CA2170313A1 - Method for treating emesis - Google Patents
Method for treating emesisInfo
- Publication number
- CA2170313A1 CA2170313A1 CA002170313A CA2170313A CA2170313A1 CA 2170313 A1 CA2170313 A1 CA 2170313A1 CA 002170313 A CA002170313 A CA 002170313A CA 2170313 A CA2170313 A CA 2170313A CA 2170313 A1 CA2170313 A1 CA 2170313A1
- Authority
- CA
- Canada
- Prior art keywords
- nitric oxide
- oxide synthase
- emesis
- synthase inhibitor
- accordance
- 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
Links
- 206010047700 Vomiting Diseases 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 19
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 claims abstract description 28
- 241001465754 Metazoa Species 0.000 claims abstract description 24
- 229940123921 Nitric oxide synthase inhibitor Drugs 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims description 13
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 9
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 9
- KCWZGJVSDFYRIX-YFKPBYRVSA-N N(gamma)-nitro-L-arginine methyl ester Chemical group COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 8
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 claims description 5
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 claims description 5
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 claims description 5
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims description 4
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- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims description 2
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 claims description 2
- 210000002540 macrophage Anatomy 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 claims 1
- 210000003038 endothelium Anatomy 0.000 claims 1
- 239000002895 emetic Substances 0.000 description 25
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 14
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- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
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- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 5
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- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 241000282341 Mustela putorius furo Species 0.000 description 2
- NTNWOCRCBQPEKQ-YFKPBYRVSA-N N(omega)-methyl-L-arginine Chemical compound CN=C(N)NCCC[C@H](N)C(O)=O NTNWOCRCBQPEKQ-YFKPBYRVSA-N 0.000 description 2
- NTNWOCRCBQPEKQ-UHFFFAOYSA-N NG-mono-methyl-L-arginine Natural products CN=C(N)NCCCC(N)C(O)=O NTNWOCRCBQPEKQ-UHFFFAOYSA-N 0.000 description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 2
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- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 2
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- 230000036982 action potential Effects 0.000 description 2
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- 229960002173 citrulline Drugs 0.000 description 2
- 235000013477 citrulline Nutrition 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
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- 229930195712 glutamate Natural products 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- GZEWDUYXKDCZJU-LURJTMIESA-N (2s)-5-amino-2-(2-iminoethylamino)pentanoic acid Chemical compound NCCC[C@@H](C(O)=O)NCC=N GZEWDUYXKDCZJU-LURJTMIESA-N 0.000 description 1
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- UYZFAUAYFLEHRC-LURJTMIESA-N L-NIO Chemical compound CC(N)=NCCC[C@H](N)C(O)=O UYZFAUAYFLEHRC-LURJTMIESA-N 0.000 description 1
- 125000002059 L-arginyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- QBNXAGZYLSRPJK-JEDNCBNOSA-N N(gamma)-nitro-L-arginine methyl ester hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O QBNXAGZYLSRPJK-JEDNCBNOSA-N 0.000 description 1
- UYZFAUAYFLEHRC-UHFFFAOYSA-N NG-iminoethyl-L-ornithine Natural products CC(N)=NCCCC(N)C(O)=O UYZFAUAYFLEHRC-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 1
- 206010038776 Retching Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000003825 glutamate receptor antagonist Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- QBNXAGZYLSRPJK-NUBCRITNSA-N methyl (2r)-2-amino-5-[[amino(nitramido)methylidene]amino]pentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CCCN=C(N)N[N+]([O-])=O QBNXAGZYLSRPJK-NUBCRITNSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A method of treating emesis in a warm blooded animal by administering an anti-emesis effective amount of a nitric oxide synthase inhibitor and compositions containing the same.
Description
METHOD FOR TRF~TING FMESIS
The present invention is directed to a method of treating emesis in a warm-blooded animal by administering to said warm-blooded animal an anti-emesis effective amount of a nitric oxide synthase inhibitor.
