CA2337507A1 - Composition for treatment of stress - Google Patents
Composition for treatment of stress Download PDFInfo
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- CA2337507A1 CA2337507A1 CA002337507A CA2337507A CA2337507A1 CA 2337507 A1 CA2337507 A1 CA 2337507A1 CA 002337507 A CA002337507 A CA 002337507A CA 2337507 A CA2337507 A CA 2337507A CA 2337507 A1 CA2337507 A1 CA 2337507A1
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- 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
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
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- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
A method of treating stress in a patient showing stress related symptoms is disclosed, where the method comprises administering to the patient an effective amount aerotoninergic drugs. Specific examples of this class of drugs are described, and include as examples, among others, the use of lithium, chlorimipramine, fluoxetine, fluvoxamine, aertraline, MK-212, Ro 60-0332/ORG 35035, Ro 60-175/ORG
35030, d,1-fenfluramine, dexfenfluramine, or their salts.
35030, d,1-fenfluramine, dexfenfluramine, or their salts.
Description
wo oaro3~oi , pc~rnrs~rn6m COHIpO~ON Fl~ TR~IATi~ENT OF STRESS
BACKS (1i' TI~3 B~IVEt~IfIO~I
F18LD OF T13E INYliINTiON
The invention rotates to a ~rov~el ps~ooed for etxess is a augeriag fram at kart one symptom of dress. More apecifiCally, the inveidtida relates to the use of drugs which eahance aerotonin-mediated neurotransmission eoolt ss lbnflaramlnee far baking stress in each a sabjoect.
DBSCRIPT7t7~t 4F THB RBT~ATED ART
At preomrt, p~ 6~otir stress related ~ea~dan are treated for their sympt~orns of stress by the use of pharmuxutieat co~pnpoa~oas og drugs such as anxiotytics or aamdimea with bets blaclrers. Amciolytica frequently used ~nolude audr as be~odiaxepines, diazepam being a specific exaosple. The beta-blodrirlg drub used i~r treatment of such pa#~ts iaofide prnprrmolol. The use of these classes ~dtugs ~ sudi trarArrraata is discamed in l~oomrd Gtl~n'a PlogfcaJ 8at~a of 7~re~alvsx~tica; Santera~r Edikion,1985, Alfred (3.
(iihrum d al., editors, pages 192-201, incorporated by r~'er~amce.
Stress is classified by cmrvdrtian as being either acute or drronic in nature.
A patient safl'ering from a stress related diaordarnsay mchibit s vrrrlaty of types of symptoms. These symptoms cm iamddy, dep~ioo, and ovae~ag. The eoaventianal t for a patimx art~ring frmn a stress related disorder is by use csFdrwga such as the beuozodiazegiaas or by use of bets blocking drugs such as propranolol. 1?isolOeed Mete is a navel treatment mdhod for stress in a patient, which method uses drugs hitherto wnlmroarrrr as useful for treating dress. The novel medrod dise>oaed herein a usetbl mqdrod riot' pt~leab g frwn dress and exhibiting at least one symptom them In a speciEe embodimmet of the inveatiaa, acid method has been fraud particularly useful f~ treding the straw fait by snbjeeta who also suffer from overeating disorders or who overeat in reaction to the stress that they see a~ari~raiag.
It ahonld be noted hoe timt not alt who aged would benefit from a treatment for alleviat<ng stress. Some people who a~ra~ ~ stress by redrming their as~g, not irxxeasing their eating behavior, Drugs that rcduoe the elects of ~tres~a in a patient might not necessarily be usatitl in alt obese patients. In the present invhdation, the stress reducing drugs that prove to be the mast uaefnt are those that elicit in patierrb, whose cr~aa~ing is stress associstod, a response that leads to s reduction in their eating behavior. I~enoe, sot all stressed people who oat would be candidates fa the treatment with dn~ that ahsttcse ear~otonin-mediated n~ro~nsmission of the invedion.
A number of compounds aro kuowm to stimnlata or enl~anoe seratonin-mediated neurotransmission end are somdimes ret~er~e~d !s as sainergic dnrgs. 'These compounds include the following: d,l-feoflurarnin0. dexirt0. tryptr~ren, lithium, ehiorimipramio0.
BACKS (1i' TI~3 B~IVEt~IfIO~I
F18LD OF T13E INYliINTiON
The invention rotates to a ~rov~el ps~ooed for etxess is a augeriag fram at kart one symptom of dress. More apecifiCally, the inveidtida relates to the use of drugs which eahance aerotonin-mediated neurotransmission eoolt ss lbnflaramlnee far baking stress in each a sabjoect.
DBSCRIPT7t7~t 4F THB RBT~ATED ART
At preomrt, p~ 6~otir stress related ~ea~dan are treated for their sympt~orns of stress by the use of pharmuxutieat co~pnpoa~oas og drugs such as anxiotytics or aamdimea with bets blaclrers. Amciolytica frequently used ~nolude audr as be~odiaxepines, diazepam being a specific exaosple. The beta-blodrirlg drub used i~r treatment of such pa#~ts iaofide prnprrmolol. The use of these classes ~dtugs ~ sudi trarArrraata is discamed in l~oomrd Gtl~n'a PlogfcaJ 8at~a of 7~re~alvsx~tica; Santera~r Edikion,1985, Alfred (3.
(iihrum d al., editors, pages 192-201, incorporated by r~'er~amce.
Stress is classified by cmrvdrtian as being either acute or drronic in nature.
A patient safl'ering from a stress related diaordarnsay mchibit s vrrrlaty of types of symptoms. These symptoms cm iamddy, dep~ioo, and ovae~ag. The eoaventianal t for a patimx art~ring frmn a stress related disorder is by use csFdrwga such as the beuozodiazegiaas or by use of bets blocking drugs such as propranolol. 1?isolOeed Mete is a navel treatment mdhod for stress in a patient, which method uses drugs hitherto wnlmroarrrr as useful for treating dress. The novel medrod dise>oaed herein a usetbl mqdrod riot' pt~leab g frwn dress and exhibiting at least one symptom them In a speciEe embodimmet of the inveatiaa, acid method has been fraud particularly useful f~ treding the straw fait by snbjeeta who also suffer from overeating disorders or who overeat in reaction to the stress that they see a~ari~raiag.
It ahonld be noted hoe timt not alt who aged would benefit from a treatment for alleviat<ng stress. Some people who a~ra~ ~ stress by redrming their as~g, not irxxeasing their eating behavior, Drugs that rcduoe the elects of ~tres~a in a patient might not necessarily be usatitl in alt obese patients. In the present invhdation, the stress reducing drugs that prove to be the mast uaefnt are those that elicit in patierrb, whose cr~aa~ing is stress associstod, a response that leads to s reduction in their eating behavior. I~enoe, sot all stressed people who oat would be candidates fa the treatment with dn~ that ahsttcse ear~otonin-mediated n~ro~nsmission of the invedion.
A number of compounds aro kuowm to stimnlata or enl~anoe seratonin-mediated neurotransmission end are somdimes ret~er~e~d !s as sainergic dnrgs. 'These compounds include the following: d,l-feoflurarnin0. dexirt0. tryptr~ren, lithium, ehiorimipramio0.
cyaaimipramine, fluoxetine, pacoxetiae, fluvoxamine, oitalopram, femoxitine, cianopraminc, ae~alin0. sibutramine, vealafaxine, ORQ 6582, RU 25391, LM 5008, DU 24565, indatpine, CGP
6085/A, WY 25093, alaqociate, ziaaelidine; trazodone, amitriptyline, imipramine, trimiptasnine, doxopin, protriptyline, nortriptyline, dibenzoocazepiue, 6epnnyl, isocarboxazide, phenelzine, tnnylcyp~omine, furamlidoa0. procarbazae, moclobatride, brofaromin, nefazodone, bud, MIC
212, DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-03$2/ORG 35035, Ro 60-0175, Org L2962, Ro 60-0332, a-methyl-5-HT, TF11~P, bufotaaia, Ru 24969, 9uipaz~e, 5-cer6oxyimidotrypbminG, sumstriptan, CGS 12066, 8-OH-DPAT, (S~2-(chlore-S»fluoro-iodol-I-y1~1-methylethytamine 1:1 C4H404, (S~2-{4,4,~-trimethyl-1,4-dihydro-indaw(1, 2-b)py~1-1-y1~1-methylethylamino I:1 GtH404, SB 206553, and ~Qally aooaprable salts thareof. Suitable salts can be formed from the above compounds, for exsmpk, as addit'ron sails using the following acids: the hydrohalie _ acids, sulfiuic acid, phoapharic acid or an org~ic acid such as aoatic acid, msteic acid, valeric acid, caproic acid, benzoic acid or nicotine acid.
By "fenfluramines" here is n~cant a cdcemie mixture of d,l-fenfluramine, which is also called N-ethyl-a-methyl-3-(trifluoro-madgrlthanamtha dextra~atory isomer In~ovm as dexfenflurarnine and also as d-fanfhn~amine; ~ the phelmaceutioally acceptable salts of these compounds. Suitable salts can be formed from dexfentluramine or d,l-f~fluramine, for example, as additi~ salts acing the following acids: the ~ acids, sulfluic acid, phosphoric acid or an organic acid such as acetic acid, malefic acid, valeric add, caproic acid, benzoic acid or nicotinic acid.
Far practicing the invention, the active aarotanin-mediaeed neurobrabamisaian stimulating compound may be administered to a patient as a pharmaceutical composition comprising the active compound admixed with a pharmacxutically acceptable carrier, including one or more excipients.
For example, ., f~fl~uxa~inea may be adminito a patient as a pharmacartieal compoaitian comprising either flwaaune or dl-fa~fluhmine admiOOed wig a plrlumacenticatly ac~bk curia, including one or moro excipieata.
The serotoninergic drugs MK-212, DOI, m-CPP, Ro 60-0175/ORG 35030 , Ro 60-35035, Ro 60-015, Org 12962, Ro 60-0332, (S~2-(olt~O-S-fluoro-indol-1-y1~1-methylethylamine 1:1 C4H404, (S~2-(4,4,7-trimethyl-1,4-dihydro-indeno(1, 2-b)pyrrol-1-yl~-1-methylethylamine 1:1 C4H404, and SB 206553 fall into the eiass of drags which a~ivate postsynaptic recxptors. These are agonist drugs which bombard the xrotonin re<:epdoe~s of posbynaptic cells and mimic the effect of large amounts of serotoaia reacting with the postsynaptac cells' aerotonin receptors.
For the purposes of this disclosure, the terms "subject" and "patient" may be wed interchangeably to refer to a human exhibiting at least one symptom of strem.
The pharmacaaically acceptable Gorier and/or excipient of choice utilized for a formulation we ooro~~oi rc-rms99n6is~
used in accordance with the invention depeiads on the mode of administration to a subject. The cotapositions of this invention are sai~ak for parenteral, buccal, sublingual ar rectal administration.
The resulting pharmaxubcsl compcadtions are, for example, tabkta, c~tad mb>ets, capsules, soft gelatin capsules, drinkable emulsions, ~upansions err solutions for oral or injeetable administration, sublingual tablets err suppoaibories. They may also be formulated into a sustained release form.
Among the various e~ccipia~ts vvhicdE may be used far Ihese purposes include talc, magnesium phosphate, lactose or silica ~ the Idce. To the solid Roans may be added a filler, a diluent, a binder such as ethyl-cellulose, dihydroxypt!op~r1 oelluloae, carboxymethyl cellulose, miancrystalline odlnhe~ gum a~abic, gum trags~ or gelatin. The oompoaitimta of this invention may also be flavored, colored or coated with a wax or a plestieixer. It is to be understood that those skilled in the art of p>mrmaoeutical formulation wit! be able to make a variety of formulations that would be within the scope of this di~loaura and the waded elahns, without depertlng from the spirit and . . ... .. ...
of the invention. It is intended that all such formulations be included in this invention.
It is to be understood that according to the teachings of the invention, the invention mercy be d by administering serotanio-mediated neurotransmission stimulating coaipovmds, for example, fentluramines, to a :ubjed as a single unit done ono or moro times per day, or as a plunslity of unit doses once a more times pa day without deviating from the teachings of the invention.
