JPH01197444A - Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blocker - Google Patents
Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blockerInfo
- Publication number
- JPH01197444A JPH01197444A JP63017500A JP1750088A JPH01197444A JP H01197444 A JPH01197444 A JP H01197444A JP 63017500 A JP63017500 A JP 63017500A JP 1750088 A JP1750088 A JP 1750088A JP H01197444 A JPH01197444 A JP H01197444A
- Authority
- JP
- Japan
- Prior art keywords
- histamine
- day
- steroidal anti
- receptor blocker
- receptor
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 title claims abstract description 15
- 239000003485 histamine H2 receptor antagonist Substances 0.000 title claims abstract description 13
- 239000000464 adrenergic agent Substances 0.000 title claims abstract description 9
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 6
- 239000000938 histamine H1 antagonist Substances 0.000 title claims abstract 7
- 230000003637 steroidlike Effects 0.000 title claims description 3
- 230000006378 damage Effects 0.000 title abstract description 9
- 210000001035 gastrointestinal tract Anatomy 0.000 title abstract 2
- 230000000694 effects Effects 0.000 title description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 21
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 17
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 16
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003223 protective agent Substances 0.000 claims abstract description 6
- 229960000195 terbutaline Drugs 0.000 claims abstract description 6
- 229960000520 diphenhydramine Drugs 0.000 claims abstract description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 4
- 230000001681 protective effect Effects 0.000 claims abstract description 4
- 229960000620 ranitidine Drugs 0.000 claims abstract description 4
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims abstract description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 22
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 13
- 229960001340 histamine Drugs 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 108090000110 Histamine H1 Receptors Proteins 0.000 claims description 7
- 102000000543 Histamine Receptors Human genes 0.000 claims description 7
- 108010002059 Histamine Receptors Proteins 0.000 claims description 7
- 239000003087 receptor blocking agent Substances 0.000 claims description 7
- 102000005962 receptors Human genes 0.000 claims description 7
- 108020003175 receptors Proteins 0.000 claims description 7
- 206010061172 Gastrointestinal injury Diseases 0.000 claims description 5
- 102000003834 Histamine H1 Receptors Human genes 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 230000000903 blocking effect Effects 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 2
- 102000003710 Histamine H2 Receptors Human genes 0.000 claims 1
- 108090000050 Histamine H2 Receptors Proteins 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 230000037396 body weight Effects 0.000 abstract 1
- 241000282472 Canis lupus familiaris Species 0.000 description 13
- 239000003814 drug Substances 0.000 description 10
- 230000002496 gastric effect Effects 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000003902 lesion Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
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- 239000002253 acid Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
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- 206010053155 Epigastric discomfort Diseases 0.000 description 2
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 2
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- 240000000249 Morus alba Species 0.000 description 2
- 235000008708 Morus alba Nutrition 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 206010037549 Purpura Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- 229960002657 orciprenaline Drugs 0.000 description 2
- 206010034754 petechiae Diseases 0.000 description 2
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- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 241000293841 Antirrhinum cyathiferum Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000011668 ascorbic acid Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000002171 ethylene diamines Chemical class 0.000 description 1
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- 229940066493 expectorants Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 229940083761 high-ceiling diuretics pyrazolone derivative Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- -1 indomethacin) Chemical class 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011976 maleic acid Chemical group 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000008267 milk Chemical class 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
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- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
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- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、非ステロイド系抗炎症薬（以下本文において
Ｎ５ＡＩＤと称する）によって生じる消化管損傷に対す
る保詮剤として、β−アドレナリン作用桑ならびにＨ，
−１およびＨ２−遮断薬およびこれらの混合物からなる
群から選択されるヒスタミン−受容体遮断薬の組合せを
含有する非ステロイド系抗炎症性組成物に関する。本発
明の組成物は、古典的にＮ５ＡＩＤの投与によって処置
されている状態および症状、例えば頭痛、関節炎および
その他の全身性疾患に伴う痛みおよび炎症、体温上昇等
々の処置に有用である。DETAILED DESCRIPTION OF THE INVENTION The present invention provides β-adrenergic mulberry and H.
The invention relates to a non-steroidal anti-inflammatory composition containing a combination of histamine-receptor blockers selected from the group consisting of -1 and H2-blockers and mixtures thereof. Compositions of the invention are useful in treating conditions and symptoms classically treated by the administration of N5AIDs, such as headaches, pain and inflammation associated with arthritis and other systemic diseases, elevated body temperature, and the like.
アスピリンおよびその他のＮ５ＡＩＤは長年に亘って個
々人の痛み、炎症および発熱の処理のための最も普及し
ている薬物であった。しかし、欠点の一つは、その投与
に時として付随してくる消化管損傷および（または）出
血である。これは、例えば関節炎の処理の場合のように
徴候をコントロールするのに大量かつ持続用量のＮ５Ａ
ＩＤを投与しなければならない場合に特別な問題となっ
ている。Aspirin and other N5AIDs have been the most popular drugs for treating pain, inflammation and fever in individuals for many years. However, one of the drawbacks is the gastrointestinal injury and/or bleeding that sometimes accompanies its administration. This requires large and sustained doses of N5A to control symptoms, for example in the treatment of arthritis.
This poses a particular problem when ID must be administered.
