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US005658955A United States Patent 19 11 Patent Number: 5,658,955 Hitzig 45 Date of Patent: *Aug. 19, 1997

54 COMBINED USE OF AND 56 References Cited SEROTONNAGONSTS IN THE TREATMENT OF IMMUNE DISORDERS PUBLICATIONS 76) Inventor: Pietr Hitzig, 1319 Blue Mount Rd., Yatham et al. Medline Abstract, No. 95308438, Can. J. Monkton, Md. 21111 Psychiatry, vol. 40, No. 2, pp. 93-96, 1995. * Notice: The term of this patent shall not extend beyond the expiration date of Pat. No. Primary Examiner-William R. A. Jarvis 5502080, Attorney, Agent, or Firm-Nixon & Vanderhye 21 Appl. No.: 548,314 57 ABSTRACT 22 Filed: Nov. 1, 1995 This invention relates to the treatment of the immune disorders fibromyalgia and chronic fatigue syndrome with Related U.S. Application Data the combination of therapeutically effective amounts of a and a dopamine agonist. In addition, a I63) Continuation-in-part of Ser. No. 333,294, Nov. 1, 1994, Pat. method of improving vector gene therapy with the combi No. 5,502,080. nation of a serotonin agonist and a dopamine agonist is (51) Int. Cl. ... A61K 31/135 provided. 52) U.S. Cl...... 514/654; 514/885 58 Field of Search ...... 514/654, 885 10 Claims, No Drawings 5,658,955 1 2 COMBINED USE OF DOPAMNE AND nant adenovirus as diminishing the activation of certain SEROTONN AGONSTS IN THE T-cells and allowing efficient readministration of recombi TREATMENT OF IMMUNE DSORDERS nant virus. See Nature Medicine, vol. 1, No. 9, September 1995, pp. 890-893. This application is a continuation-in-part of application 5 The present invention includes the administration of a of Ser. No. 08/333,294, filed Nov. 1, 1994 now U.S. Pat. No. dopamine agonist and a serotonin agonist to reduce the 5,502,080. body's immune response to gene therapy vectors, notably By distinguishing between self and non-self, the immune adenoviral vectors, and achieve transient immunosuppres system mediates the individual's relationship with his or her sion to facilitate effective gene therapy. environment. When the immune systemis working properly, 10 In a preferred aspect of the invention the serotonin it protects the organism from infection; when it is not, the agonist(s) and dopamine agonist(s) are administered in the failures of the immune system can resultin some of the most same unit dosage or pharmaceutical presentation. Current challenging and serious diseases encountered in medical information indicates the use of a serotonergic drug reduces practice. The nervous and immune systems have evolved the potentially addictive qualities of dopaminergic drugs. with an exquisite capacity to receive and respond to specific 15 Presentation in a single unit, desirably thoroughly blended forms of stimulation from the internal or external milieu. together in a pharmaceutically stable combination, renders Central nervous system neurotransmitters such as the potential for the separation of and possible abuse of the dopamine, serotonin, and prolactin modulate dopamine agonist far less likely. This aspect of the invention the immune system by both stimulating and inhibiting is particularly important in rendering the product adminis various aspects of the immune system. that 20 tered unattractive to potential or current amphetamine increase central nervous system dopamine and serotonin addicts and thus reduces the potential for abuse. have been found to act in tandem in controlling addictive In another preferred aspect of the invention dopamine cravings and psychoneuroses. Stress, or the state that occurs agonist is administered in its entirely in the morning and when the individual has his customary environment serotonin agonist is administered in two divided doses, one disturbed, has been increasing. Its increase is the price 25 in the morning with the dopamine agonist and the other in mankind is paying for disturbing man's natural environ the afternoon. ment. Low central nervous system dopamine and serotonin Clinical experiences include the treatment of patients has been found to occur in chronically stressed animals. The with severe asthma, no asymptomatic; patients with allergic addition of dopamine and serotonin results in immune rhinitis, now resolved; patients with psoriasis have experi enhancement. 