Other drugs, pnefenbly habgereted amphotrtdsinas, may also be useful to treat stress in a subject who is sut~'ering from the hind Qf stress allcwladed by the fenfiuramine treatments of the present invention. Such other useful dntgs may include specific drugs that are not halogenatod amphetamines inchding, but not limited to, effaxor, nafa~odooe, bupropioo, paroxabne, fluoxetine, and sortralin.
Dexfenflaramine sad d,l-foatino are known anorectic agents as disclosed in U.S. Patent No. 3,198,834. .. However, prior to tha,~eaent inreatuon, neither saa~otoninc~ic dcug~s_in:gatloral, nor . ., dexfenflurarnine nor d,l-fenfluramine Ms been known to be etTeetive as a dn~nent for stress in a patient.
Fentluramines aro Irnown to be alTeaive drugs for tr~ng obesity. The tacemic mixture, d,l-fenflurarnine, was disclosed in U.S. Pataant~1,452,815, granted to Wurtman and Wurtman, as being effective for inhibiteng the abrwrmal craving for carbohwhich afflicts samse people and which is associated with their obesity. Daot~lununine is abo udicated for ase in treating patients who cannot control their eating habits or appetite. The use of dexfenfluramine for this purpose was disclosed in U.S. Patent 4,309,445. In both of these patents the use proposed for fenfluramines was for ts~esung a patient's appetite or cravhtg for certain types of food.
Nowhere in these patents is the use of faifluraminea suggested for treatment of the stress fmm which a patient may be suffering.
A theoretical mechanism by v~ieb fenfluramines work for suppressing appetite for certain food types was plod by WurWan ~ Wurtman In Brain SeraLonin, Carbohydrate-Craving, Obesity and Depression, 06esity R~ncJ~ vol. 3, suppl. 4, November 4,1995, pages 477S-480S
incorporated by reference. It has bean qrapotoed t!~ dacfanfluramine is an etTative trcatmant foc the overeating that is associated with a response to dross ~ some people. People overart for a variety of reasons, however. For some people their overeating sauna to be a response to stressful situations.
Dexfenfluramine is shown in thin pablic~On to be uaelbl for tmating tho obesity suffered by such people, but there is no teaching that dexfenPiuramine is useful for treating stress itxlf.
Fentluramines are sarotoninergic arose that istwlbit the abnormal craving for high carbohydrate foods, which leads to a poi caloric b~aoce and subsequent obesity in certain pooplc. Soma, but not all, people benefit &~ the administration of dexfenfluramine by having their craving for certain foods inhibited. This shove citmd publication does not disclose or teach any use of dexfenfluzamine or d,l-fenfluramioes for treating atro~ itself in obese patients, or make any suggestion that these fenfluramines may be effectve as a tra~tment for stross itself. The publication descdbea the aerotoninergic fenfluraminca as sc4lng to facilitate weight loss in subjects in three ways:
"They accelerate tho onset of satiety and enhanao basal metabolic rata by about 100 calories per day. They also inhibit !bo 'carbolnya)~e ersving' manifested by many poople who are overweight or are becoming so, and theme is reuon to believe that this inappropriate eating behavior actually constitutes s 'serotonin banger' by the brain, in which case giving the serotoninergic drug might csuto a specific therapy for the etiologic prods causing the obesity."
Further discussion of the known fynaticuting of fentluramines is found in Wurtman and Wurtman, Brain Serotonin, Carbohydsste-Craving, Obesity and Depression, Recent Advances in TY~yptoplurn Reaear~ch, G. A. Filippini et al. eds., Plenum Press, New York, 1996, pages 35-41 incorporatod by refa~enee.
The use of dexfenflurarnino for tnsating animsle inflidad with periodic pain is discussed in Dexfentluramine: Eon Food Intake in Various Animal Models, Neil E. Rowland and Jams Carhnn, Clinical Newophra"macology, vol 1 I, suppl. l, pp. S33-S50 incorporated by reference. This article indicates in its abstract that: "...both stress-induced eating as well as a food-motivated response (running) are particularly sensitive to inhibition by dexfenfluramine:' This article discloses the administration of ~~'enfluramine to rats exhibiting inaaased eating behavior in response to tail pinching. The tails of the rats were pinched as part of an experimental protocol, which was found to cause the rats to eat larger amounts of food than rats whose tails wee not pinched. Dexfenlluraatine (DF) was found to decroase the eating behavior of the tail pinched rats. Dexfentluramine was known prior to the Rowlsnd et al.
article to depress eating activity, howav~, as shown in Wurtman ~ al., Sciexce, vol. 198, pp. I 178-1180, Dac~nbor, 1977 incorporated by reference.
wo ooro3~ol pcrnrs~n6is3 s The authors did the imply of ~lir imenta with regard to stroas-induced eating as follows on page S39 (DF indiossd»g dumtnine):
"Mild tail assure induces eatia$ and in rats, and this may be n model of stresis-induced eating in humans. (3aesl~ini nopal~ed DF potently inhibits tail presauro-induced eating, and drat the DID of 8~ is abort ~mllf of the doses eve is tlu other paradigms reviewed so far. h was ptrewitmsly roponkd that recemic fenfluramine inhibits tail pressuro-induced eating as wall ~ eonounre~t ba~riors sudr as gaswiag, locoanation, and vocalization. In the sdtdy with DF, ody the asd~at ester was reported, rather than all oral behaviors. These data thus sub lhs~t DF mQr he an apoci~r potent inhibibx of stross-related eating. Further studies are needed to clarrify the effect of DF on other oral behaviors, as well as w>it has 'sdtis~s' alawlg with its anorectic ac~ioa."
Thus, until die pru~ invartioa, it w~ otdy lutawn that dexfenfluramine inhibits eating in tail pinched rats. It was not previously known that iaergic drugs, for examplo dmcfenfluramine or d,l-fenfluramine could bo alt ofve treatment for stress.
The authors of this article indicated only that feutlur:miaa tsiil pia~ing-induced eating and other behaviors stemming from the tail pinching protocol. T'hay did not disclose that the fenfluramines could be used as ttemneets for reducing stress itself. Thu', Row~rtd et al. bad no idea dacfenflm~nine would exhibit airy stress relieving activity pet se. Indeed, it is doubtful that tail pinching and the consequent behavior from the rat ind~ad by the tail coaad save as a mesni~tal, let alone reliable, model for the types of stress experienced by inm~ua;.
The applicants' experiments hence raw pamtitled the discovery that such smistress effects csin be achieved with setotoninergic drugs in goal and i~tfluramines in particular.
On page-S39 of Rowhmd it ~ noted that ors ta~ii;p~ed rats "may be a model of stress-inducod eating in humans", but no indicahan is provided therein that the rat system was in fact an ~ model of stress-inducxd eating in hums. Since the rat system was not a valid model for human behavior, one skilled in the art wrould ue~ have bean led by the results of Rowland with rats, to treat humans suffering from stress with dexfenfhiranitrs.
SUIvHNARY OF TI~$1NY13NTION
Briefly, the pe~ese~ invention is a nonrol trodmeM for stress and symptoms of stress in a subject The appliceNs have discmrered that adaiinis~ring Page 7, line 18.
Administering serotoninergic dnrga in general and fenfluran~s in particular to a patient can bring about a reducxi~ in the stress felt by petite and the symp~ms of stress manifest by the patient. The treatment of stress and stress related symptoms of a patient with these compounds bas not been reported p~eviously.
4Q The present invention provides an splprapriate t~r~nent for stress in human patients, WO 00P03~11 t?GT/US99l16153 especially those from street-iad~se~d ovm~aat~. T'6~ invention is based on the discovery that the serotoninergic drags, for example ueam~a, each as d,l~ine, dexfrafluramine, or their salts can alleviate symptoms of stress is pafaortdt, wbea administerod in efl'rctive amounts or Accordingly, the present inveerxlon ie dineated to a method of frosting a human subject exhibiting one or more symptoms of s>ross, which oaaorprises admmisbering to the subject an effective amount of a compo~md which anharweet via-tmmdia~ed neurotransmimion such ~ d,1 fenfluramine or dexfeafluramine, or a ~utiaal~y accep~bk salt thereof. In a specific eiabodiment of the invani~, whoa the fmflaxruriae h d,1-~fiaramirn or a pharmaca~tically acceptable salt thereof, an effective doom raagm from about 1 S 1o about 150 mg/day, preferably firm I S about 40 to about 80 mg/day. When the fenflwamino is doacfemfluramine or a pharmaceutically acceptable salt thereof, an effaetive ~ eam~pes tom I~biot~ 5 b about I50 mg/day, prafaably from about I S to about 45 mg/day.
According to the present inve~ot~, a treatment is pmwided which results in a reduction in the strew level of the patient a~cperieaciag arnotlosal erxl other triads of stress.
Accordingly, 'tt is an object of the invention to provide a tresoaent for strass perceived by a stress-induced ovett?ating patient.
It is objax of the iar~c~n to pnrvide a treatment for stress which is also tuieful for controlling food make is a stress-induced ovea~eating patient.
It is another object of the invaatioa to provide a treatment for non-eating-relabsd stross symptoms of a pati~t.
It is another object of the inveetioa to pride a trestmant for strnaa is a patient, wherein the tent is with a drug other than as arudolsrtic or beta-blocking drug.
Other objects will become sippateat from the ipt~n of the invention which follows.
DETAILED DESC1~101~1 OF THB INVENTION
We have diaoorered a novel method for ira~tiag straw, said method comprising the administration of stimulators of:erobonia-mediated noarotrrutsmission such as fenfluramines to a patient with stress related symptoms. Ia one preferred embodiment, the method comprises the administration of effective amotmm of either dt»~nfl~lrarnine, dluramiae, or their salts. Other preferrod embodiments provide dateiied disclosure of the use of other compotmds which enhance serotoaia-mediated ru3urotnasmission.
A number of compounds are sho~wa to enhance seratonin-mediated neurotransmission, and thus to be ~eful is treating humans wilt ono or moro symptoms of stress. These compounds include wo ooa~~o~ rcrms99n6is3 die following: d,l-fonflununine, dexfenfluramine, tryptephari; lithium, chlorimipramine, cyanimiprsmine, fluoxetine, paroxetine, fluvoauimine, citalopram, femoxitine, cianopramine, sertraline, sibutramine, venlafaxine, ORG 6532, RU 25591, LM 5008, DU 24565, indalpine, OGP
6085/A, WY 25093, alaprociate, ziraelidina, tta~adone, amitriptyline, imiprarnine, trimipramine, doxapin, protriptyline, nortriptyline, dibanmoat~oopine, depnoqyl, isocarboxazide, phenclzine, tranylcypromine, furawlidone, proaarbsaina, tnoclobamide, bxofaromine, nefazodone, bupropion, MK-212, DOI, m- CPP, Ro 60-0175/ORG 35030; cad Pro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, a-methyl-S-HT, TFMPP, ~; Ru 24969, quipaz;ne, 5-carboxyamidottypt:mina, sumstriptan, C(3S 126, 8-OIi-DPAT, (S)-2-(chloro-S-fluoro-indol-1-yl) I-methylethylamine 1:1 C4H404, (S)"2-(4;4,7 yl-1,4-cl~ydm-indeno(1, 2-b)pyrrol-1 y1)-1 methylethylamine l: I C4H404, SB 206533, and ~tic~ally acceptable salts thereof.
The aerotoninergic drugs MK 212, DOd, m-CPP, Ro 60-0175/ORG 35030, Ro 60-35035, Ro 60-0175, Org 12962, Ro 60.0332, (S).2-(chloro-3-fluoro-indol-1-yl)-I-methylethylamine 1:l C4H404, (Sr2-(4,4,7-trimothyl-1,4-dihy~O-indeno(1, 2-b)pyrml-1-yl)~1-methylethylamine 1:1 C4H404, and SH 206553 fall into the class of dwgs vrh~h activate postsynaptic receptors. These are agonist drugs which bombard the smotonia roceptors of postsynaptic cells and mimic the offod of Large amounts of serotamin reading with the poettaynapt#c cells' setotonin rtceptors. Examples of the use of three of these drugs along with the chanicai names and sources are shown in EXAMPLES 13-1 S.
6-Chloro-2-(1-piperazinylno (MK-212), is obtained from Merck 4t Co., Inc.