β−アドレナリン作用桑とヒスタミンＨ１−１Ｈ２−受
容体遮断剤およびこの混合物からなる群から選択される
ヒスタミン受容体遮断薬との組合せをＮ５ＡＩＤと同時
に投与する場合、ＮＳＡより誘起消化管損傷が著しく減
少されることが見い出された。When a combination of β-adrenergic mulberry and a histamine receptor blocker selected from the group consisting of histamine H1-1H2-receptor blockers and mixtures thereof is administered simultaneously with N5AID, the induced gastrointestinal damage is significantly reduced compared to NSA. It was found that
米国特許第４，９９６，５７１号に指摘されているよう
に、Ｈｚ−およびＨｚ−受容体遮断薬は、Ｈｌ−および
Ｈ，−受容体部位でそれぞれヒスタミンの遮断剤として
作用する２種の周知で明白な薬理学的に活性な薬物の群
を形成している。ヒスタミン受容体部位は、これらの部
位を遮断するのに作用し得る抗ヒスタミンの群を基にし
て分類されていた。薬物が抗ヒスタミンとして同定され
る事実は、必らずしも、既知のヒスタミン受容体部位の
すべてｔｉ断するのに有効ではあるが、実際選択的であ
ってもよいことを意味し、その結果一方の部位例えばＨ
，部位で作用するが、他の部位例えばＨ２部位で作用し
ない。As pointed out in U.S. Pat. No. 4,996,571, Hz- and Hz-receptor blockers are two well-known classes of blockers of histamine that act as blockers of histamine at Hl- and H,- receptor sites, respectively. They form a group of pharmacologically active drugs. Histamine receptor sites have been classified based on the group of antihistamines that can act to block these sites. The fact that a drug is identified as an antihistamine does not necessarily mean that it is effective in blocking all known histamine receptor sites, but may be selective in nature, resulting in One part, for example H
, but not at other sites, such as the H2 site.
先行技術では、Ｈｚ−受容体遮断剤はある糧の実数動物
ではアスピリン誘起損傷に対して保護することが報告さ
れている。この研究の一つは、ガストロエンテロロジイ
（Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ ） 、第８８巻
、第５号、第２部、第１３４４頁に報告されている。ま
た、シプロヘブタジンがアスピリン誘起消化管損傷に対
する保護剤として評価されていることが報告されている
〔インディアン、Ｊ、メト。In the prior art, Hz-receptor blockers have been reported to protect against aspirin-induced damage in some fed animals. One of these studies is reported in Gastroenterology, Volume 88, No. 5, Part 2, Page 1344. It has also been reported that cyprohebutadine has been evaluated as a protective agent against aspirin-induced gastrointestinal injury [Indian, J., Met.
しｙ、（Ｉｎｄｉａｎ Ｊ、Ｍａｄ、Ｒｅ＠、）、１
９８０年、７１、第９２６−３２頁］。シブロヘプタジ
ンは若干のＨ１４容体拮抗作用を有しているが、このも
のはＨＩ受容体部位に限って作用するものではなくて、
むしろセロトニン受容体部位を優先的に遮断するように
作用する〔グツドマン（Ｇｏｏｄｍａｎ ）およびギル
マン（Ｇｉ １ｍａｎ ）、［ザ、ファーマコロジカル
・ベーシス・オブ・セラビュテイクス」（Ｔｈｅ Ｐｈ
ａｒｍａｃｅｕｔｉｃａｌ Ｂａ５ｉｓ ｏｆ Ｔｈｅ
ｒａｐｅｕｔｉｃｓ）、第７版、第１３４４頁。Shiy, (Indian J, Mad, Re@,), 1
980, 71, pp. 926-32]. Sibroheptadine has some H14 receptor antagonism, but this does not act only at the HI receptor site;
Rather, it acts to preferentially block serotonin receptor sites (Goodman and Giman, The Pharmacological Basis of Therapeutics).
armaceutical Ba5is of The
rapeutics), 7th edition, page 1344.
上述の点は別個にして、本発明は該インディアン・ジャ
ーナル中の教示とは更に顕著に異っている。この文献で
のまず一例をあけるとすれば、本発明の如く、アスピリ
ンおよびシプロヘブタジンを同時投与していない。更に
、この文献でのシブロヘブタジンによる処置は胃液の酸
性度を改変しないと報告されていて、本発明に関連して
なされた観察と反している。更にまた、このインディア
ン文献には、シプロヘブタジンをアスピリンの胃内投与
に先立って腹腔内注射によって投与されていた。これと
は反対に、本発明の組成物は経口投与に適応されていて
、この投与時にＮ５ＡＩＤおよび組合せＨｌ−およびＨ
ｚ−受容体遮断薬を同時投与している。Apart from the foregoing, the present invention differs more significantly from the teachings in the Indian Journal. The first example in this document is that aspirin and cyprohebutadine are not co-administered, as in the present invention. Furthermore, treatment with sibrohebutadine in this document was reported not to alter the acidity of gastric fluid, contrary to the observations made in connection with the present invention. Furthermore, in this Indian document, cyprohebutadine was administered by intraperitoneal injection prior to intragastric administration of aspirin. On the contrary, the compositions of the present invention are adapted for oral administration, during which administration N5AID and the combination Hl- and Hl-
A z-receptor blocker is being administered concurrently.
更にまた、前文中にあけ次先行技術には、本発明の必須
の特徴、すなわちヒスタミンＨ１−および（または）Ｈ
ｚ−受容体遮断薬と共にβ−アドレナリン作用薬を組合
せて使用することが伺も示唆されていない。Furthermore, the prior art disclosed in the preamble describes the essential features of the present invention, namely histamine H1- and/or
There is no suggestion of the use of β-adrenergic agonists in combination with z-receptor blockers.
