CA2183069A1 - Compositions comprising a mast cell degranulation-blocking agent for treatment of endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin - Google Patents
Compositions comprising a mast cell degranulation-blocking agent for treatment of endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative originInfo
- Publication number
- CA2183069A1 CA2183069A1 CA002183069A CA2183069A CA2183069A1 CA 2183069 A1 CA2183069 A1 CA 2183069A1 CA 002183069 A CA002183069 A CA 002183069A CA 2183069 A CA2183069 A CA 2183069A CA 2183069 A1 CA2183069 A1 CA 2183069A1
- Authority
- CA
- Canada
- Prior art keywords
- mast cell
- composition according
- cell degranulation
- blocking agent
- histamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
Abstract
A method for treating endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin, such as abdominal migraine and irritable bowel syndrome, entails administering a pharmaceutically effective amount of a mast cell degranulation-blocking agent, e.g. a naturally occurring polyamine, a heterocyclic histamine-1 receptor antagonist, a histamine-3 receptor agonist or an anti-female sex hormone.
Description
W0 95/21611 ~ 2 ~ ~ 3 û 6 ~
COMPOSITIONS COMPRISING A MAST CELL DEGRANULATION-BLOCKING
A6ENT FOR TREATMENT OF ENDOGENOUS, PAINFUL 6A~1~ulNl~sllNAL
CONDITIONS OF NON- INFLAMMATORY, NON-ULCERATIVE ORIGIN
Rl~ ,,J OF T~ lNV~l~lCII
The present invention relates to treating PnAggPnr~
painful gastrointestinal conditions, such as ~h~ ; nA 1 migraine and irritable bowel t~yl..ll~ -, which involve neither inf lammation nor ulcers . ~IF~.~rl~g~ in this 10 context denotes a condition that is not attributed to an ~Y~J~Y.~ casual factor such afi a food allergy, a bacterial or viral infection, ~ parasitic infestation, a drug reaction or trauma. More specifically, the present invention relates to treating a patient suffering from 15 such a condition with a pharmaceutically effective amount of ~ mast cell degranulation-~lorl~inq agent.
The phrase ~Al-' ;nAl pain" indicates pain associated with the gastrointestinal tract. Fllnr1-;r~nAl Al-' ;llAl pain usually is clafisified either as dyspepsia not 20 associated with ulcers or as irritable bowel ~yll~
Irritable bowel ~yl~dL~ - (IBS), also known as "spastic colon" and "mucous coliti~, " i5 an intestinal motility disorder and ranks among the most common pathological conditions of the intestine. IBS is 25 characterized by periodic or chronic bowel ~,y : which include Ah~- in~l pain, diarrhea, constipation, a sen~e of incomplete evacuation, bloating, and excess gas sensation. This disorder seems to afflict type A (highly driven, perfect;~ni~-t) personalities pre~ ;n:-ntly~ and 30 is two to five times more prevalent in women (20 times higher in Jewish women) than in men . It affects about 3 percent of the population. Dlos-.uo.n~ ~lospital Practice 93: 95-108 (1988).
_ _ _ W09~/21611 Pain and flatulence are~ ~e most EJL. ;nc~nt symptoms in patients suffering; from IBS. The pain is usually situated in the left lower quadrant or suprapubically.
It may be worse just before defecation and may lessen slowly afterward. Certain foods may precipitate the symptoms. When d;Arrhea is the main complaint, the stool o~ten is watery but not bloody. The diarrhea LLe~uel.Lly is worst in the morning and improves during the day.
Some patient6 l A; n of pain in the left upper quadrant that is often brought on by meals and is very consistent in nature. In these patients, plain Al ' ;llAl X-rays d LLate air in the splenic fleYure. Although this variant of IBS has been called "splenic fleYure ~ylldL~ there is no evidence t_at its pathrg~n~c;c differs from that of other manifestations of the disorder .
Many patients relate an ~YAcQrhAtion of symptoms to episodes of emotional stress. Fear of underlying cancer i8 common. In children of school age, IBS present6 primarily with pain. Pain is usually periumbilical or in the left lower quadrant and i5 cramping in nature.
Many patients also eYperience Ahal ;nAl pain that is ~ndngon~ c but that ig associated with nau6ea, bowel peristalsis and flatulence without d;Arrhl~A or constipation, the symptoms commQnly seen with IBS. Such ~- ; nA l pain also can be associated with classic symptoms of migraine, such as one-sided h~AdArh~ with p-~cc;hle involvement of one eye and visual di_LuLl,al.ces in that eye. AYon et ~1., J. Clin. GasLL.,e- terol. 13:
615-16 (1991). By the same token, about 30-50% of patients d;~A~n-ls~cl with IBS have frequent hPA~Arh~C, as ~ed to less than 15% in the control population.
Watson et al., Can. Med. Assoc. J. 118: 387-98 (1978);
Whorwell et al., Gut 27: 37-40 (1986). Finally, ~- ; nA l pain and associated symptoms can occur in the absence of a h~AdArhe and still be considered a "migraine equivalent," ~cp~c;Ally in children. Lundbert, N~ .qr 15: 122-25 (1975).
COMPOSITIONS COMPRISING A MAST CELL DEGRANULATION-BLOCKING
A6ENT FOR TREATMENT OF ENDOGENOUS, PAINFUL 6A~1~ulNl~sllNAL
CONDITIONS OF NON- INFLAMMATORY, NON-ULCERATIVE ORIGIN
Rl~ ,,J OF T~ lNV~l~lCII
The present invention relates to treating PnAggPnr~
painful gastrointestinal conditions, such as ~h~ ; nA 1 migraine and irritable bowel t~yl..ll~ -, which involve neither inf lammation nor ulcers . ~IF~.~rl~g~ in this 10 context denotes a condition that is not attributed to an ~Y~J~Y.~ casual factor such afi a food allergy, a bacterial or viral infection, ~ parasitic infestation, a drug reaction or trauma. More specifically, the present invention relates to treating a patient suffering from 15 such a condition with a pharmaceutically effective amount of ~ mast cell degranulation-~lorl~inq agent.
The phrase ~Al-' ;nAl pain" indicates pain associated with the gastrointestinal tract. Fllnr1-;r~nAl Al-' ;llAl pain usually is clafisified either as dyspepsia not 20 associated with ulcers or as irritable bowel ~yll~
Irritable bowel ~yl~dL~ - (IBS), also known as "spastic colon" and "mucous coliti~, " i5 an intestinal motility disorder and ranks among the most common pathological conditions of the intestine. IBS is 25 characterized by periodic or chronic bowel ~,y : which include Ah~- in~l pain, diarrhea, constipation, a sen~e of incomplete evacuation, bloating, and excess gas sensation. This disorder seems to afflict type A (highly driven, perfect;~ni~-t) personalities pre~ ;n:-ntly~ and 30 is two to five times more prevalent in women (20 times higher in Jewish women) than in men . It affects about 3 percent of the population. Dlos-.uo.n~ ~lospital Practice 93: 95-108 (1988).
_ _ _ W09~/21611 Pain and flatulence are~ ~e most EJL. ;nc~nt symptoms in patients suffering; from IBS. The pain is usually situated in the left lower quadrant or suprapubically.
It may be worse just before defecation and may lessen slowly afterward. Certain foods may precipitate the symptoms. When d;Arrhea is the main complaint, the stool o~ten is watery but not bloody. The diarrhea LLe~uel.Lly is worst in the morning and improves during the day.
Some patient6 l A; n of pain in the left upper quadrant that is often brought on by meals and is very consistent in nature. In these patients, plain Al ' ;llAl X-rays d LLate air in the splenic fleYure. Although this variant of IBS has been called "splenic fleYure ~ylldL~ there is no evidence t_at its pathrg~n~c;c differs from that of other manifestations of the disorder .
Many patients relate an ~YAcQrhAtion of symptoms to episodes of emotional stress. Fear of underlying cancer i8 common. In children of school age, IBS present6 primarily with pain. Pain is usually periumbilical or in the left lower quadrant and i5 cramping in nature.
Many patients also eYperience Ahal ;nAl pain that is ~ndngon~ c but that ig associated with nau6ea, bowel peristalsis and flatulence without d;Arrhl~A or constipation, the symptoms commQnly seen with IBS. Such ~- ; nA l pain also can be associated with classic symptoms of migraine, such as one-sided h~AdArh~ with p-~cc;hle involvement of one eye and visual di_LuLl,al.ces in that eye. AYon et ~1., J. Clin. GasLL.,e- terol. 13:
615-16 (1991). By the same token, about 30-50% of patients d;~A~n-ls~cl with IBS have frequent hPA~Arh~C, as ~ed to less than 15% in the control population.
Watson et al., Can. Med. Assoc. J. 118: 387-98 (1978);
Whorwell et al., Gut 27: 37-40 (1986). Finally, ~- ; nA l pain and associated symptoms can occur in the absence of a h~AdArhe and still be considered a "migraine equivalent," ~cp~c;Ally in children. Lundbert, N~ .qr 15: 122-25 (1975).
2~3~g WO95121611 ~ r~u.,~ l~9 It is appropriate, therefore, to con6ider the pathophysiology and therapy of the category of PnSn~enmlc, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin, ;nr~ ;nq but 5 not limited to ~hA~ ; nA 1 migraine and IBS .
There iB no effective therapy for IBS or related, Pn-lnrJPnnllc gagtrointestinal conditions. Thus, while variou6 _ ' have been described as useful in treating IBS, ;nnllll;nrJ 9H-fluorenyl-substituted amino acid derivative6 (U.S. patent No. 5,079,260), bPn7o~;~7orine derivative6 (U.S. patent No. 4,970,207), certain substituted sulfnnAm;~lps (European application No. 0 404 440), and mu opiate receptor antagonists or "blockers" (U.S. patent No. 4,684,620), none of the 15 ~l;cr~050cl LLeai ~ approaches in fact have proven successful. See, for example, .J. G~stroenterol. 95: 232-41 (1988).
Similarly, no effective remedy exists for Ah~lnm;nAl migraine . Development of a ~L c:a' L has been hindered 20 in part by the fact that the condition often pre6ents without hPA~ArhP and any of the ~LUdL~ y, L
(nausea, vomiting, photophobia, Snnnrhnh;A) typically associated with ordinary migraine.
For example, agent6 that prevent vasodilation, such 25 a6 the ,B-blocker ~LuyLanO101~ seem not to work, since the A~' ;nAl pain appears not to be associated with the vasculature, in contrast to the migraine hP~rhP. By the same token, none of the drugs used prophylactically or acutely (symptomatically) for the LL.~a; of 30 migraine hPA~lArhPq would be PYrectP~l to work, since the prophylactic agents prevent vasodilation while the acute agents constrict dilated vessels. ~ veL, drugs effective against migraine hPArl~rhPC must cro6s the blood-brain barrier, while a drug effective against 35 Al-' ;llAl migraine would be . u.,~ el.LLated preferentially in the intestine. Also, illLL~cLarlial mast cell6 which have been associated with migraine hPArlArhPc~ see Theoharides, ~iife Science5 46: 607-17 (1980), and U.S.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Wo 95121611 ~ g~ r~ lJY2 patent No. 5,250,529~, differ from gastrointestinal mast cells. For instance, t~heiformer but not the latter are inhibited by fl; c~ lm cromoglycate . Pierce et al ., .J.
Immunol. 128: 2481-86 (1982); Labracht-Hall et al., Neurr~ n~e 39: 199-207 (-990).
STTM~T~RY OF ~TT' INVFNTION
It is an object of the present invention, therefore, to provide an effective LL~=CI; L for the above-dcscribed category of Pnfl~Pnr~ gastrointestinal conditions which 10 avoids the lack of success and other problems associated with pa6t ef f orts to this end .