Whise Station, NJ. (S)-2-(4, 4, 7-yl-1, 4.d(hydro-indono (1, 2-B} pyrrol-1-yl-I-methylethylamine (Ro 60-175IORG 35030) is attained from )». Hotfmann-Laltoche Ltd., Hasel, Switzerland. (S)-2-(Chloro-5-fluoro-indol~1 yl)-1-mathylethylamine (Ro 60-0332/ORG 35035) is . . .a ; obtained frola F~ 1~Iof6aaan LaRocl~ Ltd., Hasel, Switzerland, l-(2,5-dim~hoxy-4-iodophec~yl)~2-sminopropane (DOI) is obtained from Raaeazch Biochemical Iaternatioasl, Natick, MA. 1-(3-Chl~ophenyl)piperazine (m-CPP) is obtained f~xn Re~rch Biochanical International, Natick, MA.
It is to be understood that the proamrt ia~a~on as disclosed herein, also includes s method of making a modica~nent for treating stress, whensin the hod comprises a step of mixing doxfenflnramine or d,l-fenfluramina with a pharmaceutically acceptable inert ingredient The invention will now be described thmu$,h ilhua~tive examples. The examples are not intended to limit the scope of the invention, which timitod only by the appended claims.
A subgroup of obese individuals ~ identifyed, which individuals describe themselves as being unable to control their eating and who attempt to ~taae an a weight-roducing diet when experiencing emotional distress. These are treated for four months by enrolling them in a wo eera~~w rcrnrs99n6~s3 weight loss program that iachxbs the o8dexfeoflnramine se 30 mg/day sad which iovolvas adherartce to s ~du~de meal post. The the of dfluramine is fend to the ability of stressed overeaten to lose weight.
Body Mass Indeac (BMI) is daftaed as ~e wauig~tt ~ kllogr~s of a wbject, divided by the subject's height in meters squared.
Applicants conduct a survey of 1g9 Ibadaia wnwea of normal body weight (Body Mass Index Q5, average Body Mme lndac 22.5 f ~.36), who are,not put on the weight ~ r~rm, and 211 obese woman (Body Mass Index >25, av~tge Bo4~y Mass Index 38.1 f 0.39). Of these obese women, SO are entered into the weight loss peoaram. Tlte majority of the obese women responding to the surrey report that amoti~sl distress or other types of stross sigaifara~~tiy increases their sasck intakes and their cravings for sweet and star~ty foods. Aiso, stress clearly decreases their ability to control their food intake and to adhere to a vmigbt leas regimen. In contrast, the mryority of the normal weight women responding to dte survey no altesatioaa is eating behavior when experiencing emotional distress of strosses. Moil obese respondents identify anxiety, dep~ion, exhaustion, boredom, angx, tansioa sad ~tion as the stc~ess-idduced emotions a symptoms most likely to make them unable to eontro~l ~reir food intakes. The kieuis of stressos that the patients indicate produce these eaaotlotts or syoms included, among othors, family and job peobiema, boa~edasn, unresolved i eos~ttias and bad news.
Objective measurements of ematlonal distross are made in some using ~e CES-D
(Center for Environmental Studies Depmssion Form) test, which measures current laveb of ernotioaal dis~u (Rsdloff and Leaotr, TJie CAD S1 ale: A Self Repor t IJ~ressiorr Scole J6r Research irr the Gsnrral Population Applied Psychological Measurement 1: 385-401,1977); and the POMS (Profile of Mood States test, flat assesses tetuapa, depression, anger and confusion (McNair, D.; lorr, M. and Droppehnan, L.; Prr~tls of blfvod s Ada~nead;San Diego: Edsl and ' Industrial 1'estuig Service, 1971); bosh of these ~~ara horeby incorporatad'by reference.
These tests are also given monthly dtnin~ tiyo tteafadmot period. At the same times, p~iea~ also complete questionnaires that ask the patients to rate thoir appetito and hunger, and also to rata their tendency to eat in response to a varkty of eaaotianat told stressfui triggers.
The patients are also weighed monthly.
The obese, stressed patients g detcfuramine eacht'bit a weight loss of 12 f 1.8 pounds (5.45 t 0.82 kg) during the four atop study period. Six women receiving dexfenflunsrnine, whose CES-D scone are above normal at dus start of ells study, also exhibit a CF.S-D scare.
Scores are lowered from 34 to 7, 37 ha $, 22 to 9, 19 to S,15 to 7, sad I S to 3, respectively, for these six woman. The mean group score, which se tho beginning of the study is 9.4, tluc~ates betvveen 7 and 8 through the treatanent period.
Scores on the appetite and abase-in~ducod avetesting scales are also reduced compared with WO 00/U3'f01 PCTNS99/16153 baseline levels. The initial scono on tho ~d 6at scale is 10.5, which deereasos to 5.0 duri~ tho treatment period. Tlm summed T~ion, Depeasaion, Anger and Confusion scores o~n the TOMS teat at baseline is 24. This number dtt~a to 1b.8 ~rilng the study period. Moreover, the score on the emotional triggers to overeatiqg report from 23.4 t 9.8 to 8.6 t g,5 ~~
d~riations by the end of the t~cnent pwiod.
Hence, tent with s fenthe~daafline, specifically promotes the ability to control food intake and to lose weigtit amdag the sleducod ova~b~s. Morn surprisingly, tent reduces the indictors of stcoss is tea pit.
In order to confirm the relatiottsbip b~lwaen which e~~hsnce serot~in-mediated neurotransmission and the amelioradien of s abd taonsequcnces of stress, i.e.
overeating and obesity, a number of serotoninergic dt~s are tell au ~o~erweight patients using the above protocols.
Specific examples of the reaulta that are a6ad with drugs which enhance serotonin-modiated aeurotraaimission are now prsovlsbd: The vu~g examples are merely intended to illustrate the invention and are not inbondsd to ibasit tba setae.
)E1;XAMP~.B 1 Example 1 involves treadneM wlth d~-dine at 30 mg/day. A preferred dosage is about 5 mg/day to about 150 mg/day.
C.H. is a 48 year old white single female. Shre s~ in her screening foams that when she is upset or sh~essed she snacks on chocoiwbe, , c~rsrs, pretzels, and candy. She antes that she overeats when feeling frust~sted, over~rheh~tad, and hanely and writes in answer to a question about whether she has difficulty in stick~g to a~ did when uhet or strossed: "In the past when 1 am not in a formalized program, somehow my brain is I'm giv!on s'license to graze to placate my emotions when strewed. I tend to break all my oven '' rules ~ ~,y~ing I want."
The results are shown in Table 1. Her ~ vwtigbt is 216 pounds (98.2 kg) and altar 4 months on dexfenfluramine, drops to 205.5 po~iads (93.4 k~. Her baseline CES-D
Mood Scores drop from 5 to 1 over the trratme~ pealed; add her eAaalional triggers decreaae from a baseline of 23 to a value of 4 after four months. Heasee, the ~tt abo greatly relieves ha emotional distress.
5 TAH1.E 1 Baseline MeMh 1 Manth M~tb 3 Month Mood 5 1 3 2 1 Scores Appetite 10 2 5 5 4 and Cravings Emotional23 2 3 2 4 I S Triggers EXaUI~IPLB 2 Exempla 2 involves treahna~t with da~cfenflura~ine hydrochloride at 30 mg/day.
A preferred dosage range is from about 15 mg/day to about 45 ritgldsy.
C.M. is a 46 year old white n~rtied physician and mother of two. She reports in her initial screening report that wlxa stressed, sbe sneaks on chocolate, candy, chips, cookies, cakelpie, and popcorn. She writes: "I was on W~ight Watchers, doing well even during vacation. But upon the start of the school year with all the schedules to handle,1 was unable to keep with the program. Then the Christmas holidays were upon us and 1 was working e~oelly hard at the office. I started gaining weight and I could not stop eating. My wppotlte has tripped and it is hard for me to say ac."
The results are shown in Tabb 2. Her starting weight is 198 poufs (90.0 kg) and at the eod of 4 months on dexfenfiuramine, her weight drop: to 1 611.7 pounds (82.6 kg).
Her baseline CES-D
Mood Scorns dry from 19 to 4 over the treatment pariod, and her emotional triggers decrease fmm a baseline of 30 to a value of 7 after fonr months. Hence, the tre~neat also greatly relieves this patie~'s stress levels.
Baseline Month Moath Month 3 Month Mood 19 5 2 3 4 CES-D
A,pp~ite 9 6 8 3 5 Cravings 8motional30 12 13 S 7 Triggers EXAMP'I:E 3 F.xampk 3 involves the tr~tmeM of a 57 year old manned femak with lithium carbonate at 900 mg/day for four months. A ~efarned dose ~ shout 600 mg/day to about 1 S00 mg/day.
D.R states in her screening forms that when she is upset or srressod she ovoroats on beer and as well as snack food such as potato chips and pemutts. This occurs when she feels stress or frustration from her employment as a government lawyer.
The results are down is Table 3. Her smiting weight is 246 pounds (111.8 kg) and after 4 months on lithium drops to 225 pounds (1023 leg). Heir baxline CES-D Mood Scores drop from 4 to 2 over the treatment period, and hor dnotional triggers dea~oase from a baseline of 15 to a value of 7 after four months. Hence, the treatment also greatly relieves her emotional distress and stress.
Baseline Month Month Month 3 Month Mood 4 . 3 3 2 2 _ Sues CES-D
Appetite 14 6 9 5 3 and Cravings EmotionalI S 16 LO 6 7 Triggers l2 F.JCAMPLE 4 Example 4 involves the tteatament of a 35 year ald single white female with fluoxetine hydrochloride at a dose from 20 mg/day for the first two weeks, 40 mg/day the ~cond two weeks, 60 mg/~y the third two weeks, and 80 mg/day through the and of the foot month trial. The preferred dose is about 10 mg/day to about 160 mglday.
The results are shown in Table 4. T.M. reports in her initial screening.
report that when stressed, she chronically overeats at meals, aldtough she eats nothing betwe~
and after meals. Her overrating takes the foam of non-atop eating, eonsoming a loaf of Mead and a stick of butter at a single meal. Her starting weight is 183 pou~dds (83.2 kg} and at the ~d of 4 months on fluoxetinc hydrochloride, her weight drops to 172 poutKis (78.2 kg). Her baseline CES-D
Mood SoorGS drop from 15 to 7 over the treatment peu~iod, and her emotional triggers decrease from a baseline of 31 bo a value of 12 after four months. Hence, the treatment also greatly relieves this patient's stress levels.
Baseline Momh 1 Month Month Month 4 Mood 15 10 2 6 7 Scones CES-D
Appetite 17 6 9 3 4 and Cravings Emotional 31 22 13 10 12 Triggers Example 5 involves the treadnent of a 76 year oW single white female with fluvoxamine mateate at a dose from 50 mg/day for the first waak,100 mg/day the second week, and 150 mglday through the end of the four month trial. The deferred dose is about 25 mg/day to about 300 mg/day.
J.B. complains of feelings of stress associated with social activities in the retirement community in which slm lives. While clearly overweight, she does not complain about weight nor apparently recognizes her condition.
The results are shown in Table 5. Her starting weight is 302 pounds ( 137.3 kg) and after 4 months on dexfenfluramiua, drc~pa to 286 pounds (130 kg). Her baseline CES-D
Mood Scores drop wo ooro3~o~ Pcrms~nb~s3 from 23 to 17 over the tmatment period, and hor annsl triggers decna~ from a baselino of 34 to a value of 24 after four months. Tip taint rolio~roa hor social stress nd has the additional bonefit of mocker weight reduction.
TABi.E 5 Baseline Month Month Month 3 Month Mood 23 26 16 15 17 Scores CES-D
Appetite 18 l6 11 12 14 and Cravings Emotional34 27 30 20 24 Triggers E7KAMP1.» 6 Example 6 involves the treatment of a 42 year old married white female with acrrraline hydrochloride at a dose from 50 mglday for the ftmt wcek,100 mg/day the second week, and 200 mg/day through the end of the four month trial. Tlte pposfarred dose is about 25 mgJday to about 400 mg/daY.
P.Q. is ~aployed as as accoua~urt, has two small childrra, and experiences stress during the tax season. She eats betvvoen meals and repo~s wakdning at night with anxiety which is relieved by consumption of ice cream.
The,;results arse shown in Tablo, b. He.r atarti~tg~ woight is 173 pound$
,(78.b kg) and at the end of 4 months on sertraline, her weight drops to 160 pow~ds (72.7 kg). Ha baseline CES-D Mood Scores drop from 20 to 12 ova the treatment periad, at~d her emotional triggers decrease from a baseline of 22 to a value of 3 after four masrd~s. Hence; the treatment c~elieves both the stress levels and the overweight.