30 enced marked improvement or complete resolution; patients This invention provides therapeutic intervention to dis with AIDS experienced significant improvement of their T orders of the immune system to restore the patient generally cell counts and patients with malignant idiopathic and particularly the immune system to its previous degree of anaphylaxis, now resolved. competence. Diverse conditions suited to the procedures of A wider variety of serotonin and dopamine this invention include, but are not limited to, immunodefi 35 agonist may be considered for use in the therapeutic meth ciency states such as AIDS and HIV-related diseases, ods and pharmaceutical compositions of the invention. The lymphoma, and multiple carcinomas; autoimmune diseases following is a non-limiting partial listing of products cur such as psoriasis and inflammatory bowel disease; allergic rently approved for use in the United States or other coun diseases including rhinitis, asthma, atopic conditions. tries or in the final stages of regulatory approval. urticaria, anaphylaxis such as allergen specific, exercise 1. Amphetamines-Athigh doses cause release of dopamine induced and idiopathic, angioedema, and neurodermatitis; from dopaminergic nerve terminals, particular in the neo and miscellaneous conditions including Crohn's disease, striatum. At still higher doses, they cause release of ulcerative colitis, chronic hepatitis B, C or D. Persian Gulf 5-hydroxytryptamine (5-HT) and dopamine in the mesolim Syndrome, fibromyalgia, chronic fatigue syndrome and der bic system. matologic and arthritis psoriasis. 45 Dextroamphetamine (Dexedrine(8) I have found that the concurrent use of a serotonin Methamphetamine (Desoxyné) agonist and a dopamine agonist, preferably administered at Fenfluramine (Pondiming)) the same time and desirably administered in the same dosage Diethypropion (Tenuate(8) unit (tablet, capsule, solution), provides highly effective, Mazindol (Mazanor(E)) predictable therapy for patients suffering from defects of the 50 Phentermine (Fastine)) immune system. Benzphetamine (Didrex®) In addition, dopamine and serotonin play important Phendimetrazine (Phenazine() immodulating roles and thus may have benefit for patients Phenmetrazine (Preluding) receiving gene therapy. Gene therapy has to date been Chlorphentermine (Pre Sate(8)* inhibited or rendered less than effective due to host immune 55 Clobenzorex response to the vector(s) used to deliver the desired gene Cloforex product. This is particularly true with adenoviral vectors. Methylphenidate (Ritalin?)) Adenoviral vector administration commonly induces Pemoline (Cylert(8) inflammation and antigen-specific cellular and humoral Clortermite (Voranil(8)* immune responses. This is true with recombinant adenoviral Dexfenfluramine vectors. Currently it is believed that it is unlikely any Ethylamphetamine modifications in vectors will fully eliminate their immuno Fenethylline genicity. Fenproporex* A need exists for a procedure causing only transient Mefenorex immunosuppression, one that minimizes effects on pre 65 Phenatine existing immunity. Yang etal describe the use of interleukin Phenbutrazate 12 or interferon-gamma coadministered with the recombi Prolintane 5,658,955 Propylhexedrine Lergotrile Triflorex Memantine 2. and other -block Metergoline the reuptake of serotonin, dopamine, and/or norepinephrine Piribedil at the neuronal membrane. The degree of potency and 5 GBR12909-investigational selectivity vary greatly among these agents. (Elavil(8) (Asendin(ë) (Wellbutrin(E)) 5. Miscellaneous (Norpraming) 10 (Buspar?&)-appears to act as a mixed agonist/ (Sinequan(8) antagonist at both the dopaminergic and serotonin receptors. Imiprsmine (Tofranil?&) (Eskalith?&)-enhances the release of serotonin, (Pamelor(8) especially in the hippocampus and may alter reuptake of (Vivactil®) catecholamines (i.e., dopamine). (Surmontil(8) 15 (Nicorette(8), Habitrol(8) patch)-stimulates (Prozac(8) release of norepinephrine and dopamine from brain tissue. (Zoloft(8) Phencyclidine-inhibits reuptake of dopamine, serotonin, (Paxil(E)) and norepinephrine by synapses. (Desyrel(8) Marihuana (cannabis) (Anafranil?&) 20 Lysergic Acid-serotonin agonist. Alaproclate Reserpine (Ser-Ap-Es(8)-inhibit reuptake of dopamine and serotonin, resulting in depletion of stores. -a precursor of serotonin. 