本発明の目的に有用なＨｌ−およびＨ２−受容体遮断薬
は数多く先行技術で知られている。本発明で使用し得る
Ｈｌ−受容体遮断薬を例示すると、次のものがあげられ
る。エタノールアミン（例えば、ジフェンヒドラミンま
たはその塩酸塩；カルピノオキサミン′またはそのマレ
イン酸塩）；エチレンジアミン（例えば、トリベレンア
ミンまたはその塩酸塩またはクエン酸塩）；アルキルア
ミン（例えば、クロルフェニラミンまたはそのマレイン
酸塩、プロムフエニラミンまたはそのマレイン酸塩）；
およびピペラジン（例えば、ヒドロキシジンまたはその
塩酸塩またはパモエート塩、サイクリジンまたはその塩
酸塩または乳識塩等）。本発明の実施化に有利に使用し
得るＨ２−受容体遮断薬の例示としては次のものがあげ
られるうシメチジン、ラニチジン、ファモチジン等。Many Hl- and H2-receptor blockers useful for the purposes of the present invention are known in the prior art. Examples of Hl-receptor blockers that can be used in the present invention include the following. Ethanolamines (e.g. diphenhydramine or its hydrochloride; carpinoxamine' or its maleate); ethylenediamines (e.g. triberenamine or its hydrochloride or citrate); alkylamines (e.g. chlorpheniramine or its maleate); maleate, prompheniramine or its maleate);
and piperazine (eg, hydroxyzine or its hydrochloride or pamoate salt, cyclizine or its hydrochloride or milk salt, etc.). Examples of H2-receptor blockers that can be advantageously used in the practice of the present invention include the following: cimetidine, ranitidine, famotidine, and the like.
Ｈ８−およびＨ２−受容体遮断薬はその塩基の形態でま
たはその製薬上許容し得る塩の形態で使用し得る。塩と
してｉいる場合、これらのものは辿常酸部分が塩酸、マ
レイン酸、アスコルビン酸、クエン酸、ハモインＦ（ｐ
ａｍｏｉｃ）、乳酸、酒石酸等であってよい酸付加塩で
ある。H8- and H2-receptor blockers may be used in their base form or in the form of their pharmaceutically acceptable salts. When in the form of salts, these salts have common acid moieties such as hydrochloric acid, maleic acid, ascorbic acid, citric acid, and hamoin F (p
ammoic), lactic acid, tartaric acid, etc.
β−アドレナリン作作用上またβ−アドレナリン受容体
部位を刺戟することによって作用することを特徴とする
相当に十分に定義された群の製薬上有効な化合物を形成
している。これらの受容体部位はβ１およびβ２部位と
称される２種のタイプがある。β−アドレナリン作作用
上部位のいずれか一方または両方のタイプで作用する。They form a fairly well-defined group of pharmaceutically active compounds characterized by their action on β-adrenergic activity and by stimulating β-adrenergic receptor sites. These receptor sites are of two types, termed β1 and β2 sites. Acts at either or both types of β-adrenergic sites.
本発明の目的に有用な数多くのβ−アドレナリン作作用
上先行技術で知られている。特に興味のあるのは、β２
作用薬であるテルブタリン（ｔｅｒｂｕｔａｌｉｎｅ
）である。本発明で使用し得るその他のβ−アドレナリ
ン作用剤を例示すると、次のものがあげられる。イング
ロテレノ〒ル、メタプロテレノール、およびアルブチロ
ール。これらはいずれもそれ自体であるいは製薬上許容
し得る塩として使用し得る。Numerous beta-adrenergic agents are known in the art that are useful for the purposes of the present invention. Of particular interest is β2
The agonist terbutaline
). Examples of other β-adrenergic agents that can be used in the present invention include the following. Ingloterenol, metaproterenol, and albutyrol. Any of these can be used by itself or as a pharmaceutically acceptable salt.
Ｎ５ＡＩＤ＃−ｉまた抗炎症鎮痛剤である周知の群の薬
物を形成している。これらは消化管粘膜に保護作用を有
するプロスタグランジンの形成を阻害する共通した性質
を有している。グツドマンおよびギルマン、「ザ・ファ
ーマコロジカル・ベイシス・フォア・セラビューティク
ス」、第７版、第６７８頁を参照。この群の薬物の経口
投与が消化管損傷および（！！たは）出血を生じる傾向
があるのは、この抑制作用に因るものであり、そして本
発明が減退あるいは除去を求めている課題の少くとも一
部である。N5AID#-i also forms a well-known group of drugs that are anti-inflammatory analgesics. These have the common property of inhibiting the formation of prostaglandins, which have a protective effect on the gastrointestinal mucosa. See Gutdman and Gilman, The Pharmacological Basis for Therapeutics, 7th edition, p. 678. It is because of this inhibitory effect that oral administration of this group of drugs tends to result in gastrointestinal injury and/or bleeding, a problem that the present invention seeks to reduce or eliminate. At least in part.
本発明を適用し得るＮ５ＡＩＤが数多く先行技術で知ら
れている。最も普通に知られている群はサリチレートで
あり、アスピリンが最も重要な例である。本発明に関連
して有用性のある他の群のＮ５ＡＩＤはゾロピオン酸誘
導体である。この群には、例えばイブプロフェンおよび
ナプロキセンが包含される。本発明で使用し得る更に仙
の群のＮ５ＡＩＤはツェナメートおよび構造が極めて類
似した化合物である。これらは例えばメフェナム酸、メ
タロフエナム酸ナトリウムおよびジクロフェナックおよ
びそのナトリウム塩のような化合物で例示することがで
きる。また、本発明が関係するＮ５ＡＩＤ群に属するも
のとして、インドール誘導体（例、インドメタシン）、
ピロールアルカン酸誘導体（例、トルメチン）；ピラゾ
ロン誘導体（例、フェニルブタシン）；オキシカム（例
、ピロキシカム）；等がある。Many N5AIDs are known in the prior art to which the present invention can be applied. The most commonly known group is the salicylates, with aspirin being the most important example. Another group of N5AIDs that have utility in connection with the present invention are zolopionic acid derivatives. This group includes, for example, ibuprofen and naproxen. A further group of N5AIDs that can be used in the present invention are compounds that are very similar in structure to zenamate. These can be exemplified by compounds such as mefenamic acid, sodium metallofenamic acid and diclofenac and its sodium salt. In addition, as those belonging to the N5AID group to which the present invention relates, indole derivatives (e.g., indomethacin),
Examples include pyrrole alkanoic acid derivatives (eg, tolmetin); pyrazolone derivatives (eg, phenylbutacin); oxicams (eg, piroxicam); and the like.