BACKGROUND OF THE INVENTION
Emesis is the complex process in some warm-blooded animals, including humans, in which the stomach is evacuated through the esophagus and mouth due tostrong muscular contractions in the abdomen. Commonly known as vomiting or retching, emesis is associated with nausea, malaise and general discomfort. The mechanism by which emesis is induced is complex. A detailed discussion of the process is disclosed in, for example, Mehernoor F. Watcha et al., "PostoperativeNausea and Vomiting", Anesthesiology, Vol. 67, pp. 162-184 (1992).
The biochemical basis of emesis stems from the presence of an emesis center within the brain. This center is located specifically in a region designated anatomically as the area postrema. This speciaiized area of the brain is distinguished from other regions of the central nervous system by the fact that it does not have a blood brain barrier to prevent substances circulating in the blood from freely entering therein.
~0 217~313 -Current work suggests that neurons in the area postrema serve as sensors of noxious substances circulating in the blood. Once these substances enter the area postrema and are sensed by the neurons as harmful, a message in the form of electrical impulses is triggered to evacuate the gastrointestinal tract. The transmission of the electrical impulses is generated when sufficient positive charge has been built up in the neurons to cause depolarization and a subsequent action potential. This action potential causes the release of a chemical neurotransmitter molecule from the pre-synaptic terminal into the synaptic cleft. The neurotransmitter molecule diffuses from one neuron through extracellular fluid, across the synapse, to a membrane receptor molecule of a post-synaptic neuron. Several chemical neurotransmitter systems involved in emesis have been identified based on the type of neurotransmitter molecule and include those based on glutamate, dopamine and serotonin.
Efforts at mediating the emetic process have focused on disrupting these neurotransmitter systems. For example, inhibitors of dopamine and serotonin havebeen used to treat emesis as disclosed in Alison L. Jones et al., "Management ofVomiting Associated With Cytotoxic Therapy", Br. J. of Hosp. Med., Vol. 45, pp. 85-88 (February 1991). Glutamate receptor antagonists, such as kynurenic acid or 7-chlorokynurenate, have also been proposed as anti-emesis agents in John W. Olney, U.S. Patent No. 5,039,528.
In the glutamate based neurotransmitter system, the presence of excess gl utamate triggers an emesis response. Under these ci rcumstances, excess calcium ions pass through a neuronal channel and upon entering the cell activate calmodulin. This 25 substance activates nitric oxide synthase which in turn is responsible for converting L-arginine into citrulline and nitric oxide. Nitric oxide is believed to activate guanylate cyclase to produce cyclic GMP which may be directly involved in triggering the emetic process.
The present invention is directed to a method of treating emesis in a warm-blooded animal by administering to said warm-blooded animal an anti-emesis effective amount of a nitric oxide synthase inhibitor.
BACKGROUND OF THE INVENTION
Emesis is the complex process in some warm-blooded animals, including humans, in which the stomach is evacuated through the esophagus and mouth due tostrong muscular contractions in the abdomen. Commonly known as vomiting or retching, emesis is associated with nausea, malaise and general discomfort. The mechanism by which emesis is induced is complex. A detailed discussion of the process is disclosed in, for example, Mehernoor F. Watcha et al., "PostoperativeNausea and Vomiting", Anesthesiology, Vol. 67, pp. 162-184 (1992).
The biochemical basis of emesis stems from the presence of an emesis center within the brain. This center is located specifically in a region designated anatomically as the area postrema. This speciaiized area of the brain is distinguished from other regions of the central nervous system by the fact that it does not have a blood brain barrier to prevent substances circulating in the blood from freely entering therein.
~0 217~313 -Current work suggests that neurons in the area postrema serve as sensors of noxious substances circulating in the blood. Once these substances enter the area postrema and are sensed by the neurons as harmful, a message in the form of electrical impulses is triggered to evacuate the gastrointestinal tract. The transmission of the electrical impulses is generated when sufficient positive charge has been built up in the neurons to cause depolarization and a subsequent action potential. This action potential causes the release of a chemical neurotransmitter molecule from the pre-synaptic terminal into the synaptic cleft. The neurotransmitter molecule diffuses from one neuron through extracellular fluid, across the synapse, to a membrane receptor molecule of a post-synaptic neuron. Several chemical neurotransmitter systems involved in emesis have been identified based on the type of neurotransmitter molecule and include those based on glutamate, dopamine and serotonin.
