|||||||IIIHIII USOO5502080A United States Patent 19 11 Patent Number: 5,502,080 Hitzig (45) Date of Patent: Mar. 26, 1996 (54) COMBINED USE OF DOPAMINE AND J. of Substance Abuse Treatment, vol. 11, No. 3, pp. SEROTONN AGONSTS IN THE 273-275, Oct. 1994, Letter to the Editor. TREATMENT OF ALLERGIC DESORDERS Maryland Medical Journal, Feb. 1993, Hitzig, "Combined 76 Inventor: Pietr Hitzig, 1319 Blue Mount Rd., dopamaine and Serotonin agonists: A synergistic approach to Monkton, Md. 2111. alcoholism and other addictive behaviors'. 21 Appl. No.: 333,294 Primary Examiner Marianne M. Cintins 22 Filed: Nov. 1, 1994 Assistant Examiner-William R. A. Jarvis (51) int. Cl. ......................................... A6K 3/135 Attorney, Agent, or Firm-Nixon & Vanderhye 52 U.S. Cl. ............................................. 514/654; 514/885 58 Field of Search ............................................... 514/654 57) ABSTRACT 56) References Cited Allergic conditions are treated and allergic symptoms miti U.S. PATENT DOCUMENTS gated or resolved by the administration of a dopamine 4,255,439 3/1981 Cooper .................................... 424/273 agonist such as fenfluramine and/or 5-hydroxytriptophan 4,895,845 1/1990 Seed ........................................ 54/252 administered concurrently or in association with a serotonin agonist Such as phentermine. OTHER PUBLICATIONS McMurray et al, Medline Abstract No. 94343376, 1994. Bravo et al, Medline Abstract No. 92309257, 1992. Riskind et al, Medline Abstract No. 91315169, 1991. 23 Claims, No Drawings 5,502,080 1. 2 COMBINED USE OF DOPAMINE AND A wider variety of serotonin agonists and dopamine SEROTONN AGONSTS IN THE agonist may be considered for use in the therapeutic meth TREATMENT OF ALLERGIC DISORDERS ods and pharmaceutical compositions of the invention. The following is a non-limiting partial listing of products cur By distinguishing between self and non-self, the immune rently approved for use in the United States or other coun system mediates the individual's relationship with his or her tries or in the final stages of regulatory approval. environment. When the immune system is working properly, 1. Amphetamines-At high doses cause release of dopamine it protects the organism from infection; when it is not, the from dopaminergic nerve terminals, particular in the neo failures of the immune system can result in some of the most striatum. At still higher doses, they cause release of 5-hy challenging and serious diseases encountered in medical droxytryptamine (5-HT) and dopamine in the mesolimbic practice. The nervous and immune systems have evolved 10 system. with an exquisite capacity to receive and respond to specific Dextroamphetamine (Dexedrine(E)) forms of stimulation from the internal or external milieu. Central nervous system neurotransmitters such as Methamphetamine (DesoxynG) dopamine, serotonin, norepinephrine and prolactin modulate Fenfluramine (Pondimin(E)) the immune system by both stimulating and inhibiting 15 Diethylpropion (Tenuate(E)) various aspects of the immune system. Medications that Mazindol (Mazanor(E)) increase central nervous system dopamine and serotonin have been found to act in tandem in controlling addictive Phentermine (FastinCE)) cravings and psychoneuroses. Stress, or the state that occurs Benzphetamine (Didrex®) when the individual has his customary environment dis 20 Phendimetrazine (Phenazine(E)) turbed, has been increasing. Its increase is the price mankind Phenmetrazine (Preludin(R)) is paying for disturbing man's natural environment. Low central nervous system dopamine and serotonin has been Chlorphentermine (Pre Sate())* found to occur in chronically stressed animals. The addition Clobenzorex of dopamine and serotonin results in immune enhancement. 25 Cloforex: This invention provides therapeutic intervention to dis Methylphenidate (Ritalin(E)) orders of the immune system to restore the patient generally and particularly the immune system to its previous degree of Pemoline (Cylert(E)) competence. Diverse conditions suited to the procedures of Clortermine (Voranil(E))* this invention include, but are not limited to, immunodefi Dexfenfluramine ciency states such as AIDS and HIV-related diseases, lym 30 Ethylamphetamine phoma, and multiple carcinomas; autoimmune diseases such as psoriasis and inflammmatory bowel disease; allergic Fenethylline diseases including rhinitis, asthma, atopic conditions, urti Fenproporex* caria, anaphylaxis such as allergen specific, exercise induced Mefenorex and idiopathic, angioedema, and neurodermatitis; and mis 35 Phenatine cellaneous conditions including Crohn's disease, ulcerative colitis, chronic hepatitis B, C or D, and dermatologic and PhenbutraZate arthritis psoriasis. Prolintane I have found that