本発明の実施化において、Ｎ５ＡＩＤ、β−アドレナリ
ン作作用上よびヒスタミン−受容体遮断薬が通常の製品
形態で同時に投与されることが企図されている。このよ
うな製品の必須成分は、ヒスタミンＨ１−および（また
は）Ｈｌ−受容体遮断薬、β−アドレナリン作用薬およ
びＮＳＡ Ｉ Ｄである。これに加えて、これらの製品
は、製品の特別な剤型例えば錠剤、カプセル剤、散剤、
懸濁剤等に大巾に左右されるその他の成分を含有してい
てもよい。In the practice of the present invention, it is contemplated that N5AID, beta-adrenergic and histamine-receptor blockers are administered simultaneously in conventional product form. Essential ingredients of such products are histamine H1- and/or H1-receptor blockers, β-adrenergic agonists and NSAIDs. In addition to this, these products are available in special dosage forms of the product such as tablets, capsules, powders,
It may also contain other ingredients depending on the amount, such as a suspending agent.
本発明の組成物に含有されるＨｌ−受容体遮断薬の量は
若干変えることができる。必要とされることのすべては
、有効量−が存在し、それによってＨ，−受容体遮断薬
がＮ５ＡＩＤ誘起消化管損傷に対する保護剤としてその
寄与をなし得るこ仁である。The amount of Hl-receptor blocker contained in the compositions of the invention can vary slightly. All that is required is that an effective amount exist so that the H,-receptor blocker can make its contribution as a protective agent against N5AID-induced gastrointestinal damage.
同様に、本発明の組成物の量もまた変υ得る。再び、必
要とされることのすべては、使用される蕾がＨ２−受容
体遮断薬を保護剤としてのその役割を果すことを可能と
する有効量であることである。Similarly, the amount of the composition of the invention may also vary. Again, all that is required is that the buds used be in an effective amount to enable the H2-receptor blocker to perform its role as a protective agent.
本発明の組成物中に含有されるβ−アドレナリン作用薬
の↑は変えることができる。再び、必要とされることゐ
すべては、本発明の組成物の一部を形成する他の活性成
分と共に使用する場合、Ｎ５ＡＩＤ誘起消化管損傷のた
めの保護剤として働くのに十分な量で存在していること
である。The amount of β-adrenergic agonist contained in the compositions of the invention can vary. Again, all that is required is that it be present in an amount sufficient to act as a protective agent for N5AID-induced gastrointestinal damage when used in conjunction with the other active ingredients forming part of the compositions of the present invention. That's what I'm doing.
Ｎ５ＡＩＤ Ｆｉ、本発明の組成物中に、経口投与が企
図されている治療Ｎ５ＡＩＤ組成物に一般に存在する濃
度で含有されている。これは通常製薬上許容し得る鎮痛
／抗炎症用量である。N5AID Fi is included in the compositions of the invention at concentrations commonly present in therapeutic N5AID compositions intended for oral administration. This is usually a pharmaceutically acceptable analgesic/anti-inflammatory dose.
本発明の製品に含まれるＮ５ＡＩＤ、β−アドレナリン
作用薬およびヒスタミンＨ，−および（または） Ｈ２
−受容体遮断薬の量的関係は、これらの成分の平均−日
量例えば岬／体重Ｋｆ／日によって表わすことができる
。これらの関係を以下の表Ｉに示し、−量的および好適
な範囲をその中で特定している。ヒスタミンＨ１−およ
びＨ２−受容体遮断薬のために特定された範囲は、Ｈｌ
またはＨ２遮断薬を使用する場合に篩用する範囲である
。ＨｌおよびＨ２遮断薬の組合せを用いるときは、製品
に含まれる各々の量を調節する。N5AID, β-adrenergic agonist and histamine H,- and/or H2 contained in the product of the invention
- The quantitative relationship of receptor blockers can be expressed in terms of the average daily dose of these components, for example Cape/Kf/day. These relationships are shown in Table I below, with quantitative and preferred ranges specified therein. The range specified for histamine H1- and H2-receptor blockers is Hl
Or, it is the range to be screened when using an H2 blocker. When using a combination of Hl and H2 blockers, adjust the amount of each included in the product.
表 ■
Ｎ５ＡＩＤ １□−１００□１５≠１−７５□本発明の
ための１回投与剤型は通常の経口投与のために処方され
ている。各成分の量の範囲を以下の表■に記載する。ヒ
スタミンＨ１−およびＨ２−受容体遮断薬のための特定
された範囲は、Ｈ１逍断薬まｆｃはＨ２遮断系を用いる
ときに適用する範囲でるる。ＨｌおよびＨ２遮断薬の組
合せを用いるときは、製品中の各々のｔを調節する。Table ■ N5AID 1□-100□15≠1-75□ Single dose forms for the present invention are formulated for conventional oral administration. The range of amounts of each component is listed in Table 3 below. The ranges specified for histamine H1- and H2-receptor blockers are the ranges applicable when using H1 blockers or H2 blockade systems. When using a combination of Hl and H2 blockers, adjust the t of each in the product.
