, 25, 305-319; Stokkan et al. (l99l) "Food restriction retards aging oi~ the pineal gland." Brain Research, 545, 66-72; Laudon et al.
(1988) " Melatonin receptors in discrete brain areas of the male rat. Impact of aging on density and on circadian rhythmicity.
NeurQendQcrinoloqYl 48, 577-583; Reiter et al. (1980) "Pineal melatonin rhythm:reduction in aging syrian hamster~." Science, 210, 1372-1373) . Moreover, it has been suggested that the pineal gland regulates the necessary genetic switching occurring in the cells throughout the body which cause the aging process (Kloeden et al. (l990) "Does a centralized clock ~or ageing exist?" GerontoloaY, 36, 314-322) .
According to this hypothesis aging is a process related to melatonin deficiency as ablation o~ the pineal gland in rodents produced pathological changes resembling senescence which are reversed by the administration of a pineal extract or melatonin (Malm et al. (1959) "The ef~ect o~ pinealectomy on bodily growth, survival rate and P32 uptake in the rat." Acta Endocrinoloqica, 30, 22-28; Dilman et al. (1979) "Increase in life span in rats ~ollowing polypeptide pineal extract treatment.~ Experimenl~al Patholoqy, 17, 539-545; Pierpaoli and Maestroni (1987) "Melatonin: a principal neuroimmunoregulatory and anti-stress hormone:its anti-aging ef Eects.~ Immunoloqy Letters, 16, 355-362) . Moreover, senescence is also inhibited and li~e span is prolonged when the pineal glands of young mice are grafted into old animals (Pierpaoli et al. (l99l) "The pineal control of aging: the efi~ects of melatonin and pineal CA 022~7279 1998-12-02 W 097/46244 PCT~US96/09440 grafting on the survival of older mice." A~nals of the New York Academy of Sciences, 621, 291-313; Pierpaoli and Regelson (1994) "Pineal control of aging: effect of melatoni~n and pineal grafting on aging mice." Proceedinqs of the Na~ional Academy of Sciences, USA, 91, 787-791; Walker et al. (1978) "Pineal gland structure and respiration as affected by age and hypocaloric diet.'~ Ex~erimental Gerontoloqy, 13, 91-99).
One of the mechanisms by which melatonin acts as an anti-aging hormone is through the promotion of the release of growth hormone (Martin (1976) "Pathophysiology of growth hormone regulation." In Martini and Ganong (Eds.), "Frontiers in neuroendocrinoloqy" (pp.129-168) New York:Raven Press; Smythe and Lazarus (1974) "Growth hormone responses to melatonin in man. Il Science, 1984, 1373; Petterborg et al. (1991) "EfEect of = melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin." Brain Research Bulletin, 27, 181-185). Growth hormone secretion declines dramatically with aging accounting for several features associated with aging such as memory loss, obesity, decreased motor activity, increased incidence of sleep disturbances, and increased susceptibility to hypothermia (Plum and van Uitert (1978) "Nonendocrine diseases and disorders of the hypothalamus." In Reichlin et al. (Eds.), "The Hy~othalamus" (pp. 415-473) New York:Raven Press;
Finkelstein et al. (1972) " Age-related change in the twenty-four hour spontaneous secretion of growth hormone." Journal o:E
Clinical Endocrinoloqv and Metabolism, 35, 665-670; Carlson et al. (1972) " Absence of sleep related growth hormone peaks in aged normal subjects and in acromegaly." Journal of Clinical Endocrinoloqy and Metabolism 34, 1102-1105; Van Coevorden et al. (1991) "Neuroendocrine rhythms and sleep in aging men."
American Journal of Physioloqy/ 260, E651-661).
The clinical consequences of melatonin deficiency include, among others, decrease in cerebral energy metabolism with decline in memory and other cognitive functions, tendency to = depressive mood, decline in the percentage o~ alpha brain waves, deterioration of sleep efficiency with increased number of nocturnal awakenings, increased daytime sleepiness, diminished immune functions with increased probability of cancer and autoimmune diseases, deterioration of metabolic and endocrine CA 022~7279 1998-12-02 homeostasis, impaired gastrointestinal motility, ~usce~tibility to the development o~ psoriasis, acceleration of atherosclerosis, poor wound healing, and decreased longevity (Reiter, R.J. ~1992) "The ageing pineal gland and its physiological consequences." BioEssaYs, 14, 169-175; Okawa et al. (199g) "Morning bright light therapy ~or sleep and behavior disorders in elderly patients with dementia." Acta Psvchiatrica Scandinavica, 89, 1-7; Birau and Schloot (1979) "Pathological nyctohumeral rhythm of melatonin secretion in psoriasis.~ IRCS
Me~lical Scier~ce, 7, 400; Lieberman (1986) "Behavior, sleep and melatonin." Journal of Neural Transmission, 21 (suppl), 233-241;
Bartsch et al. (1981) "Urinary melatonin levels in human breast cancer patients. Il Journal of Neural Transmission, 52, 281-294;
Tamarkin et al. (1982) "Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer.
Science, 216, 1003-1005; Haimov et al. (1994) "Sleep disorders and melatonin rhythms in elderly people." British Medical Journal, 309, 167; Miles and Philbrick (1988) "Melatonin and psychiatry. Il Bioloaical PsychiatrY, 23, 405-425; Pavel et al.
(1980) I'Vasotocin, melatonin and narcolepsy: possible involvement o~ the pineal gland in its pathophysiological mechanism." Pe~tides, 1, 281-284; Rozencwaig et al. (1987) "The role of melatonin and serotonin in aging.~ Medical Hvpotheses, 23, 337-352; Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?" Medical Hv~otheses, 34, 300-309) .
Melatonin has been considered a chronobiotic hormone, i.e., a hormone that can act as a synchronizer or "Zeitgeberll to reset the phase o~ biological rhythms by acting on the circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus (Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?" Medical HY~otheses, 34, 300-309) .
Consequently, diminished pineal melatonin functions may result - in the disruption o:E blological rhythms of numerous biochemical, physiological, hormonal, and behavioral systems leading to ~ disease and aging (Armstrong and Redman (1991) "Melatonin: a chronobiotic with anti-aging properties?" Medical Hv~otheses, 34, 300-309; Ingram et al., (1982) "Circadian rhythmicity and sleep:e~ects of aging in laboratory animals." Neurobioloqy of CA 022~7279 1998-12-02 W O 97/46244 PCT~US96/09440 Aqinq, 3, 287-297; Van Gool et al. (1987~ "~ge-related changes in circadian sleep-wake~ullness rhythms in male rats isolated from time cues.'~ Braln Research, 413, 384-387).
Since melatonin is a chronobiotic hormone it may be used ~therapeutically to re-entrain short-term dissociated or long-term desynchronized circadian rhythms or physiologically prevent their disruption following environmental insult and thus correct many o~ the pathological conditions which are associated with pineal failure associated with aging. For instance, the fact that melatonin administered to humans alleviates the deleterious effects of jet-lag, prolongs deep stages o~ sleep (i.e., restores youth~ul sleep patterns) and improves mood (Arendt et al. (1987) "Some ef~ects of jet-lag and their alleviation by melatonin. Il Erqonomics, 30, 1379; Kales and Kales (1974) "Sleep - disorders: recent findings in the diagnosis and treatment of disturbed sleep." New Enqland Journal of Medicine, 290, 487-499; Haimov et al. (1994) "Sleep disorders and melatonin rhythms in elderly people. ~r British Medical Journal, 309, 167) supports its chronobiotic properties as are the ~indings that bright light, which synchronizes biological rhythms, improves sleep and behavior disorders in the elderly and patients with Alzheimer's dementia (Okawa et al. (1994) "Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia.'~
Acta Psvchiatrica Scandinavica, 89-1-7; Satlin et al.(1992) ~sright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease.~ American Journal of Psychiatrv, 149, 1028-1032)and the findings that melatonin extends the life span in experimental animals (Pierpaoli and Maestroni (1987) "Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging ef~ects." Immunoloqv Letters, 16, 355-362; Pierpaoli and Regelson (1994) "Pineal control of aging: effect o~ melatonin and pineal grafting on aging mice." Proceedinqs of the National AcademY of Sciences, USA, 91, 787-791).