5-hydroxytriptophan-a metabolite of tryptophan, may 25 be administered in doses ranging from 30 to 500 mg per day Clovoxamine in single or divided doses. Oxitriptan-a precursor of serotonin. Dichlofensine Methylxanthenes generally including Xanthines and methylxanthines including caffeine, Dothiepin 30 theophylline, Pentoxiphylline and theobromine Femoxetine Ibogaine Thalidomide prindole Supidamide In the above listing * indicates products not available in the 35 United States and **products to be marketed soon by Solvay Pharmaceuticals in the United States. Noxiptyline The preferred agents are fenfluramine and phentermine. Fenfiuramine is a racemic mixture of a drug which releases serotonin to the central and peripheral nervous system and inhibits serotonin reuptake into the neuron. Either optical isomer or a racemic mixture may be used. Preferably the 3. (MAO) Inhibitors-block deamina mount administered is from 10 to 120 mg/day preferably 80 tion of dopemine and serotonin. mg/day in single or preferably divided doses of 40 mg each. Isoearboxazid (Marplan?8) Phentermine is an adrenergic compound structurally (Nardil(8) 45 related to amphetamines. Such agents typically increase (Parnate(8) dopamine and noradrenaline concentrations at their respec (Deprenyl(8) tive receptor sites in the brain. Preferably the daily mount Clorgyline administered is 15 to 500 mg. preferably 30-60 mg mg of phentermine, in single or divided doses. A single dose in the 50 morning is preferred. Alternatively 5-hydroxytriptophan may be administered in mounts ranging from 30 to 500 mg in daily or divided doses. For most treatments the above noted drugs are used in the dosage ranges and mounts indicated in the directions for use 55 and labeling provided by the manufacturer of the product 4. Dopamine Agonists-immediate metabolic precursor of and/or stated in the relevant scientific literature. In dopamine in the basal ganglia or release of dopemine from particular, see the following sources: Gilman et al., The central neurons in the basal ganglia (i.e., nigrostriatal Pharmacological Basis of Therapeutics, 7th ed. New York: neurons). Macmillan Publishing Co., 1985; McEvoy GK, ed. AHFS Levodopa/ (Sinemet(8) Drug Information, Bethesda, MD, American Society of Amantadine (Symmetrel(8) Hospital Pharmacists, Inc., 1993; and Reynolds JE, ed. Bromocriptine (Parlodel(8) Martindale: The Extra Pharmacopoeia, 29th ed. London, Pergolide (Permax8) The Pharmaceutical Press, 1989, Apomorphine Although no particular mechanism of action is apparent, 65 it appears that a decrease in serotonin is important in the Lysuride stress reaction cascade. Since the stress reaction includes a Mesulergine loss of competence in the immune system, the increase of 5,658,955 5 6 serotonin, especially from a powerful serotonin releaser In addition to the above carrier ingredients the therapeutic such as fenfiuramine, most likely through the downgrading formulations for the various routes of administration of the stress reaction, increases the competence of the described above may include, as appropriate, one or more immune system. additional carrier ingredients such as diluents, buffers fla Suitable formulations include those suitable for oral, voring agents, binders, surface active agents, thickeners, rectal and parenteral (including subcutaneous, intradermal, lubricants, preservatives (including anti-oxidants) and the intramuscular and intravenous) administration. The formu like, and substances included for the purpose of rendering lation may, where appropriate, be conveniently presented in the fomulation isotonic with the blood of the intended discrete dosage units and may be prepared by any of the recipient. methods well known in the art of pharmacy. The oral route of administration is preferred, desirably in 10 This invention is further explained with reference to the a single dosage unit as appropriate to the dosage regimen. following non-limiting examples. Therapeutic formulations suitable for oral administration in which the carrier is a solid are most preferably presented as EXAMPLE 1. unit dose formulations such as boluses, capsules or tablets A 43 year old registered nurse presented for treatment of each containing a predetermined amount of the active ingre 15 idiopathic anaphylaxis. She had previously been diagnosed dients. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Com after an anaphylactic episode three years ago. Since then she pressed tablets may be prepared by compressing in a suitable had suffered roughly ten episodes a year and had become machine the active ingredients in a flee-flowing form such as increasingly refractory to corticosteroids, catecholamines, a powder or granules optionally mixed with a binder, 20 and antihistamines and was considered to be in the malig lubricant, inert diluent, lubricating agent, surface-active nant phase of her condition. While the remainder of her agent or dispersing agent. Molded tablets may be made by anaphylactic triggers were unknown, shellfish ingestion molding active ingredients with an inert liquid diluent. invariably produced shock. Nearly constant asthma was a Tablets may be optionally coated and, if uncoated, may severe handicap. She was never free of bronchospastic optionally be scored. Capsules may be prepared by filling 25 symptoms for more than three straight days over the past the active ingredients, either alone or in admixture with one three years. She was previously treated unsuccessfully with or more accessory ingredients, into the capsule shells and corticosteroids, catecholamines, and a bevy of antihista then sealing them in the usual manner. Cachets are analo mines including ketotifen. gous to capsules in which the active ingredient together with An hour after initiation of treatment consisting of 40 mg. any accessory ingredient(s) is sealed in a rice paper enve of fenfluramine and 30 mg of phentermine, the patient's lope. 30 wheezing and dyspnea disappeared. Despite the patient's Formulations suitable for use in the invention also include dispersible granules, which may for example be suspended personal decision to halt conventional therapy, she contin in water before administration, or sprinkled on food. The ued to be without symptoms except for mild bronchospasm granules may be packaged, e.g. in a sachet. Formulations at three A.M. successfully treated by an increase in the suitable for oral administration where the carrier is a liquid 35 phentermine dose. Eleven days after the initiation of may be presented as a solution or a suspension in an aqueous treatment, emboldened by her clinical response, she ate liquid or a non-aqueous liquid, or as an oil-in-water liquid shellfish with no ill-effect. Other than xerostomia, she has emulsion. Suffered no side-effects. The cessation of corticosteroids and Formulations for oral administration include controlled the anorectic effect of the fenfluramine/phentermine treat release dosage forms, e.g. tablets where the active ingredi ment caused her to decrease her weight from 195 to 165 lbs. ents are formulated in on appropriate release-controlling in the first two weeks of treatment. Three months into matrix, or are coated with a suitable release-controlling film, treatment, she has lost a total of 49 lbs. Serum , Therapeutic formulations suitable for rectal administra previously markedly elevated, is now within normal range. tion where the carrier is a solid are most preferably presented She is totally asymptomatic. as unit dose suppositories. Suitable carriers include cocoa 45 butter and other materials commonly used in the art. The EXAMPLE 2 suppositories may be conveniently formed by admixture of A33 year old male. HTV positive and advancing towards the active ingredients with the softened or melted carrier(s) full blown AIDS. had a CD4+ count of 170.Therapy with 80 followed by chilling and shaping in molds. mg daily doses of fenfluramine and 30 mg of phentermine Therapeutic formulations suitable for parenteral adminis 50 was initiated and following 2 days/weeks of this treatment tration include sterile solutions or suspensions of the active the patient's CD4+ values increased to 480 and other clinical ingredients in aqueous or oleaginous vehicles. Injectable conditions including depression, and anxiety improved. preparations may be adapted for bolus injection or continu ous infusion. Such preparations are conveniently presented EXAMPLE 3 in unit dose or multi-dose containers which are sealed after 55 introduction of the formulation until required for use. A 28 year old male, depressed and craving cocaine was Alternatively, the active ingredient may be in powder form treated with 40 mg offenfluramine and 30 mg of phenter which is constituted with a suitable vehicle, such as sterie, mine in the morning and 40 mg of fenfluramine in the pyrogen-free water, before use. afternoon. At the beginning of treatment the patient's CD4+ Also contemplated but less preferred are products formu level was 530. At the end of 6 weeks therapy the patient's lated as long-acting depot preparations, which may be CD4+ level increased to 800 and the patient's craving for administered by intramuscular injection or by implantation, cocaine was resolved and depressed state improved. e.g. Subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydropho EXAMPLE 4 bic materials, or ion-exchange resins. Such long-acting 65 An author in his mid 40's presented for weight reduction. formulations