WO OOViCi701 PCTNS99I16133 Baseline Maatb 1 M~ 2 Moatb Mmtth 4 Mood 20 16 16 10 12 S
cores CES-D
Appetite I S I2 S 3 I
and Cravings Emotional 22 12 13 5 3 Triggers IS
EXAMPLE ?
Example ? involves the t of a 38 year old single white female with venlafaxiae hydrochloride at a dose from ?5 mg/day fa the first week, I00 mglday the saca~nd week, and 150 mglday through the end of the four month trial. The preferred dose is about 50 mgJday to about 300 mg/day.
L.Z., a single mother of four children, opa~ea a day care in !roc home and complains of continual stress. She eats baked goods excessively in the evening after the children have gone home or to bed.
The results are shown in Table ?. Her stattictg weight is 184 pounds (83.6 kg) anti after 4 mosdhs on daocfanflnraraine, drops to 169 pounds (?6.B kg). H~ baseline CES-D
Mood Soores drop from 8 to 2 over the treatment period, and her emotional triggers decrease from a baseline of 14 to a vaiup of 2 after, four. months. Hence, the treatment also greatly reliewe$ her emotional distress.
wo ooro~oi pcrnJS99nslsa Baseline 1 Month 2 Month Month 4 Mood 8 4 6 2 2 Scorns CES-D
10 Appatite 10 6 7 3 1 and Em~ional 14 9 4 6 2 Triggers EXAMP'LB 8 Examp~ 8 involves the treafrneat of a 44 year old single white femsle with amitriptyline hydrochlori~b at a dose fmm 75 mg/day fa the first week, to 100 mg/day through the ~d of the four month trial. The preferred dose is about SO mg/day to about 200 mglday.
E.E. reports stroll from ha employment as a dispatcher for a trucking compamr.
Ha discomfort is relieved by eating fried folds, especially $iod potsoboes.
The results are shown in Table 8. Her starting weight is pounds (90.0 kg) and at the end of 4 myths on dexfa~fluramine, her weight drops to pounds (82.6 kg). Her baseline CES-D Maod Scores drop from 29 to 18 over the treatment period, ~d her emotional triggers decreem from a baxline of 25 to a value of 3 aRa four months. Hence, the traadnettt also groatly relievos this patient's stress levels.
we ooro3no~ pcTius99n6is3 Baseline Month Month 2 Month Month 4 Mood 29 22 20 23 18 Scoros CES-D
Appetite 19 16 8 13 8 and Emotional 25 22 13 5 3 Triggers Example 9 involves the tr~hneat of a 30 year old married white female with trazodone hydrochloride at a dose of 100 mg/day in divided doses of 50 mg each through the ~d of the four month trial. The prefornod dose is about 50 mglday to 200 mg/day.
N.1. , with throe small childron, rapats an unhappy and stressful home life with an interfering mother in-law and ineffectual husband. Her stmss seems relieved by life-night snacking on sweet food.
The results are shown in Table 9. Her starting weight is 203 pounds (923 kg) and at the ~d of 4 months on serd~alino, har weight drops to 160 pounds (72.7 kg). Her baseline CES-D Mood Scores drop from 9 to 1 over the traatnaent perlad, and her wnotional triggers decrease from a .. _ ... . baseline of l2,to a value.of 3 after four manths. Honeq, the treatment relieves both the. dress lavols and the overweight.
Hasaline Month I Month Month Month 4 Mood 9 16 16 10 1 S
cores CBS-D
Appetite 9 5 5 3 5 and Cravings Emotional 12 12 9 5 3 Triggers EXAMPLE IO
Example 10 involves the tresatment of a 31 year aW married white female with imipramine hydrochloride at an intramuscular cbae of 75 mgfday through the end of the four month trial. The preferred dose is about 50 mg/day to about 156 mg/day.
A.R., is employed at a consulting engineering firm and atturda law school at night. Her regimented schedule and lack of exeuciae array oo~iibute to hor feelings of stress, which ayenders over-eating.
The results are shown in Table 10. Her starting weight is 163 pounds (74.1 kg) and after 4 months oo imipramine, drops to 155 pounds (70.4 kg). Her baseline CES-D Mood Scores drop from 36 to 20 over the treatment period, and her emationa! triggeas decrease from a baseline of 22 to a value of 8 after four months. Nonce, the treatment also greatly relieves hex emotional distress.
Baseline Month 1 Month Month 3 Month Mood 36 34 26 21 20 Scores CES-D
Appetite 15 12 7 3 6 and Cravings Emotional 22 15 14 6 8 Triggers Example I 1 involves the trnat~nant of a married 42 year old white female with trimipramine maleate at a dose from 75 mglday for the first week, to 100 mglday through the end of the four month trial. The preferred dose is about 50 mg/day to about 200 mg/day.
A.8., a teacher in a metrapolitsn school, reports stress which she attributes to her work and gd~ally unhappy home life. She is anaek to control qrisodic bingo eating of ice cream and cake.
The results are shown in Table 11. Her starting weight is 180 pounds (81.8 kg) and at the end of 4 moaths on trimipramine, her weight drops to 158 pounds (71.8 kg). Her baseline CES-D Mood Scores drop from 25 to 13 over the treatment period, and her emotional triggers decrease from a baseline of 14 to a value of 3 after fouc months. Haace, the treatment also greatly relieves this patient's stress levels.
WO OO/A370t PCTNS99/16153 Hasoline MaMh 1 Month 2 Month Month Mood 25 22 20 15 13 Scores CES-D
Appetite 11 9 8 13 6 and Cravings Emotional14 8 13 6 3 Triggers Example 12 involves the troatment of a single 50 year old white female with ph~lzine sulfate at a dose from 45 mg/day for the first week, to 60 mg/day through the eeul of the four month trial, each daily dose taken in throe portions. The proferrod dose is about 15 mg/day to about 120 mg/day.
D.C. is a suburban bus driver and finds driving in traffic strossful. She ceWtly diets but is unablo to successfully lose weight.
The rosults aro shown in Table 12. Her startiag weight is 184 pounds (83.6 kg) and at the end of 4 months on phonelzine, her weight drops to 174 pounds (79.1 kg). Her baseline CES-D Mood Sooros drop from 20 to 14 over tho treatment period, and her emotional triggers decrease from a baseline of 20 to a value of 7 after four months. Hence, the troatment also greatly rolieves this patient's stross levels.
wo ooro3~oi pcrivs99n6tsa Baseline Month health Mouth Month 4 Mood 20 22 20 15 14 Sores CES-D
10 Appetite 19 15 8 13 12 and Cravings Emotional 20 8 13 6 7 Triggers EXAIMp'LE 13 The effect of the hydrochloride salt of 6-Chloro-a-( 1-pipera~anyl)pyrazine (MK-212, which is obtained from Merck dt Co., Inc. Whitehouse Station, NJ, on stress relatod oating in animals is determined through the observation of the effect of imental compounds on stress-rehuad eating in adult Sprague-Dawlay rats. Those rats are widely used as a recognized animal model useful in predicting tho effect of st~onin~gie drugs in h!amas~s.
In those experiments, a group of 5 adult female sad S adult male Sluagtm-Dawley rats weighing betwo~ 200 and 250 grams each are used as control animals. An undghtared clamp is placed on the tail of those animals. The untightaned clamp provides the unstressed condition. Eacb aeimal is planed in an individual cage and allowad free access to food. The amount of food consumed is determined at 2, 4 and 8 hours after the initiation of the trial.
A similar group of rats has . a.elamp tighteapd.on.tho tail. Tho amount of food caused by this streased,gcoup of rats is shown t in the 0 mg/kg column. Three similar groups of atr~ed rats are injected with 1, 2, 5, or 10 mg/kg body weight of MK-212 ono hour before initiation of the expariment.
The results aro shown in Table 13. The average sanount of food in mg which is consumed per rgt 8 hours after initiation of the trials is shown in the following table. The relative amounts of stress eating with the amount at 0 mg/kg MK-212 as I00'/o is also shown in the Stress Eating row.
The preferred daily dose of MK-212 is about 1 mg/kg body weight to about 10 mg/kg body weight.
Table 13 shows MK-212 reduces stress-related eating which indicates MK-212 reduces wo ooro3m rc~rms9sn61s3 MK 212 0 mg/kg 1 mglkg 2 mgfkg 5 mg/kg 10 mg/kg Control 1.25 1.32 1.20 1.16 1.03 Rats Stressed 4.63 4.14 3.78 2.01 .97 Rats Stress 3.38 (100Yo)2.82 (83%)2.58 (76'q"o)0.85 (25%)0.0 (0%) Eating Example 14 shows the effect of (S)-2-(4, 4, ?-trimethyl-1, 4-dihydro-indol (1, 2-B) pyrrol-1-yl-L-methylethyhunine (Ro 60-175lORG 35030) which is obtainod from F. HofFmann-LaRoche Ltd., Basel, Switzerland, on stress-induced eating. The dent is done as in Example 13 and Table 13 . u~pt tit Ro 60-1.75/ORG 35030 is used iastead of MK-212. The prefomed daily dose of Ro 60-175/ORG 35030 is about 1 mg/kg body weight to about 10 mglkg body weight.
Table 14 shows that Ro 60-175JORG 35030 reduces stress related eating which indicates Ro 60-1?S/ORG 35030 reducos stress.
Ro 60- 0 mgllcg 1 mglkg 2 mg/kg 5 mg/kg 10 mg/kg Control 1.31 1.28 1.30 1.20 1.13 Rats Stressed 4.51 3.6b 1.43 1.30 1.16 Rats Stress 3.20 (100%)2.38 (74%)0.13 (4"/a)0.10 (3%)0.03 (1%) Eating The effect of (S}.2-(Chloro-5-tluoro-indol-1~y1~1-mathylethylamine (Ro 60-35035) which is obtaiaed from F. Hotfmann LaRoche Ltd., Basel, Switzerland, on eating in rats is determined as in EXAMPLE 13 and Table 13, except Ro b0-0332/ORG 35035 is uxd than MK-212. The prefemd daily dose of Ro 60-033210RG 35035 is about 1 mg/kg body weight to about 10 mg/kg body weight.
Table 15 shows that Ro 60~0332/ORG 35035 reduces stress-related eating which indicates Ro 60-0332/ORG 35035 reduces stress.
WO OOI03~01 PC1'IUS99/16153 Ro 60- 0 mg/lcg 1 mglfCg 2 m,~ACg S mg/kg 10 mg/kg Control 1.23 1.29 1.20 1.21 128 Rats Stressed 4.7Z 4.87 2.19 1.83 1.74 Rats Stress 3.49 (100~Yv)3.58 (103'9~L)0.99 (289:0)0.60 (17%)0.46 (1395) Eating ~ ~ , I I
~
While the invention has been daaorlbed heroin with r~ofer~ce to specific ami preferred ambodimeMS, 'tt is understood that chan8as, modiEo~oes, stda~iims and omissi~s may be made without departing from the spirit snd scvpe.of the imon~on, which is limited only by the appended
6085/A, WY 25093, alaqociate, ziaaelidine; trazodone, amitriptyline, imipramine, trimiptasnine, doxopin, protriptyline, nortriptyline, dibenzoocazepiue, 6epnnyl, isocarboxazide, phenelzine, tnnylcyp~omine, furamlidoa0. procarbazae, moclobatride, brofaromin, nefazodone, bud, MIC
212, DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-03$2/ORG 35035, Ro 60-0175, Org L2962, Ro 60-0332, a-methyl-5-HT, TF11~P, bufotaaia, Ru 24969, 9uipaz~e, 5-cer6oxyimidotrypbminG, sumstriptan, CGS 12066, 8-OH-DPAT, (S~2-(chlore-S»fluoro-iodol-I-y1~1-methylethytamine 1:1 C4H404, (S~2-{4,4,~-trimethyl-1,4-dihydro-indaw(1, 2-b)py~1-1-y1~1-methylethylamino I:1 GtH404, SB 206553, and ~Qally aooaprable salts thareof. Suitable salts can be formed from the above compounds, for exsmpk, as addit'ron sails using the following acids: the hydrohalie _ acids, sulfiuic acid, phoapharic acid or an org~ic acid such as aoatic acid, msteic acid, valeric acid, caproic acid, benzoic acid or nicotine acid.