表 ■
Ｎ５ＡＩＤ ２００■−６００１１１ｉＪβ−
アドレナリン作用剤 ０．７η−７０巧ヒ
スタミンＨ８−受容体遮断薬（用時） ０．０１
＋＋ｖ−７０■ヒスタミンＨ２−受容体遮断薬（用時）
０．５■−３５０■使用される剤型によって１本発明の
製品は特別な剤型を処方または投与するのに有用な他の
佐剤をも含有していてよい。それで、例えは、錠剤とし
て投与する場合、本発明の製品は滑沢剤、添加剤、結合
剤、崩壊剤、着香剤等を含有していてもよい。更に、こ
れらの製品はその他の製薬上の活性成分、例えば、うっ
血除去薬、鎮痛佐剤、去たん剤、鎮咳剤、利尿剤、他の
鎮痛剤、他の抗炎症剤、解熱剤、抗リウマチ剤、抗酸化
剤、血管拡張剤、平滑筋弛緩剤、骨格筋弛緩剤、気管支
拡張剤、ビタミン、微量ミネラル、アミノ酸および生物
学的ペプチドを含有していてもよい。Table ■ N5AID 200■-600111iJβ-
Adrenergic agent 0.7η-70 Histamine H8-receptor blocker (when used) 0.01
++v-70 ■ Histamine H2-receptor blocker (when used)
Depending on the dosage form used, the products of the invention may also contain other adjuvants useful in formulating or administering the particular dosage form. Thus, for example, when administered as a tablet, the product of the invention may contain lubricants, additives, binders, disintegrants, flavoring agents, and the like. In addition, these products may contain other pharmaceutically active ingredients, such as decongestants, analgesics, expectorants, antitussives, diuretics, other analgesics, other anti-inflammatory agents, antipyretics, antirheumatic agents, It may contain antioxidants, vasodilators, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids and biological peptides.
前文に示したとおり、本発明の製品は錠剤の形態をとり
得る。しかし、とねらはキャブレットとして処方されて
もよいし、あるいは摂取可能なカプセル例えばゼラチン
カプセルに入った粉末もしくは顆粒の形態であってもよ
い。本発明の製品はまた適当な液体媒質中の活性成分の
ＷＩ？’ｌ剤まｆＣ，は液剤として、あるいはまた適当
な紙包みに詰めた散剤として調製してもよい。As indicated in the preamble, the products of the invention may be in the form of tablets. However, the toner may also be formulated as a caplet or in the form of a powder or granules in an ingestible capsule, such as a gelatin capsule. The products of the invention also contain the active ingredients in a suitable liquid medium. The drug may be prepared as a liquid or alternatively as a powder packed in suitable paper packets.
次に実施例を挙け１本発明を更に具体的に説明する。し
かしながら、本発明はこれらの実施例に限定されるもの
ではないことが明白である。Next, the present invention will be explained in more detail with reference to Examples. However, it is clear that the invention is not limited to these examples.
実施例１
アスピリン ３２５ １１９ジフエ
ンヒドラミン塩酸塩 １６．６７ｑ上記成分を粉末
または顆粒の形態で混合し、そしてゼラチンカプセルに
充填する。Example 1 Aspirin 325 119 Diphenhydramine Hydrochloride 16.67q The above ingredients are mixed in powder or granule form and filled into gelatin capsules.
実施例２
アスピリン ３２５ １１１９ラニ
チジン塩酸塩 ３．３３１Ｎｉ実施例１
に記載の如くして調製する。Example 2 Aspirin 325 1119 Ranitidine Hydrochloride 3.331Ni Example 1
Prepared as described in .
実施例３
アスピリン ３２５ １１ｑメタプ
ロテレノール桃酸塩 ０１８３１Ｎ？実施例１に
記載の如くして調製する。Example 3 Aspirin 325 11q Metaproterenol peach salt 01831N? Prepared as described in Example 1.
用量
必要に応じて４時間毎に２カプセル。医師による指示の
ない限り、２４時間で８カプセルを超えてはならないし
、ｔ７’ｃ１２オ以下の小児に投与してはならない。Dosage 2 capsules every 4 hours as needed. Do not exceed 8 capsules in 24 hours and do not administer to children below t7'c12 o unless directed by a physician.
Ｎ５ＡＩＤ−誘起消化管損傷に対して冑を保護するのに
、β−アドレナリン作用薬とヒスタミンＨｗ −’ｊた
Ｆ’１Ｈｚ−受容体遮断薬との組合せの有効性を試験す
るために次の実験を行つｔｏこれらの研究で、使用した
ヒスタミンＨ１−受容体ａ薬はジフェンヒドラミンであ
り、そしてこのものはその塩酸塩の形態で用いた。用い
たヒスタミンＨ２−受容体遮断薬はラニチジンであり、
そして同じくその塩酸塩の形態で用いた。この試験で用
いた本発明の例示であるβ−アドレナリン作用薬はテル
ブタリンであった。このものは塩基で用いた。The following experiments were conducted to test the effectiveness of the combination of a β-adrenergic agonist and a histamine Hw-F'1Hz-receptor blocker in protecting against N5AID-induced gastrointestinal damage. In these studies, the histamine H1-receptor drug used was diphenhydramine, which was used in its hydrochloride form. The histamine H2-receptor blocker used was ranitidine;
It was also used in the form of its hydrochloride. The illustrative beta-adrenergic agonist of the invention used in this study was terbutaline. This product was used as a base.
アスピリンの標準投与量９７５ηを経口投与して消化管
損傷のペンチマークを得る。ヒスタミンＨ，−およびＨ
２−受容体遮断薬およびβ−アドレナリン作用薬を、ア
スピリンの標準投与量９７５■と一緒に、アスピリンの
標準試験投与量９７５■と共に投与したときのβ−アド
レナリン作用薬とヒスタミンＩ（ビまたはＨ２−受容体
遮断薬との組合せで得られる刺戟結果との比較のために
、別々に試験したつ犬の胃内壁を内視鋳で検査し、そし
て損傷の度合を評価する。結果を以下に示す方法論に従
って表に示す。A standard dose of aspirin, 975η, is administered orally to obtain pincer marks of gastrointestinal injury. Histamine H, - and H
2-receptor blockers and β-adrenergic agonists with the standard dose of aspirin, 975■; - For comparison with the stimulation results obtained in combination with receptor blockers, the stomach lining of the dogs tested separately is examined with an endoscopic cast and the degree of damage is assessed.The results are presented below. The methodology is shown in the table.