35 = I believe that one of the mechanisms by which melatonin acts as an anti-aging hormone is through the promotion of the release of growth hormone. Growth hormone is an anabolic hormone which stimulates protein synthesis, bone growth and glucose metabolism. In addition, it promotes inhibition o~ fat CA 022~7279 l998-l2-02 W 097/46244 PCT~US96/0944~ -formation and causes improved sleep energy, enhancement o~
immune functions, and stimulation of nerve growth factors (Quabbe (1985) '!Hypothalamic control of GH
secretion:pathophysiology and clinical implications. Il Acta Neurochirurqica, 75, 60-71; Astrom and Trojaborg (1992) "Effect of growth hormone on human sleep energy.~' Clinical Endocrinoloqy, 36, 241-245; Rusovan and Kanje (1992) "Magnetic fields stimulate peripheral nerve regeneration in hypophysectomized rats." NeuroRe~ort, 3, 1039-1041). The secretion o~ growth hormone from the pituitary gland particularly during sleep declines gradually with aging thus accounting for several features associated with aging such as decreased protein synthesis, bone loss, decline in immune functions, decline in the activity of nerve growth factors, 15 progressive memory loss, obesity, decreased motor activity, increased incidence of sleep disturbances and increased susceptibility to hypothermia (Meites (1986) "The neuro-endocrinology of hypothalamic aging." In Muller E.E. and MacLeod, R.M. (~3ds.), Neuroendocrine persl~ectives, vol. 5 (pp.
179-189). Amsterdam: Elsevier; Plum and van Uitert (1978) "Nonendocrine diseases and disorders of the hypothalamus" In Reichlin et al. (Eds.), "The hypothalamus" (pp. 415-473) New York:Raven Press; Van Coevorden et al. (1991)" Neuroendocrlne rhythms and sleep in aging men." American Journal o~ Phvsioloqy, 260, E651-661).
It is my belief based on my knowledge in the field, that the anti-aging ef~ect of the pulsed magnetic ~ield is ennanced by prior administrations of agents which promote growth hormone release. Thus my present invention additionally includes administering an effective amount of an agent which promotes growth hormone release prior to application of the AC pulsed magnetic ~ield. The amino acids L-arginine and L-ornithine both stimulate the release of growth hormone in humans (Martin and - Reichlin (1987) "Regulation of growth hormone secretion and its disorders~' In Clinical neuroendocrinQloqY (p. 237) F.A. Davis:
Philadelphia).
In addition to the ambient light/dark cycle, the activity of the pineal gland and hence the rate of melatonin secretion is influenced also by the earth's geomagnetic ~ield which is in the CA 022~7279 1998-12-02 W O 97/46244 PCT~US9~1G~ 110 order of 30,000 - 60,000 nanotesla (0.3 - 0.6 Gauss). The earth's magnetic field is primarily a nontime-varying (DC) field with angle of incidence to the earth's surface increasing with increasing latitude. For comparison, anthropogenic magnetic ~ields are primarily time varying at 50 or 60 Hz and harmonic of these fre~uencies. Typical magnetic fields measured in residential settings range from 0.1 microtesla to 3 microtesla at 60 ~z frequency. The geomagnetic field has been a part of the environment throughout the evolution of animals and is used by certain species in their adaptive strategies. Organisms are capable of perceiving its intensity, polarity, and direction (Gould (1984) 'IMagnetic field sensitivity in animals.~ Annual Review of PhYsioloaY, 46, 585-598). It is thought that the circadian rhythmicity of the earth's magnetic ~ield may have an additional "Zeitgeber" (time cue) ~unction in the organization of biological rhythms (Cremer-Bartels et al.(1984) 'IMagnetic ~ield of the earth as additional zeitgeber ~or endogenous rhythms?l' Naturwissenscha~ten, 71, 567-574; Wever (1968) "Einfluss Schwacher Elektro-magnetischer Felder auf die Circadiane Periodik des Menschen." Naturwissenschaften,55, 29-32; Bartsch et al. (1994) 'rSeasonality of pineal melatonin production in the rat: possible synchronization by the geomagnetic field." Chronobiolo~y International, 11, 21-26).
Since the activity o~ the pineal gland is sensitive to the in~luences o~ the geomagnetic field it has been suggested that it functions as a magnetoreceptor as well (Semm et al.(1980) "Effects of an earth-strength magnetic field on electrical activity of pineal cells." Na~ure, 288, 607-608; Semm (1983) "Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons.~ Comparative Biochemistry and PhYsioloqY, 76A, 683-689; Olcese et al.(1988) "Geomagnetic field detection in rodents." Life Sciences, 42, 605-613; Demaine and Semm (1985) "The avian pineal gland as an independent magnetic sensor." Neuroscience Letters, 62, ll9-122; Rudolph et al.(1988) "Static magnetic fields decrease nocturnal pineal cAMP in the rat." Brain Research, 446, 159-160). Based on histological studies and electrophysiological single unit recordings ~rom the pineal gland o~ rodents and pigeons, it has been estimated that 20~-30~ o~ pineal cells CA 022~7279 l998-l2-02 W 097/46244 PCT~US96/09440 respond to magnetic ~ields (Semm (1983) "Neurobiological investigations on the magnetic sensitivity o~ the pineal gland in rodents and pigeons." ComParative Biochemistry and Ph~,rsioloqy, 76A, 683-689). Electrophysiological studies by ~ 5 Reuss et al.((1983) "Di~ferent types o~ magnetically sensitive cells ln the rat pineal gland" Neuroscience Letters, 40, 23-26) have demonstrated the presence o~ di~erent types o~
magnetically sensitive cells in the pineal gland of the rat.
Furthermore, short-term exposure o~ experimental animals to magnetic ~ields o~ various intensities has been shown to alter temporarlly the secretion of melatonin while more chronic exposure may even induce ultrastructural morphological changes in the pineal gland ~Bardasano et al. (1985) "Ultrastructure oi~
the pineal cells o~ the homing pigeon Columba livia and magnetic :f~ields (first trials)." Journal Fuer Hirni~orschunq, 26, 471-475; Semm et al. (1980) "EfEects oE an earth-strength magnetic field on electrical activity o~ pineal cells." Nature, 288 607-608; Welker et al. (1983) "E~ects of an artif~icial magnetic ~ield on serotonin N-acetyltrans~erase activity and melatonin content o~ the rat pineal gland." Experimental Brain Research 50, 426-432; Wilson et al. (1981) "Neuroendocrine mediated e~ects o~ electromagnetic ~ield exposure: possible role o~ the pineal gland." Li~e Sciences, 45, 1319-1332).
The human pineal gland, likewise, is believed to be sensitive to changes in the environmental magnetic :Eields.
Howard et al. ((1965) "Psychiatric ward behaviour and geophysical parameters." Nature, 205, 1050-1052) made the seminal observations o~ a relationship between increased geomagnetic activity and the rate o~ admission of patients to psychiatric ~acilities. Rajaram and Mitra (1981) "Correlation between convulsive seizure and geomagnetic activity."
Neuroscience Le~ers, 24, 187-191 and Venkatraman ((1976) "Epilepsy and solar activity. An hypothesis." Neuroloqy (India), 24, 1-5) reported an association between changes in the geomagnetic :Eield due to magnetic storms and ~re~uency oi~
seizures in epileptic patients. Semm (1992) "Pineal ~unction in mammals and birds is altered by earth-strength magnetic ~ields.~' In Moore-Ede, Campbell, and Reiter (Eds.), Electromaqnetic Fields aIld Circadian Rhvthmicit~, (pp. 53-62), Birkhauser:

CA 022~7279 l998-l2-02 W 097/46244 PCTrUS96/091~0 Boston) observed in normal subjects placed in the center of a ~elmholtz coil system that inversion of the horizontal component o~ the ambient magnetic field for 30 minutes at midnight resulted in a significant (70~) depression of plasma melatonin - concentrations.