In accomplishing this objective and others, there has been provided, in accordance with one aspect of the present invention, a method for treating endogenous, 15 painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin, which method comprises administering to a patient a rhArr-^olo~ lly effective amount of a mast cell de,~L~ ulation hlorking agent.
In a preferred emhofl;- L, the mast cell-20 degranulation hlo~kin~ agent is selected from the groupconsisting of naturally occurring polyamines, heterocyclic histamine-1 receptor antagonists, histamine-
There iB no effective therapy for IBS or related, Pn-lnrJPnnllc gagtrointestinal conditions. Thus, while variou6 _ ' have been described as useful in treating IBS, ;nnllll;nrJ 9H-fluorenyl-substituted amino acid derivative6 (U.S. patent No. 5,079,260), bPn7o~;~7orine derivative6 (U.S. patent No. 4,970,207), certain substituted sulfnnAm;~lps (European application No. 0 404 440), and mu opiate receptor antagonists or "blockers" (U.S. patent No. 4,684,620), none of the 15 ~l;cr~050cl LLeai ~ approaches in fact have proven successful. See, for example, .J. G~stroenterol. 95: 232-41 (1988).
Similarly, no effective remedy exists for Ah~lnm;nAl migraine . Development of a ~L c:a' L has been hindered 20 in part by the fact that the condition often pre6ents without hPA~ArhP and any of the ~LUdL~ y, L
(nausea, vomiting, photophobia, Snnnrhnh;A) typically associated with ordinary migraine.
For example, agent6 that prevent vasodilation, such 25 a6 the ,B-blocker ~LuyLanO101~ seem not to work, since the A~' ;nAl pain appears not to be associated with the vasculature, in contrast to the migraine hP~rhP. By the same token, none of the drugs used prophylactically or acutely (symptomatically) for the LL.~a; of 30 migraine hPA~lArhPq would be PYrectP~l to work, since the prophylactic agents prevent vasodilation while the acute agents constrict dilated vessels. ~ veL, drugs effective against migraine hPArl~rhPC must cro6s the blood-brain barrier, while a drug effective against 35 Al-' ;llAl migraine would be . u.,~ el.LLated preferentially in the intestine. Also, illLL~cLarlial mast cell6 which have been associated with migraine hPArlArhPc~ see Theoharides, ~iife Science5 46: 607-17 (1980), and U.S.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Wo 95121611 ~ g~ r~ lJY2 patent No. 5,250,529~, differ from gastrointestinal mast cells. For instance, t~heiformer but not the latter are inhibited by fl; c~ lm cromoglycate . Pierce et al ., .J.
Immunol. 128: 2481-86 (1982); Labracht-Hall et al., Neurr~ n~e 39: 199-207 (-990).
STTM~T~RY OF ~TT' INVFNTION
It is an object of the present invention, therefore, to provide an effective LL~=CI; L for the above-dcscribed category of Pnfl~Pnr~ gastrointestinal conditions which 10 avoids the lack of success and other problems associated with pa6t ef f orts to this end .
In accomplishing this objective and others, there has been provided, in accordance with one aspect of the present invention, a method for treating endogenous, 15 painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin, which method comprises administering to a patient a rhArr-^olo~ lly effective amount of a mast cell de,~L~ ulation hlorking agent.
In a preferred emhofl;- L, the mast cell-20 degranulation hlo~kin~ agent is selected from the groupconsisting of naturally occurring polyamines, heterocyclic histamine-1 receptor antagonists, histamine-
3 L c:Ct:~tvl agonists, and agents that counteract the influence of female sex h~ -- (female sex hormone 25 antagonists or inhibitors, referred to collectively as " anti-f emale sex h~ - Y " ) . In other pref erred ~ i- Ls the mast cell dey~ ulation blocking agent is crPrminP or spPl-m;flinP~ lLv,-y~ine or ketotifen, ~
difluoro-N-fluvr, L}lyl histamine, tamoxifen or a 30 gonadotropin-releasing hormone (leutinizing hormone rPl~cin~ hormone) i~ns~logllP. In yet other preferred -'ir Ls, the mast cell dey~-r-ulation hlorkin~ agent is N-dimethyl histamine, R-methyl histamine, ~, ,B-dimethyl-N(dimethyl) histamine, ~ -difluoro-N(dimethyl) 35 histamine, ~-methyl,,B-fluoro-N(fluv, ' yl) histamine, _, _ _ _ _ _ _ _ , . . . . .
~ f`~ I $~
WO 95/21611 PCI`/US95/01392 ., clnm;rhPnP, mifepristone, tamoxifen, and a GnRH analogue such as LrJpRoN~
Other objects, features and advantages of the present invention will become ~a~ l to those skilled in the 5 art from the following detailed description. It is to be understood, however, that the dPt~i lPd description and specific eYamples, while indicating preferred Pmho~li - Ls of the present invention, are given by way of illustration and not limitation. Many changes and 10 modif ications within the scope of the present invention may be made without departing from the spirit thereof, and the invention ; nnl ~ all such modif ications .
n~Tr.Fn ~ OF Tr~ KI~ .rll'l~-r~-M~
Mast cells are normal -~ts of the connective 15 and mucosal tissues and play an important role in allergy . These cells are mostly 1 OCA 1 i 7~d in the gastrointestinal mucosa, skin and lung. Mast cells are so located, it is ~elieved, because these tissues are the main entry points for infective organisms and allergens, 20 the rh~minAl~ that trigger the body's immune ~ l3~.
Recent evidence indicates that mast cells in the mucosa of the small intestine differ from mast cells in other tissues, Psp~iAl ly cnnnective tissues as well as brain. These mucosal mast cells also have been shown to 25 be in close proximity to nerve endings. See Stead et al., J. Gastroenterol. 97: 575-85 tl989).
Every mast cell nnntA;n~ up to 500 se~;L~:t~y granules, each storing more than 20 potent biological S. Mast cells secrete the contents of these 3 0 granules , i . e ., degranulate , when triggered by various specific and non-spec;f;c An;, . Accordingly, "degranulation" is used in this description to denote the relea~e of ~ny or all mediators from any or all mast cell secretory granules, whether in parallel, differentially 35 or selectively.
_ _ _ _ .
O 95J21611 ~ PCT/US95/01392 The degranulation of ma6t cells in ~en~ul.se to various agents i5 uBually a biological consequence of the activation of one or- more receptors located on the surface of the mast cell. The best known of these are 5 the immunoglobulin E (IgE) receptors involved in allergic reactions, to date the most fully characterized pathological proces6es that involve mast cells. In this context IgE binds strongly to mast cells through its Fc receptor. When mast cell-bound IgE reacts with an lO antigen, the latter bridges two or more IgE molecules and causes mast cell degranulation with subsequent release of mediators, either stored or synthesized during mast cell degranulation .
There also is evidence that neurotransmitters such 15 as acetylcholine and neuLuueuLides such as substance P, all being--lPcl~lPF that are released from neurons in the central (brain) and peripheral (gastrointestinal) nervous systems, may augment or trigger mast cell degranulation primarily through specific receptors, for example, in 20 ~e~uu~.ne to stress. In particular, research has shown that direct nerve stimulation causes mast cell activation and release of relevant rhPmirAl agents. 5ee, for instance, Dimitriadou et al., Neurosclence 44: 97-112 (1991); Theoharides, Life Sripnrpc 46: 607-17 (1990).
25 Female sex h~ - such as estradiol and progesterone likewise may augment or trigger mast cell degranulation.
See Vliagoftis et al., Int'l Arch. Allergy Immunol. 98:
398-409 (1992); 93: 113-19 (1990). Thus, it has been shown that rat hAcorh;l;c le~lkPm;A (RBL) cells, which 30 mimic mucosal mast cells, bind progesterone. Kouretas et Al,, Clinical Res. 39: 320 (1991).
ûther triggers of mast cell degranulation include viral and bacterial toxins, drugs such as aspirin, morphine and curare, eullLLc~ media used in radiology, 35 extreme heat, cold, solar radiation and 1Iy~eL~ Lic media. It is deemed; LallL, therefore, to block the mast cell degranulation which all of these stimuli Wo 95/21611 ~ 6 9 PCT/US95/01392 elicit, rather than to antagonize specific LeC~:~
such as opioid receptors as taught in U. S . patent No. 4,684,620.
The r ,_ '~ released by the mast cells following 5 degranulation are known to cause many biological processe8 which are part of the overall reD,uo1.se of the body to invasion by infective organisms and allergens.
Examples of such ~Luc~D~e5 are vasoc~..DLriction or vasodilation, leukocyte chemotaxis, and pain.
C '- released by mast cell degranulation which may be associated with irritable bowel DylldL - include bradykinin, histamine, leukotrienes, prostA~l2~n~;n~
serotonin, tumor necrosis factor and vasoactive intestinal peptide. Interleukins and proteolytic 15 enzymes, which can arfect intestinal function, can augment pain or cause pain directly.
EIistamine and other mediators bind to ~ra~; ~; c receptors on the surface of endothelial cells on vessels or on peripheral sensory neurons which become activated, 20 directly or indirectly (through vessel tone), to transmit pain stimuli. Vasodilation and rh LLLaction permit ly ' - _y Les to leave the circulation and enter the tissue, where they cause additional mast cell degranulation and other L es~ullSe5 . The process of 25 degranulation continues, eventually involving many mast cells .
Mast cell degranulation, ~periAlly in L.:.2Ju..De to n~:uL 1 triggers, now has been discuv-Led to contribute to the symptoms experienced by patients 30 suffering from 2Ih-1~ ;n2~1 migraine, irritable bowel Dyll~lL - and other ~ J~ - us, painful gastrointestinal conditions of non-infl2 Lory, non-ulcerative origin.
It also has been found an effective tL_ai L for such conditions entails the administration of a mast cell 35 degranulation-hlorl~in~ agent, i.e., a __ that counteracts mast cell degranulation-;n~l~c;n~ stimuli, either by binding to specific Le~ 2.~tuLD or by inactivating crucial steps in the degranulation process.
.. . .. . .. _ _ _ _ _ _ _ _ . .
Wo 95121611 = ~ ~ PCTIU595/01392 ~, ` ? ~ `
The aforementioned correlation between mucosal mast cells and stimuli associated with IBS and related, -"l~CJ~- ~C condition6 has not been do. Led heretofore. '~
For instance, histologic sections of colonic tissue 5 biopsied from a patient with irritable bowel ay~
were stained with ~ ~ ?lon~l anti-tryptase antibody to identify tryptase-; aactive mast cells, and other sections were stained with polyclonal anti-SP antibody to reveal nerve fibers positive for substance P, a lO nociceptive neuropeptide capable of degranulating mast cells. Microscopic examination of the sections revealed numerous mast cells, identifiable by staining for tryptase~ a proteolytic enzyme which is specific for the mast cells, and numerous nerve fibers stained for their 15 content of substance P. Particularly noteworthy in this context was the close anatomic association observed to exist between mucosal mast cells and substance P-containing nerve fibers.
For the purposes of this description, the range of 20 ~'mast cell degranulation-;nra~ ;n~ stimuli" is illustrated by: (i) immune molecules, for example, immunoglobulin (IgE), anaphylatoxins such a6 C5a, and cytokines such as tumor necrosis factor; (ii) neural SU?`.~a-allCeS, ;nnllln;n~
~ uLuL,dnsmitters such as acetylcholine and nt?ur~.?~c?yLides 25 such as substance P, calcitonin gene related peptide and vasoactive intestinal peptide; (iii) h~ --, such as ~aLLocJ~11s and progestins; and (iv) any other molecules that may be liberated wit_in the body during Pnr ngPno1~c conditions such as stress. Particularly preferred mast 30 cell degranulation-blnr~;n~ agents are: (a) natural polyamines; (b) certain heterocyclic histamine-l receptor ~ntagonists; (c) histamine-3 ~c~:?yLol agonists and (d) anti-female sex h- .