供試処方物はすべて試験当日に調製する。カプセルを犬
ののどの奥に入れる。漏斗付きの胃カテーテルを犬の胃
にとりつけ、そして脱イオン水５０ｍ１を投与する。All test formulations are prepared on the day of the test. Place the capsule in the back of your dog's throat. A gastric catheter with a funnel is placed in the dog's stomach and 50 ml of deionized water is administered.
雄または雌の健康なピーグル成因を試験用に選択する。Select a healthy male or female peagle for testing.
犬を***物が通過するように格子床のステンレス鋼ケー
ジ中で個別に飼育するっ飼育室および実験室の室温を６
５丁〜８５下および相対湿度３０チー８０％に維持する
。室幻は午前６時から午後４時までともしておく。Dogs are housed individually in stainless steel cages with a grid floor to allow waste to pass through.
Maintain 5 to 85 below and relative humidity 30 to 80%. Murogen will be lit from 6 a.m. to 4 p.m.
各々の犬を、つりひも支持体１［する支柱枠に立つよう
に、そしてその口に結びつけられたくつわを受は入れる
ように訓練する。くつわを通して内視鏡を犬の南中に入
れる。Each dog is trained to stand on a sling frame and to accept a bit tied to its mouth. Insert the endoscope into the dog's mouth through the bit.
この訓練にはたいていの犬で１０日乃至２週間を要する
。This training takes 10 days to 2 weeks for most dogs.
犬が試験の目的に適っているか否かを決定するには、そ
の胃を正常粘膜について検査し、そしてそのＮ５ＡＩＤ
に対する前反応性を評価する（試験操作の項の如く）。To determine whether a dog is suitable for the purpose of the study, its stomach should be examined for normal mucosa and its N5AID
Assess the pre-reactivity to (as in the section on test procedures).
許容し得る犬は投与後２時間での腔の胃刺戟スコア５以
上を有していなければならないっ
試験前２４時間および試験中供試犬から餌をとり除き、
そして水は適宜摂取させる。犬を犬舎からはなれた拘束
領域に移す。雄まｆｃは雌の絶食させた犬を内視鏡で検
査してその胃内壁が正常の健全な粘膜内壁を有している
ことを確認する。犬を供試処方物で経口投与し、この処
方物σ脱イオン水５０ｆ１１ｔで南中に流し込む。次に
、２時間および４時間後に次の基準に従って胃点状出血
および他の出血徴候を再検査する。Acceptable dogs must have a cavity gastric irritation score of 5 or higher 2 hours after dosing. Food must be removed from the dog for 24 hours before and during the test.
And drink water as needed. Move the dog to a restraining area away from the kennel. The male fc examines a fasted female dog with an endoscope to confirm that the stomach lining has a normal and healthy mucosal lining. Dogs are dosed orally with the test formulation and flushed with 50 tons of deionized water. Then re-examine gastric petechiae and other bleeding signs after 2 and 4 hours according to the following criteria.
０＝均一な、淡乃至礎ピンク色粘膜
１＝より濃いピンク色あるいはしみだらけの粘膜２＝点
状出血および（または）明るい赤色の条痕３＝数少い小
さい損傷
４＝数多くの捷たは連結した小さい損傷（線条）５＝数
少い大きい損傷
６＝数多くの大きい損傷
７＝大きな出血性損傷
各々の処理および各々の時間での損傷の程度を平均胃刺
戟スコアとして算出する。0 = uniform, pale to basic pink mucosa 1 = darker pink or blotchy mucosa 2 = petechiae and/or bright red streaks 3 = few small lesions 4 = numerous creases or Connected small lesions (striae) 5=few large lesions 6=many large lesions 7=large hemorrhagic lesions The degree of injury at each treatment and each time is calculated as an average gastric irritation score.
各々の犬の胃粘膜の内視鏡による観察に加えて、胃液の
量的特徴を記録し、そして胃液についてｐＨを測定する
。In addition to endoscopic observations of each dog's gastric mucosa, the quantitative characteristics of the gastric fluid are recorded and the pH of the gastric fluid is measured.
これらはいずれも供試化合物の投与後２時間で行う。All of these are conducted 2 hours after administration of the test compound.
アスピリン９７５■単独投与後種々のパラメーターを測
定することによって基本線を確定する。安静な正常な冑
は刺戟スコアＯおよび５−５．５のｐＨを有する。アス
ピリンは２時間後に約５．６のスコアの損傷を生成させ
、そしてこの時点での冑液ｐＨハ約３．１である。A baseline is established by measuring various parameters after administering Aspirin 975■ alone. A normal helmet at rest has an irritation score of O and a pH of 5-5.5. Aspirin produces lesions with a score of about 5.6 after 2 hours, and the solution pH at this point is about 3.1.
表 ■
アスピリン９７５岬 ８ ５．
５ ３．３テルブタリン１．２９η＋アスピリン９
７５ｍｐ ４ ４．０ １９１ ２．５
０岬＋ Ｉ ９７５岬 ４ ＺＯ３，８〃
５．０ωη＋ 〃 ９７５岬 ８ １．４
４．Ｏｔｒ １０．０■＋ ｐ ９７５＊
５ １．２ ４．６ジフエンヒドラミン１２．
５＋η＋アスピリン９７５Ｈｉ４ ５．５
１．４７Ｆ ２５．０■＋ 〃９７５ｎｉ４
５．７５ ２．．１＃ ５０．０■＋
〃９７５η ４４゜０３．６５０■＋アスビリ：／９
７Ｆ）＋Ｉｖ
表 ■Table ■ Aspirin 975 Cape 8 5.