By "fenfluramines" here is n~cant a cdcemie mixture of d,l-fenfluramine, which is also called N-ethyl-a-methyl-3-(trifluoro-madgrlthanamtha dextra~atory isomer In~ovm as dexfenflurarnine and also as d-fanfhn~amine; ~ the phelmaceutioally acceptable salts of these compounds. Suitable salts can be formed from dexfentluramine or d,l-f~fluramine, for example, as additi~ salts acing the following acids: the ~ acids, sulfluic acid, phosphoric acid or an organic acid such as acetic acid, malefic acid, valeric add, caproic acid, benzoic acid or nicotinic acid.
Far practicing the invention, the active aarotanin-mediaeed neurobrabamisaian stimulating compound may be administered to a patient as a pharmaceutical composition comprising the active compound admixed with a pharmacxutically acceptable carrier, including one or more excipients.
For example, ., f~fl~uxa~inea may be adminito a patient as a pharmacartieal compoaitian comprising either flwaaune or dl-fa~fluhmine admiOOed wig a plrlumacenticatly ac~bk curia, including one or moro excipieata.
The serotoninergic drugs MK-212, DOI, m-CPP, Ro 60-0175/ORG 35030 , Ro 60-35035, Ro 60-015, Org 12962, Ro 60-0332, (S~2-(olt~O-S-fluoro-indol-1-y1~1-methylethylamine 1:1 C4H404, (S~2-(4,4,7-trimethyl-1,4-dihydro-indeno(1, 2-b)pyrrol-1-yl~-1-methylethylamine 1:1 C4H404, and SB 206553 fall into the eiass of drags which a~ivate postsynaptic recxptors. These are agonist drugs which bombard the xrotonin re<:epdoe~s of posbynaptic cells and mimic the effect of large amounts of serotoaia reacting with the postsynaptac cells' aerotonin receptors.
For the purposes of this disclosure, the terms "subject" and "patient" may be wed interchangeably to refer to a human exhibiting at least one symptom of strem.
The pharmacaaically acceptable Gorier and/or excipient of choice utilized for a formulation we ooro~~oi rc-rms99n6is~
used in accordance with the invention depeiads on the mode of administration to a subject. The cotapositions of this invention are sai~ak for parenteral, buccal, sublingual ar rectal administration.
The resulting pharmaxubcsl compcadtions are, for example, tabkta, c~tad mb>ets, capsules, soft gelatin capsules, drinkable emulsions, ~upansions err solutions for oral or injeetable administration, sublingual tablets err suppoaibories. They may also be formulated into a sustained release form.
Among the various e~ccipia~ts vvhicdE may be used far Ihese purposes include talc, magnesium phosphate, lactose or silica ~ the Idce. To the solid Roans may be added a filler, a diluent, a binder such as ethyl-cellulose, dihydroxypt!op~r1 oelluloae, carboxymethyl cellulose, miancrystalline odlnhe~ gum a~abic, gum trags~ or gelatin. The oompoaitimta of this invention may also be flavored, colored or coated with a wax or a plestieixer. It is to be understood that those skilled in the art of p>mrmaoeutical formulation wit! be able to make a variety of formulations that would be within the scope of this di~loaura and the waded elahns, without depertlng from the spirit and . . ... .. ...
of the invention. It is intended that all such formulations be included in this invention.
It is to be understood that according to the teachings of the invention, the invention mercy be d by administering serotanio-mediated neurotransmission stimulating coaipovmds, for example, fentluramines, to a :ubjed as a single unit done ono or moro times per day, or as a plunslity of unit doses once a more times pa day without deviating from the teachings of the invention.
Other drugs, pnefenbly habgereted amphotrtdsinas, may also be useful to treat stress in a subject who is sut~'ering from the hind Qf stress allcwladed by the fenfiuramine treatments of the present invention. Such other useful dntgs may include specific drugs that are not halogenatod amphetamines inchding, but not limited to, effaxor, nafa~odooe, bupropioo, paroxabne, fluoxetine, and sortralin.
Dexfenflaramine sad d,l-foatino are known anorectic agents as disclosed in U.S. Patent No. 3,198,834. .. However, prior to tha,~eaent inreatuon, neither saa~otoninc~ic dcug~s_in:gatloral, nor . ., dexfenflurarnine nor d,l-fenfluramine Ms been known to be etTeetive as a dn~nent for stress in a patient.
Fentluramines aro Irnown to be alTeaive drugs for tr~ng obesity. The tacemic mixture, d,l-fenflurarnine, was disclosed in U.S. Pataant~1,452,815, granted to Wurtman and Wurtman, as being effective for inhibiteng the abrwrmal craving for carbohwhich afflicts samse people and which is associated with their obesity. Daot~lununine is abo udicated for ase in treating patients who cannot control their eating habits or appetite. The use of dexfenfluramine for this purpose was disclosed in U.S. Patent 4,309,445. In both of these patents the use proposed for fenfluramines was for ts~esung a patient's appetite or cravhtg for certain types of food.
Nowhere in these patents is the use of faifluraminea suggested for treatment of the stress fmm which a patient may be suffering.
A theoretical mechanism by v~ieb fenfluramines work for suppressing appetite for certain food types was plod by WurWan ~ Wurtman In Brain SeraLonin, Carbohydrate-Craving, Obesity and Depression, 06esity R~ncJ~ vol. 3, suppl. 4, November 4,1995, pages 477S-480S
incorporated by reference. It has bean qrapotoed t!~ dacfanfluramine is an etTative trcatmant foc the overeating that is associated with a response to dross ~ some people. People overart for a variety of reasons, however. For some people their overeating sauna to be a response to stressful situations.
Dexfenfluramine is shown in thin pablic~On to be uaelbl for tmating tho obesity suffered by such people, but there is no teaching that dexfenPiuramine is useful for treating stress itxlf.
Fentluramines are sarotoninergic arose that istwlbit the abnormal craving for high carbohydrate foods, which leads to a poi caloric b~aoce and subsequent obesity in certain pooplc. Soma, but not all, people benefit &~ the administration of dexfenfluramine by having their craving for certain foods inhibited. This shove citmd publication does not disclose or teach any use of dexfenfluzamine or d,l-fenfluramioes for treating atro~ itself in obese patients, or make any suggestion that these fenfluramines may be effectve as a tra~tment for stross itself. The publication descdbea the aerotoninergic fenfluraminca as sc4lng to facilitate weight loss in subjects in three ways:
"They accelerate tho onset of satiety and enhanao basal metabolic rata by about 100 calories per day. They also inhibit !bo 'carbolnya)~e ersving' manifested by many poople who are overweight or are becoming so, and theme is reuon to believe that this inappropriate eating behavior actually constitutes s 'serotonin banger' by the brain, in which case giving the serotoninergic drug might csuto a specific therapy for the etiologic prods causing the obesity."
Further discussion of the known fynaticuting of fentluramines is found in Wurtman and Wurtman, Brain Serotonin, Carbohydsste-Craving, Obesity and Depression, Recent Advances in TY~yptoplurn Reaear~ch, G. A. Filippini et al. eds., Plenum Press, New York, 1996, pages 35-41 incorporatod by refa~enee.
The use of dexfenflurarnino for tnsating animsle inflidad with periodic pain is discussed in Dexfentluramine: Eon Food Intake in Various Animal Models, Neil E. Rowland and Jams Carhnn, Clinical Newophra"macology, vol 1 I, suppl. l, pp. S33-S50 incorporated by reference. This article indicates in its abstract that: "...both stress-induced eating as well as a food-motivated response (running) are particularly sensitive to inhibition by dexfenfluramine:' This article discloses the administration of ~~'enfluramine to rats exhibiting inaaased eating behavior in response to tail pinching. The tails of the rats were pinched as part of an experimental protocol, which was found to cause the rats to eat larger amounts of food than rats whose tails wee not pinched. Dexfenlluraatine (DF) was found to decroase the eating behavior of the tail pinched rats. Dexfentluramine was known prior to the Rowlsnd et al.
article to depress eating activity, howav~, as shown in Wurtman ~ al., Sciexce, vol. 198, pp. I 178-1180, Dac~nbor, 1977 incorporated by reference.
wo ooro3~ol pcrnrs~n6is3 s The authors did the imply of ~lir imenta with regard to stroas-induced eating as follows on page S39 (DF indiossd»g dumtnine):
"Mild tail assure induces eatia$ and in rats, and this may be n model of stresis-induced eating in humans. (3aesl~ini nopal~ed DF potently inhibits tail presauro-induced eating, and drat the DID of 8~ is abort ~mllf of the doses eve is tlu other paradigms reviewed so far. h was ptrewitmsly roponkd that recemic fenfluramine inhibits tail pressuro-induced eating as wall ~ eonounre~t ba~riors sudr as gaswiag, locoanation, and vocalization. In the sdtdy with DF, ody the asd~at ester was reported, rather than all oral behaviors. These data thus sub lhs~t DF mQr he an apoci~r potent inhibibx of stross-related eating. Further studies are needed to clarrify the effect of DF on other oral behaviors, as well as w>it has 'sdtis~s' alawlg with its anorectic ac~ioa."
Thus, until die pru~ invartioa, it w~ otdy lutawn that dexfenfluramine inhibits eating in tail pinched rats. It was not previously known that iaergic drugs, for examplo dmcfenfluramine or d,l-fenfluramine could bo alt ofve treatment for stress.
The authors of this article indicated only that feutlur:miaa tsiil pia~ing-induced eating and other behaviors stemming from the tail pinching protocol. T'hay did not disclose that the fenfluramines could be used as ttemneets for reducing stress itself. Thu', Row~rtd et al. bad no idea dacfenflm~nine would exhibit airy stress relieving activity pet se. Indeed, it is doubtful that tail pinching and the consequent behavior from the rat ind~ad by the tail coaad save as a mesni~tal, let alone reliable, model for the types of stress experienced by inm~ua;.
The applicants' experiments hence raw pamtitled the discovery that such smistress effects csin be achieved with setotoninergic drugs in goal and i~tfluramines in particular.
On page-S39 of Rowhmd it ~ noted that ors ta~ii;p~ed rats "may be a model of stress-inducod eating in humans", but no indicahan is provided therein that the rat system was in fact an ~ model of stress-inducxd eating in hums. Since the rat system was not a valid model for human behavior, one skilled in the art wrould ue~ have bean led by the results of Rowland with rats, to treat humans suffering from stress with dexfenfhiranitrs.
SUIvHNARY OF TI~$1NY13NTION
Briefly, the pe~ese~ invention is a nonrol trodmeM for stress and symptoms of stress in a subject The appliceNs have discmrered that adaiinis~ring Page 7, line 18.
Administering serotoninergic dnrga in general and fenfluran~s in particular to a patient can bring about a reducxi~ in the stress felt by petite and the symp~ms of stress manifest by the patient. The treatment of stress and stress related symptoms of a patient with these compounds bas not been reported p~eviously.
4Q The present invention provides an splprapriate t~r~nent for stress in human patients, WO 00P03~11 t?GT/US99l16153 especially those from street-iad~se~d ovm~aat~. T'6~ invention is based on the discovery that the serotoninergic drags, for example ueam~a, each as d,l~ine, dexfrafluramine, or their salts can alleviate symptoms of stress is pafaortdt, wbea administerod in efl'rctive amounts or Accordingly, the present inveerxlon ie dineated to a method of frosting a human subject exhibiting one or more symptoms of s>ross, which oaaorprises admmisbering to the subject an effective amount of a compo~md which anharweet via-tmmdia~ed neurotransmimion such ~ d,1 fenfluramine or dexfeafluramine, or a ~utiaal~y accep~bk salt thereof. In a specific eiabodiment of the invani~, whoa the fmflaxruriae h d,1-~fiaramirn or a pharmaca~tically acceptable salt thereof, an effective doom raagm from about 1 S 1o about 150 mg/day, preferably firm I S about 40 to about 80 mg/day. When the fenflwamino is doacfemfluramine or a pharmaceutically acceptable salt thereof, an effaetive ~ eam~pes tom I~biot~ 5 b about I50 mg/day, prafaably from about I S to about 45 mg/day.
According to the present inve~ot~, a treatment is pmwided which results in a reduction in the strew level of the patient a~cperieaciag arnotlosal erxl other triads of stress.