Among the ?yLer~L ~ ~d polyamines are spP~m;nP and 35 ~r~ a.;nP~ as well as metabolites, ;n~ ;n~ acetylated metabolites thereof and nYi~q;7ed metabolites, of these two _ a_~ 6ee Vliagoftis et f~l., Bioche~.
_ . _ . _ , . . ....
WO95121611 ~831~g PCTIUS95/01392 _g_ phz~ ol. 43: 2237-45 (1992), the contents of which are hereby inCULUUL~ted by reference.
Exemplary of the heterocyclic histamine-l (H-l) receptor AntA~rmi~:ts which are particularly suitable for 5 the present invention, by virtue of their potency in inhibiting neuronally-induced mast cell secretion (as distinct from immunologic degranulation of ma6t cells), are Azelastine, Azatadine, Cetirizine, Hydroxyzine, Ketotifen, Loratadine and Oxatomide. A particularly l0 suitable agent of this type is Ketotifen (Sigma ChPmiCA1f:; St. Louis, Missouri) and the rhArm=re~1tically acceptable, non-toxic salts thereof.
Pursuant to the present invention, suitable H-l receptor antagonists are those that display an affinity 15 for t_e H-l receptor that is greater than about 5 x 10-~ N. It is; _ L~ in this regard to distinguish such high-affinity H-l receptor antagonists ~rom others of lower affinity which actually cause mast cell degranulation and, hence, should be avoided. See Pini et ~l., Agents ~ Actions 8: 491-96 (1978). Examples of the latter type of __ ' appear in Table l.
Table l HISTAMINE-l ~sc~ ok AN'l`A~'flNT!::TS
T~AT CAUSE MAST CELL DEGRANULATION
C ,~1 ED20 for Histamine Release Clorphenyramine l0~ M
Cyclizine 5 x 104 M
Diphenhydramine l0~ M
Promethazine 104 N
EDzo = effective dose causing 20% secretion.
M = molar uu.lu~=l.LL~tion.
Illustrative histamine-3 receptor agonists include 35 Na-methyl histamine (cAlh;r~h~m Corporation, LaJolla, California), N~-methyl-(dimethyl) histamine and ,,B-difluoro-N~(fluuL~ yl) histamine.
~1~3~69 Wo 95/21611 PCT/US95/01392 --lo--Particularly prefe,~éd among the anti-female sex hl ~F are tamoxifen or NOLVADEX (Zeneca ph~rr--e~ltical6; Wilmington, Delaware), ~ m;rhono or ~ ;~UY~ S (Serono Labs; Norwell, r~csanhllcetts), and 5 AnAlO~lPC of gonadotropin roloAc;ng hormone (GnRH), a/k/a "leutinizing hormone rPlpAc;n~ hormone" (LHRH), such as Ll~PRON (TAP phArr--o~lticalsl Deerfield, Illinois).
Some of the classes of drugs which f all into the above-fl; Cc~lccod category of mast cell degranulation-lO blocking agents are listed below, along with specificexamples under each class:
An~hr~n; 1 i C Acil~ Deriv~tiv~
N-(3,4-11; ~hnYyl-'.;~ 1) anthranilic acids Anti-Female S~x r~
15 t~1 1 ; rhPnP
Nif epristone TamoYif en GnRH analogues llr~rhi~n;c Aci~ N~tllbolit--s 20 Leukotriene D~
Lipoxin B
Prostaglandin E
Prostn/Jl An~l; n E~
}li~tamill~-3 re-, Lo~ Agoni~t~
25 N"-methyl histamine N~-dimethyl histamine RQ ~ y l histamine Q, ~-dimethyl-N (dimethyl ) histamine Q, ~-di~luoro-N~ (dimethyl ) histamine 3 0 Q-methyl, ,B- f luoro-N~ ( f lu~ y 1 ) hi stamine ~,B-di~luoro-N~(~lu~ yl) histamine ~i~t~nin~-1 n~ or Ant~goni~t3 r~t--riz~d by A .hL~ e ~ing l;LL~CL~
PiPer; 1 i n~ derivatives Azelastine Azatadine Burfroline Dv~ LLozole Forskolin Ketotifen I,odr~Y~m tl~ tromethamine Loperam de Loratad_ne Myricet_n Oxatomide Pizotifen Proxicromil Pi~erazin~ derivatives l- ( 5 -isoquinol inylsul f ony l ) -2 -methy lp iperaz ine 1-(1 ~lydLu~cy-5-i~:o~linnlinylsulfonyl)piperazine 1-t2-hydroxy-3-[ (4-I1Y-1LU~-3 nitrocoumarin-7-yl) oxyl ] propyl ] -4 - ( 4 -chlorobenzyl ) piperaz ine Cetiriz ine 6-t3-[4-(4-chlorobenzyl) -1-piperazinyl]
propoxy] [l]benzo-pyranc [2,3-d]-1,2,3-triazol-9 ( 1_) -one Etodroxizine HY.1L U,.Y ~ine N-(optionally substitutedbellzlly-lL~l) -N'-(optionally substituted) piperaz ines 9-chluLu 5 ~xu 7-(lH-tetrazol-5yl)-5H-~1]-benzopyrano t2, 3-b]pyridine sodium salt pentahydrate p~ptide~
L-Asp-Ser-asp-Pro-Arg Cyclosporin A
FUL .~ a~l antibody Interleukin-1 L~:CC:~LOL antagonist Ly ` - y Le Inhibitory Factor (LIF) Substance P-receptor antagonist
difluoro-N-fluvr, L}lyl histamine, tamoxifen or a 30 gonadotropin-releasing hormone (leutinizing hormone rPl~cin~ hormone) i~ns~logllP. In yet other preferred -'ir Ls, the mast cell dey~-r-ulation hlorkin~ agent is N-dimethyl histamine, R-methyl histamine, ~, ,B-dimethyl-N(dimethyl) histamine, ~ -difluoro-N(dimethyl) 35 histamine, ~-methyl,,B-fluoro-N(fluv, ' yl) histamine, _, _ _ _ _ _ _ _ , . . . . .
~ f`~ I $~
WO 95/21611 PCI`/US95/01392 ., clnm;rhPnP, mifepristone, tamoxifen, and a GnRH analogue such as LrJpRoN~
Other objects, features and advantages of the present invention will become ~a~ l to those skilled in the 5 art from the following detailed description. It is to be understood, however, that the dPt~i lPd description and specific eYamples, while indicating preferred Pmho~li - Ls of the present invention, are given by way of illustration and not limitation. Many changes and 10 modif ications within the scope of the present invention may be made without departing from the spirit thereof, and the invention ; nnl ~ all such modif ications .
n~Tr.Fn ~ OF Tr~ KI~ .rll'l~-r~-M~
Mast cells are normal -~ts of the connective 15 and mucosal tissues and play an important role in allergy . These cells are mostly 1 OCA 1 i 7~d in the gastrointestinal mucosa, skin and lung. Mast cells are so located, it is ~elieved, because these tissues are the main entry points for infective organisms and allergens, 20 the rh~minAl~ that trigger the body's immune ~ l3~.
Recent evidence indicates that mast cells in the mucosa of the small intestine differ from mast cells in other tissues, Psp~iAl ly cnnnective tissues as well as brain. These mucosal mast cells also have been shown to 25 be in close proximity to nerve endings. See Stead et al., J. Gastroenterol. 97: 575-85 tl989).
Every mast cell nnntA;n~ up to 500 se~;L~:t~y granules, each storing more than 20 potent biological S. Mast cells secrete the contents of these 3 0 granules , i . e ., degranulate , when triggered by various specific and non-spec;f;c An;, . Accordingly, "degranulation" is used in this description to denote the relea~e of ~ny or all mediators from any or all mast cell secretory granules, whether in parallel, differentially 35 or selectively.
_ _ _ _ .
O 95J21611 ~ PCT/US95/01392 The degranulation of ma6t cells in ~en~ul.se to various agents i5 uBually a biological consequence of the activation of one or- more receptors located on the surface of the mast cell. The best known of these are 5 the immunoglobulin E (IgE) receptors involved in allergic reactions, to date the most fully characterized pathological proces6es that involve mast cells. In this context IgE binds strongly to mast cells through its Fc receptor. When mast cell-bound IgE reacts with an lO antigen, the latter bridges two or more IgE molecules and causes mast cell degranulation with subsequent release of mediators, either stored or synthesized during mast cell degranulation .
There also is evidence that neurotransmitters such 15 as acetylcholine and neuLuueuLides such as substance P, all being--lPcl~lPF that are released from neurons in the central (brain) and peripheral (gastrointestinal) nervous systems, may augment or trigger mast cell degranulation primarily through specific receptors, for example, in 20 ~e~uu~.ne to stress. In particular, research has shown that direct nerve stimulation causes mast cell activation and release of relevant rhPmirAl agents. 5ee, for instance, Dimitriadou et al., Neurosclence 44: 97-112 (1991); Theoharides, Life Sripnrpc 46: 607-17 (1990).
25 Female sex h~ - such as estradiol and progesterone likewise may augment or trigger mast cell degranulation.
See Vliagoftis et al., Int'l Arch. Allergy Immunol. 98:
398-409 (1992); 93: 113-19 (1990). Thus, it has been shown that rat hAcorh;l;c le~lkPm;A (RBL) cells, which 30 mimic mucosal mast cells, bind progesterone. Kouretas et Al,, Clinical Res. 39: 320 (1991).
ûther triggers of mast cell degranulation include viral and bacterial toxins, drugs such as aspirin, morphine and curare, eullLLc~ media used in radiology, 35 extreme heat, cold, solar radiation and 1Iy~eL~ Lic media. It is deemed; LallL, therefore, to block the mast cell degranulation which all of these stimuli Wo 95/21611 ~ 6 9 PCT/US95/01392 elicit, rather than to antagonize specific LeC~:~
such as opioid receptors as taught in U. S . patent No. 4,684,620.
The r ,_ '~ released by the mast cells following 5 degranulation are known to cause many biological processe8 which are part of the overall reD,uo1.se of the body to invasion by infective organisms and allergens.
Examples of such ~Luc~D~e5 are vasoc~..DLriction or vasodilation, leukocyte chemotaxis, and pain.
C '- released by mast cell degranulation which may be associated with irritable bowel DylldL - include bradykinin, histamine, leukotrienes, prostA~l2~n~;n~
serotonin, tumor necrosis factor and vasoactive intestinal peptide. Interleukins and proteolytic 15 enzymes, which can arfect intestinal function, can augment pain or cause pain directly.
EIistamine and other mediators bind to ~ra~; ~; c receptors on the surface of endothelial cells on vessels or on peripheral sensory neurons which become activated, 20 directly or indirectly (through vessel tone), to transmit pain stimuli. Vasodilation and rh LLLaction permit ly ' - _y Les to leave the circulation and enter the tissue, where they cause additional mast cell degranulation and other L es~ullSe5 . The process of 25 degranulation continues, eventually involving many mast cells .
Mast cell degranulation, ~periAlly in L.:.2Ju..De to n~:uL 1 triggers, now has been discuv-Led to contribute to the symptoms experienced by patients 30 suffering from 2Ih-1~ ;n2~1 migraine, irritable bowel Dyll~lL - and other ~ J~ - us, painful gastrointestinal conditions of non-infl2 Lory, non-ulcerative origin.
It also has been found an effective tL_ai L for such conditions entails the administration of a mast cell 35 degranulation-hlorl~in~ agent, i.e., a __ that counteracts mast cell degranulation-;n~l~c;n~ stimuli, either by binding to specific Le~ 2.~tuLD or by inactivating crucial steps in the degranulation process.
.. . .. . .. _ _ _ _ _ _ _ _ . .