5 3.3 Terbutaline 1.29η + Aspirin 9
75mp 4 4.0 191 2.5
0 Cape + I 975 Cape 4 ZO3,8〃
5.0ωη+ 975 Cape 8 1.4
4. Otr 10.0■+p 975*
5 1.2 4.6 Diphenhydramine 12.
5+η+aspirin 975Hi4 5.5
1.47F 25.0■+ 〃975ni4
5.75 2. ．． 1# 50.0■+
〃975η 44゜03.650■+Asbiri: /9
7F)+Iv Table ■
Claims (1)
アドレナリン作用剤およびヒスタミンＨ＿１−受容体遮
断薬およびヒスタミンＨ＿２−受容体遮断薬およびヒス
タミンＨ＿１−受容体遮断薬およびヒスタミンＨ＿２−
受容体遮断薬の組合せからなる群から選択されるヒスタ
ミン受容体遮断成分からなる保護剤の保護量を包含する
ことを特徴とする消化管損傷に対して減少効力を有する
非ステロイド系抗炎症組成物。 ２、前記ヒスタミン−受容体遮断成分がヒスタミンＨ＿
１−受容体遮断剤である特許請求の範囲第１項記載の組
成物。 ３、前記非ステロイド系抗炎症剤がアスピリンまたはイ
ブプロフエンである特許請求の範囲第２項記載の組成物
。 ４、前記非ステロイド系抗炎症剤がアスピリンである特
許請求の範囲第３項記載の組成物。 ５、前記β−アドレナリン作用剤がテルブタリンおよび
その製薬上許容し得る塩であり、そして前記ヒスタミン
Ｈ＿１−受容体遮断薬がジフエンヒドラミンまたはその
製薬上許容し得る塩である特許請求の範囲第４項記載の
組成物。 ６、存在する各成分の量が次のとおりの種々の成分の平
均１日用量を提供するのに十分である特許請求の範囲第
１項〜第５項のいづれか１項記載の組成物。 （ａ）前記非ステロイド系抗炎症剤、約１０−１００ｍ
ｇ／Ｋｇ／日、 （ｂ）前記β−アドレナリン作用薬、約０．３０μｇ／
Ｋｇ／日乃至約５００ｍｇ／Ｋｇ／日、 （ｃ）前記ヒスタミンＨ＿１−受容体遮断薬、約２．５
μｇ／Ｋｇ／日乃至約５００ｍｇ／Ｋｇ／日。 ７、存在する各成分の量が次のとおりの種々の成分の平
均１日用量を提供するのに十分である特許請求の範囲第
１項〜第５項のいづれか１項記載の組成物。 （ａ）前記非ステロイド系抗炎症剤、約１０−７５ｍｇ
／Ｋｇ／日、 （ｂ）前記β−アドレナリン作用薬、約０．０１−１０
ｍｇ／Ｋｇ／日、 （ｃ）前記ヒスタミンＨ＿２−受容体遮断薬、約０．１
−５０ｍｇ／Ｋｇ／日。 ８、１日用量当り次の量で成分を含有する１日投与剤型
の特許請求の範囲第１項〜第５項のいづれか１項記載の
組成物。 （ａ）前記非ステロイド系抗炎症剤、約２００−６００
ｍｇ、（ｂ）前記β−アドレナリン作用薬、約０．７−
７０ｍｇ、（ｃ）前記ヒスタミンＨ＿１−受容体遮断薬
、約０．０１−７０ｍｇ。 ９、前記ヒスタミン−受容体遮断成分がヒスタミンＨ＿
２−受容体遮断薬である特許請求の範囲第１項記載の組
成物。 １０、前記非ステロイド系抗炎症剤がアスピリンまたは
イブプロフエンである特許請求の範囲第９項記載の組成
物。 １１、前記非ステロイド系抗炎症剤がアスピリンである
特許請求の範囲第１０項記載の組成物。 １２、前記β−アドレナリン作用剤がテルブタリンまた
はその製薬上許容し得る塩であり、そして前記ヒスタミ
ンＨ＿２−受容体遮断薬がラニチジンまたはその製薬上
許容し得る塩である特許請求の範囲第１１項記載の組成
物。 １３、存在する各成分の量が次のとおりの種々の成分の
平均１日用量を提供するのに十分である特許請求の範囲
第９項〜第１２項のいづれか１項記載の組成物。 （ａ）前記非ステロイド系抗炎剤、約１０−１００ｍｇ
／Ｋｇ／日、 （ｂ）前記β−アドレナリン作用薬、約０．３０μｇ／
Ｋｇ／日乃至約５００ｍｇ／Ｋｇ／日、 （ｃ）前記ヒスタミンＨ＿２−受容体遮断薬、約１０μ
ｇ／Ｋｇ／日乃至約１ｇ／Ｋｇ／日。 １４、存在する各成分の量が次のとおりの種々の成分の
平均１日用量を提供するのに十分である特許請求の範囲
第９項〜第１２項のいづれか１項記載の組成物。 （ａ）前記非ステロイド系抗炎症剤、約１５−７５ｍｇ
／Ｋｇ／日、 （ｂ）前記β−アドレナリン作用薬、約０．０１−１０
ｍｇ／Ｋｇ／日、 （ｃ）前記ヒスタミンＨ＿２−受容体遮断薬、約０．０
１−１０ｍｇ／Ｋｇ／日。 １５、１日用量当り次の量で成分を含有する１日投与剤
型の特許請求の範囲第９項〜第１２項のいづれか１項記
載の組成物。 （ａ）前記非ステロイド系抗炎症剤、約２００−６００
ｍｇ、（ｂ）前記β−アドレナリン作用薬、約０．７−
７０ｍｇ、（ｃ）前記ヒスタミンＨ＿２−受容体遮断薬
、約０．５−３５０ｍｇ。[Claims] 1. Anti-inflammatory amount of non-steroidal anti-inflammatory agent, and β-
Adrenergic agents and histamine H_1-receptor blockers and histamine H_2-receptor blockers and histamine H_1-receptor blockers and histamine H_2-
A non-steroidal anti-inflammatory composition having reduced efficacy against gastrointestinal injury characterized in that it includes a protective amount of a protective agent consisting of a histamine receptor blocking component selected from the group consisting of combinations of receptor blockers. . 2. The histamine-receptor blocking component is histamine H_
The composition according to claim 1, which is a 1-receptor blocker. 3. The composition according to claim 2, wherein the non-steroidal anti-inflammatory agent is aspirin or ibuprofen. 4. The composition according to claim 3, wherein the non-steroidal anti-inflammatory agent is aspirin. 5. The β-adrenergic agent is terbutaline and a pharmaceutically acceptable salt thereof, and the histamine H_1-receptor blocker is diphenhydramine or a pharmaceutically acceptable salt thereof. Composition according to item 4. 6. A composition according to any one of claims 1 to 5, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 10-100 m
g/Kg/day, (b) the β-adrenergic agonist, about 0.30 μg/day;
Kg/day to about 500 mg/Kg/day, (c) the histamine H_1-receptor blocker, about 2.5
μg/Kg/day to about 500 mg/Kg/day. 7. A composition according to any one of claims 1 to 5, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 10-75 mg;
/Kg/day, (b) the β-adrenergic agonist, about 0.01-10
mg/Kg/day, (c) the histamine H_2-receptor blocker, about 0.1
-50mg/Kg/day. 8. The composition according to any one of claims 1 to 5, which is in a daily dosage form and contains the following ingredients per daily dose: (a) the non-steroidal anti-inflammatory agent, about 200-600