Accordingly, 'tt is an object of the invention to provide a tresoaent for strass perceived by a stress-induced ovett?ating patient.
It is objax of the iar~c~n to pnrvide a treatment for stress which is also tuieful for controlling food make is a stress-induced ovea~eating patient.
It is another object of the invaatioa to provide a treatment for non-eating-relabsd stross symptoms of a pati~t.
It is another object of the inveetioa to pride a trestmant for strnaa is a patient, wherein the tent is with a drug other than as arudolsrtic or beta-blocking drug.
Other objects will become sippateat from the ipt~n of the invention which follows.
DETAILED DESC1~101~1 OF THB INVENTION
We have diaoorered a novel method for ira~tiag straw, said method comprising the administration of stimulators of:erobonia-mediated noarotrrutsmission such as fenfluramines to a patient with stress related symptoms. Ia one preferred embodiment, the method comprises the administration of effective amotmm of either dt»~nfl~lrarnine, dluramiae, or their salts. Other preferrod embodiments provide dateiied disclosure of the use of other compotmds which enhance serotoaia-mediated ru3urotnasmission.
A number of compounds are sho~wa to enhance seratonin-mediated neurotransmission, and thus to be ~eful is treating humans wilt ono or moro symptoms of stress. These compounds include wo ooa~~o~ rcrms99n6is3 die following: d,l-fonflununine, dexfenfluramine, tryptephari; lithium, chlorimipramine, cyanimiprsmine, fluoxetine, paroxetine, fluvoauimine, citalopram, femoxitine, cianopramine, sertraline, sibutramine, venlafaxine, ORG 6532, RU 25591, LM 5008, DU 24565, indalpine, OGP
6085/A, WY 25093, alaprociate, ziraelidina, tta~adone, amitriptyline, imiprarnine, trimipramine, doxapin, protriptyline, nortriptyline, dibanmoat~oopine, depnoqyl, isocarboxazide, phenclzine, tranylcypromine, furawlidone, proaarbsaina, tnoclobamide, bxofaromine, nefazodone, bupropion, MK-212, DOI, m- CPP, Ro 60-0175/ORG 35030; cad Pro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, a-methyl-S-HT, TFMPP, ~; Ru 24969, quipaz;ne, 5-carboxyamidottypt:mina, sumstriptan, C(3S 126, 8-OIi-DPAT, (S)-2-(chloro-S-fluoro-indol-1-yl) I-methylethylamine 1:1 C4H404, (S)"2-(4;4,7 yl-1,4-cl~ydm-indeno(1, 2-b)pyrrol-1 y1)-1 methylethylamine l: I C4H404, SB 206533, and ~tic~ally acceptable salts thereof.
The aerotoninergic drugs MK 212, DOd, m-CPP, Ro 60-0175/ORG 35030, Ro 60-35035, Ro 60-0175, Org 12962, Ro 60.0332, (S).2-(chloro-3-fluoro-indol-1-yl)-I-methylethylamine 1:l C4H404, (Sr2-(4,4,7-trimothyl-1,4-dihy~O-indeno(1, 2-b)pyrml-1-yl)~1-methylethylamine 1:1 C4H404, and SH 206553 fall into the class of dwgs vrh~h activate postsynaptic receptors. These are agonist drugs which bombard the smotonia roceptors of postsynaptic cells and mimic the offod of Large amounts of serotamin reading with the poettaynapt#c cells' setotonin rtceptors. Examples of the use of three of these drugs along with the chanicai names and sources are shown in EXAMPLES 13-1 S.
6-Chloro-2-(1-piperazinylno (MK-212), is obtained from Merck 4t Co., Inc.
Whise Station, NJ. (S)-2-(4, 4, 7-yl-1, 4.d(hydro-indono (1, 2-B} pyrrol-1-yl-I-methylethylamine (Ro 60-175IORG 35030) is attained from )». Hotfmann-Laltoche Ltd., Hasel, Switzerland. (S)-2-(Chloro-5-fluoro-indol~1 yl)-1-mathylethylamine (Ro 60-0332/ORG 35035) is . . .a ; obtained frola F~ 1~Iof6aaan LaRocl~ Ltd., Hasel, Switzerland, l-(2,5-dim~hoxy-4-iodophec~yl)~2-sminopropane (DOI) is obtained from Raaeazch Biochemical Iaternatioasl, Natick, MA. 1-(3-Chl~ophenyl)piperazine (m-CPP) is obtained f~xn Re~rch Biochanical International, Natick, MA.
It is to be understood that the proamrt ia~a~on as disclosed herein, also includes s method of making a modica~nent for treating stress, whensin the hod comprises a step of mixing doxfenflnramine or d,l-fenfluramina with a pharmaceutically acceptable inert ingredient The invention will now be described thmu$,h ilhua~tive examples. The examples are not intended to limit the scope of the invention, which timitod only by the appended claims.
A subgroup of obese individuals ~ identifyed, which individuals describe themselves as being unable to control their eating and who attempt to ~taae an a weight-roducing diet when experiencing emotional distress. These are treated for four months by enrolling them in a wo eera~~w rcrnrs99n6~s3 weight loss program that iachxbs the o8dexfeoflnramine se 30 mg/day sad which iovolvas adherartce to s ~du~de meal post. The the of dfluramine is fend to the ability of stressed overeaten to lose weight.
Body Mass Indeac (BMI) is daftaed as ~e wauig~tt ~ kllogr~s of a wbject, divided by the subject's height in meters squared.
Applicants conduct a survey of 1g9 Ibadaia wnwea of normal body weight (Body Mass Index Q5, average Body Mme lndac 22.5 f ~.36), who are,not put on the weight ~ r~rm, and 211 obese woman (Body Mass Index >25, av~tge Bo4~y Mass Index 38.1 f 0.39). Of these obese women, SO are entered into the weight loss peoaram. Tlte majority of the obese women responding to the surrey report that amoti~sl distress or other types of stross sigaifara~~tiy increases their sasck intakes and their cravings for sweet and star~ty foods. Aiso, stress clearly decreases their ability to control their food intake and to adhere to a vmigbt leas regimen. In contrast, the mryority of the normal weight women responding to dte survey no altesatioaa is eating behavior when experiencing emotional distress of strosses. Moil obese respondents identify anxiety, dep~ion, exhaustion, boredom, angx, tansioa sad ~tion as the stc~ess-idduced emotions a symptoms most likely to make them unable to eontro~l ~reir food intakes. The kieuis of stressos that the patients indicate produce these eaaotlotts or syoms included, among othors, family and job peobiema, boa~edasn, unresolved i eos~ttias and bad news.
Objective measurements of ematlonal distross are made in some using ~e CES-D
(Center for Environmental Studies Depmssion Form) test, which measures current laveb of ernotioaal dis~u (Rsdloff and Leaotr, TJie CAD S1 ale: A Self Repor t IJ~ressiorr Scole J6r Research irr the Gsnrral Population Applied Psychological Measurement 1: 385-401,1977); and the POMS (Profile of Mood States test, flat assesses tetuapa, depression, anger and confusion (McNair, D.; lorr, M. and Droppehnan, L.; Prr~tls of blfvod s Ada~nead;San Diego: Edsl and ' Industrial 1'estuig Service, 1971); bosh of these ~~ara horeby incorporatad'by reference.
These tests are also given monthly dtnin~ tiyo tteafadmot period. At the same times, p~iea~ also complete questionnaires that ask the patients to rate thoir appetito and hunger, and also to rata their tendency to eat in response to a varkty of eaaotianat told stressfui triggers.
The patients are also weighed monthly.
The obese, stressed patients g detcfuramine eacht'bit a weight loss of 12 f 1.8 pounds (5.45 t 0.82 kg) during the four atop study period. Six women receiving dexfenflunsrnine, whose CES-D scone are above normal at dus start of ells study, also exhibit a CF.S-D scare.
Scores are lowered from 34 to 7, 37 ha $, 22 to 9, 19 to S,15 to 7, sad I S to 3, respectively, for these six woman. The mean group score, which se tho beginning of the study is 9.4, tluc~ates betvveen 7 and 8 through the treatanent period.
Scores on the appetite and abase-in~ducod avetesting scales are also reduced compared with WO 00/U3'f01 PCTNS99/16153 baseline levels. The initial scono on tho ~d 6at scale is 10.5, which deereasos to 5.0 duri~ tho treatment period. Tlm summed T~ion, Depeasaion, Anger and Confusion scores o~n the TOMS teat at baseline is 24. This number dtt~a to 1b.8 ~rilng the study period. Moreover, the score on the emotional triggers to overeatiqg report from 23.4 t 9.8 to 8.6 t g,5 ~~
d~riations by the end of the t~cnent pwiod.
Hence, tent with s fenthe~daafline, specifically promotes the ability to control food intake and to lose weigtit amdag the sleducod ova~b~s. Morn surprisingly, tent reduces the indictors of stcoss is tea pit.
In order to confirm the relatiottsbip b~lwaen which e~~hsnce serot~in-mediated neurotransmission and the amelioradien of s abd taonsequcnces of stress, i.e.
overeating and obesity, a number of serotoninergic dt~s are tell au ~o~erweight patients using the above protocols.
Specific examples of the reaulta that are a6ad with drugs which enhance serotonin-modiated aeurotraaimission are now prsovlsbd: The vu~g examples are merely intended to illustrate the invention and are not inbondsd to ibasit tba setae.
)E1;XAMP~.B 1 Example 1 involves treadneM wlth d~-dine at 30 mg/day. A preferred dosage is about 5 mg/day to about 150 mg/day.
C.H. is a 48 year old white single female. Shre s~ in her screening foams that when she is upset or sh~essed she snacks on chocoiwbe, , c~rsrs, pretzels, and candy. She antes that she overeats when feeling frust~sted, over~rheh~tad, and hanely and writes in answer to a question about whether she has difficulty in stick~g to a~ did when uhet or strossed: "In the past when 1 am not in a formalized program, somehow my brain is I'm giv!on s'license to graze to placate my emotions when strewed. I tend to break all my oven '' rules ~ ~,y~ing I want."
The results are shown in Table 1. Her ~ vwtigbt is 216 pounds (98.2 kg) and altar 4 months on dexfenfluramine, drops to 205.5 po~iads (93.4 k~. Her baseline CES-D
Mood Scores drop from 5 to 1 over the trratme~ pealed; add her eAaalional triggers decreaae from a baseline of 23 to a value of 4 after four months. Heasee, the ~tt abo greatly relieves ha emotional distress.
5 TAH1.E 1 Baseline MeMh 1 Manth M~tb 3 Month Mood 5 1 3 2 1 Scores Appetite 10 2 5 5 4 and Cravings Emotional23 2 3 2 4 I S Triggers EXaUI~IPLB 2 Exempla 2 involves treahna~t with da~cfenflura~ine hydrochloride at 30 mg/day.
A preferred dosage range is from about 15 mg/day to about 45 ritgldsy.
C.M. is a 46 year old white n~rtied physician and mother of two. She reports in her initial screening report that wlxa stressed, sbe sneaks on chocolate, candy, chips, cookies, cakelpie, and popcorn. She writes: "I was on W~ight Watchers, doing well even during vacation. But upon the start of the school year with all the schedules to handle,1 was unable to keep with the program. Then the Christmas holidays were upon us and 1 was working e~oelly hard at the office. I started gaining weight and I could not stop eating. My wppotlte has tripped and it is hard for me to say ac."
The results are shown in Tabb 2. Her starting weight is 198 poufs (90.0 kg) and at the eod of 4 months on dexfenfiuramine, her weight drop: to 1 611.7 pounds (82.6 kg).
Her baseline CES-D
Mood Scorns dry from 19 to 4 over the treatment pariod, and her emotional triggers decrease fmm a baseline of 30 to a value of 7 after fonr months. Hence, the tre~neat also greatly relieves this patie~'s stress levels.
Baseline Month Moath Month 3 Month Mood 19 5 2 3 4 CES-D
A,pp~ite 9 6 8 3 5 Cravings 8motional30 12 13 S 7 Triggers EXAMP'I:E 3 F.xampk 3 involves the tr~tmeM of a 57 year old manned femak with lithium carbonate at 900 mg/day for four months. A ~efarned dose ~ shout 600 mg/day to about 1 S00 mg/day.