Wo 95121611 = ~ ~ PCTIU595/01392 ~, ` ? ~ `
The aforementioned correlation between mucosal mast cells and stimuli associated with IBS and related, -"l~CJ~- ~C condition6 has not been do. Led heretofore. '~
For instance, histologic sections of colonic tissue 5 biopsied from a patient with irritable bowel ay~
were stained with ~ ~ ?lon~l anti-tryptase antibody to identify tryptase-; aactive mast cells, and other sections were stained with polyclonal anti-SP antibody to reveal nerve fibers positive for substance P, a lO nociceptive neuropeptide capable of degranulating mast cells. Microscopic examination of the sections revealed numerous mast cells, identifiable by staining for tryptase~ a proteolytic enzyme which is specific for the mast cells, and numerous nerve fibers stained for their 15 content of substance P. Particularly noteworthy in this context was the close anatomic association observed to exist between mucosal mast cells and substance P-containing nerve fibers.
For the purposes of this description, the range of 20 ~'mast cell degranulation-;nra~ ;n~ stimuli" is illustrated by: (i) immune molecules, for example, immunoglobulin (IgE), anaphylatoxins such a6 C5a, and cytokines such as tumor necrosis factor; (ii) neural SU?`.~a-allCeS, ;nnllln;n~
~ uLuL,dnsmitters such as acetylcholine and nt?ur~.?~c?yLides 25 such as substance P, calcitonin gene related peptide and vasoactive intestinal peptide; (iii) h~ --, such as ~aLLocJ~11s and progestins; and (iv) any other molecules that may be liberated wit_in the body during Pnr ngPno1~c conditions such as stress. Particularly preferred mast 30 cell degranulation-blnr~;n~ agents are: (a) natural polyamines; (b) certain heterocyclic histamine-l receptor ~ntagonists; (c) histamine-3 ~c~:?yLol agonists and (d) anti-female sex h- .
Among the ?yLer~L ~ ~d polyamines are spP~m;nP and 35 ~r~ a.;nP~ as well as metabolites, ;n~ ;n~ acetylated metabolites thereof and nYi~q;7ed metabolites, of these two _ a_~ 6ee Vliagoftis et f~l., Bioche~.
_ . _ . _ , . . ....
WO95121611 ~831~g PCTIUS95/01392 _g_ phz~ ol. 43: 2237-45 (1992), the contents of which are hereby inCULUUL~ted by reference.
Exemplary of the heterocyclic histamine-l (H-l) receptor AntA~rmi~:ts which are particularly suitable for 5 the present invention, by virtue of their potency in inhibiting neuronally-induced mast cell secretion (as distinct from immunologic degranulation of ma6t cells), are Azelastine, Azatadine, Cetirizine, Hydroxyzine, Ketotifen, Loratadine and Oxatomide. A particularly l0 suitable agent of this type is Ketotifen (Sigma ChPmiCA1f:; St. Louis, Missouri) and the rhArm=re~1tically acceptable, non-toxic salts thereof.
Pursuant to the present invention, suitable H-l receptor antagonists are those that display an affinity 15 for t_e H-l receptor that is greater than about 5 x 10-~ N. It is; _ L~ in this regard to distinguish such high-affinity H-l receptor antagonists ~rom others of lower affinity which actually cause mast cell degranulation and, hence, should be avoided. See Pini et ~l., Agents ~ Actions 8: 491-96 (1978). Examples of the latter type of __ ' appear in Table l.
Table l HISTAMINE-l ~sc~ ok AN'l`A~'flNT!::TS
T~AT CAUSE MAST CELL DEGRANULATION
C ,~1 ED20 for Histamine Release Clorphenyramine l0~ M
Cyclizine 5 x 104 M
Diphenhydramine l0~ M
Promethazine 104 N
EDzo = effective dose causing 20% secretion.
M = molar uu.lu~=l.LL~tion.
Illustrative histamine-3 receptor agonists include 35 Na-methyl histamine (cAlh;r~h~m Corporation, LaJolla, California), N~-methyl-(dimethyl) histamine and ,,B-difluoro-N~(fluuL~ yl) histamine.
~1~3~69 Wo 95/21611 PCT/US95/01392 --lo--Particularly prefe,~éd among the anti-female sex hl ~F are tamoxifen or NOLVADEX (Zeneca ph~rr--e~ltical6; Wilmington, Delaware), ~ m;rhono or ~ ;~UY~ S (Serono Labs; Norwell, r~csanhllcetts), and 5 AnAlO~lPC of gonadotropin roloAc;ng hormone (GnRH), a/k/a "leutinizing hormone rPlpAc;n~ hormone" (LHRH), such as Ll~PRON (TAP phArr--o~lticalsl Deerfield, Illinois).
Some of the classes of drugs which f all into the above-fl; Cc~lccod category of mast cell degranulation-lO blocking agents are listed below, along with specificexamples under each class:
An~hr~n; 1 i C Acil~ Deriv~tiv~
N-(3,4-11; ~hnYyl-'.;~ 1) anthranilic acids Anti-Female S~x r~
15 t~1 1 ; rhPnP
Nif epristone TamoYif en GnRH analogues llr~rhi~n;c Aci~ N~tllbolit--s 20 Leukotriene D~
Lipoxin B
Prostaglandin E
Prostn/Jl An~l; n E~
}li~tamill~-3 re-, Lo~ Agoni~t~
25 N"-methyl histamine N~-dimethyl histamine RQ ~ y l histamine Q, ~-dimethyl-N (dimethyl ) histamine Q, ~-di~luoro-N~ (dimethyl ) histamine 3 0 Q-methyl, ,B- f luoro-N~ ( f lu~ y 1 ) hi stamine ~,B-di~luoro-N~(~lu~ yl) histamine ~i~t~nin~-1 n~ or Ant~goni~t3 r~t--riz~d by A .hL~ e ~ing l;LL~CL~
PiPer; 1 i n~ derivatives Azelastine Azatadine Burfroline Dv~ LLozole Forskolin Ketotifen I,odr~Y~m tl~ tromethamine Loperam de Loratad_ne Myricet_n Oxatomide Pizotifen Proxicromil Pi~erazin~ derivatives l- ( 5 -isoquinol inylsul f ony l ) -2 -methy lp iperaz ine 1-(1 ~lydLu~cy-5-i~:o~linnlinylsulfonyl)piperazine 1-t2-hydroxy-3-[ (4-I1Y-1LU~-3 nitrocoumarin-7-yl) oxyl ] propyl ] -4 - ( 4 -chlorobenzyl ) piperaz ine Cetiriz ine 6-t3-[4-(4-chlorobenzyl) -1-piperazinyl]
propoxy] [l]benzo-pyranc [2,3-d]-1,2,3-triazol-9 ( 1_) -one Etodroxizine HY.1L U,.Y ~ine N-(optionally substitutedbellzlly-lL~l) -N'-(optionally substituted) piperaz ines 9-chluLu 5 ~xu 7-(lH-tetrazol-5yl)-5H-~1]-benzopyrano t2, 3-b]pyridine sodium salt pentahydrate p~ptide~
L-Asp-Ser-asp-Pro-Arg Cyclosporin A
FUL .~ a~l antibody Interleukin-1 L~:CC:~LOL antagonist Ly ` - y Le Inhibitory Factor (LIF) Substance P-receptor antagonist
4 0 Somatostatin - Inhibitor Okadaic acid Calyculin Quercetin Raempferol Nedocromil Mino~
Cromolyn _ _ _ _ _ WO95121611 2~g~G6 !~ r~ /CI~
, --12--Poly~min~
Putrescine Sp~rm i .1 i nc~ v Cp-~rm; n-~ -.
Cromolyn _ _ _ _ _ WO95121611 2~g~G6 !~ r~ /CI~
, --12--Poly~min~
Putrescine Sp~rm i .1 i nc~ v Cp-~rm; n-~ -.
5 Protcin ICinn~ Inhibitors 3-10-Dihydroxy-10[ (dimethylamino) methyl~-2,3,9,10,11,12-hexahydLù 9 - Lhyl-9,12,-epoxy-lH-diindolot1,2,3-~-3 ' ,2 ' ,1'-Kd] pyrrolo [3,4-c] [2,6] h~n70~l;A~ocin-l-one (UCH-01) sLdULU~UULin Prot~oglyc~n~
Heparin Herudin Quinolin~ D~riv~tiv~
1, 3 -ûxazolo [ 4, 5-h] quinolines 2-CaLLu~y~yL imidoquinolines 3 -Aminoquinolines 'I'h; ~ D~riv~tiv~
l-Methyl-2 (1,3,4-oxadiazol-2 (3H) -one-5-y1) RPn7im;-l~7ole M;~ C _ _ --2-Substituted 3-dimethylamino-5, 6-methyl~nP~l i nyydines 2-o-PLu~uu~y~ y 1-8-azapurin-6-one 2-EthoYyethyl-5-chloro-b~n~YA7ole-2 c,-LI,u~ylate 5 -Amino-4 - i m; (:1 A ~ - r }~ ribos ide 7-Nethyl-5-propyl-s-triazole [ 1, 5c] pyrimidine-2 -amine 7-(2-Hy~Lu~cyt:tlloxy) ~ u,~u,~-l,Lhene-2~ L~u..ylic acid Amiloride ~1nYAl ~r~ide Deoxycof ormycin Fisetin Flufenamic acid Nilidrine hydrorh 1 t~r i fl~
p-r,L- ~ ^nAr-yl bromide Pimozide AAAAAAA.I AAAAAAAAAAAAAAAAAAAAAAAAAAA
Phosphatase inhibitors make up another class of '- which is characterized by mast cell ~ -~t83~
Wo 95/21611 PCTNS95/01392 degranulation-inhibitory activity. Exemplary r.. L,~ lc in this class are I~e~o~;L~ ; 1, Minocromil, Kaempferol, Quercetin, 2'-carboxyl-ato_lL ~ 5'-yl-2 l~ydLv~cy~L~Lc-~e derivatives, 1,3-bis [2'-[[(acetoxymethyl)oxyl]
5 carbonyl]~l.L ~ 5'-yl] 2 hydL~syLJL~ane~ pyrano [3,2,-] quinoline-2, 8-dicarboxylic acid derivatives, and 5-chlorobenzoxazole-2-carboxylic acid. These _ _ '- and others in this class obstruct a phoshatase from mediating protein ~ rhns~h~rylation~ an integral step in various 10 rhnsrh~lrylation/~l~rhn6rhnrylation events which are essential to intrA--~llul;~r regulation.
In particular, protein phosphatase inhibitors have been shown to attenuate the release of histamine and leukotriene mediators from human lung mast cells.
Peachell et al., .T. I~urlunol. 151: 3808 (1993).
Phosphatase inhibitors are distingll;Rh~hl~ by an ability to inhibit one of the four major classes of phosphatases.
Type 1 phosphatase (PP1) ~l~rh~s~hnrylates the beta subunit of phosphorylase kinase and is inhibited by 20 +. h. L~lble inhibitors 1 and 2 and inactivated by okadaic acid (LC Services Corporation, Nottingham, UK).
Type 2 phosphatases include three subtypes (PP2A, PP2B, and PP2C), each of which rl~rhocrhnrylates the alpha subunit of pho~ ,Lylase kinase. Each of PP2A and PP2B
25 ~re inhibited by okadaic acid. PP2C is insensitive to okadaic acid but is completely ~lorpn~l~nt on Mg2+.
Accordingly, the class of protein phosphatase inhibitors also i nrlll~Pc okadaic acid, analogues of okadaic acid, okadaol and nor-nk~ n~ (LC Services 30 Corporation, supra; Biomol, Plymouth Meeting, PA), and okadaic acid methyl ester [see Nishiwaki, Carcinogenesis 11: 1837 (1990) ], as well as calyculin (LC Services Corporation) .
It is not n~ cs:-ry to the operability of the present 35 invention that each member of the foregoing classes inhibits mast cell degranulation to the same extent. The ability of a particular substance to inhibit mast cell degranulation can be readily det~rmin~r1 empirically.