Efforts at mediating the emetic process have focused on disrupting these neurotransmitter systems. For example, inhibitors of dopamine and serotonin havebeen used to treat emesis as disclosed in Alison L. Jones et al., "Management ofVomiting Associated With Cytotoxic Therapy", Br. J. of Hosp. Med., Vol. 45, pp. 85-88 (February 1991). Glutamate receptor antagonists, such as kynurenic acid or 7-chlorokynurenate, have also been proposed as anti-emesis agents in John W. Olney, U.S. Patent No. 5,039,528.
In the glutamate based neurotransmitter system, the presence of excess gl utamate triggers an emesis response. Under these ci rcumstances, excess calcium ions pass through a neuronal channel and upon entering the cell activate calmodulin. This 25 substance activates nitric oxide synthase which in turn is responsible for converting L-arginine into citrulline and nitric oxide. Nitric oxide is believed to activate guanylate cyclase to produce cyclic GMP which may be directly involved in triggering the emetic process.
There are at least three distinct forms of nitric oxide synthase (NOS) found in the body. The first type is neuronal NOS found principally in the brain and in non-adrenergic, non-cholinergic (NANC) neurons in the gut. Endothelial NOS and inducible NOS (found in macrophages) are the second and third types. Endothelial5 NOS, found in the endothelial tissues, affects blood circulation by producing nitric oxide which acts as a vasodilator. Accordingly, endothelial NOS has been implicated in such conditions as hypertension, endotoxin shock (e.g. septic shock) and thrombosis.
Inducible NOS triggers the production of nitric oxide when the body is exposed 10 to an endotoxin, and has been associated with such chronic ailments as ulcerative colitis and arthritis.
The production of nitric oxide can be inhibited by a class of compounds known as NOS inhibitors. For example, Interleukin-1 and lipopolysaccharides are known to 15 inhibit the activity of macrophage NOS such as disclosed in Joseph R. Williamson et al., U.S. Patent Nos. 5,245,970 and 5,246,971. Analogues of L-arginine including NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO) and NG-nitro-L-arginine methyl ester (L-NAME) have been shown to inhibit endothelial NOS. D.D.
Rees et al., Br. I. Pharmacol, Vol. 101, pp. 746-752 (1990).
The present invention is premised on the discovery that compounds which effectively inhibit nitric oxide synthase, especially neuronal NOS, when administered in effective doses, can be employed as potent anti-emesis agents.
SUMMARY OF THE INVENTION
The present invention provides a method of treating emesis in a warm blooded animal comprising administering to said warm blooded animal an anti-emesis effective amount of a nitric oxide synthase inhibitor. In a preferred form of the invention, the 30 nitric oxide synthase inhibitor is one which inhibits at least neuronal nitric oxide 2~7~313 synthase in the conversion of L-arginine to citrulline and nitric oxide. In a preferred form of the invention, the nitric oxide synthase inhibitor substantially inhibits the activity of neuronal nitric oxide synthase and minimally inhibits the activity of endothelial and/or inducible nitric oxide synthases. The administration of a nitric oxide synthase inhibitor in accordance with the present invention minimizes or eliminates the production of nitric oxide and thus the production of cyclic GMP. As a result, the emetic process is attenuated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method of treating emesis through the administration of a nitric oxide synthase inhibitor. The term "treating" as utilized herein is intended to mean both prophylactic and curative applications. The compounds of the invention can be administered after the onset of emesis, at the first appearance of symptoms indicating potential emesis, and in those situations wh Specific examples of the nitric oxide synthase inhibitors for use in the presentinvention include L-NG-nitro-arginine methyl ester (L-NAME) and L-NG-nitro-arginine (L-NOARG). The nitric oxide synthase inhibitors of the present invention may be administered to a warm-blooded animal in amounts of at least 0.0001 mg/kg of body weight of said animal, preferably from about 0.0001 to 10.0 mg/kg of body weight.