D.R states in her screening forms that when she is upset or srressod she ovoroats on beer and as well as snack food such as potato chips and pemutts. This occurs when she feels stress or frustration from her employment as a government lawyer.
The results are down is Table 3. Her smiting weight is 246 pounds (111.8 kg) and after 4 months on lithium drops to 225 pounds (1023 leg). Heir baxline CES-D Mood Scores drop from 4 to 2 over the treatment period, and hor dnotional triggers dea~oase from a baseline of 15 to a value of 7 after four months. Hence, the treatment also greatly relieves her emotional distress and stress.
Baseline Month Month Month 3 Month Mood 4 . 3 3 2 2 _ Sues CES-D
Appetite 14 6 9 5 3 and Cravings EmotionalI S 16 LO 6 7 Triggers l2 F.JCAMPLE 4 Example 4 involves the tteatament of a 35 year ald single white female with fluoxetine hydrochloride at a dose from 20 mg/day for the first two weeks, 40 mg/day the ~cond two weeks, 60 mg/~y the third two weeks, and 80 mg/day through the and of the foot month trial. The preferred dose is about 10 mg/day to about 160 mglday.
The results are shown in Table 4. T.M. reports in her initial screening.
report that when stressed, she chronically overeats at meals, aldtough she eats nothing betwe~
and after meals. Her overrating takes the foam of non-atop eating, eonsoming a loaf of Mead and a stick of butter at a single meal. Her starting weight is 183 pou~dds (83.2 kg} and at the ~d of 4 months on fluoxetinc hydrochloride, her weight drops to 172 poutKis (78.2 kg). Her baseline CES-D
Mood SoorGS drop from 15 to 7 over the treatment peu~iod, and her emotional triggers decrease from a baseline of 31 bo a value of 12 after four months. Hence, the treatment also greatly relieves this patient's stress levels.
Baseline Momh 1 Month Month Month 4 Mood 15 10 2 6 7 Scones CES-D
Appetite 17 6 9 3 4 and Cravings Emotional 31 22 13 10 12 Triggers Example 5 involves the treadnent of a 76 year oW single white female with fluvoxamine mateate at a dose from 50 mg/day for the first waak,100 mg/day the second week, and 150 mglday through the end of the four month trial. The deferred dose is about 25 mg/day to about 300 mg/day.
J.B. complains of feelings of stress associated with social activities in the retirement community in which slm lives. While clearly overweight, she does not complain about weight nor apparently recognizes her condition.
The results are shown in Table 5. Her starting weight is 302 pounds ( 137.3 kg) and after 4 months on dexfenfluramiua, drc~pa to 286 pounds (130 kg). Her baseline CES-D
Mood Scores drop wo ooro3~o~ Pcrms~nb~s3 from 23 to 17 over the tmatment period, and hor annsl triggers decna~ from a baselino of 34 to a value of 24 after four months. Tip taint rolio~roa hor social stress nd has the additional bonefit of mocker weight reduction.
TABi.E 5 Baseline Month Month Month 3 Month Mood 23 26 16 15 17 Scores CES-D
Appetite 18 l6 11 12 14 and Cravings Emotional34 27 30 20 24 Triggers E7KAMP1.» 6 Example 6 involves the treatment of a 42 year old married white female with acrrraline hydrochloride at a dose from 50 mglday for the ftmt wcek,100 mg/day the second week, and 200 mg/day through the end of the four month trial. Tlte pposfarred dose is about 25 mgJday to about 400 mg/daY.
P.Q. is ~aployed as as accoua~urt, has two small childrra, and experiences stress during the tax season. She eats betvvoen meals and repo~s wakdning at night with anxiety which is relieved by consumption of ice cream.
The,;results arse shown in Tablo, b. He.r atarti~tg~ woight is 173 pound$
,(78.b kg) and at the end of 4 months on sertraline, her weight drops to 160 pow~ds (72.7 kg). Ha baseline CES-D Mood Scores drop from 20 to 12 ova the treatment periad, at~d her emotional triggers decrease from a baseline of 22 to a value of 3 after four masrd~s. Hence; the treatment c~elieves both the stress levels and the overweight.
WO OOViCi701 PCTNS99I16133 Baseline Maatb 1 M~ 2 Moatb Mmtth 4 Mood 20 16 16 10 12 S
cores CES-D
Appetite I S I2 S 3 I
and Cravings Emotional 22 12 13 5 3 Triggers IS
EXAMPLE ?
Example ? involves the t of a 38 year old single white female with venlafaxiae hydrochloride at a dose from ?5 mg/day fa the first week, I00 mglday the saca~nd week, and 150 mglday through the end of the four month trial. The preferred dose is about 50 mgJday to about 300 mg/day.
L.Z., a single mother of four children, opa~ea a day care in !roc home and complains of continual stress. She eats baked goods excessively in the evening after the children have gone home or to bed.
The results are shown in Table ?. Her stattictg weight is 184 pounds (83.6 kg) anti after 4 mosdhs on daocfanflnraraine, drops to 169 pounds (?6.B kg). H~ baseline CES-D
Mood Soores drop from 8 to 2 over the treatment period, and her emotional triggers decrease from a baseline of 14 to a vaiup of 2 after, four. months. Hence, the treatment also greatly reliewe$ her emotional distress.
wo ooro~oi pcrnJS99nslsa Baseline 1 Month 2 Month Month 4 Mood 8 4 6 2 2 Scorns CES-D
10 Appatite 10 6 7 3 1 and Em~ional 14 9 4 6 2 Triggers EXAMP'LB 8 Examp~ 8 involves the treafrneat of a 44 year old single white femsle with amitriptyline hydrochlori~b at a dose fmm 75 mg/day fa the first week, to 100 mg/day through the ~d of the four month trial. The preferred dose is about SO mg/day to about 200 mglday.
E.E. reports stroll from ha employment as a dispatcher for a trucking compamr.
Ha discomfort is relieved by eating fried folds, especially $iod potsoboes.
The results are shown in Table 8. Her starting weight is pounds (90.0 kg) and at the end of 4 myths on dexfa~fluramine, her weight drops to pounds (82.6 kg). Her baseline CES-D Maod Scores drop from 29 to 18 over the treatment period, ~d her emotional triggers decreem from a baxline of 25 to a value of 3 aRa four months. Hence, the traadnettt also groatly relievos this patient's stress levels.
we ooro3no~ pcTius99n6is3 Baseline Month Month 2 Month Month 4 Mood 29 22 20 23 18 Scoros CES-D
Appetite 19 16 8 13 8 and Emotional 25 22 13 5 3 Triggers Example 9 involves the tr~hneat of a 30 year old married white female with trazodone hydrochloride at a dose of 100 mg/day in divided doses of 50 mg each through the ~d of the four month trial. The prefornod dose is about 50 mglday to 200 mg/day.
N.1. , with throe small childron, rapats an unhappy and stressful home life with an interfering mother in-law and ineffectual husband. Her stmss seems relieved by life-night snacking on sweet food.
The results are shown in Table 9. Her starting weight is 203 pounds (923 kg) and at the ~d of 4 months on serd~alino, har weight drops to 160 pounds (72.7 kg). Her baseline CES-D Mood Scores drop from 9 to 1 over the traatnaent perlad, and her wnotional triggers decrease from a .. _ ... . baseline of l2,to a value.of 3 after four manths. Honeq, the treatment relieves both the. dress lavols and the overweight.
Hasaline Month I Month Month Month 4 Mood 9 16 16 10 1 S
cores CBS-D
Appetite 9 5 5 3 5 and Cravings Emotional 12 12 9 5 3 Triggers EXAMPLE IO
Example 10 involves the tresatment of a 31 year aW married white female with imipramine hydrochloride at an intramuscular cbae of 75 mgfday through the end of the four month trial. The preferred dose is about 50 mg/day to about 156 mg/day.
A.R., is employed at a consulting engineering firm and atturda law school at night. Her regimented schedule and lack of exeuciae array oo~iibute to hor feelings of stress, which ayenders over-eating.
The results are shown in Table 10. Her starting weight is 163 pounds (74.1 kg) and after 4 months oo imipramine, drops to 155 pounds (70.4 kg). Her baseline CES-D Mood Scores drop from 36 to 20 over the treatment period, and her emationa! triggeas decrease from a baseline of 22 to a value of 8 after four months. Nonce, the treatment also greatly relieves hex emotional distress.
Baseline Month 1 Month Month 3 Month Mood 36 34 26 21 20 Scores CES-D
Appetite 15 12 7 3 6 and Cravings Emotional 22 15 14 6 8 Triggers Example I 1 involves the trnat~nant of a married 42 year old white female with trimipramine maleate at a dose from 75 mglday for the first week, to 100 mglday through the end of the four month trial. The preferred dose is about 50 mg/day to about 200 mg/day.
A.8., a teacher in a metrapolitsn school, reports stress which she attributes to her work and gd~ally unhappy home life. She is anaek to control qrisodic bingo eating of ice cream and cake.
The results are shown in Table 11. Her starting weight is 180 pounds (81.8 kg) and at the end of 4 moaths on trimipramine, her weight drops to 158 pounds (71.8 kg). Her baseline CES-D Mood Scores drop from 25 to 13 over the treatment period, and her emotional triggers decrease from a baseline of 14 to a value of 3 after fouc months. Haace, the treatment also greatly relieves this patient's stress levels.
WO OO/A370t PCTNS99/16153 Hasoline MaMh 1 Month 2 Month Month Mood 25 22 20 15 13 Scores CES-D
Appetite 11 9 8 13 6 and Cravings Emotional14 8 13 6 3 Triggers Example 12 involves the troatment of a single 50 year old white female with ph~lzine sulfate at a dose from 45 mg/day for the first week, to 60 mg/day through the eeul of the four month trial, each daily dose taken in throe portions. The proferrod dose is about 15 mg/day to about 120 mg/day.
D.C. is a suburban bus driver and finds driving in traffic strossful. She ceWtly diets but is unablo to successfully lose weight.
The rosults aro shown in Table 12. Her startiag weight is 184 pounds (83.6 kg) and at the end of 4 months on phonelzine, her weight drops to 174 pounds (79.1 kg). Her baseline CES-D Mood Sooros drop from 20 to 14 over tho treatment period, and her emotional triggers decrease from a baseline of 20 to a value of 7 after four months. Hence, the troatment also greatly rolieves this patient's stross levels.
wo ooro3~oi pcrivs99n6tsa Baseline Month health Mouth Month 4 Mood 20 22 20 15 14 Sores CES-D
10 Appetite 19 15 8 13 12 and Cravings Emotional 20 8 13 6 7 Triggers EXAIMp'LE 13 The effect of the hydrochloride salt of 6-Chloro-a-( 1-pipera~anyl)pyrazine (MK-212, which is obtained from Merck dt Co., Inc. Whitehouse Station, NJ, on stress relatod oating in animals is determined through the observation of the effect of imental compounds on stress-rehuad eating in adult Sprague-Dawlay rats. Those rats are widely used as a recognized animal model useful in predicting tho effect of st~onin~gie drugs in h!amas~s.
In those experiments, a group of 5 adult female sad S adult male Sluagtm-Dawley rats weighing betwo~ 200 and 250 grams each are used as control animals. An undghtared clamp is placed on the tail of those animals. The untightaned clamp provides the unstressed condition. Eacb aeimal is planed in an individual cage and allowad free access to food. The amount of food consumed is determined at 2, 4 and 8 hours after the initiation of the trial.
A similar group of rats has . a.elamp tighteapd.on.tho tail. Tho amount of food caused by this streased,gcoup of rats is shown t in the 0 mg/kg column. Three similar groups of atr~ed rats are injected with 1, 2, 5, or 10 mg/kg body weight of MK-212 ono hour before initiation of the expariment.
The results aro shown in Table 13. The average sanount of food in mg which is consumed per rgt 8 hours after initiation of the trials is shown in the following table. The relative amounts of stress eating with the amount at 0 mg/kg MK-212 as I00'/o is also shown in the Stress Eating row.
The preferred daily dose of MK-212 is about 1 mg/kg body weight to about 10 mg/kg body weight.