mg, (b) said β-adrenergic agonist, about 0.7-
70 mg, (c) about 0.01-70 mg of said histamine H_1-receptor blocker. 9. The histamine-receptor blocking component is histamine H_
2. The composition according to claim 1, which is a 2-receptor blocker. 10. The composition according to claim 9, wherein the non-steroidal anti-inflammatory agent is aspirin or ibuprofen. 11. The composition according to claim 10, wherein the non-steroidal anti-inflammatory agent is aspirin. 12. Claim 11, wherein the β-adrenergic agent is terbutaline or a pharmaceutically acceptable salt thereof, and the histamine H_2-receptor blocker is ranitidine or a pharmaceutically acceptable salt thereof. Composition of. 13. The composition of any one of claims 9 to 12, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) The non-steroidal anti-inflammatory drug, about 10-100 mg
/Kg/day, (b) the β-adrenergic agonist, about 0.30 μg/day;
Kg/day to about 500 mg/Kg/day, (c) the histamine H_2-receptor blocker, about 10μ
g/Kg/day to about 1 g/Kg/day. 14. The composition of any one of claims 9 to 12, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 15-75 mg;
/Kg/day, (b) the β-adrenergic agonist, about 0.01-10
mg/Kg/day, (c) the histamine H_2-receptor blocker, about 0.0
1-10mg/Kg/day. 15. The composition according to any one of claims 9 to 12 in a daily dosage form containing the following ingredients per daily dose: (a) the non-steroidal anti-inflammatory agent, about 200-600
mg, (b) said β-adrenergic agonist, about 0.7-
70 mg, (c) about 0.5-350 mg of said histamine H_2-receptor blocker.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63017500A JPH01197444A (en) | 1986-03-04 | 1988-01-29 | Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blocker |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83626486A | 1986-03-04 | 1986-03-04 | |
| US06/867,882 US4757060A (en) | 1986-03-04 | 1986-04-29 | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 and H2, receptor blockers |
| EP87311172A EP0320551A1 (en) | 1986-03-04 | 1987-12-18 | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 and H2 receptor blockers |
| AU82995/87A AU602375B2 (en) | 1986-03-04 | 1987-12-23 | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain h1 and h2 receptor blockers |
| CA000555703A CA1319887C (en) | 1986-03-04 | 1987-12-31 | Non-steroidal anti-inflammatory compositions protected against gastro-intestinal injury with a combination of certain h _and h _receptor blockers |
| JP63017500A JPH01197444A (en) | 1986-03-04 | 1988-01-29 | Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blocker |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01197444A true JPH01197444A (en) | 1989-08-09 |
Family
ID=27542862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63017500A Pending JPH01197444A (en) | 1986-03-04 | 1988-01-29 | Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blocker |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01197444A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5865215A (en) * | 1981-09-04 | 1983-04-18 | グラクソ・グル−プ・リミテツド | Medicinal composition |
| JPS61501393A (en) * | 1984-02-08 | 1986-07-10 | リチヤ−ドソン−ビツクス，インコ−ポレイテイド | Analgesic and anti-inflammatory composition comprising diphenhydramines |
| EP0248150A1 (en) * | 1986-04-29 | 1987-12-09 | Bristol-Myers Squibb Company | Gastroprotective process and compositions |
-
1988
- 1988-01-29 JP JP63017500A patent/JPH01197444A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5865215A (en) * | 1981-09-04 | 1983-04-18 | グラクソ・グル−プ・リミテツド | Medicinal composition |
| JPS61501393A (en) * | 1984-02-08 | 1986-07-10 | リチヤ−ドソン−ビツクス，インコ−ポレイテイド | Analgesic and anti-inflammatory composition comprising diphenhydramines |
| EP0248150A1 (en) * | 1986-04-29 | 1987-12-09 | Bristol-Myers Squibb Company | Gastroprotective process and compositions |
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