In addition to melatonin and light,human circadian rhythms may be synchronized by magnetic fields. Fo~r instance, there is increasing evidence that the earth's magnetic ~ield, which also undergoes diurnal and seasonal variations (Cremer-Bartels et al.
(1984) "Magnetic ~ield o~ the earth as additional zeitgeber for endogenous rhythms?" Naturwissenschaften, 71, 567-574), provides a "Zeitgeber" (time cue~ for the synchronization of endogenous circadian rhythms in mammals and humans (Wever) (1968) "Einfluss schwacher elektro-magnetischer felder auf die =circadiane Periodik des Menschen." Naturwissenscha~ten, 55, 29-32; Bliss and Heppner (1976) "~ircadian activity rhythms influenced by near zero magnetic field." Nature, 261, 411-412).
~or instance, Wever (1968) "Ein~luss schwacher elektro-magnetischer fe-lder auf die circadiane Periodik des Menschen "
20 ~~Naturwissenschaften, 55, 29-32) demonstrated that shielding of the ambient magnetic fields signlficantly desynchronized human circadian rhythms. Individuals placed in an underground bunker showed gradual desynchronization and lengthening of circadian rhythms, which could be resynchronized when an artificial 10-Hz, ~25-mV/cm magnetic ~ield was applied under similar conditions.
Thus, it is thought that the circadian rhythmici~y of the earth's magnetic field may have an additional "Zeitgeber"
~unction in the organization of biological rhythms (Cremer-Bartels et al. (1984) "Magnetic field of the earth as additional zeitgeber for endogenous rhythms?" Naturwissenscha~ten, 71, 567-574). The e~fect o~ magnetic ~ields on human circadian rhythms is supported also by the observation in epileptic patients in whom treatment with picotesla range pulsed magnetic fields was shown to alter the circadian periodicity of seizures = (Sandyk and Anninos (1992) "Magnetic fields alter the circadian periodicity of seizures." International Journal of Neuroscience, 63, 265-274).
The synchronizing ef~ects of magnetic fields on circadian rhythms is mediated largely via the pineal gland which serves as CA 022~7279 1998-12-02 W O 97/46244 PCT~US96/09440 a magnetoreceptor organ (Semm et al. (1980) "E~ects of an earth-strength magnetic field on electrical activity of pineal cells." Natuxe, 288, 607-608; Semm (1983) 'INeurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons." Com~arative Biochemistrv and Physioloqv, 76A, 683-689; Olcese et al. (1988) "Geomagnetic - field detection in rodents." Life Sciences, 42, 605-613; Welker et al.(1983) "Effects of an artificial magnetic ~ield on serotonin N-acetyltransferase activity and melatonin content o~
the rat pineal gland." ~xperimental Brain Researc~, 50, 426-432). Experimental data indicate that exposure o~ animals and humans to magnetic ~ields is associated with a temporary inhibition of melatonin secretion (Welker et al. (1983) 'IE~fects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal gland.l' Ex~erimental Brain Research, 50, 426-432; Wilson et al. (1986) "60-Hz electric-~ield e~ects on pineal melatonin rhythms: time course for onset and recovery." Bioelectromaqnetics, 7, 239-242). ~owever, with termination of magnetic ~ields exposure melatonin plasma levels usually return to their preexposure level and may even rise to higher levels over the following hours as shown by experiments performed by the inventor with subjects exposed nocturnally to picotesla range intensity magnetic fields (unpublished data). These changes in pineal melatonin ~unctions in response to magnetic fields exposure are thought to induce significant biological ef~ects through a process involving the synchronization of the biological rhythms including those of hormone release as well as neurotransmitter synthesis and release.
Since melatonin is a "master hormone~ involved in the programming of the aging process and as aging is associated with pineal failure and administration of melatonin or pineal extracts prolongs life span in experimental animals, I believe that activation of the pineal gland by periodic application oL
pulsed magnetic ~ields may be used to retard the aging process and therapeutically to improve pathological states which are linked to or result ~rom pineal ~ailure due to aging such as sleep disturbances, loss of memory ~unctions, disturbances o~
behavior, and depressive mood.
~5 CA 022~7279 l998-l2-02 W O 97/46244 PCT~US~6/0~1~0 This is supported by the observations that pulsed magnetic fields have been shown in normal elderly subjects to alleviate the deleterious effects of jet-lag (i.e., fatigue, malaise), improve sleep efficiency, restore dream recall, increase level of energy and improve mood, promote relaxation, improve level of concentration, enhance sexual functions, improve bowel functions with resolution of constipation, normalize previously increased plasma levels of cholesterol, normalize previously elevated blood glucose levels, normalize previously elevated blood -pressure, diminish the activity o~ psoriatic skin lesions, and enhance immune functions (i.e., prevent exacerbation of herpes infection; diminish ~requency of influenza infections). The most dramatic ef~ects of pulsed magnetic fields in normal adult and elderly subjects included improvement in sleep, mood, _behavior (agitation and impulsive aggressive behavior), and short-term memory functions.
In patients with Parkinson's disease and Alzheimer's disease, which are both diseases o~ aging (Knoll (1990) "Nigrostriatal dopaminergic activity, deprenyl treatment and longevity.~ In Strei~ler et al. "Advances in neuroloqy:
Parkinson's disease: anatomv, ~atholoqv and therapie." New York: Raven Press; Langston (1988) "Aging, neurotoxins, and neurodegenerative disease."In R.D. Terry (Ed.), Aqinq and the brain (pp. 149-164). New York : Raven Press), application of AC
pulsed magnetic fields once to twice per week has been shown to improve sleep efficiency, abolish nocturnal awakenings, restore dream recall, improve short-term memory functions, improve concentration and level of energy, restore alpha brain wave activity on the EEG record (which is diminished with aging), enhance sexual functions, improve gastrointestinal ~unctions (i.e., constipation), diminish the extent of psoriatic skin lesions, normalize previously recorded high blood pressure, and increase plasma growth hormone, luteinizing hormone (LH) and testosterone levels (Sandyk (1992) "Weak magnetic ~ields in the ~treatment o~ Parkinson's disease with the "on-off" phenomenon.
International Journal o~ Neuroscience, 66, 97-106; Sandyk and Derpapas (1993) "Further observations on the unique e~ficacy of picotesla magnetic fields in Parkinson's disease."
International Journal of Neuroscience, 69, 167-183; Sandyk CA 022~7279 1998-12-02 W O 97/46244 PCTrUS96/09440 (1995) "Improvement in short-term visual memory by weak elec~romagnetic fields in Parkinson's disease." International Journal of Neuroscience, 81, 67-82; Sandyk and Derpapas (1993) "The effects of external picotesla range magnetic fields on the - 5 EEG in Parkinson's disease." International Journal of Neuroscience, 70, 85-96; Sandyk (1994) "A drug naive - Parkinsonian patient successfully treated with electromagnetic fields." International Journal Q:f~ Neuroscience, 79, 99-110;
Sandyk (1994) "Alzheimer's disease: Improvement of visual memory and visuoconstructive performance by treatment with picotesla range magnetic fields." International Journal of Neuroscience, 76, 185-225; Sandyk (1994) "The effects of external picotesla range magnetic fields on the EEG in Parkinson's disease: a follow up study." International Journal of Neurosçiencç, 76, 227-229), features which are consistent with the notion that pulsed magnetic fields improve age-related disturbances linked to pineal failure. These therapeutic effects appeared to be significantly augmented when pulsed magnetic fields were administered in con~unction with my pharmacological-nutritional composition described in my parent application Serial No. 181,677 and my continuation-in-part thereof ~iled concurrently herewith (RS1). The use of my composition is important because the therapeutic efficacy of externally applied magnetic fields, as described in the prior art, is limited by several factors:
(a) The pineal gland tends to undergo an increased rate of calcification with age and particularly in association with various systemic disorders (Trentini et al.(1987) I'Pineal calcification in different physiopathological conditions in humans.~ In Trentini et al. Fundamentals an~ clinics in ~ineal research(pp. 291-304) New York: Raven Press; Welsh (1985) "Pineal calcification: structural and functional aspects.