The nitric oxide synthase inhibitors of the present invention are typically combined with a pharmaceutically acceptable carrier which is selected depending on whether the inhibitor is water-soluble or water insoluble. Examples of suitable carriers include isotonic saline, distilled water, dilute hydrochloric acid, bicarbonates, dimethyl sulfoxide, mixtures of alcohols, such as ethanol and propylene glycol, and saline, and the like. For example, effective carriers include a mixture of 10% by volume of ethanol, 40% by volume of propylene glycol, and 50% by volume of saline as well as a mixture of 10% by volume (ethanol and emulphor), 60% by volume propylene glycol and 30% by volume of saline.
~.~
Compositions for parenteral administration contain from about 0.1% to about 50% by weight of the nitric oxide synthase inhibitors of the subject invention. The amount present will depend on the potency of the active ingredient and its solubility in the pharmaceutical vehicle. In general, the compositions contain sufficient active 5 ingredient so that the practioner may titrate the dosage if desired and still be able to administer the maximum dosage in a parenteral container without giving the patient an unduly large amount of fluid. The nitric oxide synthase inhibitors may be combined with the carrier at room temperature; particularly when they are highly soluble in the carrier. For nitric oxide synthase inhibitors of lower solubility, it may be desirable to 10 heat the carrier to temperatures below its boiling point to effect solution.
The composition containing the nitric oxide synthase inhibitor is administered parentally, preferably by intravenous injection. The composition of the present invention upon administration to a warm blooded animal, effectively prevents and15 alleviates emesis, particularly severe episodes which result from the application of chemotherapeutic agents, opiates or systemic anesthesic agents. An example of the advantageous breadth of anti-emesis activity of the nitric oxide synthase inhibitors of the present invention is their effectiveness against emesis induced by the admin istration of cisplatin. Few conventional anti-emesis agents have been shown to be effective 20 against cisplatin-induced emesis.
Six naive male ferrets (castrated, descented; Triple F Farms) were individually 25 cared for in a vivarium for one week prior to testing with regularly available supplies of food and water. Each ferret, weighing between 1 and 2 kilograms on the day of the test was allowed to acclimate to the laboratory environment for at least 30 minutes.
Each ferret was anesthetized with 5% isoflurane-oxygen mixture delivered by a Fortec vaporizer for 2 to 5 minutes until the animals lost their righting reflex.
The test animals were maintained at this level of anesthesia and then injected intravenously with one ml/kg of a composition containing NG-nitro-L-arginine methyl ester (L-NAME) in saline in the dosage amounts shown in Table 1. The injection was made into the cephalic vein of the dorsal aspect of the front paw. Thereafter, the 5 anesthetic agent was withdrawn and 30 minutes later, morphine sulfate (0.3 mg/kg of body weight of the test animals) was administered subcutaneously into the nape of the neck. The animals were observed for emetic episodes which are defined as the oral expulsion of solids or liquids and retches which are rhythmic abdominal contractions with no expulsion of material. Observations were recorded for 30 minutes following 10 morphine administration.
The mean and standard error of the mean (SEM) for emetic episodes was determined for each dose group and controls. The effect of the treatment is calculated as the percent protection of emetic episodes according to the following formula:
M~n episodes of vehicle - mean episodes of inhibitor x 100 = % protection Mean episodes of vehicle The results are shown in Table 1.
Table 1 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean ~ SEM) Emetic Episodes 0 11.3 ~ 1.3 0 0.0001 7.5 + 2.5 34 0.001 6.3 + 1.6 44 0.01 4.2 + 0.8 63 0.1 5.2 + 1.2 54 1.0 2.8 + 0.4 75 As shown in Table l, administration of just 0.0001 mg/kg of body weight of the nitric oxide synthase inhibitor resulted in a significant improvement in the protection of the test animals against emetic episodes induced by morphine sulfate. As the dose was increased to 1.0 mg/kg of body weight, the percentage protection increased to 5 75%.