~Q 6 g WO95/21611 ~ ' PCr/USs5/01392 Thus, mast cells from rats (piece5 of small intestine) or humans (inte6tinal biopsies) ean be obtained; otherwise, RB~ eells or immortalized human mucosal-like mast cells (HNC-l) are kept in culture. Any of these cells then are 5 exposed to various ~ulleel-LLlltions of a putative inhibitory c __ ', to allow for aetion by the putative inhibitor at eritieal sites. Effieaey with respeet to inhibition of mast eell degranulation then is aseertained; that is, the intestinal biopsies, explants l0 or eultured cell6 thus treated are used as such or washed free of unbound test __ ' before ~ JO~ULe: to a stimulus known to induce mast cell degranulation. A
' suitable for use in accordanee with the present invention is rocoqni7od as one that ~Lt:v~ L~ the stimulus 15 from eausing degranulation, ~L~_ hly by binding to speeifie receptors or by inactivating a crucial step in the degranulation process.
While it is possible in principle that a particular ~- ~uul~d in one of the a}.u~_ ~ Lioned classes, by virtue 20 of its activity, could be employed in the described manner, it is true generally that the advisability of using any mast eell-degranulation inhibitor according to the present invention must be tempered by rl inirAl considerations, inrl~ ing toxicity, bioav~ hility, 25 distribution, half-life and clearanee, whieh are conventional to this field. See, for example, GOODM
AND GILMAN ' S THE Pt~T~M~ TnGICAL BASIS OF THERAPEUTICS
SS I & XVII (7th ed. ) .
Thus, dosage f orms f or the delivery of the selected 30 mast cell degranulation hlrrkin~ agent should be those that aehieve and retain high levels of the drug in the gastrointestinal traet with reasonable rapidity. These dosage forms are adapted for a variety of eonventional routes of administration, inrlll~in~ oral, parenteral and 35 rectal.
Pursuant to the present invention, a mast cell degranulation-h1Orl~i n~ agent is administered in a rhAr~ tieallY effeetive amount. The dosage range for ... . ... . _ ... = = . = .. _ . _ . _ .. .. _ Wo 9~/21611 F~l~u~
rh~ tttical effectiveness can be det-~rm;n-~rl by reference to standard laboratory test6 for inhibition of gastrointe6tinal mast cell degranulation, as ~i~cl-cced above .
A pharmaceutically effective dose for a given mast cell degranulation-hlorkin~ agent can be approximated by its ID20, which is the dose nPr-~CC~ry to cau6e 20%
inhibition in mast cells when applied to mast cells stimulated in vitro. The ID20 values ror sel~ct~d 10 inhibitor _ ~ are shown in Table 2.
Table 2 UU.~UU..L~S WHICH INHIBIT RAT NUCOSAL
NAST CELL DEGRANUI,ATION IN VITRO
r __ ~ ID20 for histamine release Azatadine 10-7 N
Hydroxyzine 5 x 10 ~ M
Ketotifen 10~ N
N-methyl histamine 10-7 N
Oxatomide 10-7 N
Sp~-rmi n~ 5 x 10~ M
Tamoxifen 5 x 10~ N
ID20 = inhibitory dose causing 20% inhibition.
25 N = molar CUII~ L'- tion.
The agent can best be admini6tered syst~m i c~ l l y or directly in the intestinal loops (suppository, enema or injection) of the live mammal. The mast cell inhibitory effect of certain of t7tese ~__ ' has been described 30 for non-intestinal mast cells. See, for example, Vliagoftis et al., Biochem. phArr-~o7. 43: 2237-45 (1992), Rn~:nil~rki et al. in PROC. 8TH INT'~ C~Nt:RT'qS
T711M77N-TnGy 159 (Budapest 1992), Rn~n;erki et al., FASEB
J. 6: A1554 (1992), and Rachmilewitz et al., Ga~troenterol. 102: A235 (1992).
An assay by which efficacy of a mast cell degranulation-bl orki n~ agent can be tested systemically in the present context is the rat-; -'-ili7ation assay, in which a rat is pre-treated with an agent and then restrained for one hour in a clear plexiglass cylinder.
After the immobil~ization, a specific gastrointestinal mast cell mediator, rat mast cell protease II (RNCPII), is measured. This assay is accepted as a non-ulcerogenic 5 model of stress. See Williams et al., Am. J. Physiol.
253: 582-86 (1987).
Results from testing ketotifen in the rat-immobilization assay are presented in Table 3 below.
Ketotifen was administered intraperitoneally to rats (l l0 mg/kg body weight, twice daily) for four days prior to immobilization .
Table 3 ON BY K~~ kl~ OF
~AT l~ll;ollN ~L RNCPII IN A TRESS NODEL
15 Time T ' ' 1 i .-"i Non~ Le~l wt min) ~n = 3) (n ~ 3) FketoTL~ifen (n - 3) 60 4.85- 0.3 0.5 120 12.4- 0.7 0.8-ng/ml; 1 = number o rats tested 20 * p < 0 . 05 vs. non-; ~ c~
** p < 0 . 00l vs. immobilized Table 3 shows that intestinal mast cells are activated during stress to secrete a specific proteolytic enzyme, RNCPII, and that ketotifen acts as a mast cell 25 degranulation-blocking agent in preventing secretion of RNCPII from such cells. The equivalent proteolytic enzyme in humans is tryptase, which also can be measured from colonic fluid or hir~p~
It is essential to the present invention that the 30 selected agent inhibit mucosal mast-cell secretion.
Thus, mast cell degranulation-blorlr;rlrJ agents, such as d;~:od;11m cromoglycate (~mMnTyN), which do not have an inhibitory effect specifically on mucosal mast cells, see Pearce et Pl., J. Immunol. 128: 2481-86 (1982), are not 35 within the scope of the present invention. No work has 1,4 ~3~
wo 951~1611 PCT/US95/01392 -80 far involved H3 receptor agonists in the inhibition of gastrointestinal mast cell degranulation.
A mast cell degranulation-hlorlrin~ agent can be administered, according to the present invention, in the 5 form of the active agent itself or as a pharmaceutically acceptable salt of the active agent. The phrase "rh~rr~ tically acceptable salt" denotes a non-toxic, substantially non-irritating salt of the - _I.d used.
Typical salts are ; llm salts and salts containing an 10 cation that is an alkali metal or AlkAl ;n~ earth metal, such as sodium, potassium, calcium or magnesium. The category of suitable cations for the salt also ; nrlllt9~
sulphate, phosphate, tartrate and citrate. Other acceptable salts are those with non-toxic organic acids, 15 such as fatty acids of one to six carbon atoms in length.
Pursuant to the present invention, a mast cell degranulation-~lork;n7 agent can be delivered via methods known for drug administration. The agents are typically administOEed as rhArr~--putical compositions in 20 combination with rhArr--eutically acceptable carriers.
Such compositions may be pLèp~Led from conv~n~;nn materials by ~Lvcedu~es well known in the art.
Compositions within the present invention can be adapted for oral or parenteral administration, as well as 25 for enteral administration or through mucous membranes, such as trAn~nr~-l ly. An oral formulation which will keep the drug for an ~Yt~n~l~A time in the gastrointestinal tract is preferred, since such a formulation allows long e~oauLe of the mucosal mast 30 cells present there to the drug.
Forms suitable for oral administration include tablets, dispersible powders, granules, capsules, syrups, elixirs and suspensions. Also preferred in this regard are encapsulated f orms . For instance, a pref erred mode 35 of administration would be via l ;rr~s~ --, mUlt~ Ar phospholipid vesicles, or l ;r~ é5~ which protect the active agênt from destruction in the stomach and allows for slow release in the intestine as each phospholipid _ _ _ _ .. . . . , _ _ _ _ _ 3 ~ ~.9 ~`
Wo 95121611 PcrluS95/01392 ~ 18--layer is dissolved, resulting in sustained high intestinal levels of the drug. Alving, C.R., S.
Shichijo, I. Mattsby-Baltzec, R.L. Richards and N.N.
Wassef, "Preparation and U8e of T.1, - in I_munologic 5 Studie6, " in LIPOSOME TE:C}~NOLOGY, 2nd ed., vol. III, G.
Gregoriadis, ed., CRC Pres6, Boca Raton, FL, pp.317-343, 1984; Amselem, 5., C.R. Alving, and A.J. Domb, Polymers for Advanced Terhnn7Ogiesl 3:351-357 (1992); and Amselem, et al. Vaccine Research 1: 383-385 (1992).
Compositions for oral use contain one or more conventional adjuvants, such as sweetPnin~ agents, flavoring agents, coloring agents and preserving agents, in order to provide a presentable and palatable preparation. Tablet6 may contain the active ingredients 15 in a mixture with conventional rh~ P71tically acceptable eYcipients. These include inert carriers, such as calcium ~.~LI,.,~ Le, sodium carbonate, lactose, and talc; granulating and disintegrating agents, such as starch and alginic acid; bin~ing agents such as starch, 20 gelatin acacia; and lubricating agents, such a6 m-gnPcj~lm stearate, stearic acid and talc. Tablets may be uncoated or coated by known techniques to delay disintegration and ab60rption in the gastrointestinal tract, thereby providing a sustained action over a longer period of 25 time. Similarly, s~lqpPnqions, syrups and elixirs may contain active ingredients in mixture with any of the conventional ~y~ipipntF utilized in the preparation of such compositions. This inr~ pc 5llqpPn~ling agents such as methylcPlllllosel tragacanth and sodium alginate;
30 wetting agents such as lecithin, polyuxy-:Lllylene stearate or polyu~y~Ulylene sorbitan monoleate; and preservatives.
e~rS1ll Pq may contain the active ingredients alone or in an admixture with an inert solid carrier, such as calcium carbonate, calcium phosphate or kaolin. These 35 pharmaceutical compositions may contain up to 90~6 of active ingredients in combination with the carrier or adjuvant. The '~ preferably are put up in unit dosage forms, particularly for oral administration, for _ . _ _ . _ . _ . . ...
wo 9~/21611 PcT/US95/01392 example, in 20 mg tablets. Such forms may contain the active ingredient separately, for example in separate - layers.
The agents can be administered in sustained release 5 form or in divided dosages.
Oral administration often is preferred if the mast cell degranulation-blocking agent is orally active.
TrAnc~ administration also is preferred. More specifically, in the case of mast cell degranulation-10 blorkin~ agents which are substantially destroyed ordeactivated upon oral administration, or where a more prolonged duration of activity is desired, a mast cell degranulation-blocking agent also can be administered trAne~c-rr-l ly or via other body membranes, such as 15 rectally.
A preferred forrll~t;on within the present invention comprises both a suitable mast cell deyL~ lation inhibitor and an agent that inhibits or counteracts intestinal motility, thereby increasing the transit time 20 and, hence, the effect of the inhibitor in the intestinal tract. Such a suitable antimotility agent is dicyclomine rArSlllQe, such as BENTYL (Taylor phA~rqreuticAl Company, Decatur, Illinois). The use of an antimotility agent in this context is ~cre~jAlly ~l~ftLLe:d when the mast cell-25 degranulation inhibitor is contained in a lipid-containing delivery vehicle, as ~i~cllq~Qd above. Thus, the antimotility agent can be "co-administered" with the delivery vehicle, i.e., can be administered in such a way that the motility-counteractive inf luence of the agent 3 0 increases the rQci~n~-e time of the delivery vehicle in the intestine.
The following illustrative examples further describe the present invention.
J
r le l The following experiment was performed in order to evaluate rat mucosal mast cell t~C) degranulation by .
WO 95/21611 PCr/US95/01392 t~, measuring rat mast cell protease II (RNCPII), a specific marker f or MMC, and by electron microscopy .