Pineal Research Reviews,3,41-68). It is believed that calclfication of the pineal gland may interfere with its magnetosensitivity. The calcified material which consists of - hydroxyapatite and calcium carbonate apatite crystals as well as high concentrations of several trace elements such as iron, magnesium, zinc, copper, and manganese (Humbert and Pevet (1991) "Calcium content and concretions of pineal glands of young and CA 022~7279 1998-12-02 W O 97/46244 PCTnUS96/09440 old rats." Cell and Tissue Research, 263, 593-596) may alter the physlcochemical properties of the gland and inter~ere with the ability o~ the pineal gland to release melatonin in response to magnetic fields;
(b) Reduction in the activity of the pineal gland in aging may be related to various factors including, among others,increased accumulation of aging pigment in the pinealocytes, decrease in pineal receptor sensitivity and/or density, decline in the availability of nutritional co-factors ~or serotonin and melatonin synthesis, decline in the capacity of pineal cells to synthesize serotonin ~rom tryptophan, and decrease sympathetic nervous system activity which provides a stimulus ~or melatonin syntheses (Tang et al.(1985) "Aging and diurnal rhythms of pineal serotonin, 5-hydroxyindoleacetic acid, ~norepinephrine, dopamine and serum melatonin in the male rat.
Neuroendocrinoloqy, 40, 160-164; Dax and Sugen (1988) "Age-associated changes in pineal adrenergic receptors and melatonin synthesizing enzymes in the Whistar rat." Journal of Neurochemistry, 50, 468-472 Wildi and Frauchiger :~(1965)l'Modi~ications histologiques de l'epiphyse humaine pendant l'enfance, l'age adulte et le vieillissement." Proqress in Brain Research, 10, 218-233); and (c) Aging is associated with diminished serotonin receptor density and cerebral concentrations of serotonin, a precursor of melatonin synthesis. In addition, levels of the amino-acid tryptophan, a precursor of serotonin synthesis, are reduced in the blood of a proportion of elderly people who ~ail to absorb tryptophan (Ingram et al. (1982) "Circadian rhythmicity and sleep: effects of aging in laboratory animals.~' Neurobioloqy of Aqinq, 3, 287-297; Gottfries (1990) "Disturbance of the 5-hydroxytryptamine metabolism in brain~ from patients with Alzheimer's dementia.~' Journal of Neural Transmission, 30 (suppl)(33-43); Goldman-Rakic and Brown (1981) "Regional changes of monoamines in cerebral cortex and subcortical structures o~
aging rhesus monkeys." Neuroscience, 6, 177-187; Gross-Isseroff et al. (1990) "Autoradiographic analysis o~ age-dependent changes in serotonin 5-HT~ receptors of the human brain postmortem." Brain Research, 519, 223-227;Chen Shih and Young (1978)"The alteration o~ serotonin binding sites in aged human CA 022~7279 1998-12-02 W 097146244 PCT~US96/09440 brain.~ Life Scie~ces, 23, 1441-144~3; L~hm~nn, (1979) 'IHow to investigate malabsorption and the value o~ repeated tryptophan loads. In Schou, M. and Stromgren, ~. (Eds.), Oriqin, ~revention and trea~ment o~ af~ective disorders (pp. 125-1~8) - 5 London:Academic Press). Brain serotonin de~iciency contributes to the development o~ sleep, mood and memory disturbances in the -- elderly. Moreover, many o~ the biological e~ects o~ melatonin are mediated via the serotonin system (Smith and Kappers (1975) "E~ect of pinealectomy, gonadectomy, pCPA and pineal extracts on the rat parvocellular neurosecretory hypothalamic system: a fluorescence histochemical investigation.~ Brain Research, 86, 353-371; Anton-Tay et al. (1968) "Brain serotonin concentration:
elevation ~ollowing intraperitoneal administration o~
melatonin." Science, 162, 277-278; Anton-Tay (1974) "Melatonin:e~ect on brain ~unction." Advances in BioGhemiçal Psycho~harmacoloqv, ll, 315-324; Olcese (1985) "Enhancement o~
melatonin's antigonadal action by daily injections o~ the serotonin uptake inhibitor fluoxetine in male hamsters."
~ournal o~ Neural Transmission, 64, 151-161; Gaffori and Van Ree (1985) "Serotonin and antidepressant drugs antagonize melatonin-induced behavioral change a~ter in~ection into the nucleus accumbens o~ rats." Neuro~harmacoloqy, 24, 237-24~).

SUMMARY OF THE INVENTION
The present invention relates to the use o~ a pulsed magnetic ~ield in combination with a pharmacological-nutritional composition to retard the aging process and improve age-related disease conditions. More particularly, the present invention relates to the enhancement o~ the activity o~ the pineal gland and speci~ically the production o~ its principal hormone melatonin which is considered a "master hormone'1 in the regulation o~ biological~rhythms. The purpose o~ the composition is to sensitize the pineal gland to the e~ects of ~ magnetic ~ields.
My invention includes a method oL retarding the aging ~ 35 process and improving the symptoms o~ age-related disease conditions in humans which comprises administering to a human in need thereo~ an e~ective amount o~ a composition which increases serotonin transmission to such human rollowed by the CA 022~7279 1998-12-02 W O 97t46244 PCTAUS96/09440 application to the brain o~ the human of an effective amount of an AC pulsed magnetic field of proper inten5ity, frequency and waveform. This composition is preferably supplemented by a dietary composition rich in the amino-acid tryptophan.
Optionally, my invention includes administering an effective amount of an agent which promotes growth hormone release prior to the application of the AC pulsed magnetic field. My invention also includes the above referred to composition for increasing serotonin transmission to humans, which composition may optionally include an effective amount of an agent which promotes growth hormone release.

DETAILED DESCRIPTIO~
Based on studies I have conducted in experimental animals, the data provided in the literature presented above and my medical experience treating elderly people, it appears that aging is related to a decline in pineal melatonin functions and serotonin neurotransmission and that several pathological conditions associated with aging such as &leep disorders, mood and conduct disturbances such as depression and aggressive behavior, decline in memory functions, rise in blood pressure, impairment o~ glucose tolerance and the like in elderly, are related to pineal failure which is part of the aging process.
By periodically stimulating the pineal gland and increasing melatonin production using pulsed magnetic fields in the picotesla range intensity, ~ believe, based on my experience with elderly people, particularly patients with Parkinson's disease, Alzheimer's disease and multiple sclerosis, that one can retard the aging process and can improve conditions related to pineal failure such as sleep and mood disturbances as well as memory functions. To retard the aging process which is due to diminished pineal melatonin functions and reduced serotonin neurotransmission, application o~ an appropriate magnetic field once per week which should preferably consist of two successive AC pulses each o~ 10 to 15 minutes provides a significant improvement.
More enhanced results, however, are achieved according to my invention by the use o~ my novel pharmacological-nutritional composition which increases serotonin transmission together with CA 022~7279 1998-12-02 W O 97/46244 PCTrUS96/09440 the A~ pulsed magnetic field as described in more detaii herein.