are particularly convenient for prophylactic Coincident with his severe obesity (343 lbs), he was found Sc. to suffer from depression, anxiety, OCD, and psoriasis. After 5,658,955 7 8 two weeks of therapy (80 mg offenfluramine and 30 mg of What is claimed is: phentermine) he reported total relief of his neurotic symp 1. A method of treating a disorder to the immune system toms. His nails, previously bitten to the quick, had begun to selected from the group consisting of fibromyalgia and grow out. His psoriatic lesions were markedly improved. chronic fatigue syndrome comprising administering to a After two months of treatment, he has lost 33 lbs and was patient in need of same an effective amount of at least one continuing to enjoy marked relief from his food craving. His serotonin agonist and at least one dopamine agonist wherein psoriatic lesions were gone. the combination of the serotonin agonist and the dopamine agonist are present in an amount effective to treat the EXAMPLE 5 patient's condition. A 32 year old unemployed male sought assistance in 10 2. The method of claim 1 in which the serotonin agonist treating his cocaine, , and heroin addiction. He had and dopamine agonist are administered simultaneously. started to drink alcohol at the age of 5 and was alcohol 3. The method of claim 1 in which the serotonin agonist addicted by the age of 15. In the past, he had a narcotic and dopamine agonist are intimately mixed together and addiction and developed a cocaine addiction ten years ago. 15 administered in a single dosage unit. Two years ago he was found to be HIV+. His CD4+ count 4. The method of claim 1 in which the serotonin, in rapidly declined and was at 170/m prior to treatment. agonist is fenfluramine and the dopamine agonist is phen Before treatment, his SCL psychometric evaluation termine. showed him to be more than three standard deviations above 5. The method of claim 4 in which 10 to 90 mg of normal in the anxiety, depression, somaticism, hostility, and fenfluramine and 15 to 500 mg of phentermine are admin global severity Sub-scales. He was acutely craving cocaine. 20 istered to the patient per day in single or divided doses. Within ninety minutes of initial treatment with 40 mg of 6. The method of claim 1 in which the immune disorder fenfluramine and 30 mg of phentermine, his cravings and is fibromyalgia. dysphoria ceased. Treatment continued with 80 mg offen 7. The method of claim 1 in which the immune disorder fluramine and 30 mg of phentermine daily. Two weeks later, 25 is chronic fatigue syndrome. his SCL was within normal limits. He reported that he felt 8. A method of improving vector gene therapy by reduc totally normal without any distress except for a legitimate ing an immune response to a gene therapy vector comprising concern about his finances and his immune status. His CD4+ administering to a patient in need of same an effective count increased to 480/mm. He continued to do well for the amount of at least one serotonin agonist and at least one next four months. There were no AIDS related symptoms. dopamine agonist wherein the combination of the serotonin Unfortunately, he was accused of petty larceny and was 30 agonist and the dopamine agonist are present in an amount threatened with incarceration. His phone calls reflected total effective to treat the patient's condition. return of his depression and other stress related dysphoria. 9. The method of claim 8 wherein the vector is an His CD4+ cell count dropped to 180/mm. He has been lost adenoviral vector. to follow up although attempts to reach him continue. 35 10. A method of treating a disorder to the immune system One aspect of my invention includes treating disorders oft Selected from the group consisting of fibromyalgia and he immune system including allergic rhinitis, asthma, idio chronic fatigue syndrome comprising administering to a pathis anaphylaxis and psoriasis. Another aspect of my patient in need of same 10 to 90 mg offenfluramine and 15 invention includes the treatment of disorders of the immune to 160 mg of phentermine per day in single or divided doses system selected from anaphylaxis to specificallergen, exer 40 wherein the combination of the serotonin agonist and the cise induced anaphylaxis, chronic hepatitis C, chronic hepa dopamine agonist is present in an amount effective to treat titis B, Crohn's Disease, ulcerative colitis, rheumatoid the patient's condition. arthritis, psoriatic arthritis, Reiter's Syndrome, scleroderma and lupus erythematosus