The test described in Example 1 was repeated except that cisplatin (10 mg/kg l O of body weight) was used as the emesis inducing stimulus. Cisplatin, which is generally regarded as a more severe emetic than morphine sulfate, does not respond to treatment with most conventional anti-emesis agents.
Due to a comparatively slow onset of activity, cisplantin was administered 15 intravenously 30 minutes prior to the administration of the nitric oxide synthase inhibitor (L-NAME). The anesthetic agent was administered for from 2 to 5 minutes during each injection. The test animals were observed for 60 minutes following administration of L-NAME. The results are shown in Table 2.
Table 2 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean + SEM) Emetic Episodes 0 20.0 + 4.5 0 0.001 11.3 + 3.5 44 o.ol 12.3 + 5.2 39 0.1 9.3 + 3.1 54 l.0 6.3 + 2.2 69 10.0 - 4.3 + 1.7 79 The results shown in Table 2 indicate that significant improvement in protectionof the test animals against emetic episodes caused by cisplatin is obtained by employing the composition of the present invention.
The test described in Example 1 was repeated except that the nitric oxide synthase inhibitor was L-NG-nitro-arginine in the dosage amounts set forth in Table 3.
The results are shown in Table 3.
Table 3 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean i SEM) Emetic Episodes 0 11.0 + 1.4 0 0.01 9.3 + 2.0 15 0.1 6.7 + 2.0 41 1.0 5.5 + 1.5 51 10.0 2.2 + 0.9 81 As shown in Table 3, the administration of the composition of the present invention results in significant protection of the test animals against emetic episodes 25 induced by morphine sulfate.
The test described in Example 2 was repeated except that the nitric oxide 30 synthase inhibitor was L-NG-nitro-arginine in the dosage amounts set forth in Table 4.
The results are set forth in Table 4.
~ 1 703 1 3 T~hle 4 Dose Emetic Episodes % Protection of (mg/l<g, iv) (mean + SEM) Emetic Episodes 0 18.8 + 3.8 0 0.001 12.7 + 5.0 32 001 73 + 1.0 61 0.1 5.0 + 0.5 73 1.0 9.0 + 2.2 52 10.0 3.0 + 0.9 84 As shown in Table 4, the administration of the composition of the present 15 invention results in significant protection of the test animals against emetic episodes induced by cisplantin.
The procedure described in Example 1 was repeated except that NG-nitro-D-arginine methyl ester (D-NAME), a stereoisomer of L-NAME which is devoid of NOS
inhibiting activity, was employed in the dosage amount set forth in Table 5. Theresults are shown in Table 5.
T~hle 5 Dose Emetic Episodes % Protection of (mg/kg, iv) (mean ~ SEM) Emetic Episodes 0 7.3 + 1.0 0 1.0 7.0 + 1.2 4 21 7()313 As shown in Table 5, the administration of D-NAME was ineffective and therefore did not provide protection for the test animals against emetic episodes induced by morphine sulfate.
The procedure described in Example 2 was repeated except that D-NAME in the dosage amount set forth in Table 6 was employed. The results are shown in Table 6.
T~hle 6 Dose Emetic Episodes% Protection of (mglkg, iv) (mean + SEM) Emetic Episodes 0 17.5 + 2.0 0 10.0 14.4+1.3 18 As shown in Table 6, the administration of D-NAME was ineffective and 20 therefore did not provide protection for the test animals against emetic episodes induced by cisplatin.
~.
Inducible NOS triggers the production of nitric oxide when the body is exposed 10 to an endotoxin, and has been associated with such chronic ailments as ulcerative colitis and arthritis.