My co~position comprises an effectlve amount of a serotonin precursor, an effective amount of a stimulant to facilitate the transport of a serotonin precursor into the brain, an effective amount of an agent to increase plasma tryptophan concentrations, an ef~ective amount of a stimulant of serotonin synthesis, an - effective amount of a stimulant of serotonin release and an effective amount of a stimulant of serotonin receptors, and is preferably supplemented by an effective amount of a dietary composition rich in the amino-acid tryptophan.
Plasma melatonin concentrations decline progressively with age with a steeper decline occurring in men at about the age of 50 years while in women a more dramatic decline occurs perimenopausally starting at the age of 45 years (Nair et al.
(1986) "Plasma melatonin- an index of brain aging in humans?'l Bioloqical Psychiatry, 21, 141-150; Sack et al. (1986) "Human melatonin production decreases with age." Journal of Pineal Research, 3, 379-388). Consequently, it is advocated that the procedure to retard the aging process in men should begin at about the age of 50 while in women the procedure should begin earlier a~ound the age of ~5 years coincident with the fall of pineal melatonin production perimenopausally.
It is preferred for maximum effect that the AC pulsed magnetic field is applied to the brain of the human in two applications separated by an interval of time. Preferably the duration of the first AC pulsed magnetic ~ield is 10 to 15 minutes. The duration of the second AC pulse is also preferably 10 to 15 minutes. It is preferred that the time delay between the application of the first AC pulse and the application of the second AC pulse is 15 to 30 minutes.
According to one embodiment of my invention, the composition comprises one or more of the following: an effective amount of a serotonin precursor, an effective amount ~ of a stimulant to facilitate the transport of a serotonin precursor into the brain,an effective amount of an agent to increase plasma tryptophan concentrations, an effective amount of a stimulant of serotonin synthesis, an effective amount of a stimulant of serotonin release and an effective amount of a stimulant of serotonin receptors. The effective amount of a CA 022~7279 1998-12-02 W 097/46244 PCT~US96/09440 dietary composition rich in the amino-acid tryptophan is a preferred supplement to my composition and comprises including in the diet of the person to be treated various foods which are rich in tryptophan. My composition may optionally include an eEf~ective amount of an agent which promotes growth hormone release.
According to a further embodiment Q:E the present invention, the serotonin precursor is L-tryptophan (L-TP)or L-5-hydroxytryptophan (L-5-HTP).Since serotonin present in the blood is excluded by the blood brain barrier from entry into the brain, the administration of precursors such as L-TP or L-5-HTP
is used to increase brain concentrations of serotonin (Wurtman and Fernstrom ~1975) "Control of brain monoamine synthesis by diet and plasma amino-acids." The American Journal of C inical 15 = Nutrition, 28, 638-647).
According to a further embodiment of the present invention, the stimulant to facilitate the transport of a serotonin precursor into the brain is one which facilitates the transport o~ tryptophan into the brain. It is preEerably vitamin B3, chromium (preferably chromium picolinate) or a mixture thereoi~.
Chromium is an essential co-~actor to insulin production and action (Rabinowitz et al. (1983) "Effects of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men.~ Diabetes Care, 6, 319-327). Insulin, in turn, 25 --facilitates the entry of tryptophan into the brain by inhibiting the uptake o~ the branched chain amino-acids leucine, isoleucine, and valine which compete with tryptophan for entry into the brain (Wurtman and Fernstrom (1976) "Control of brain neurotransmitter synthesis by precursor availability and nutritional state." Biochemical Pharmacoloay, 25, 1691-1696).
According to a ~urther embodiment of the present invention the agent to increase plasma tryptophan concentrations is a salicylate. L-tryptophan is usually transported in the blood in a bound or complexed form with the protein albumin. It has been 35 _ shown that various salicylates displace tryptophan from its protein binding site with albumin in blood plasma thereby raising the free or unbound tryptophan concentration in the blood. The bond-breaking effect exerted by salicylates on the binding of tryptophan to albumin causes a greater availability W O 97/46~44 PCT~US96/09440 of free tryptophan for diffusion into the brain (~agliamonte et al. (1973) "Increase o~ brain tryptophan and stimulation of serotonin synthesis by salicylate." Journal o~ Neurochemistry, 20, 909-912). While aspirin is the salicylate preferred, any other pharmaceutically acceptable salicylate such as sodium salicylate would serve as well.
According to a ~urther embodiment of the present invention, the stimulant of serotonin synthesis is preferably vitamin Bl,vitamin B2, vitamin B3, vitamin B6, biotin, S-adenosylmethionine, folic acid, ascorbic acid, magnesium,coenzyme Qlo~ piracetam or mixtures of two or more thereof.
According to a further embodiment of the present invention, the stimulant o~ serotonin release is preferably ~enfluramine (Fuller (1986) "Pharmacologic modification of serotonergic functions: drugs for the study and treatment of psychiatric and other disorders." Journal Qf (~linical Psychiatrv, 47 (6uppl 4), 4-8).
According to a further embodiment of the present invention, the stimulant of serotonin receptors i8 preferably ergoloid mesylates (Hydergine~). Hydergine~ has been shown to improve mental alertness and memory functions in normal subjects and those with organic mental deterioration an ef~ect which is related partly to its stimulating properties of serotonin receptors in the brainstem reticular formation (Depoortere et al. (1975) "Neuropharmacological studies on Hydergine."
Trianqle, 14, 73-79).
According to a ~urther embodiment of the present invention, the dietary composition should include foods which are rich in the amino-acid tryptophan such as turkey (4 ounces twice a week), milk (8 ounces per day of whole, low-~at, or skim), bananas (1 per day), nuts (1-2 ounces per day) and dry-roasted sunflower seeds (3-4 ounces per day).
I prefer the use of L-arginine or L-ornlthine as agents to promote growth hormone release. Preferably, these agents would be administered the night before and most preferably one to two hour prior to the application of the AC pulsed magnetic field.
It is preferred that the intensity of the magnetic field be in the range of 7.5 - 75 picotesla. The magnetic field is a time varying field with a wave form which is sinusoidal, CA 022~7279 1998-12-02 triangular, trapezoidal, square or a composite thereof.
It is pre~erred that the patient's eyes be shielded during the application o:E the AC pulsed magnetic fields. The fields are preferably applied to the subject's head using a helmet-like ~transducer array. The helmet-like transducer array preferably comprises an array of coils which are flat or helical.
It is pref~erred that the AC magnetic field frequency is SHz-8Hz.
For the retardation of the aging process resulting from diminished pineal melatonin functions and reduced serotonin neurotransmission, it is preferred that the AC pulsed magnetic field is applied to the human head once per week.
To improve disorders o~ sleep, mood, behavior, and memory functions, it is preferred that the AC pulsed magnetic field is ~applied to the human head once or twice per week.
For the treatment of hypertension, it is preferred that the AC pulsed magnetic field is applied once or twice per week to the human head.
For the treatment of hypercholesterolemia, it is preferred that the AC pulsed magnetic field is applied to the human head once or twice per week.
For the treatment of glucose intolerance and overt diabetes mellitus, it is preferred that the AC pulsed magnetic field is applied to the human head once or twice per week.
For the treatment o~ loss or diminished libido, it is preferred that the AC pulsed magnetic field is applied to the human head once or twice per week.
For the treatment of bowel constipation, it is pre~erred that the AC pulsed magnetic field is applied to the human head ~once or twice per week.
For the treatment of psoriasis vulgaris including psoriatic arthropathy, it is preferred that the AC pulsed magnetic field is applied to the human head once or twice per week.
For the treatment of osteoarthritis, it is preferred that the AC pulsed magnetic field is applied once or twice per week.
For the treatment of osteoporosis, it is preferred that the AC pulsed magnetic field is applied once or twice per week.
For the treatment of prostate hypertrophy, it is preferred that the AC pulsed magnetic field is applied once o~ twice per CA 022~7279 1998-12-02 W O 97146244 PCT~US96/09440 week.