Rats were treated intragastrically for four (4) days with either 0.5 ml of saline containing ketotifen (1 5 mg/kg twice daily) or saline alone. On day five, the animals were euth~ni~P~ ileum was removed and ileal explants were placed in orgari culture. The explants were incubated at 37C in a medium containing either 5 ~g/ml of toxin A in 0 . 01 ml of 50 mM Tris buffer, or buffer 10 alone. Aliquots (50 ~Ll) of medium were collect~ at specified times and RMCPII levels were detprminl~d~
Results are ~uL~ssed in Table 4 as nanograms of RMCPII
released per milligram of tissue wet weight (pothmll:~k;~:
et al., Gastroenterology 105:701-707, 1993).
Table 4 ON BY Khl~ hl~ OF RAT l~lh~llNAL
RMCP II SECRETION -NDUCED BY TOYIN A
Time Buffer Toxin A Ketotifen+
(min) (n = 10) (n = 7) Toxin A
(n = 6) 20 30 3.4 ~ 0.8 5.0 + 1.2 2.9 + 1.0 60 6.2 + 0.9 7.2 + 1.7 3.0 + 1.1+
120 7.6 $ 1.2 12.6 i: 2.1- 4.2 + 0.9++
180 11.3 + 2.1 24.0 + 4.8-- 6.7 + 1.9++
p < 0 . 05 v buff er 25 ** p < 0 . 01 " "
+ p < 0. 05 vs Toxin A
++ p < O. 01 " "
Electron miuLus~:u~Uy showed significant mucosal mast 30 cell degranulation in rat ileum within 15 minutes of ~,UOaULe to toxin A, and complete degranulation at 60 minutes. These results, obtained by J. Castagliuolo, J.T. LaMont, R. Letourneau, C. Relly, J.C. O'Keane, A.
Jaffer, T.C. Theoharides and C. Pothoulakis, ~ LL~-Le 35 that ketotifen effectively inhibits the release of RMCPII
from rat ileal explant6 and, hence, inhibits mucosal mast cell degranulation.
WO 9SIZ1611 ~ 8 3 ~ ~ 9 PCT~ sgsl0l392 Similar results were obtained using the substance P
receptor antagonist (Pothoulakis et al., Proc. Natl.
Acad. Sci., USA 91:947-951, 1994).
r le 2 A female patient, age 49, suffered from irritable bowel s.ylldLI - for approximately 10 years. symptom~ were so severe that she had difficuity in functioning as a nurse, mother and wife. After treatment with 11y-1Lu,cy~ine hydrochloride (ATARAX; 50 mg/day) for three months, her gastrointestinal dis~ -UL L waB almost completely eliminated, and she was able to resume her professional and family responsibilities. On several orr~ion~ when she attempted to withdraw from the use of ilydL~,~y4ine hydrochloride, she experienced a marked increase in symptoms of irritable bowel iy.,~ . The symptoms d;~lrp~Ared when she resumed taking the medication.
r le 3 A female patient, age 32, had a four-year history of irritable bowel sy~l~ ~ and had dif f iculty in carrying out her profPcc;nn;~l duties as a nurse. She was treated for 4 months with 50 mg/day of ~ly-lL~ y~ine pamoate (VISTARIL). She experienced a noticeable; ~ uv, I' of her ~y.u~ and was able to resume her professional activities .
r le 4 A female patient, age 39, suffered from irritable bowel ~.ylldL - for over two years. Her gymptoms ;nrll~d~9 c.,.._L~..L pain at the cnnn~ct;nn of the buttocks with the upper legs, as well as painful defecation. After 30 L- t:ai L with ketotifen (ZADITEN; 4 mg/day) for two months, her pain 5~lhci~d signif icantly .
r le 5 A female patient, age 39, with a five-year history of irritable bowel ~ylldr~ , experienced uu--~,L~I-L
, ~
W095121611 ~ P~ . 1392 A`-' ;n~l pain which was not relieved by any of a variety of narcotic and non-narcotic analgesics and anti-inflammatory drugs. Her symptom6 were F-Y~r~rhated during LLu~ltion. Treatment with tamoxifen citrate (NOVADEX;
5 40 mg/day, administered orally) for two months substantially eliminated her pain.
r le 6 A female patient, age 32, with a two-year history of AI ~ ; ns~ 1 migraine, experienced C.~ L~l- L gastrointestinal 10 pain which was cnn~ ably worse immediately YL~ LLUCI11Y. After treatment with the Gn-RH analogue LUPRON (3 ~g/day subcutaneous injection) for four months, she was symptom-free.
Heparin Herudin Quinolin~ D~riv~tiv~
1, 3 -ûxazolo [ 4, 5-h] quinolines 2-CaLLu~y~yL imidoquinolines 3 -Aminoquinolines 'I'h; ~ D~riv~tiv~
l-Methyl-2 (1,3,4-oxadiazol-2 (3H) -one-5-y1) RPn7im;-l~7ole M;~ C _ _ --2-Substituted 3-dimethylamino-5, 6-methyl~nP~l i nyydines 2-o-PLu~uu~y~ y 1-8-azapurin-6-one 2-EthoYyethyl-5-chloro-b~n~YA7ole-2 c,-LI,u~ylate 5 -Amino-4 - i m; (:1 A ~ - r }~ ribos ide 7-Nethyl-5-propyl-s-triazole [ 1, 5c] pyrimidine-2 -amine 7-(2-Hy~Lu~cyt:tlloxy) ~ u,~u,~-l,Lhene-2~ L~u..ylic acid Amiloride ~1nYAl ~r~ide Deoxycof ormycin Fisetin Flufenamic acid Nilidrine hydrorh 1 t~r i fl~
p-r,L- ~ ^nAr-yl bromide Pimozide AAAAAAA.I AAAAAAAAAAAAAAAAAAAAAAAAAAA
Phosphatase inhibitors make up another class of '- which is characterized by mast cell ~ -~t83~
Wo 95/21611 PCTNS95/01392 degranulation-inhibitory activity. Exemplary r.. L,~ lc in this class are I~e~o~;L~ ; 1, Minocromil, Kaempferol, Quercetin, 2'-carboxyl-ato_lL ~ 5'-yl-2 l~ydLv~cy~L~Lc-~e derivatives, 1,3-bis [2'-[[(acetoxymethyl)oxyl]
5 carbonyl]~l.L ~ 5'-yl] 2 hydL~syLJL~ane~ pyrano [3,2,-] quinoline-2, 8-dicarboxylic acid derivatives, and 5-chlorobenzoxazole-2-carboxylic acid. These _ _ '- and others in this class obstruct a phoshatase from mediating protein ~ rhns~h~rylation~ an integral step in various 10 rhnsrh~lrylation/~l~rhn6rhnrylation events which are essential to intrA--~llul;~r regulation.
In particular, protein phosphatase inhibitors have been shown to attenuate the release of histamine and leukotriene mediators from human lung mast cells.
Peachell et al., .T. I~urlunol. 151: 3808 (1993).
Phosphatase inhibitors are distingll;Rh~hl~ by an ability to inhibit one of the four major classes of phosphatases.
Type 1 phosphatase (PP1) ~l~rh~s~hnrylates the beta subunit of phosphorylase kinase and is inhibited by 20 +. h. L~lble inhibitors 1 and 2 and inactivated by okadaic acid (LC Services Corporation, Nottingham, UK).
Type 2 phosphatases include three subtypes (PP2A, PP2B, and PP2C), each of which rl~rhocrhnrylates the alpha subunit of pho~ ,Lylase kinase. Each of PP2A and PP2B
25 ~re inhibited by okadaic acid. PP2C is insensitive to okadaic acid but is completely ~lorpn~l~nt on Mg2+.
Accordingly, the class of protein phosphatase inhibitors also i nrlll~Pc okadaic acid, analogues of okadaic acid, okadaol and nor-nk~ n~ (LC Services 30 Corporation, supra; Biomol, Plymouth Meeting, PA), and okadaic acid methyl ester [see Nishiwaki, Carcinogenesis 11: 1837 (1990) ], as well as calyculin (LC Services Corporation) .
It is not n~ cs:-ry to the operability of the present 35 invention that each member of the foregoing classes inhibits mast cell degranulation to the same extent. The ability of a particular substance to inhibit mast cell degranulation can be readily det~rmin~r1 empirically.
~Q 6 g WO95/21611 ~ ' PCr/USs5/01392 Thus, mast cells from rats (piece5 of small intestine) or humans (inte6tinal biopsies) ean be obtained; otherwise, RB~ eells or immortalized human mucosal-like mast cells (HNC-l) are kept in culture. Any of these cells then are 5 exposed to various ~ulleel-LLlltions of a putative inhibitory c __ ', to allow for aetion by the putative inhibitor at eritieal sites. Effieaey with respeet to inhibition of mast eell degranulation then is aseertained; that is, the intestinal biopsies, explants l0 or eultured cell6 thus treated are used as such or washed free of unbound test __ ' before ~ JO~ULe: to a stimulus known to induce mast cell degranulation. A
' suitable for use in accordanee with the present invention is rocoqni7od as one that ~Lt:v~ L~ the stimulus 15 from eausing degranulation, ~L~_ hly by binding to speeifie receptors or by inactivating a crucial step in the degranulation process.
While it is possible in principle that a particular ~- ~uul~d in one of the a}.u~_ ~ Lioned classes, by virtue 20 of its activity, could be employed in the described manner, it is true generally that the advisability of using any mast eell-degranulation inhibitor according to the present invention must be tempered by rl inirAl considerations, inrl~ ing toxicity, bioav~ hility, 25 distribution, half-life and clearanee, whieh are conventional to this field. See, for example, GOODM
AND GILMAN ' S THE Pt~T~M~ TnGICAL BASIS OF THERAPEUTICS
SS I & XVII (7th ed. ) .
Thus, dosage f orms f or the delivery of the selected 30 mast cell degranulation hlrrkin~ agent should be those that aehieve and retain high levels of the drug in the gastrointestinal traet with reasonable rapidity. These dosage forms are adapted for a variety of eonventional routes of administration, inrlll~in~ oral, parenteral and 35 rectal.
Pursuant to the present invention, a mast cell degranulation-h1Orl~i n~ agent is administered in a rhAr~ tieallY effeetive amount. The dosage range for ... . ... . _ ... = = . = .. _ . _ . _ .. .. _ Wo 9~/21611 F~l~u~
rh~ tttical effectiveness can be det-~rm;n-~rl by reference to standard laboratory test6 for inhibition of gastrointe6tinal mast cell degranulation, as ~i~cl-cced above .
A pharmaceutically effective dose for a given mast cell degranulation-hlorkin~ agent can be approximated by its ID20, which is the dose nPr-~CC~ry to cau6e 20%
inhibition in mast cells when applied to mast cells stimulated in vitro. The ID20 values ror sel~ct~d 10 inhibitor _ ~ are shown in Table 2.
Table 2 UU.~UU..L~S WHICH INHIBIT RAT NUCOSAL
NAST CELL DEGRANUI,ATION IN VITRO
r __ ~ ID20 for histamine release Azatadine 10-7 N
Hydroxyzine 5 x 10 ~ M
Ketotifen 10~ N
N-methyl histamine 10-7 N
Oxatomide 10-7 N
Sp~-rmi n~ 5 x 10~ M
Tamoxifen 5 x 10~ N
ID20 = inhibitory dose causing 20% inhibition.
25 N = molar CUII~ L'- tion.
The agent can best be admini6tered syst~m i c~ l l y or directly in the intestinal loops (suppository, enema or injection) of the live mammal. The mast cell inhibitory effect of certain of t7tese ~__ ' has been described 30 for non-intestinal mast cells. See, for example, Vliagoftis et al., Biochem. phArr-~o7. 43: 2237-45 (1992), Rn~:nil~rki et al. in PROC. 8TH INT'~ C~Nt:RT'qS
T711M77N-TnGy 159 (Budapest 1992), Rn~n;erki et al., FASEB
J. 6: A1554 (1992), and Rachmilewitz et al., Ga~troenterol. 102: A235 (1992).
An assay by which efficacy of a mast cell degranulation-bl orki n~ agent can be tested systemically in the present context is the rat-; -'-ili7ation assay, in which a rat is pre-treated with an agent and then restrained for one hour in a clear plexiglass cylinder.