The production of nitric oxide can be inhibited by a class of compounds known as NOS inhibitors. For example, Interleukin-1 and lipopolysaccharides are known to 15 inhibit the activity of macrophage NOS such as disclosed in Joseph R. Williamson et al., U.S. Patent Nos. 5,245,970 and 5,246,971. Analogues of L-arginine including NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO) and NG-nitro-L-arginine methyl ester (L-NAME) have been shown to inhibit endothelial NOS. D.D.
Rees et al., Br. I. Pharmacol, Vol. 101, pp. 746-752 (1990).
The present invention is premised on the discovery that compounds which effectively inhibit nitric oxide synthase, especially neuronal NOS, when administered in effective doses, can be employed as potent anti-emesis agents.
SUMMARY OF THE INVENTION
The present invention provides a method of treating emesis in a warm blooded animal comprising administering to said warm blooded animal an anti-emesis effective amount of a nitric oxide synthase inhibitor. In a preferred form of the invention, the 30 nitric oxide synthase inhibitor is one which inhibits at least neuronal nitric oxide 2~7~313 synthase in the conversion of L-arginine to citrulline and nitric oxide. In a preferred form of the invention, the nitric oxide synthase inhibitor substantially inhibits the activity of neuronal nitric oxide synthase and minimally inhibits the activity of endothelial and/or inducible nitric oxide synthases. The administration of a nitric oxide synthase inhibitor in accordance with the present invention minimizes or eliminates the production of nitric oxide and thus the production of cyclic GMP. As a result, the emetic process is attenuated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method of treating emesis through the administration of a nitric oxide synthase inhibitor. The term "treating" as utilized herein is intended to mean both prophylactic and curative applications. The compounds of the invention can be administered after the onset of emesis, at the first appearance of symptoms indicating potential emesis, and in those situations wh Specific examples of the nitric oxide synthase inhibitors for use in the presentinvention include L-NG-nitro-arginine methyl ester (L-NAME) and L-NG-nitro-arginine (L-NOARG). The nitric oxide synthase inhibitors of the present invention may be administered to a warm-blooded animal in amounts of at least 0.0001 mg/kg of body weight of said animal, preferably from about 0.0001 to 10.0 mg/kg of body weight.
The nitric oxide synthase inhibitors of the present invention are typically combined with a pharmaceutically acceptable carrier which is selected depending on whether the inhibitor is water-soluble or water insoluble. Examples of suitable carriers include isotonic saline, distilled water, dilute hydrochloric acid, bicarbonates, dimethyl sulfoxide, mixtures of alcohols, such as ethanol and propylene glycol, and saline, and the like. For example, effective carriers include a mixture of 10% by volume of ethanol, 40% by volume of propylene glycol, and 50% by volume of saline as well as a mixture of 10% by volume (ethanol and emulphor), 60% by volume propylene glycol and 30% by volume of saline.
~.~
Compositions for parenteral administration contain from about 0.1% to about 50% by weight of the nitric oxide synthase inhibitors of the subject invention. The amount present will depend on the potency of the active ingredient and its solubility in the pharmaceutical vehicle. In general, the compositions contain sufficient active 5 ingredient so that the practioner may titrate the dosage if desired and still be able to administer the maximum dosage in a parenteral container without giving the patient an unduly large amount of fluid. The nitric oxide synthase inhibitors may be combined with the carrier at room temperature; particularly when they are highly soluble in the carrier. For nitric oxide synthase inhibitors of lower solubility, it may be desirable to 10 heat the carrier to temperatures below its boiling point to effect solution.
The composition containing the nitric oxide synthase inhibitor is administered parentally, preferably by intravenous injection. The composition of the present invention upon administration to a warm blooded animal, effectively prevents and15 alleviates emesis, particularly severe episodes which result from the application of chemotherapeutic agents, opiates or systemic anesthesic agents. An example of the advantageous breadth of anti-emesis activity of the nitric oxide synthase inhibitors of the present invention is their effectiveness against emesis induced by the admin istration of cisplatin. Few conventional anti-emesis agents have been shown to be effective 20 against cisplatin-induced emesis.
Six naive male ferrets (castrated, descented; Triple F Farms) were individually 25 cared for in a vivarium for one week prior to testing with regularly available supplies of food and water. Each ferret, weighing between 1 and 2 kilograms on the day of the test was allowed to acclimate to the laboratory environment for at least 30 minutes.
Each ferret was anesthetized with 5% isoflurane-oxygen mixture delivered by a Fortec vaporizer for 2 to 5 minutes until the animals lost their righting reflex.
The test animals were maintained at this level of anesthesia and then injected intravenously with one ml/kg of a composition containing NG-nitro-L-arginine methyl ester (L-NAME) in saline in the dosage amounts shown in Table 1. The injection was made into the cephalic vein of the dorsal aspect of the front paw. Thereafter, the 5 anesthetic agent was withdrawn and 30 minutes later, morphine sulfate (0.3 mg/kg of body weight of the test animals) was administered subcutaneously into the nape of the neck. The animals were observed for emetic episodes which are defined as the oral expulsion of solids or liquids and retches which are rhythmic abdominal contractions with no expulsion of material. Observations were recorded for 30 minutes following 10 morphine administration.
The mean and standard error of the mean (SEM) for emetic episodes was determined for each dose group and controls. The effect of the treatment is calculated as the percent protection of emetic episodes according to the following formula:
M~n episodes of vehicle - mean episodes of inhibitor x 100 = % protection Mean episodes of vehicle The results are shown in Table 1.
Table 1 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean ~ SEM) Emetic Episodes 0 11.3 ~ 1.3 0 0.0001 7.5 + 2.5 34 0.001 6.3 + 1.6 44 0.01 4.2 + 0.8 63 0.1 5.2 + 1.2 54 1.0 2.8 + 0.4 75 As shown in Table l, administration of just 0.0001 mg/kg of body weight of the nitric oxide synthase inhibitor resulted in a significant improvement in the protection of the test animals against emetic episodes induced by morphine sulfate. As the dose was increased to 1.0 mg/kg of body weight, the percentage protection increased to 5 75%.
The test described in Example 1 was repeated except that cisplatin (10 mg/kg l O of body weight) was used as the emesis inducing stimulus. Cisplatin, which is generally regarded as a more severe emetic than morphine sulfate, does not respond to treatment with most conventional anti-emesis agents.
Due to a comparatively slow onset of activity, cisplantin was administered 15 intravenously 30 minutes prior to the administration of the nitric oxide synthase inhibitor (L-NAME). The anesthetic agent was administered for from 2 to 5 minutes during each injection. The test animals were observed for 60 minutes following administration of L-NAME. The results are shown in Table 2.
Table 2 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean + SEM) Emetic Episodes 0 20.0 + 4.5 0 0.001 11.3 + 3.5 44 o.ol 12.3 + 5.2 39 0.1 9.3 + 3.1 54 l.0 6.3 + 2.2 69 10.0 - 4.3 + 1.7 79 The results shown in Table 2 indicate that significant improvement in protectionof the test animals against emetic episodes caused by cisplatin is obtained by employing the composition of the present invention.
The test described in Example 1 was repeated except that the nitric oxide synthase inhibitor was L-NG-nitro-arginine in the dosage amounts set forth in Table 3.
The results are shown in Table 3.
Table 3 Dose Emetic Episodes% Protection of (mg/kg, iv) (mean i SEM) Emetic Episodes 0 11.0 + 1.4 0 0.01 9.3 + 2.0 15 0.1 6.7 + 2.0 41 1.0 5.5 + 1.5 51 10.0 2.2 + 0.9 81 As shown in Table 3, the administration of the composition of the present invention results in significant protection of the test animals against emetic episodes 25 induced by morphine sulfate.
The test described in Example 2 was repeated except that the nitric oxide 30 synthase inhibitor was L-NG-nitro-arginine in the dosage amounts set forth in Table 4.