When an e~fective amount of an agent which promotes growth hormone release is administered, it is administered prior to appllcation of the AC pulsed magnetic field. Preferred agents are L-arginine or L-ornithine. The agent is preferably administered the ni~ht before preferably one to two hours prior ~ to the application of the AC pulsed magnetic field.
It is also preferred that the composition be a~ministe~ed four to eight weeks before the application o~ the first AC
pulsed magnetic field.
It is pre~erred that the AC pulsed magnetic field is a time-varying field with a waveform which is sinusoidal, triangular, trapezoidal, square or a composite thereof. It is also preferable that the subject's eyes are shielded during the application of each AC pulsed magnetic field. The fields may be applied to the subject's head usin~ a helmet-like transducer array as illustrated in the drawings. The helmet-like transducer array pre~erably comprises an array of coils which are flat, i.e. two dimensional or helical, i.e. three dimensional.
I find particularly good results achieved according to my invention when the AC pulsed magnetic field is applied at night, preferably after 8:00 p.m. I believe this is because plasma melatonin levels begin to rise after about 8:00 p.m. reaching a peak between midnight and 2:00 a.m. (Waldhauser et al. (1984) "Melatonin in human body fluids: clinical significance~ In Reiter, R.J.(Ed.), The ~ineal qland (pp. 345 370) New York:
Raven Press). Since pulsed magnetic fields alter circadian melatonin secretion, the optimal response to the magnetic field would be expected to occur at night, the time the pineal gland is maximally active.
My composition which is useful for retarding the aging process and improving age-related disease conditions in humans - when administered to a human followed by the application to the brain of the human of an effective amount of an AC pulsed - magnetic ~ield of proper intensity, frequency and waveform comprises an effective amount of a composition which increases serotonin transmission to the human and may optionally include an effective amount of an agent which promotes growth hormone CA 022~7279 1998-12-02 W O 97/46244 PCT~US96/09440 release.
According to one embodiment, my compOSitiQn comprises one or more of the following: an effective amount of a serotonin precursor,an effective amount of a stimulant to facilitate the transport of a serotonin precursor into the brain, an e~fective amount of an agent to increase plasma tryptophan concentrations, an effective amount of a stimulant of serotonin synthesis, an effective amount of a stimulant of serotonin release and an effective amount of a stimulant of serotonin receptors.
Pre~erably, the serotonin precursor is L-tryptophan or L-5-hydroxytryptophan.
Preferably, the stimulant to facilitate the transport of a serotonin precursor into the brain is vitamin B3, chromium or a mixture thereo~.
Preferably, the agent to increase plasma tryptophan concentration is a salicylate.
Preferably, the stimulant of serotonin synthesis is vitamin Bl, vitamin B2, vitamin B3, vitamin B6, biotin, S-adenosylmethionine, folic acid, ascorbic acid, magnesium, coenzyme Q,0, piracetam or mixtures of two or more thereof.
Preferably, the stimulant of serotonin release is fenfluramine.
Preferably, the stimulant of serotonin receptors is an ergoloid mesylate.

~ DETAILED ~E~CRIPTION
According to my present invention, the treatment procedure which I have found to be most effective is when the patient is given my composition supplemented by the dietary composition, beginning 4-8 weeks,preferably 6-8 weeks, prior to the application of the first AC pulsed magnetic ~ield which pulsed magnetic field is preferably applied in two treatments.
In the initial treatment phase, the patient is given the composition which comprises the stimulants to facilitate the transport of the serotonin precursor into the brain, an agent which increases plasma tryptophan concentrations, the composition comprising the stimulants of serotonin synthesis, the stimulant of serotonin receptors, and the dietary composition rich in the amino-acid tryptophan.

CA 022~7279 1998-12-02 W O 97/46244 PCT~US96/09440 On the night prior to application of the magnetic fields the subject is given a serotonin precursor to augment thc synthesis of serotonin and melatonin and an agent to promote the release of growth hormone. For the purpose of increasing serotonin synthesis the inventor recommends a preparation containing the essential amino-acid tryptophan to be taken at bedtime (L-tryptophan 500 mg-3g, orally)or a preparation containing L-5-hydroxytryptophan (L-5-HTP) (25-50 mg, orally) taken at bedtime.
L-tryptophan is the preferred serotonin precursor due to its low side ef~ect profile and low risk of toxicity (Young (1986) "The clinical psychopharmacology of tryptophan.'l ~n Wurtman, R.~. and Wurtman, J.J. (Eds.), Nutrition and the brain (pp. 49-88), vol.
7. New York: Raven Press). For the purpose of promoting growth hormone release the inventor uses L-arginine or L-ornithine (500 mg-1,000 mg) to be taken at bedtime.
One to two hours prior to application of the ~irst magnetic treatment the patient is given a stimulant of serotonin release.
For this purpose the inventor uses the drug fenfluramine hydrochloride(Pondimin~; 10-20 mg, orally). In addition, the subject is given again an agent to promote the release of growth hormone such as L-arginine or L-ornithine (500 mg- 1,000 mg).
The first magnetic pulse is given for a period of 10-15 minutes using an AC frequency of 5Hz-7Hz preferably an AC
frequency o~ 5~z. A~ter a break of 1~-30 minutes, a second magnetic pulse is applied for a period of 10-15 minutes using a higher AC frequency of 7Hz-8Hz. It is my experience that the application of the second AC pulse is extremely beneficial for the treatment of neurological and mental disorders and it is therefore preferred to use a second pulse also in the case where the treatment procedure is applied ~or retardation of the aging process and for the treatment of age-related disease conditions.

Best results are obtained when the AC pulsed magnetic field is administered at night, preferably after 8:00 p.m.
The AC pulsed magnetic fields are preferably applied via an r 35 external magnetic coil assembly, or transducer. The transducer is constructed of flexible substrate which allows the ~ransducer to be bent and positioned on the head of a patient in the ~orm of a helmet. The transducer is constructed of a set of coils CA 022~7279 1998-12-02 W O 97/46244 PCTrUS96/09440 positioned side-by-side in a two-dimensional array. In the ~~
preferred embodiment of the invention as shown in Figs. 1-4, the transducer is constructed of 16 coils arranged in a matrix of four rows by four columns, and the area of each coil is preferably 3.14 cm~. When these coils are carrying an electric current, they produce magnetic fields with lines of force parallel to the axes of the respective coils. The locations of the coils are such that the resultant magnetic fields are uniform. The produced magnetic fields are alternating and their intensity can be less than approximately 60 microtesla.For therapeutic purposes herein, it is preferred to employ magnetic fields strength in the range of 7.5 to 75 picotesla with an AC
frequency in the range of 5Hz-8Hz. In the experience of the inventor higher amplitudes of the exposed magnetic fields above 75 picotesla and up to 1,000 picotesla did not provide an additional benefit for patients with neurological and mental disorders and it is believed that amplitudes above 75 picotesla will not provide an additional benefit also ~or subjects undergoing this treatment procedure for retardation of the aging process and for the treatment of age-related disease conditions.

To maintain the e~ects of the treatment, ~'maintenance therapy" is implemented during which time the procedure is repeated once to twice per week. During the period of ~maintenance therapy" the subject continues to take the ~ pharmacological-nutritional composition except for the compositions which are administered the night be~ore (i.e., L-tryptophan and L-arginine) and just prior to the application of magnetic fields (i.e., fenfluramine and L-arginine). It is recommended that during the period of "maintenance therapy" the su~ject should spend at least one hour daily outdoors to maximize sunlight exposure to enhance serotonin functions and synchronize melatonin circadian rhythms (Wurtman and Wurtman (1989)"Carbohydrates and depression." Scienti~ic American, January, 68-75). During the "maintenance therapy" the subject ~ may continue to receive medications for his/her particular disease. For instance, in the case of hypercholesterolemia the subject may continue to use his cholesterol lowering drugs while receiving the composition and the magnetic field therapy. In CA 022~7279 1998-12-02 W O 97/46244 PCT~US~6/09~0 some instances, such as in the case where this treatment procedure produced normalization o~ blood pressure antihypertensive drugs may be reduced or discontinued based on prior consultation with a physician.