After the immobil~ization, a specific gastrointestinal mast cell mediator, rat mast cell protease II (RNCPII), is measured. This assay is accepted as a non-ulcerogenic 5 model of stress. See Williams et al., Am. J. Physiol.
253: 582-86 (1987).
Results from testing ketotifen in the rat-immobilization assay are presented in Table 3 below.
Ketotifen was administered intraperitoneally to rats (l l0 mg/kg body weight, twice daily) for four days prior to immobilization .
Table 3 ON BY K~~ kl~ OF
~AT l~ll;ollN ~L RNCPII IN A TRESS NODEL
15 Time T ' ' 1 i .-"i Non~ Le~l wt min) ~n = 3) (n ~ 3) FketoTL~ifen (n - 3) 60 4.85- 0.3 0.5 120 12.4- 0.7 0.8-ng/ml; 1 = number o rats tested 20 * p < 0 . 05 vs. non-; ~ c~
** p < 0 . 00l vs. immobilized Table 3 shows that intestinal mast cells are activated during stress to secrete a specific proteolytic enzyme, RNCPII, and that ketotifen acts as a mast cell 25 degranulation-blocking agent in preventing secretion of RNCPII from such cells. The equivalent proteolytic enzyme in humans is tryptase, which also can be measured from colonic fluid or hir~p~
It is essential to the present invention that the 30 selected agent inhibit mucosal mast-cell secretion.
Thus, mast cell degranulation-blorlr;rlrJ agents, such as d;~:od;11m cromoglycate (~mMnTyN), which do not have an inhibitory effect specifically on mucosal mast cells, see Pearce et Pl., J. Immunol. 128: 2481-86 (1982), are not 35 within the scope of the present invention. No work has 1,4 ~3~
wo 951~1611 PCT/US95/01392 -80 far involved H3 receptor agonists in the inhibition of gastrointestinal mast cell degranulation.
A mast cell degranulation-hlorlrin~ agent can be administered, according to the present invention, in the 5 form of the active agent itself or as a pharmaceutically acceptable salt of the active agent. The phrase "rh~rr~ tically acceptable salt" denotes a non-toxic, substantially non-irritating salt of the - _I.d used.
Typical salts are ; llm salts and salts containing an 10 cation that is an alkali metal or AlkAl ;n~ earth metal, such as sodium, potassium, calcium or magnesium. The category of suitable cations for the salt also ; nrlllt9~
sulphate, phosphate, tartrate and citrate. Other acceptable salts are those with non-toxic organic acids, 15 such as fatty acids of one to six carbon atoms in length.
Pursuant to the present invention, a mast cell degranulation-~lork;n7 agent can be delivered via methods known for drug administration. The agents are typically administOEed as rhArr~--putical compositions in 20 combination with rhArr--eutically acceptable carriers.
Such compositions may be pLèp~Led from conv~n~;nn materials by ~Lvcedu~es well known in the art.
Compositions within the present invention can be adapted for oral or parenteral administration, as well as 25 for enteral administration or through mucous membranes, such as trAn~nr~-l ly. An oral formulation which will keep the drug for an ~Yt~n~l~A time in the gastrointestinal tract is preferred, since such a formulation allows long e~oauLe of the mucosal mast 30 cells present there to the drug.
Forms suitable for oral administration include tablets, dispersible powders, granules, capsules, syrups, elixirs and suspensions. Also preferred in this regard are encapsulated f orms . For instance, a pref erred mode 35 of administration would be via l ;rr~s~ --, mUlt~ Ar phospholipid vesicles, or l ;r~ é5~ which protect the active agênt from destruction in the stomach and allows for slow release in the intestine as each phospholipid _ _ _ _ .. . . . , _ _ _ _ _ 3 ~ ~.9 ~`
Wo 95121611 PcrluS95/01392 ~ 18--layer is dissolved, resulting in sustained high intestinal levels of the drug. Alving, C.R., S.
Shichijo, I. Mattsby-Baltzec, R.L. Richards and N.N.
Wassef, "Preparation and U8e of T.1, - in I_munologic 5 Studie6, " in LIPOSOME TE:C}~NOLOGY, 2nd ed., vol. III, G.
Gregoriadis, ed., CRC Pres6, Boca Raton, FL, pp.317-343, 1984; Amselem, 5., C.R. Alving, and A.J. Domb, Polymers for Advanced Terhnn7Ogiesl 3:351-357 (1992); and Amselem, et al. Vaccine Research 1: 383-385 (1992).
Compositions for oral use contain one or more conventional adjuvants, such as sweetPnin~ agents, flavoring agents, coloring agents and preserving agents, in order to provide a presentable and palatable preparation. Tablet6 may contain the active ingredients 15 in a mixture with conventional rh~ P71tically acceptable eYcipients. These include inert carriers, such as calcium ~.~LI,.,~ Le, sodium carbonate, lactose, and talc; granulating and disintegrating agents, such as starch and alginic acid; bin~ing agents such as starch, 20 gelatin acacia; and lubricating agents, such a6 m-gnPcj~lm stearate, stearic acid and talc. Tablets may be uncoated or coated by known techniques to delay disintegration and ab60rption in the gastrointestinal tract, thereby providing a sustained action over a longer period of 25 time. Similarly, s~lqpPnqions, syrups and elixirs may contain active ingredients in mixture with any of the conventional ~y~ipipntF utilized in the preparation of such compositions. This inr~ pc 5llqpPn~ling agents such as methylcPlllllosel tragacanth and sodium alginate;
30 wetting agents such as lecithin, polyuxy-:Lllylene stearate or polyu~y~Ulylene sorbitan monoleate; and preservatives.
e~rS1ll Pq may contain the active ingredients alone or in an admixture with an inert solid carrier, such as calcium carbonate, calcium phosphate or kaolin. These 35 pharmaceutical compositions may contain up to 90~6 of active ingredients in combination with the carrier or adjuvant. The '~ preferably are put up in unit dosage forms, particularly for oral administration, for _ . _ _ . _ . _ . . ...
wo 9~/21611 PcT/US95/01392 example, in 20 mg tablets. Such forms may contain the active ingredient separately, for example in separate - layers.
The agents can be administered in sustained release 5 form or in divided dosages.
Oral administration often is preferred if the mast cell degranulation-blocking agent is orally active.
TrAnc~ administration also is preferred. More specifically, in the case of mast cell degranulation-10 blorkin~ agents which are substantially destroyed ordeactivated upon oral administration, or where a more prolonged duration of activity is desired, a mast cell degranulation-blocking agent also can be administered trAne~c-rr-l ly or via other body membranes, such as 15 rectally.
A preferred forrll~t;on within the present invention comprises both a suitable mast cell deyL~ lation inhibitor and an agent that inhibits or counteracts intestinal motility, thereby increasing the transit time 20 and, hence, the effect of the inhibitor in the intestinal tract. Such a suitable antimotility agent is dicyclomine rArSlllQe, such as BENTYL (Taylor phA~rqreuticAl Company, Decatur, Illinois). The use of an antimotility agent in this context is ~cre~jAlly ~l~ftLLe:d when the mast cell-25 degranulation inhibitor is contained in a lipid-containing delivery vehicle, as ~i~cllq~Qd above. Thus, the antimotility agent can be "co-administered" with the delivery vehicle, i.e., can be administered in such a way that the motility-counteractive inf luence of the agent 3 0 increases the rQci~n~-e time of the delivery vehicle in the intestine.
The following illustrative examples further describe the present invention.
J
r le l The following experiment was performed in order to evaluate rat mucosal mast cell t~C) degranulation by .
WO 95/21611 PCr/US95/01392 t~, measuring rat mast cell protease II (RNCPII), a specific marker f or MMC, and by electron microscopy .
Rats were treated intragastrically for four (4) days with either 0.5 ml of saline containing ketotifen (1 5 mg/kg twice daily) or saline alone. On day five, the animals were euth~ni~P~ ileum was removed and ileal explants were placed in orgari culture. The explants were incubated at 37C in a medium containing either 5 ~g/ml of toxin A in 0 . 01 ml of 50 mM Tris buffer, or buffer 10 alone. Aliquots (50 ~Ll) of medium were collect~ at specified times and RMCPII levels were detprminl~d~
Results are ~uL~ssed in Table 4 as nanograms of RMCPII
released per milligram of tissue wet weight (pothmll:~k;~:
et al., Gastroenterology 105:701-707, 1993).
Table 4 ON BY Khl~ hl~ OF RAT l~lh~llNAL
RMCP II SECRETION -NDUCED BY TOYIN A
Time Buffer Toxin A Ketotifen+
(min) (n = 10) (n = 7) Toxin A
(n = 6) 20 30 3.4 ~ 0.8 5.0 + 1.2 2.9 + 1.0 60 6.2 + 0.9 7.2 + 1.7 3.0 + 1.1+
120 7.6 $ 1.2 12.6 i: 2.1- 4.2 + 0.9++
180 11.3 + 2.1 24.0 + 4.8-- 6.7 + 1.9++
p < 0 . 05 v buff er 25 ** p < 0 . 01 " "
+ p < 0. 05 vs Toxin A
++ p < O. 01 " "
Electron miuLus~:u~Uy showed significant mucosal mast 30 cell degranulation in rat ileum within 15 minutes of ~,UOaULe to toxin A, and complete degranulation at 60 minutes. These results, obtained by J. Castagliuolo, J.T. LaMont, R. Letourneau, C. Relly, J.C. O'Keane, A.
Jaffer, T.C. Theoharides and C. Pothoulakis, ~ LL~-Le 35 that ketotifen effectively inhibits the release of RMCPII
from rat ileal explant6 and, hence, inhibits mucosal mast cell degranulation.
WO 9SIZ1611 ~ 8 3 ~ ~ 9 PCT~ sgsl0l392 Similar results were obtained using the substance P
receptor antagonist (Pothoulakis et al., Proc. Natl.
Acad. Sci., USA 91:947-951, 1994).
r le 2 A female patient, age 49, suffered from irritable bowel s.ylldLI - for approximately 10 years. symptom~ were so severe that she had difficuity in functioning as a nurse, mother and wife. After treatment with 11y-1Lu,cy~ine hydrochloride (ATARAX; 50 mg/day) for three months, her gastrointestinal dis~ -UL L waB almost completely eliminated, and she was able to resume her professional and family responsibilities. On several orr~ion~ when she attempted to withdraw from the use of ilydL~,~y4ine hydrochloride, she experienced a marked increase in symptoms of irritable bowel iy.,~ . The symptoms d;~lrp~Ared when she resumed taking the medication.
r le 3 A female patient, age 32, had a four-year history of irritable bowel sy~l~ ~ and had dif f iculty in carrying out her profPcc;nn;~l duties as a nurse. She was treated for 4 months with 50 mg/day of ~ly-lL~ y~ine pamoate (VISTARIL). She experienced a noticeable; ~ uv, I' of her ~y.u~ and was able to resume her professional activities .
r le 4 A female patient, age 39, suffered from irritable bowel ~.ylldL - for over two years. Her gymptoms ;nrll~d~9 c.,.._L~..L pain at the cnnn~ct;nn of the buttocks with the upper legs, as well as painful defecation. After 30 L- t:ai L with ketotifen (ZADITEN; 4 mg/day) for two months, her pain 5~lhci~d signif icantly .
r le 5 A female patient, age 39, with a five-year history of irritable bowel ~ylldr~ , experienced uu--~,L~I-L
, ~
W095121611 ~ P~ . 1392 A`-' ;n~l pain which was not relieved by any of a variety of narcotic and non-narcotic analgesics and anti-inflammatory drugs. Her symptom6 were F-Y~r~rhated during LLu~ltion. Treatment with tamoxifen citrate (NOVADEX;
5 40 mg/day, administered orally) for two months substantially eliminated her pain.
r le 6 A female patient, age 32, with a two-year history of AI ~ ; ns~ 1 migraine, experienced C.~ L~l- L gastrointestinal 10 pain which was cnn~ ably worse immediately YL~ LLUCI11Y. After treatment with the Gn-RH analogue LUPRON (3 ~g/day subcutaneous injection) for four months, she was symptom-free.