the concurrent use of a serotonin Propylhexedrine agonist and a dopamine agonist, preferably administered at 40 Trifiorex the same time and desirably administered in the same dosage unit (tablet, capsule, solution), provides highly effective, 2. Tricyclic antidepressants and other antidepressants predictable therapy for patients suffering from defects of the block the reuptake of serotonin, dopamine, and/or norepi immune system. nephrine at the neuronal membrane. The degree of potency In a preferred aspect of the invention the serotonin and selectivity vary greatly among these agents. agonist(s) and dopamine agonist(s) are administered in the 45 Amitriptyline (Elavil(E)) same unit dosage or pharmaceutical presentation. Current Amoxapine (Asending) information indicates the use of a serotonergic drug reduces the potentially addictive qualities of dopaminergic drugs. Bupropion (Wellbutring) Presentation in a single unit, desirably thoroughly blended Desipramine (Norpramin(E)) together in a pharmaceutically stable combination, renders 50 Doxepin (Sinequan(E)) the potential for the separation of and possible abuse of the Imipramine (TofranilCE)) dopamine agonist far less likely. This aspect of the invention is particularly important in rendering the product adminis Nortriptyline (Pamelor(E)) tered unattractive to potential or current amphetamine Protriptyline (Vivactil(E)) addicts and thus reduces the potential for abuse. 55 Trimipramine (Surmontil(E)) In another preferred aspect of the invention dopamine Fluoxetine (ProzacQ) agonist is administered in its entirely in the morning and serotonin agonist is administered in two divided doses, one Sertraline (Zoloft()) in the morning with the dopamine agonist and the other in Paroxetine (Paxil(E)) the afternoon. 60 Trazodone (Desyrel(E)) Clinical experiences include the treatment of patients Clomipramine (Anafranil?) with severe asthma, no asymptomatic; patients with allergic Alaproclate* rhinitis, now resolved; patients with psoriasis have experi Amineptine enced marked improvement or complete resolution; patients with AIDS experienced significant improvement of their T 65 Butriptyline cell counts and patients with malignant idiopathic anaphy Cianopramine laxis, now resolved. Citalopram 5,502,080 4. Clovoxamine Marihuana (cannabis) Dibenzepin* Lysergic Acid-serotonin agonist. Dichlofensine Reserpine (Ser-Ap-Es(E)-inhibit reuptake of dopamine and serotonin, resulting in depletion of stores. Dimetacrine Tryptophan-a precursor of serotonin. Dothiepin 5-hydroxytriptophan-a metabolite of tryptophan, may Fennoxetine be administered in doses ranging from 30 to 500 mg per day Fluvoxamine in single or divided doses. Iprindole Oxitriptan-a precursor of serotonin. Lofepramine 10 Methylxanthenes generally including Melitracen Xanthines and methylxanthines including caffeine, theo phylline, Pentoxiphylline and theobromine Minaprine Ibogaine Noxiptyline:* Thalidomide Opipramol 15 Supidamide Propizepine In the above listing * indicates products not available in the Quinupramine United States and **products to be marketed soon by Solvay Viloxazine Pharmaceuticals in the United States. 3. Monoamine Oxidase (MAO) Inhibitors-block deamina The preferred agents are fenfluramine and phentermine. tion of dopamine and serotonin. 20 Fenfluramine is a racemic mixture of a drug which releases Isocarboxazid (Marplan(E)) serotonin to the central and peripheral nervous system and inhibits serotonin reuptake into the neuron. Either optical Phenelzine (Nardil(R) isomer or a racemic mixture may be used. Preferably the Tranylcypromine (Parnate(R) amount administered is from 10 to 120 mg/day preferably 80 Selegiline (Deprenyl(R) 25 mg/day in single or preferably divided doses of 40 mg each. Clorgyline Phentermine is an adrenergic compound structurally Iproclozide related to amphetamines. Such agents typically increase Iproniazid dopamine and noradrenaline concentrations at their respec Mebanazine tive receptor sites in the brain. Preferably the daily amount 30 administered is 15 to 500 mg, preferably 30-60 mg mg of Moclobemide phentermine, in single or divided doses. A single dose in the Nialamide morning is preferred. Alternatively 5-hydroxytriptophan Safrazine may be administered in amounts ranging from 30 to 500 mg Toloxatone in daily or divided doses. 4. Dopamine Agonists-immediate metabolic precursor of 35 For most treatments the above noted drugs are used in the dopamine in the basal ganglia or release of dopamine from dosage ranges and amounts indicated in the directions for central neurons in the basal ganglia (i.e., nigrostriatal neu use and labeling provided by the manufacturer of the prod rons). uct and/or stated in the relevant scientific literature. In Levodopa/carbidopa (Sinemet(E)) particular,