~ 5 With reference to Figs. 1-4, there is shown a transducer 30 which is employed in the practice o~ the invention to apply - magnetic fields upon the brain of a patient. The transducer 30 comprises a set o~ coils 32, and is placed on the head of a patient 34. Upon energization of the coils 32 with electric current, the coils 32 produce magnetic fields which are directed into the brain, and particularly into the area of the pineal gland, of the patient 34. The patient 34 holds a cup 36 to demonstrate the inventive feature of ingesting various pharmacological and nutritional components of the composition prior to application of the magnetic ~ields. Electric current is applied to the coils 32 by a driver 38, the driver 38 including a voltage generator 40 and an output resistor 42 by which the generator 40 is coupled to the coils 32. Also included in the driver 38 is a timer 44 for activating the generator 40 to provide a sequence o~ pulses of output voltage which are applied to the resistor 42. The resistor 42 has a resistance of approximately 0.5 megohm in the preferred embodiment of the invention, and the coils 32 are connected in series to provide a total resistance of approximately one ohm between the terminals 46 and 48 of the transducer 30. A volt meter 50 is connected between output terminals 52 and 54 of the generator 40 to provide an indication of the magnitude of the output voltage of the generator 40.
The coils 32 and the resistor 42 constitute a series circuit between the terminals 52 and ~4 of the generator 40.
~ince the internal impedance o~ the driver 38, as provided by the resistor 42, is several orders of magnitude greater than that of the transducer 30, the voltage generator 40 in combination with the resistor 42 acts as a current source to provide a current to the transducer 30 proportional to the ~ voltage outputted by the generator 40. In view of the current-source function of the driver 38, the meter 50 also provides an indication of the magnitude of the current flow in the coils 32 of the transducer 30. The intensity of the magnetic fields CA 022~7279 l998-l2-02 W 097/46244 PCTrUS96/09440 produced by the current in the coils 32 is proportional to the magnitude o~ the current and, accordingly, the reading of the meter 50 serves also as an indication of the intensity of the magnetic fields applied by the transducer 30 to the patient 34.
~ The generator 40 is of well-known construction and provides a voltage with a periodic waveform. The generator 40 includes controls for selecting the AC frequency of the voltage, the waveform of the voltage, and the amplitude of the voltage. By way of example, the voltage may be a steady DC voltage, or may lo _ be varied in ~requency over a range o~ o.l Hz to lo,ooo Hz. The waveform may be sinusoidal, triangular, trapezoidal, square or a combination of more than one of these waveforms such as the sum of square plus sinusoid as shown in Fig. 5,~by way of example.

The transducer 30 comprises a substrate 56 which supports 15 ~ the coils 32 in their respective positions in a two-dimensional array 58. By way of example in the practice of the invention, in one embodiment o:E transducer 30, the array 58 has a total of 16 of the coils 32 arranged in four rows, each o~ the rows having four of the coils 32, as shown in Fig. 5. Each coil 32 has, typically four or five turns, and has a diameter of approximately two centimeters, with an area of approximately three square centimeters. In a second embodiment o~ the transducer 30A, there is array 58A of the coils 32A having a total o~ 24 coils arranged ln four rows each having six coils 32A, as shown in Fig. 5A. A cover layer 60 is disposed on top of the substrate 56 and the coils 32. The substrate 56 and the cover layer 60 are formed of a flexible electrically-insulating plastic material which permits flexing of the transducer 30 to conform to the curvature o~ the subject's head. The coils 32 are formed of a flexible electrically-conductive material such as copper which permits the ~oregoing flexing of the transducer 30.
In the case o~ energization of the coils 32 with a sinusoidal current, the generator 40 is operated to output a 35 ~- peak voltage, typically, of four volts relative to ground. This voltage provides a peak current of eight microamperes which is more than enough current to provide a peak magnetic field intensity of 60 picotesla. The output voltage of the generator CA 022~7279 1998-12-02 W 097146244 PCTrUS96/09440 40 is adjusted to provide a desired intensity to the resultant alternating magnetic ~ields. If desired, the resistance of the resistor 42 may be reduced to provide still larger values of current for greater intensity of magnetic fields. Upon energization of the coils 32 with electric current, the resultant magnetic fields have lines of force parallel to the axes 62 of the respective coils 32. The locations of the coils 32 provide that the resultant magnetic fields are uniform. The driver 38 and the transducer 30 or 3OA are capable of providing alternating magnetic fields in a frequency range of 0.1 Hz to 10 K~z, and intensity up to 60 microtesla. Typically, in the practice of the invention, the intensity of the alternating magnetic fields is in the range of 7.5 to 75 picotesla, and the frequency is in the range of 5Hz-8Hz.
Fig. 5 shows a sequence o~ two pulses o~ magnetic fields wherein the direction and amplitude of the magnetic fields alternate in sinusoidal fashion. The sinusoidal form of the alternating magnetic fields is employed in the preferred embodiment of the invention. However, it i~ understood that some other waveform such as the aforementioned triangular or trapezoidal or square waveform may be used if desired. For example, in the case of the trapezoidal waveform, the rise and the ~all times of the wave~orm together may occupy ~rom 20~ to 40~ of each period of the waveform. Within each pulse, the AC
frequency is held constant in the preferred embodiment of the invention. However, if desired, the AC frequency may be altered, as by a ~requency ramp wherein the frequency increases during the pulse, such that the end frequency is greater than the initial frequency by 10~ - 30~.
Fig. 5 also shows the duration, A, of the first AC pulse, and the duration, B, of a rest interval or break between the AC
pulses, and the duration, C, of the second AC pulse.
The transmission of signals in the nervous system is such that within the neuron (nerve cell) transmission is accomplished by propagation o~ an electrical signal while between neurons signal propagation is accomplished via the mediation of a neurotransmitter. A neurotransmitter is a molecule, such as a molecule of serotonin, dopamine, acetylcholine, and histamine, or other neurotransmitter by way o~ example. During the CA 022~7279 1998-12-02 W O 97/46244 PCT~US96/09440 propagation of an electrical signal the neurotransmitter is released from the transmitter neuron ("presynaptic neuron~') into the synaptic cleft from which it diffuses across the synaptic cleft to reach speci~ic receptors in the receiving neuron (~postsynaptic neuron"). Activation of these receptors at the postsynaptic neuron causes either excitation or inhibition of the postsynaptic neuron. The transmitter neuron and the receiving receptor at the postsynaptic neuron are specific to only one type of neurotransmitter so that a plurality of differ-ent forms o~ the neuron transmitter/receptor allow for transmis-sion of different forms of signals by respective ones of the neurotransmitter.
Neurotransmitters are produced in numerous locations throughout the nervous system. For instance, serotonin is _produced in neurons that originate in the median raphe of the brainstem and which project to numerous brain areas including the spinal cord, cerebellum, hypothalamus, limbic system, and cortex. In the central nervous system serotonin a~ects mood, sleep and arousal, satiety, emesis, cardiovascular regulation, temperature control, pain, sedation, anxiety and depression. In the peripheral nervous system, the primary actions o~ serotonin are on the gastrointestinal tract and cardiovascular system, but it also a~fects the respiratory tract and genito-urinary system.

Claims (47)

    What is claimed is:
  1. Claim 1. A method of retarding the aging process and improving age-related disease conditions in humans which comprises administering to a human in need thereof an effective amount of a composition which increases serotonin transmission to said human followed by the application to the brain of the human of an effective amount of an AC pulsed magnetic field of proper intensity, frequency and waveform.
  2. Claim 2. A method according to Claim 1 wherein the AC
    pulsed magnetic field is applied to the brain of the human in two applications, separated by an interval of time.
  3. Claim 3. A method according to Claim 1 wherein the composition comprises one or more of the following: an effective amount of a serotonin precursor, an effective amount of a stimulant to facilitate the transport of a serotonin precursor into the brain, an effective amount of a stimulant to increase plasma tryptophan concentrations, an effective amount of a stimulant of serotonin synthesis, an effective amount of a stimulant of serotonin release and an effective amount of a stimulant of serotonin receptors, and is supplemented by an effective amount of a dietary composition rich in the amino-acid tryptophan.
  4. Claim 4. A method according to Claim 2 wherein the duration of the first AC pulsed magnetic field is 10-15 minutes.
  5. Claim 5. A method according to Claim 2 wherein the time delay between the application of the first AC pulsed magnetic field and the second AC pulsed magnetic field is 15-30 minutes.
  6. Claim 6. A method according to Claim 2 wherein the duration of the second AC pulsed magnetic field is 10-15 minutes.
  7. Claim 7. A method according to Claim 1 wherein the AC
    frequency is 5-8Hz.
  8. Claim 8. A method according to Claim 1 wherein the AC
    pulsed magnetic field is applied once per week.
  9. Claim 9. A method according to Claim 7 to improve age-related disorders of sleep, mood, behavior, and memory functions wherein the AC pulsed magnetic field is applied once or twice per week.
  10. Claim 10. A method according to Claim 7 for the treatment of hypertension wherein the AC pulsed magnetic field is applied once or twice per week.
  11. Claim 11. A method according to Claim 7 for the treatment of hypercholesterolemia wherein the AC pulsed magnetic field is applied once or twice per week.
  12. Claim 12. A method according to Claim 7 for the treatment of glucose intolerance and overt diabetes mellitus wherein the AC pulsed magnetic field is applied once or twice per week.
  13. Claim 13. A method according to Claim 7 for the treatment of loss or diminished libido wherein the AC pulsed magnetic field is applied once or twice per week.
  14. Claim 14. A method according to Claim 7 for the treatment of bowel constipation wherein the AC pulsed magnetic field is applied once or twice per week.
  15. Claim 15. A method according to Claim 7 for the treatment of psoriasis vulgaris including psoriatic arthropathy wherein the AC pulsed magnetic field is applied once or twice per week.
  16. Claim 16. A method according to Claim 7 for the treatment of osteoarthritis wherein the AC pulsed magnetic field is applied once or twice per week.
  17. Claim 17. A method according to Claim 7 for the treatment of osteoporosis wherein the AC pulsed magnetic field is applied once to twice per week.
  18. Claim 18. A method according to Claim 7 for the treatment of prostate hypertrophy wherein the AC pulsed magnetic field is applied once to twice per week.
  19. Claim 19. A method according to Claim 1 which additionally comprises administering an effective amount of an agent which stimulates growth hormone release prior to application of the first AC pulsed magnetic field.
  20. Claim 20. A method according to Claim 19 wherein the agent is L-arginine or L-ornithine.
  21. Claim 21. A method according to Claim 19 wherein the agent is administered one to two hours prior to the application of the AC pulsed magnetic field.
  22. Claim 22. A method according to Claim 1 wherein the composition is administered four to eight weeks before the application of the first AC pulsed magnetic field.
  23. Claim 23. A method according to Claim 1 wherein the AC

    pulsed magnetic field is a time varying field with a waveform which is sinusoidal, triangular, trapezoidal, square or a composite thereof.
  24. Claim 24. A method according to Claim 1 wherein the patient's eyes are shielded during the application of each AC
    pulsed magnetic field.
  25. Claim 25. A method according to Claim 1 wherein the magnetic fields are applied to the head using a helmet-like transducer array.
  26. Claim 26. A method according to Claim 25 wherein the helmet-like transducer array comprises an array of coils which are flat or helical.
  27. Claim 27. A method according to Claim 1 wherein the AC
    pulsed magnetic field is applied at night.
  28. Claim 28. A method according to Claim 23 wherein the application is after 8:00 p.m.
  29. Claim 29. A method according to Claim 1 which includes the serotonin precursor which is L-tryptophan or L-5-hydroxytryptophan.
  30. Claim 30. A method according to Claim 1 which includes the stimulant to facilitate the transport of a serotonin precursor into the brain which is vitamin B3, chromium or a mixture thereof.
  31. Claim 31. A method according to Claim 1 which includes the stimulant to increase plasma tryptophan concentrations which is a salicylate.
  32. Claim 32. A method according to Claim 1 which includes the stimulant of serotonin synthesis which is vitamin B1, vitamin B2, vitamin B3, vitamin B6, biotin, S-adenosylmethionine, folic acid, ascorbic acid, magnesium, coenzyme Q10, piracetam, or mixtures of two or more thereof.
  33. Claim 33. A method according to Claim 1 which includes the stimulant of serotonin release which is fenfluramine.
  34. Claim 34. A method according to Claim 1 which includes the stimulant of serotonin receptors which is an ergoloid mesylate.
  35. Claim 35. A method according to Claim 1 wherein the dietary composition rich in the amino-acid tryptophan includes one or more of the following: turkey, milk, bananas, nuts and dry-roasted sunflower seeds.
  36. Claim 36. A method according to Claim 1 wherein the composition additionally comprises an effective amount of an agent which promotes growth hormone release.
  37. Claim 37. A method according to Claim 36 wherein the agent is L-arginine or L-ornithine.
  38. Claim 38. A composition useful for retarding the aging process and improving age-related disease conditions in humans when administered to a human followed by the application to the brain of the human of an effective amount of an AC pulsed magnetic field of proper intensity, frequency and waveform, which composition comprises an effective amount of a composition which increases serotonin transmission to said human.
  39. Claim 39. A composition according to Claim 38 wherein the composition comprises one or more of the following: an effective amount of a serotonin precursor, an effective amount of a stimulant to facilitate the transport of a serotonin precursor into the brain, an effective amount of a stimulant to increase plasma tryptophan concentrations, an effective amount of a stimulant of serotonin synthesis, an effective amount of a stimulant of serotonin release and an effective amount of a stimulant of serotonin receptors.
  40. Claim 40. A composition according to Claim 39 which includes the serotonin precursor which is L-tryptophan or L-5-hydroxytryptophan.
  41. Claim 41. A composition according to Claim 39 which includes the stimulant to facilitate the transport of a serotonin precursor into the brain which is vitamin B3, chromium or a mixture thereof.
  42. Claim 42. A composition according to Claim 39 which includes the stimulant to increase plasma tryptophan concentrations which is a salicylate.
  43. Claim 43. A composition according to Claim 39 which includes the stimulant of serotonin synthesis which is vitamin B1, vitamin B2, vitamin B3, vitamin B6, biotin, S-adenosylmethionine, folic acid, ascorbic acid, magnesium, coenzyme Q10, piracetam or mixtures of two or more thereof.
  44. Claim 44. A composition according to Claim 39 which includes the stimulant of serotonin release which is fenfluramine.
  45. Claim 45. A composition according to Claim 39 which includes the stimulant of serotonin receptors which is an ergoloid mesylate.
  46. Claim 46. A composition according to Claim 38 which additionally comprises an effective amount of an agent which promotes growth hormone release.
  47. Claim 47. A composition according to Claim 46 wherein the agent is L-arginine or L-ornithine
CA002257279A 1996-06-06 1996-06-06 Compositions and method which retard the aging process and which improve age-related disease conditions Abandoned CA2257279A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/US1996/009440 WO1997046244A1 (en) 1996-06-06 1996-06-06 Compositions and method which retard the aging process and which improve age-related disease conditions
IL12740096A IL127400A0 (en) 1996-06-06 1996-06-06 Compositions and method which retard the aging process and which improve age-related disease conditions
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