Table 13 shows MK-212 reduces stress-related eating which indicates MK-212 reduces wo ooro3m rc~rms9sn61s3 MK 212 0 mg/kg 1 mglkg 2 mgfkg 5 mg/kg 10 mg/kg Control 1.25 1.32 1.20 1.16 1.03 Rats Stressed 4.63 4.14 3.78 2.01 .97 Rats Stress 3.38 (100Yo)2.82 (83%)2.58 (76'q"o)0.85 (25%)0.0 (0%) Eating Example 14 shows the effect of (S)-2-(4, 4, ?-trimethyl-1, 4-dihydro-indol (1, 2-B) pyrrol-1-yl-L-methylethyhunine (Ro 60-175lORG 35030) which is obtainod from F. HofFmann-LaRoche Ltd., Basel, Switzerland, on stress-induced eating. The dent is done as in Example 13 and Table 13 . u~pt tit Ro 60-1.75/ORG 35030 is used iastead of MK-212. The prefomed daily dose of Ro 60-175/ORG 35030 is about 1 mg/kg body weight to about 10 mglkg body weight.
Table 14 shows that Ro 60-175JORG 35030 reduces stress related eating which indicates Ro 60-1?S/ORG 35030 reducos stress.
Ro 60- 0 mgllcg 1 mglkg 2 mg/kg 5 mg/kg 10 mg/kg Control 1.31 1.28 1.30 1.20 1.13 Rats Stressed 4.51 3.6b 1.43 1.30 1.16 Rats Stress 3.20 (100%)2.38 (74%)0.13 (4"/a)0.10 (3%)0.03 (1%) Eating The effect of (S}.2-(Chloro-5-tluoro-indol-1~y1~1-mathylethylamine (Ro 60-35035) which is obtaiaed from F. Hotfmann LaRoche Ltd., Basel, Switzerland, on eating in rats is determined as in EXAMPLE 13 and Table 13, except Ro b0-0332/ORG 35035 is uxd than MK-212. The prefemd daily dose of Ro 60-033210RG 35035 is about 1 mg/kg body weight to about 10 mg/kg body weight.
Table 15 shows that Ro 60~0332/ORG 35035 reduces stress-related eating which indicates Ro 60-0332/ORG 35035 reduces stress.
WO OOI03~01 PC1'IUS99/16153 Ro 60- 0 mg/lcg 1 mglfCg 2 m,~ACg S mg/kg 10 mg/kg Control 1.23 1.29 1.20 1.21 128 Rats Stressed 4.7Z 4.87 2.19 1.83 1.74 Rats Stress 3.49 (100~Yv)3.58 (103'9~L)0.99 (289:0)0.60 (17%)0.46 (1395) Eating ~ ~ , I I
~
While the invention has been daaorlbed heroin with r~ofer~ce to specific ami preferred ambodimeMS, 'tt is understood that chan8as, modiEo~oes, stda~iims and omissi~s may be made without departing from the spirit snd scvpe.of the imon~on, which is limited only by the appended
Claims (39)
1. A method of treating a human subject exhibiting one or more symptoms of stress, which comprises administering to said subject an effective amount of a compound which enhances serotonin-mediated neurotransmission, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the compound which enhances serotonin-mediated neurotransmission or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 5 mg/day to about 150 mg/day.
3. A method of treating a human subject exhibiting one or more symptoms of stress, which comprises administering to said subject an effective amount of a compound selected from the group of compounds consisting of d,1-fenfluramine, dexfenfluramine tryptophan, lithium, chlorimipramine, cyanimipramine, fluoxetine, paroxetine, flavoxamine, citalopram, femoxitine, cianopramine, sertraline, sibutramine, venlafaxine, ORG 6582, RU 25591, LM
5008, DU 24565, indalpine, CGP 6085/A, WY 25093, alaprociate, zimelidine, trazodone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, nortriptyline, dibenzoxazepine, deprenyl, isocarboxazide, phenelzine, tranylcypromine, furazolidone, procarbazine, moclobemide, brofaromine, nefazodone, bupropion, MK-212,DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, .alpha.-methyl-5-HT, TFMPP, bufotenin, Ru 24969, quipazine, 5-carboxyamidotryptamine, sumatriptan, CGS 12066, 8-OH-DPAT,(S)-2-(chloro-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4, (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4, SB 206553, and pharmaceutically acceptable salts thereof.
5008, DU 24565, indalpine, CGP 6085/A, WY 25093, alaprociate, zimelidine, trazodone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, nortriptyline, dibenzoxazepine, deprenyl, isocarboxazide, phenelzine, tranylcypromine, furazolidone, procarbazine, moclobemide, brofaromine, nefazodone, bupropion, MK-212,DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, .alpha.-methyl-5-HT, TFMPP, bufotenin, Ru 24969, quipazine, 5-carboxyamidotryptamine, sumatriptan, CGS 12066, 8-OH-DPAT,(S)-2-(chloro-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4, (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4, SB 206553, and pharmaceutically acceptable salts thereof.
4. The method of claim 3 wherein the compound that enhances serotonin-mediated neurotransmission or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 5 mg/day to about 1500 mg/day.
5. A method of treating a human subject exhibiting one or more symptoms of stress, which comprises administering to said subject an effective amount of d,1fenfluramine, dexfenfluramine, or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 which comprises administering an effective amount of d,1-fenfluramine or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 in which said d,1-fenfluramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 15 to about 15 mg/day.
8. The method of claim 6 in which said d,1-fenfluramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging form about 40 to about 80 mg/day.
9. The method of claim 5 which comprises administering an effective amount of dexfenfluramine or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 in which said dexfenfluramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 5 to about 150 mg/day.
11. The method of claim 9 in which said dexfenfluramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 15 to about 45 mg/day.
12. The method of claim 3 which comprises administering an effective amount of lithium or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 in which said lithium or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 600 mg/day to about 1500 mg/day.
14. The method of claim 3 which comprises administering an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 in which said fluoxetine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 10 mg/day to about 160 mg/day.
16, The method of claim 3 which comprises administering an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 at which said fluvoxamine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 25 mg/day to about 300 mg/day.
18. The method of claim 3 which comprises administering an effective amount of sertraline or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 in which said sertraline or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 25 mg/day to about 400 mg/day.
20. The method of claim 3 which comprises administering an effective amount of venlafaxine or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 in which said venlafaxine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50 mg/day to about 300 mg/day.
22. The method of claim 3 which comprises administering an effective amount of amitriptyline or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 in which said amitriptyline or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50 mg/day to about 200 mg/day.
24, The method of claim 3 which comprises administering an effective amount of trazodone or a pharmaceutically acceptable salt thereof.
25. The method of claim 24 in which said pharmaceutically or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50 mg/day to about 200 mg/day.
26. The method of claim 3 which comprises administering an effective amount of imipramine or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 in which said imipramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50 mg/day to about 150 mg/day.
28. The method of claim 3 which comprises administering an effective amount of trimipramine or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 in which said trimipramine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50 mg/day to about 200 mg/day.
30. The method of claim 3 which comprises administering an effective amount of phenelzine or a pharmaceutically acceptable salt thereof.
31. The method of claim 30 in which said phenelzine or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 15 mg/day to about 120 mg/day.
32. The method of claim 1 wherein the compound which enhances serotonin-mediated neurotransmission is a compound which activates postsynaptic serotonin receptors.
33. The method of claim 32 wherein the compound which activates postsynaptic serotonin receptors is selected from the group of compounds consisting of MK-212, DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4, (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1, 2-b)pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4, and SB 206553.
34. The method of claim 33 which comprises administering an effective amount of MK-212 or a pharmaceutically acceptable salt thereof.
35. The method of claim 34 wherein said MK-212 or a pharmaceutically acceptable thereof is administered at a daily dose ranging from about 0.1 mg/kg body weight to about 10.0 mg/kg body weight.
36. The method of claim 33 which comprises administering an effective amount of Ro 60-175/ORG 35030 or a pharmaceutically acceptable salt thereof.
37. The method of claim 36 wherein said Ro 60-175/ORG 35030 or a pharmaceutically acceptable salt thereof is administered at a daily dose ranging from about 0.1 mg/kg body weight to about 10.0 mg/kg body weight.
38. The method of claim 33 which comprises administering an effective amount of Ro 60-0332/ORG 35035 or a pharmaceutically acceptable salt thereof.
39. The method of claim 38 wherein said Ro 60-0332/ORG 35035 or a pharmaceutically acceptable salt thereof is administered at a daily dose ranging from about 0.1 mg/kg body weight to about 10.0 mg/kg body weight.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9301398P | 1998-07-16 | 1998-07-16 | |
| US60/093,013 | 1998-07-16 | ||
| PCT/US1999/016153 WO2000003701A1 (en) | 1998-07-16 | 1999-07-16 | Composition for treatment of stress |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2337507A1 true CA2337507A1 (en) | 2000-01-27 |
Family
ID=22236330
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002337507A Abandoned CA2337507A1 (en) | 1998-07-16 | 1999-07-16 | Composition for treatment of stress |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1096927A4 (en) |
| JP (1) | JP2002520353A (en) |
| CA (1) | CA2337507A1 (en) |
| WO (1) | WO2000003701A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR021155A1 (en) | 1999-07-08 | 2002-06-12 | Lundbeck & Co As H | TREATMENT OF NEUROTIC DISORDERS |
| AU2002243097A1 (en) * | 2002-04-03 | 2003-10-13 | Hyundai Pharm. Ind. Co., Ltd. | Quinoline derivatives, their preparation and pharmaceutical compositions comprising the same |
| WO2003090743A1 (en) * | 2002-04-24 | 2003-11-06 | Cypress Bioscience, Inc. | Prevention and treatment of functional somatic disorders, including stress-related disorders |
| RU2617512C1 (en) | 2015-10-23 | 2017-04-25 | Общество с ограниченной ответственностью "Нормофарм" | Means with antistress, anxiolytic and antidepressant activity and composition based thereon |
| GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
| KR20220008824A (en) | 2019-04-17 | 2022-01-21 | 컴퍼스 패쓰파인더 리미티드 | How to treat anxiety disorders, headache disorders and eating disorders with psilocybin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1593659A1 (en) * | 1983-12-29 | 1990-09-23 | Московская ветеринарная академия им.К.И.Скрябина | Method of preventing stress of chickens |
| JPH06699B2 (en) * | 1984-08-11 | 1994-01-05 | カネボウ食品株式会社 | Mental stability chewing gum |
| HU202108B (en) * | 1986-07-30 | 1991-02-28 | Sandoz Ag | Process for producing pharmaceutical compositions containing serotonine antqgonistic derivatives of indol-carboxylic acid or imidazolyl-methyl-carbazol |
| US5114976A (en) * | 1989-01-06 | 1992-05-19 | Norden Michael J | Method for treating certain psychiatric disorders and certain psychiatric symptoms |
| KR950700063A (en) * | 1992-02-21 | 1995-01-16 | 베르너 발데크 | Brofaromine as an agent for treating post-traumatic stress |
| DE69434872T2 (en) * | 1993-06-28 | 2007-04-05 | Wyeth | New treatments using phenethyl derivatives |
| FR2710916B1 (en) * | 1993-10-04 | 1995-12-22 | Pasteur Institut | Compounds of a peptide nature having a modulating activity of the serotonergic response; diagnostic and therapeutic applications. |
| TW344661B (en) * | 1993-11-24 | 1998-11-11 | Lilly Co Eli | Pharmaceutical composition for treatment of incontinence |
| US5597826A (en) * | 1994-09-14 | 1997-01-28 | Pfizer Inc. | Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist |
| US5502080A (en) * | 1994-11-01 | 1996-03-26 | Hitzig; Pietr | Combined use of dopamine and serotonin agonists in the treatment of allergic disorders |
| JPH0940648A (en) * | 1995-08-02 | 1997-02-10 | Yamanouchi Pharmaceut Co Ltd | New 8-(2-aminoalkoxy)quinoline derivative |
| US5852020A (en) * | 1996-11-22 | 1998-12-22 | Bristol-Myers Squibb Company | Nefazodone: use in treating post traumatic stress disorder |
-
1999
- 1999-07-16 CA CA002337507A patent/CA2337507A1/en not_active Abandoned
- 1999-07-16 JP JP2000559836A patent/JP2002520353A/en active Pending
- 1999-07-16 WO PCT/US1999/016153 patent/WO2000003701A1/en not_active Application Discontinuation
- 1999-07-16 EP EP99934107A patent/EP1096927A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002520353A (en) | 2002-07-09 |
| EP1096927A1 (en) | 2001-05-09 |
| WO2000003701A1 (en) | 2000-01-27 |
| EP1096927A4 (en) | 2002-09-04 |
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