The results are set forth in Table 4.
~ 1 703 1 3 T~hle 4 Dose Emetic Episodes % Protection of (mg/l<g, iv) (mean + SEM) Emetic Episodes 0 18.8 + 3.8 0 0.001 12.7 + 5.0 32 001 73 + 1.0 61 0.1 5.0 + 0.5 73 1.0 9.0 + 2.2 52 10.0 3.0 + 0.9 84 As shown in Table 4, the administration of the composition of the present 15 invention results in significant protection of the test animals against emetic episodes induced by cisplantin.
The procedure described in Example 1 was repeated except that NG-nitro-D-arginine methyl ester (D-NAME), a stereoisomer of L-NAME which is devoid of NOS
inhibiting activity, was employed in the dosage amount set forth in Table 5. Theresults are shown in Table 5.
T~hle 5 Dose Emetic Episodes % Protection of (mg/kg, iv) (mean ~ SEM) Emetic Episodes 0 7.3 + 1.0 0 1.0 7.0 + 1.2 4 21 7()313 As shown in Table 5, the administration of D-NAME was ineffective and therefore did not provide protection for the test animals against emetic episodes induced by morphine sulfate.
The procedure described in Example 2 was repeated except that D-NAME in the dosage amount set forth in Table 6 was employed. The results are shown in Table 6.
T~hle 6 Dose Emetic Episodes% Protection of (mglkg, iv) (mean + SEM) Emetic Episodes 0 17.5 + 2.0 0 10.0 14.4+1.3 18 As shown in Table 6, the administration of D-NAME was ineffective and 20 therefore did not provide protection for the test animals against emetic episodes induced by cisplatin.
~.
Claims (10)
1. A method of treating emesis in a warm blooded animal comprising administering to said warm blooded animal an anti-emesis effective amount of a nitric oxide synthase inhibitor.
2. A method in accordance with Claim 1, wherein said nitric oxide synthase inhibitor inhibits the activity of at least neuronal nitric oxide synthase.
3. A method in accordance with Claim 2, wherein said nitric oxide synthase inhibitor substantially inhibits the activity of neuronal nitric oxide synthase and minimally inhibits the activity of at least one of endothelial nitric oxide synthase and inducible nitric oxide synthase.
4. A method in accordance with Claim 1, wherein the anti-emesis effective amount of the nitric oxide synthase inhibitor is at least 0.0001 mg/kg of body weight of said animal.
5. A method in accordance with Claim 4, wherein the anti-emesis effective amount of the nitric oxide synthase inhibitor is from about 0.0001 to 10.0 mg/kg of body weight of said animal.
6. A method in accordance with Claim 1, wherein the nitric oxide synthase inhibitor is selected from the group consisting of L-NG-nitro-arginine methyl ester and L-NG-nitro-arginine.
7. A composition comprising an anti-emesis effective amount of a nitric oxide synthase inhibitor and a pharmaceutically acceptable carrier for parenteral administration.
8. A composition in accordance with Claim 7, wherein said nitric oxide synthase inhibitor inhibits the activity of at least neuronal nitric oxide synthase.
9. A composition in accordance with Claim 8, wherein said nitric oxide synthase inhibitor substantially inhibits the activity of neuronal nitric oxide synthase and minimally inhibits the activity of at least one of endothelium nitric oxide synthase and macrophage nitric oxide synthase.
10. A composition in accordance with Claim 7, containing from about 0.1 %
to about 50% by weight of said nitric oxide synthase inhibitor.
to about 50% by weight of said nitric oxide synthase inhibitor.
Priority Applications (1)
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CA002170313A CA2170313A1 (en) | 1996-02-26 | 1996-02-26 | Method for treating emesis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CA002170313A CA2170313A1 (en) | 1996-02-26 | 1996-02-26 | Method for treating emesis |
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Publication Number | Publication Date |
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CA002170313A Abandoned CA2170313A1 (en) | 1996-02-26 | 1996-02-26 | Method for treating emesis |
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1996
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