Claims (21)
1. A method of manufacturing a medicament or the treatment of an endogenous painful gastrointestinal condition of non-inflammatory, non-ulcerative origin which comprises a mast cell degranulation-blocking agent in an amount sufficient to affect said condition in a pharmaceutically acceptable carrier.
2. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is a naturally occurring polyamine.
3. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is selected from the group consisting of spermine, spermidine, and metabolites thereof.
4. The composition according to claim 3, wherein said mast cell degranulation-blocking agent is spermine.
5. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is administered orally.
6. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is contained in a lipid-containing delivery vehicle.
7. The composition according to claim 6, wherein said lipid-containing delivery vehicle is co-administered with an antimotility agent.
8. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is a heterocyclic histamine-1 receptor antagonist.
9. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is selected from the group consisting of azatadine, azelastine, cetirizine, forskolin, hydroxyzine, ketotifen and oxatomide .
10. The composition according to claim 9, wherein said mast cell degranulation-blocking agent is ketotifen.
11. The composition according to claim 10, wherein said ketotifen is in the form of a pharmaceutically acceptable salt.
12. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is a histamine-3 receptor agonist.
13. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is selected from the group consisting of N.alpha.-dimethyl histamine, R.alpha.-methyl histamine, .alpha.,.beta.-dimethyl-N.alpha.(dimethyl) histamine, .alpha.,.beta.-difluoro-N.alpha.(dimethyl) histamine, .alpha.-methyl, .beta.-fluoro-N.alpha.(fluoromethyl) histamine and .alpha.,.beta.-difluoro-N.alpha.(fluoromethyl) histamine.
14. The composition according to claim 13, wherein said mast cell degranulation-blocking agent is .alpha.,.beta.-difluoro-N.alpha.(fluoromethyl) histamine.
15. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is an anti-female sex hormone.
16. The composition according to claim 1, wherein said mast cell degranulation-blocking agent is clomiphene, mifepristone, tamoxifen and a GnRH analogue.
17. The composition according to claim 16, wherein said mast cell degranulation-blocking agent is tamoxifen.
18. The composition according to claim 16, wherein said mast cell degranulation-blocking agent is LUPRON.
19. The composition according to claim 18, wherein said LUPRON is administered subcutaneously.
20. The composition according to claim 1, wherein said condition is abdominal migraine.
21. The composition according to claim 1, wherein said condition is irritable bowel syndrome.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/193,597 US5648355A (en) | 1994-02-09 | 1994-02-09 | Method of treatment of endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin |
| US08/193,597 | 1994-02-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2183069A1 true CA2183069A1 (en) | 1995-08-17 |
Family
ID=22714282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002183069A Abandoned CA2183069A1 (en) | 1994-02-09 | 1995-02-09 | Compositions comprising a mast cell degranulation-blocking agent for treatment of endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5648355A (en) |
| EP (2) | EP1203586A3 (en) |
| AT (1) | ATE221776T1 (en) |
| AU (1) | AU1741295A (en) |
| CA (1) | CA2183069A1 (en) |
| DE (1) | DE69527706T2 (en) |
| ES (1) | ES2180626T3 (en) |
| WO (1) | WO1995021611A2 (en) |
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| US6861053B1 (en) * | 1999-08-11 | 2005-03-01 | Cedars-Sinai Medical Center | Methods of diagnosing or treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth |
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| US5888529A (en) * | 1997-03-28 | 1999-03-30 | The Regents Of The University Of California | Ileus treatment method |
| US6689748B1 (en) * | 1998-04-08 | 2004-02-10 | Theoharis C. Theoharides | Method of treating mast cell activation-induced diseases with a proteoglycan |
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| US20050220909A1 (en) * | 2004-03-30 | 2005-10-06 | Theoharides Theoharis C | Composition for protection against superficial vasodilator flush syndrome |
| US6984667B2 (en) * | 1998-04-08 | 2006-01-10 | Theta Biomedical Consulting And Development Co. | Synergistic proteoglycan compositions for inflammatory conditions |
| US20080153761A1 (en) * | 1998-04-08 | 2008-06-26 | Theoharides Theoharis C | Compositions for protection against superficial vasodilator flush syndrome, and methods of use |
| US20040230559A1 (en) * | 1999-08-09 | 2004-11-18 | Mark Newman | Information processing device and information processing method |
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| WO2003013245A1 (en) * | 2001-08-07 | 2003-02-20 | Wisconsin Alumni Research Foundation | Polyamines and analogs for protecting cells during cancer chemotherapy and radiotherapy |
| US20030185778A1 (en) * | 2002-02-07 | 2003-10-02 | Fahl William E. | Polyamine compounds and compositions for use in conjunction with cancer therapy |
| EP1501822B1 (en) * | 2002-04-30 | 2010-12-15 | Kudos Pharmaceuticals Limited | Phthalazinone derivatives |
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| GB0305681D0 (en) | 2003-03-12 | 2003-04-16 | Kudos Pharm Ltd | Phthalazinone derivatives |
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| US20050020608A1 (en) * | 2003-03-25 | 2005-01-27 | Dr. Reddy's Laboratories Limited | Crystalline cetirizine monohydrochloride |
| ATE446791T1 (en) | 2003-05-16 | 2009-11-15 | Univ Laval | CNS CHLORIDE MODULATION AND USE THEREOF |
| US20050124965A1 (en) * | 2003-12-08 | 2005-06-09 | Becton, Dickinson And Company | Phosphatase inhibitor sample collection system |
| US7923043B2 (en) * | 2004-03-30 | 2011-04-12 | Theta Biomedical Consulting & Development Co., Inc. | Method for protecting humans against superficial vasodilator flush syndrome |
| AU2005244036A1 (en) | 2004-05-14 | 2005-11-24 | Universite De Laval | Phospholipase C gamma modulation and uses thereof for management of pain and nociception |
| GB0419072D0 (en) | 2004-08-26 | 2004-09-29 | Kudos Pharm Ltd | Phthalazinone derivatives |
| GB0428111D0 (en) * | 2004-12-22 | 2005-01-26 | Kudos Pharm Ltd | Pthalazinone derivatives |
| WO2006122069A2 (en) * | 2005-05-09 | 2006-11-16 | Azur Pharma | Formulations of mast cell stabilizing agents for delivery to the colon |
| GB0521373D0 (en) * | 2005-10-20 | 2005-11-30 | Kudos Pharm Ltd | Pthalazinone derivatives |
| US20070286892A1 (en) * | 2006-06-13 | 2007-12-13 | Uri Herzberg | Compositions and methods for preventing or reducing postoperative ileus and gastric stasis in mammals |
| EP2041110A1 (en) * | 2006-06-15 | 2009-04-01 | Kudos Pharmaceuticals Limited | 2 -oxyheteroarylamide derivatives as parp inhibitors |
| JP2009541217A (en) * | 2006-06-15 | 2009-11-26 | クドス ファーマシューティカルズ リミテッド | 2-Oxybenzamide derivatives as PARP inhibitors |
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| US20090023727A1 (en) * | 2007-07-05 | 2009-01-22 | Muhammad Hashim Javaid | Phthalazinone derivatives |
| WO2009034326A1 (en) | 2007-09-14 | 2009-03-19 | Astrazeneca Ab | Phthalazinone derivatives |
| KR101598231B1 (en) * | 2007-10-17 | 2016-02-26 | 쿠도스 파마슈티칼스 리미티드 | 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| AR070221A1 (en) | 2008-01-23 | 2010-03-25 | Astrazeneca Ab | DERIVATIVES OF FTALAZINONA POLYMERASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USES OF THE SAME TO PREVENT AND / OR TREAT CANCERIGENE TUMORS, ISCHEMICAL INJURIES AND OTHER ASSOCIATED DISEASES. |
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| LT2346495T (en) * | 2008-10-07 | 2016-10-10 | Astrazeneca Uk Limited | Pharmaceutical formulation 514 |
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| US9176146B2 (en) * | 2009-08-03 | 2015-11-03 | Theta Biomedical Consulting & Development Co., Inc. | Methods of treating autism spectrum disorders and compositions for same |
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| WO2017193024A1 (en) | 2016-05-06 | 2017-11-09 | Tricida, Inc. | Hcl-binding compositions for and method of treating acid-base disorders |
| AU2018360867A1 (en) | 2017-11-03 | 2020-04-30 | Tricida, Inc. | Compositions for and method of treating acid-base disorders |
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| US4507321A (en) * | 1982-02-17 | 1985-03-26 | The Research Foundation Of State University Of New York | Epithelial cell growth regulating composition containing polyamines and a method of using same |
| FR2630328B1 (en) * | 1988-04-22 | 1990-08-24 | Inst Nat Sante Rech Med | HISTAMINE DERIVATIVE, ITS PREPARATION AND ITS THERAPEUTIC APPLICATION |
| US4843074A (en) * | 1988-05-17 | 1989-06-27 | Marion Laboratories, Inc. | 1-azabicyclo[2.2.2]octan-3-yl 2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts |
| IN171746B (en) * | 1989-11-02 | 1992-12-26 | Mcneil Ppc Inc | |
| US5250529A (en) * | 1990-02-08 | 1993-10-05 | Kos Pharmaceuticals, Inc. | Method alleviating migraine headache with mast cell degranulation blocking agents |
| US5057322A (en) * | 1990-08-10 | 1991-10-15 | Baker Cummins Dermatologicals, Inc. | Method of treating mast cell disease |
| AU672772B2 (en) * | 1991-12-27 | 1996-10-17 | Theta Biomedical Consulting & Development Co., Inc. | Alleviating or prevention of migraine headache onset with mast cell degranulation blocking agents |
-
1994
- 1994-02-09 US US08/193,597 patent/US5648355A/en not_active Expired - Lifetime
-
1995
- 1995-02-09 AU AU17412/95A patent/AU1741295A/en not_active Abandoned
- 1995-02-09 AT AT95909451T patent/ATE221776T1/en not_active IP Right Cessation
- 1995-02-09 CA CA002183069A patent/CA2183069A1/en not_active Abandoned
- 1995-02-09 EP EP02075270A patent/EP1203586A3/en not_active Withdrawn
- 1995-02-09 EP EP95909451A patent/EP0748217B1/en not_active Expired - Lifetime
- 1995-02-09 WO PCT/US1995/001392 patent/WO1995021611A2/en active IP Right Grant
- 1995-02-09 DE DE69527706T patent/DE69527706T2/en not_active Expired - Fee Related
- 1995-02-09 ES ES95909451T patent/ES2180626T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0748217B1 (en) | 2002-08-07 |
| US5648355A (en) | 1997-07-15 |
| DE69527706D1 (en) | 2002-09-12 |
| ATE221776T1 (en) | 2002-08-15 |
| WO1995021611A3 (en) | 1995-10-05 |
| EP1203586A2 (en) | 2002-05-08 |
| EP0748217A1 (en) | 1996-12-18 |
| DE69527706T2 (en) | 2002-11-28 |
| AU1741295A (en) | 1995-08-29 |
| EP1203586A3 (en) | 2002-10-30 |
| WO1995021611A2 (en) | 1995-08-17 |
| ES2180626T3 (en) | 2003-02-16 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |