Pharmacology of Sinomenine, an Anti-Rheumatic Alkaloid from Sinomenium Acutum

Acta Medica Okayama

Volume 30, Issue 1 1976 Article 1 FEBRUARY 1976

Pharmacology of sinomenine, an anti-rheumatic alkaloid from Sinomenium acutum

Hidemasa Yamasaki∗

∗Okayama University,

Hidemasa Yamasaki

Abstract

The root and stem decoctions of Sinomenium acutum Rehd. et Wils. (formerly Sinomenium diversifolius Diels, one type of Fang-chi (Chinese)) have been used as a folk remedy for neuralgia and rheumatoid arthritis in many areas of the Far East. In Japan and China various viny plants have been identified as Fang-chi (Boi in Japanese) since antiquity. This uncertain nomenclature has made it difficult to evaluate the efficacy of the Fang-chi described in the classic literature. Among traditional Fang-chi plants only Sinomeniumacutum has been demonstrated to contain the alkaloid sinomenine, which is now known to be effective in neuralgia and rheumatic diseases. Sinomenine is a unique plant alkaloid, as it potently releases histamine in association with degranulation of tissue mast cells in mammalian tissues. This action occurs preferentially in the skin and joint capsules. The released histamine is responsible for the dominant pharmacological actions of sinomenine, such as vasodilatation, increased vascular permeability, acceleration of the thoracic and peripheral lymph flow, contraction of plain muscles, increased peristalsis of the intestines, and stimulation of gastric acid secretion. At toxic doses of sinomenine, convulsive central excitation was observed in most laboratory animals. Clinical side effects encountered with high doses of injected sinomenine or of decocted Sinomenium acutum were: injection site flare, pruritus in the head and upper part of the body, edema around the lips and eyelids, and temporary cephalalgia. Most of these side effects were reduced by classical antihistamines (H1-receptor antagonists). Daily subcutaneous injections of sinomenine for more than one week produced an analgesic effect in mice. Granulation tissue growth and adjuvant arthritis induced in rats were both inhibited by daily injections of a small dose of sinomenine hydrochloride or histamine dihydrochloride. These inhibitory effects were mediated through histamine H2-receptors probably on fibroblasts (for granulation tissue growth) and on T-cells (for adjuvant arthritis), since these effects were clearly inhibited by the H2-antagonist burimamide but not by the H1-antagonist mepyramine. The anti-rheumatic effect on Sinomenium acutum are probably genuine and can probably be attributed to the histamine-releasing properties of sinomenine.

∗PMID: 61710 [PubMed - indexed for MEDLINE] Copyright c OKAYAMA UNIVERSITY MEDICAL SCHOOL Yamasaki: Pharmacology of sinomenine, an anti-rheumatic alkaloid from

Acta Med. Okayama 30, 1-20 (1976)

PHARMACOLOGY OF SINOMENINE, AN ANTI-RHEUMATIC ALKALOID FROM SINOJ.IENIUM ACUTUJI

Hidemasa YAMASAKI Department of Pharmacology, Okayama University Medical School, Okayama, Japan Receivedfor publication, November 18, 1975

Abstract: The root and stem decoctions of Sinomenium acutum Rehd. et Wils. (formerly Sinomenium diversifolius Diels, one type of Fang-chi (Chinese)) have been used as a folk remedy for neuralgia and rheuma toid arthritis in many areas of the Far East. In Japan and China various viny plants have been identified as Fang-chi (Hoi in Japanese) since antiquity. This uncertain nomenclature has made it difficult to evaluate the efficacy of the Fang-chi described in the classic literature. Among traditional Fang-chi plants only Sinomenium acutum has been demonstrated to contain the alkaloid sinomenine, which is now known to be effective in neuralgia and rheumatic diseases. Sinomenine is a unique plant alkaloid, as it potently releases histamine in association with degranulation of tissue mast cells in mammalian tissues. This action occurs preferentially in the skin and joint capsules. The released histamine is responsible for the dominant pharmacological actions of sinomenine, such as vasodilatation, increased vascular permeability, acceleration of the thoracic and peripheral lymph flow, contraction of plain muscles, increased peristalsis of the intestines, and stimulation of gastric acid secretion. At toxic doses of sinomenine, convulsive central excitation was observed in most laboratory animals. Clinical side effects encountered with high doses of injected sinomenine or of decocted Sinomenium acutum were: injection site flare, pruritus in the head and upper part of the body, edema around the lips and eyelids, and temporary cephalalgia. Most of these side effects were reduced by classical antihistamines (HI-receptor antagonists). Daily subcutaneous injections of sinomenine for more than one week pro duced an analgesic effect in mice. Granulation tissue growth and adjuvant arthritis induced in rats were both inhibited by daily injec tions of a small dose of sinomenine hydrochloride or histamine dihy drochloride. These inhibitory effects were mediated through histamine H~receptors probably on fibroblasts (for granulation tissue growth) and on T-cells (for adjuvant arthritis), since these effects were clearly inhibited by the Hz-antagonist burimamide but not by the HI-antago nist mepyramine. The anti-rheumatic effect of Sinomenium acutum are probably genuine and can probably be attributed to the histamine. releasing properties of sinomenine.

INTRODUCTION Sinomenium acutum Rehd. et Wils. (Fam. Menispermaceae) is a wild plant found in the warm valleys of southern Japan. This plant is hardy with twin-

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2 H. YAMASAKI

ing vines sometimes growing to a height of 20 feet. The sterns and roots are stripped and hairless. The leaves are long-stalked, ovate or multilobed, acuminate, usually cordate at the base, palmated to 5 to 7 divisions, and the surfaces glabrous and brilliant (Fig. I). In summer the flower stalks grow from the axilla of the leaves. The flowers are small, light greenish, and organized in slender panicles. The drupes are compressed and bluish black. The roots and stems in cross sections are whitish and are characterized by a very distinct radiating pattern of ducts. The decocted dried roots and stems of this plant have been used as a folk remedy for neuralgia and rheumatoid

Fig. 1. Sinomenium acutum Rehd. et Wils.

arthritis since antiquity in Japan. This plants is now included in the Japanese pharmacopoeia under the name of Sinomeni Caulis et Rhizoma or EDi. The plant Fang-chi (~B), probably Sinomenium acutum, is mentioned in the Chinese Shen Nung Pen Ts'ao (1$~*1j1r.g, "Herbal")* (I) which was probably written about the first century B. C., during the Western Han dynasty. Fang-chi was recommended for the treatment of many diseases such as rheu matism, fevers, dropsies and pulmonary diseases in the Chin K'uei Yao Liieh (~I.~~, "Synopsis of the Golden Chamber") written by Chang Chung ching (2) in the same dynasty and also in the Ming I Pieh Lu (:g~1l1j~,

... Shen Nung is the popularly ascribed mythical emperor who reigned in 2838-2698 B. C. Shen Nung Pen Ts'ao, 3 volumes, contains descriptions of 365 kinds of herbs (1).

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Pharmacology of Sinomenine 3 "Formulas of Famous Physicians") compiled by T'ao Hung-ching ,(3) of the Liang dynasty 502 A.D. and which is said to be the first official pharmacopoeia in China. Among the prescriptions of Chang Chung-ching four contained Fang-chi. The Shen Nung Pen Ts'ao (1) distinguishes between the plant Han Fang-chi (~Itf5B) and Mu Fang-chi (*Itf5S). The former plant is probably Sinomenium acutum, since it was prescribed' for diseases now considered to be rheumatoid' arthritis and neuralgia, while the latter was pre scribed for many other diseases (2-4). In subsequent periods, varieties ,of viny plants have been used for the original plant for medical treatment in China and in japan, as many Menispermaceae plants closely resemble each other in taxonomy. This has confused the identity and efficacy of Fang-chi among traditional physicians of Chinese medicine for a long time, (5,6). Nevertheless, it is curious that the original plant has continued to be 'Used as a folk remedy for rheumatic diseases in many districts of japan (7). In 1920 an alkaloid sinomenine was isolated from Sinomenium acutum (8). This alkaloid 'has been demonstrated to be effective in relieving the pains of rheumatoid arthritis and neuralgia in extensive clinical trials (9-12). Pharma cological studies on this plant have been conducted at several institutions in japan and China. The special interest of this alkaloid is the presence of a histamine-releasing feature that is probably important in the mechanism of the anti-rheumatic effect. The present paper presents a brief survey of pharma cological studies on this alkaloid, with special reference to its anti-rheumatic effect.

SINOMENIUM ALKALOIDS In 1909 jujiro Honda (13), then professor of pharmacology at Okayama Medical School, presented a paper at a meeting of ,the Okayama Medical Association on chemical and pharmacological properties of two toxic ingre dients that he extracted from Sinomenium acutum, but a complete account of this presentation does not remain. In 191 7Ishikawa (14) of Kyushu University remarked briefly in a note that a picrotoxin-like convulsant action was found in frogs injected in the lymph sac with a crystalline ingredient obtained from this plant. During this early period, Taguchi and Ohta (1919)(15) conducted investigations on this plant under Prof. Kurata Morishima, at the Pharma cological Department of Kyoto University. They described the circumstances of their entering into this investigation: "February, 26, 1916, Mr. S. Masa gaki (probably a stranger) visited Prof. Morishima and asked the professor earnestly to study this plant. The younger brother of the visitor suffered from rheumatoid arthritis for many years and had difficult walking. This

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4 H. YAMASAKI

younger brother took the decoction of this plant several times, with a few days interval. A dramatic relief occurred." Taguchi and Ohta. obtained a crystal line colorless ingredient from the extracts of the roots and stems of Sinomenium acutum using the procedure of Stas and Otto. These early investigators found that this crystalline induced convulsions in frogs. In the middle of these studies they moved to Kitasato Institute in Tokyo, where they isolated two kinds of convulsant alkaloid: cocculin C17H29N03 o3H20 (15) (later kukolin C16H20N0303H20 (16, 17)) and diversin C16H:wN04 (16, 18). The form.er was a crystalline and the latter amorphous. Ishiwari (8) at Kyoto University continued the same line of study after the departure of Taguchi and Ohta. He isolated from roots and stems a crystalline alkaloid and estimated the molecular formula as C16H19NOg 0H20, and called the compound sinomenine. This molecular formula was later corrected but the generic name sinomenine was maintained. The chemical structure of sinomenine with the molecular formula of C19H 230 4 N was estab lished as shown in Fig. 2 by Kondo and Ochiai HO (19), and Goto and his colleagues (20) (cj. reviews in refs. 21, 22). These studies on sinomenine marked the first step in a series of chemical stu dies in Japan on the alkaloids of Menispermaceae o and other plants. Several alkaloids of Sinomenium acutum other than sinomenine have been succes sively isolated and the chemical structures estab Fig. 2. Chemical structure of sinomenine lished. Most of these studies were conducted by Goto and Tomita and their colleagues. The isolated alkaloids included disinomenine (23, 24), sinacutine (25), tuduranine (26-28), acutumine (29), acutumidine (29), magnoflorine (30), sinoacutine (31), michelalbine (32) and stepharine (32). The neutral substances ,B-sito sterol and stigmasterol were also isolated (33). The sinomenine content in the plant is 1.0-2.0% as a base in water-extracts (34) or 1.09% as hydrochloride (35). The percentages of other alkaloids are not known. Sinomenine has not been isolated in other Menispermaceae plants. Pharmacological studies of Sinomenium alkaloids have thus far been limited to sinomenine and rnagnoflo rine. The claimed chemical properties of diversine and parasinomenine have not been confirmed, and the reported alkaloid isosinomenine has been shown to be an artefact (36).

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Pharmacology of Sinomenine 5

ANTI-RHEUMATIC EFFECTS OF SINOMENINE AND SINOMENIUM ACUTUM Decocted Sinomenium acutum has been used widely in the treatment of rheumatic diseases in Kyushu, Shikoku, Kinki and other districts of Japan and in Korea and Formosa with favorable reputations for remedy (7). The usual daily dose is prepared from 8-15 g of dried cut roots and stems. The re markable beneficial effects of sinomenine were first reported scientifically by Ishiwari (9) and Takaori (10) in 1921, and since then, a considerable clinical literature (12) has confirmed their findings. Sinomenine administered subcu taneously (s.c.) or orally (p.o.) was remarkably effective in relieving pain, swelling and other symptoms of acute and chronic rheumatoid arthritis and· reduced pain in many types of neuralgia, such as sciatic neuritis, lumbalgia and muscular rheumatism. The s.c. injections were more effective than oral usage. Injections were usually started at 20 mg (dosages are expressed as hydrochloride) once daily and were increased by 10-15 mg every three to four days thereafter. Beneficial effects have been noted after two or three injections, and most acute phase symptoms subsided after eight to nine admin istrations, near a daily maximum dose of 90 - 100 mg. In chronic types of arthritis, swelling and oppressive pain in the affected joints decreased gradu ally, and the margins of the articular movements were increased. After the initial injection, a relapse in pain usually occurred but on repeated injections the periods of relief were prolonged. For oral usage, 30 - 120 mg per day in three divided doses has been recommended. Side effects. An itchy flare of 4-5 em in diameter appeared occasionally around the s.c. injection site. Pruritus and facial edema occurred with large doses of sinomenine (s.c.) or decocted Sinomenium acutum. The pruritus was predominant in the upper parts of the body and the edema remarkable around the eyelids and lips. Cephalalgia was encountered infrequently. These symp toms were temporary and abatement usually followed in about 30 min. There is a case report of a serious side effect in a patient who was probably injected sinomenine into the subcutaneous vein by error (37). Edema and itching induced by sinomenine were suppressed experimentally by the usual antihistamines (38). The usual antihistamines did not interfere with the therapeutic effects of sinomenine on experimentally-induced arthritis or on granulation tissue growth, as stated later in more detail. Prior to 1935 when clinical usage of sinomenine was common among physicians, antihista mines were not available.

PHARMACOLOGICAL PROPERTIES OF SINOMENINE Properties inherent to the morphinoid chemical structure. Sinomenine is the

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only morphinoid base so far obtained from Menispermaceae plants. The phe nanthropiperidine moiety in its chemical structure is shared with morphine and other natural opium alkaloids and with semisynthetic opiate derivatives. Sinomenine possesses certain pharmacological properties similar to those of morphine and related compounds. At large doses sinomenine elicits con vulsant-type central excitation which is also found in morphine and its surrogates (39). The most prominent pharmacological property of sinomenine is histamine release. This action is also present in morphine, codeine, apo morphine (40), ethylmorphine (41,42) and meperidine (43, 44). Meperidine is a synthetic opioid containing r-phenyl-N-methoxypiperidine in structure like morphine and sinomenine. One distinct difference between sinomenine and morphine or congeners is that sinomenine may be less toxic due to the absence of prominent central nervous actions that are inherent in morpnine, and because the major pharmacological and probably therapeutic effects of sinomenineare due to the potent histamine-releasing property, while for the morphine-type analgesics, histamine release is a side effect of clinical usage. Toxicity. Subtoxic doses of sinomenine (s.c. or p.o.) resulted in decreased motility in mice, rats, rabbits, dogs and monkeys (8, 45). At toxic or lethal doses (s.c. or intravenous (i.v.)) this apparent sedation was soon followed by an increased reflex excitability or by clonic-tetanic convulsions in frogs (8), mice (8, 45, 46), rabbits (8) and dogs (47-49). After the seizure, the animals showed general muscular weakness and slow respiration, leading in some cases to fatal asphyxia. Dogs after receiving a s.c. injection of 3-5 mg/kg of sinomenine, licked their lips, then scratched around the ear lobes, neck and jaw, where intense itching seemed to be present. At 10 - 40 mg/kg (s.c.) pruritic giant edema appeared in the face forming several vertical stripes in the snout. The animals violently scratched the face and ear lobes and rubbed their bodies against a burrowed hole. Urticaria-like macular erythemas were also visible in the breast and abdominal skin areas. At these dose levels profuse saliva tion, vomiting and defecation were not uncommon. The vomiting did not appear to be due to the direct action of sinomenine on the chemoreceptor trigger zone (CTZ) , since direct application of 1% sinomenine onto the caudal angle of exposed rhomboid fossa did not provoke vomiting while apo morphine induced vomitings (47). Increased peristalses of the intestines were observed through the abdominal walls of dogs lying on their sides. At these dose levels, reflex excitability increased. At doses of 60 mg/kg or more (lethal dose), the animals laid down and were able only to stagger ataxically when placed on their feet. Respiration was initially accelerated but soon became weak and slow. Increased reflex excitability gradually intensified.

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Pharmacology of Sinomenine 7

The animals cried aloud, and then manifested trismus and convulsive move ments in the extremities. This was soon followed by a generalized clonic tetanic convulsion initiated spontaneously or with inciting events, and occasionally culminated in opisthotonus.. With seizures at short intervals, the animals prostrated and died in respiratory paralysis. Sinomenine injected i.v. at 2.5 or 3 mg/kg produced these symptoms more acutely than s.c. injection at the same dose and frequently led to death (47-49). Autopsy findings included congestion of the mesenteric veins and the liver (47, 50, 51). Cats receiving 10 mg/kg sinomenine s.c. scratched their heads and ear lobes and licked or bit areas of the body. Defecation also occurred (47). In rats, after single intraperitoneal (i.p.) injection of 50 mg/kg, vascular dilatation or reddening was observed around the ears, mouth, snout, paws, and scrotum (52). The animals scratched their faces with the forelegs. These hyperemic areas were initially bright pink, changing progressively to blue as respiration failed. Edema gradually developed in hyperemic areas. These changes were quite obvious on visual inspection, and they were indistinguish able from the effects produced by an i.p. injection of egg-white, dextran or compound 48/80. Convulsions were not observed in rats even at 300 mg/kg, i.p. (52). A single injection of sinomenine at this dose to a group of rats reduced the histamine content of the abdominal skin by 32.5% com pared to the initial level. When sinomenine was injected for 6 consecutive days starting at the initial dose of 50 mg/kg X 2 and increased daily 50 mg/ kg X 2 (total dose of 2,100 mg/kg), an 88.2% reduction in histamine content was found in the abdominal skin. The symptoms, however, decreased gradually after subsequent injections in spite of increased dosages (52). Rats injected 40 - 80 mg/kg daily, i.p. for 14 consecutive days showed no body weight or food consumption effects. No changes in the blood picture or histology were observed (45). Mice injected with sinomenine at 300-400 mg/km, i.p. showed redden ing of the snout, ear lobes, feet and tail; edema was prominent in the distal extremities. Clonic-tetanic convulsions were observed at these dosages (46, 53, 54). Skin reactions produced in rabbits; mice (46), rats (55) and dogs (48) were reduced by appropriate doses of standard antihistamines, such as mepy ramine and diphenhydramine. In mice at the same dosage, these antihista mines did not prevent sinomenine deaths (46); Rabbits (8,53,56) and guinea pigs (56) responded with convulsions to high doses (s.c. or i.v.) of sinomenine. The toxic symptoms of sinomenine,' especially on the skin. resembled those of componnd 48/80;" One difference is that at high doses sinomenine caused convulsions while compound 48/80 resulted in severe prostration in most examined animals (57). This suggests that the convulsive actions-of

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TABLE I. LETHAL DOSES AND MINIMUM EFFECTIVE DOSES (CONVULSION, HYPOTENSION AND OTHER REACTIONS) OF SINOMENINE HYDROCHLORIDE

Lethal dose Minimum effective dose Species Route Reference (mg/kg) for indicated reaction Reference (mg/kg) Frog Lymph 500 8 300 Convulsion 8 sac 600 58 500 Convulsion 58 650 53 Mouse s.c. 400 58 300 Convulsion 54, 59 483* 46 50t Marked skin reaction 46 500 54 550 53 p.o. 580* 45 i. v. 250 53 Rat p.o. 964t Sedation 45 i.p. 50t Marked skin reaction 52, 60 Guinea pig s. c. 350 56 Rabbit s.c. 250 8 280 58 300 53, 58 i. v. 120 58 5 Hypotension 50 150 8 i. cyst. 1.2 Convulsion 56 Dog s.c. 60 47 40-60 Convulsion 47 >60 53 i. v. =5 51 0.3 Hypotension 51 0.5 Hypotension 47 Cat s.c. 10 Convulsion 47 i. v. I Hypotension 61 Monkey p.o. 95t Sedation 45 i. v. 13.5t Prostration 45

* L D50, t without convulsion.

sinomenine may not be related to the release of histamine. Table 1 shows the lethal doses of sinomenine for different species of laboratory animals and the minimum effective doses for inducing convulsion and hypotension. Cardiovascular actions. Sinomenine decreased the contraction force and frequency of excised or perfused frog heart. Rabbit aural vessels dilated when the perfusion fluid contained serum (47,53). Intravenous injection of sinome nine induced hypotension in dogs (>0.1 mg/kg, irreversible at 3 - 5 mg/kg) (47, 48), cats (>0.1 mg/kg) (61, 62) and rabbits (>5 mg/kg) (50). In dogs an increase occurred in the volume of the liver, intestines and extremities, and the portal pressure rose at an early stage of hypotension (50, 51). Likewise

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Pharmacology of Sinomenine 9 in cats an increase was observed in the portal pressure and the liver volume (61). The flow of thoracic lymph was markedly accelerated in dogs (50,51), cats (61) and rabbits (50) in this order, and cervical lymph was increased in dogs (51). The lymph became rich in protein content, and the blood and lymph did not coagulate in sinomenine-shocked dogs (50, 51) and cats (61). Tachyphylaxis of these sinomenine actions was marked, especially in dogs (50, 51). When a small amount of sinomenine (0.05 ml of 0.1 - 0.3% solution) was injected intracutaneously (Lc.), the human skin responded with a triple response which was characteristic in that the wheal grew more slowly extending more prominent pseudopod-like processes along cutaneous veins than by histamine. A brief pain that was followed by itching of about 10 min duration usually occurred at the injection site. Occasional cephalalgia was encountered, due probably to the extention of cranial vascular walls. Effects on plain muscles. Intravenous injection of sinomenine increased the rhythmic contraction of the uterus, which culminated in contracture at very high doses in cats and rabbits but this action was much weaker than that of quinine (63). An increase of intestinal peristalsis has been experienced in man after sinomenine injection or ingestion of the plant decoction. Gastric acid secretion increased after s.c. injection of sinomenine in dogs (38). Histamine-releasing action. After Lv. injection of sinomenine in dogs, histamine and heparin levels elevate markedly in blood and lymph plasma, as first reported from this laboratory (51,62,64,65). These actions of sinome nine were proved to be responsible for the hypotension, the rise in the portal pressure, the increased volumes of the liver and extremities, and the inco agulability of blood and lymph produced by this substance; this explains the development of tachyphylaxis in all these reactions (51). Cardiovascular changes were completely inhibited by pretreatment with antihistamines such as mepyramine, although the hypotension was partially inhibited (65). In dogs i.v. injection of sinomenine depleted histamine of the skin pre ferentially (62, 64, 66). This response differed from compound 48/80 which releases liver histamine more easily in dogs (62, 64, 66). After sinomenine injection in dogs, edema or itchy erythem.a was prominent in the ear lobes, eyelids, around the mouth and nose, and in the areolae of nipples and genito anal regions, where abundant histamine and mast cells are contained (49). Joint capsule histamine was released more readily than skin histamine (49). In tissues depleted of histamine, mast cells were disrupted at various stages, such as granule discharge, fragmentation and disappearance of cells. In the recovery process, a few mast cells appeared initially but gradually increased in population and granule density. For complete recovery of the cell popula tion the usual period required was more than 40 days for the skin and about 2

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weeks for the joint capsules. This coincides with the recovery course of the depleted histamine in the respective tissues (67). Occasional temporary headaches after sinomenine injection may be due to histamine release. Fourteen (51) to 21 percent (68) of mongrel dogs were found to be re fractory to both sinomenine and compound 48/80 (cross-tolerance). These non-reactive dogs responded normally to polyvinylpyrrolidone and tween 20 and showed normal sensitivity to histamine. The incidence of non-reactors was similar in both sexes (68). The mechanism of histamine release by sinomenine has been studied (69 73, reviews 74, 75). Analgesic and local anesthetic effect. Daily s.c. injection of histamine in mice caused analgesia which reached maximum after 6-8 days of injection. Similar analgesia developed under the same injection .schedule with sino menine. When the injection of histamine and that of sinomenine were alter nated daily at doses causing about the same degree of analgesia, neither agent produced an analgesic effect. The development of analg.esia by histamine or sinomenine was not blocked by the concurrent use of an antihistamine mepy ramine. The hypothermic effect of s.c. injection of histamine or sinomenine gradually decreased on repeated daily injections. Such desensitization of the hypothermic effect did not appear when histamine and sinomenine were in jected on alternate days. In mice receiving repeated injections 'of sino menine, the sensitivity to histamine increased as measured by the hypothermic effect (76). The close similarity between the development of analgesia and the desensitization of the hypothermic effect suggests the presence of histamine receptors in the sensory nerve endings that is similar to the skin vessels, and that histamine liberated by physical stimuli is a possible mediator of cutaneous pain in a manner similar to its mediation of vasodilatation. Sino menine has a local anesthetic action as shown by i.c. injection or by instilla tion onto the conjunctiva (77,78). Anti-inflammatory and anti-allergic actions. Sinomenine inhibited eggwhite edema (52) but not carrageenin edema in rat paws (79). Daily injections to rats of sinomenine at high dose suppressed both the increase in the weight of croton-oil granuloma pouch and its histological inflammatory changes (60). Canine anaphylactic shock was prevented by an Lv. or s.c. injection of sino menine. (48) although this effect was not evident in guinea pigs (80). A recent report indicates that a small amount of histamine inhibits the allergic hista mine release from human basophils (81) .. We have shown that histamine and also sinomenine inhibit .certain types of inflammation, as described in more detail later. Other pharmacological actions. Sinomenine lowered rabbit body temperature

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Pharmacology of Sinomenine 11 raised by heat puncture or adrenaline injection (8). Since the body temperature is also lowered by sinomenine in normal mice (76), the hypothermic effect of sinomenine may be due largely to the dilatation of cutaneous vessels by re leased histamine. Sinomenine produced hypo- and hyperglycemia in rabbits depending upon the dosage (82). In rabbits daily injections of sinomenine caused neutrophilia while erythrocyte count and hemoglobin concentration remained unchanged (83). Old Chinese medical books describe the diuretic effect of Han Fang-chi and Mu Fang-chi, but this effect has not been demon strated so far in sinomenine (8) and trilobine (84). The latter alkaloid is an active principle of Cocculus trilobus D.C. which is one kind of Mu Fang-chi. Absorption and excretion of sinomenine and the fate of released histamine. The absorption of sinomenine was estimated in rats by the amount of urinary histamine. Sinomenine was rapidly absorbed by s.c., Lv. and i.p. injec tions, but hardly absorbed by intramuscular (Lm.) injection. Peroral absorp tion was slower but better than by i.m. injection (85). This is consistent with the experimental results of sinomenine on gastric acid secretion (38). In rabbits, urinary excretion of sinomeninedepended upon the s.c. dosage injected, but the excretion gradually decreased on repeated injections (86). A major part of 'released histamine converts to I, 4-methylimidazole acetic acid and imidazole acetic acid riboside; the remaining part is mostly excreted as free histamine but a small quantity of histamine remains for several hours in .tissues (76, 85).. The latter histamine probably has the therapeutic effects of sinomenine or Boi, as discussed in the next paragraph.

PHARMACOLOGICAL PROPERTIES OF SINOMENINE PROBABLY CONNECTED TO THE ANTI-RHEUMATIC EFFECT J. Inhibitory effect of histamine and sinomenine on connective tissue growth. A characteristic pathological feature of rheumatoid arthritis is the thick ening of the articular soft tissues. Synovial edema accompanied by cellular infiltration is the first sign of disease which is followed by synovial growth, formation of granulation tissue, accumulation of inflammatory exudates in articular cavities, and then fibrous or bony ankylosis of the joints. Hence, the suppression of connective tissue growth (granuloma formation) appears therapeutically important. To study. the effects of sinomenine and histamine on connective tissue growth, we (87,88) placed filter-paper disks, soaked in 7% aqueous form aldehyde solution, in the subcutaneous tissue of each axillary and inguinai area of male Wistar rats under sterile conditions. On the seventh day after the operation, the granulomas including the filter-paper disks were extirpated.

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12 H. YAMASAKI To intensify the pink hue of the granulation tissue, the animals were killed by carbon monoxide poisoning. Effects of histamine and sinomenine. Subcutaneous injections of 0.05 mg/kg of histamine twice a day (the dose of histamine is expressed as base, but for other drugs as salt or ester) decreased the weight of dry-defatted granu lomas and their contents in hydroxyproline and hexosamine. These inhibitory effects became more marked when the dose was increased to 1 mg/kg/day. The hydroxyproline and hexosamine values per milligram of dry-defatted weight of gra.nuloma were not significantly altered by histamine and other drugs tested with the exception of prednisolone at large dose. The gain in body weight during the 7-day period from disk implantation to the removal of granuloma was increasingly reduced by increasing dose of histamine, but this effect attained statistical significance only at doses higher than 1 mg/kg/ day. Thymus weight was not affected at any dose. The effects of sinomenine were tested at two different doses. In rats given large doses of sinomenine before disk implantation and during granu loma growth period*, the histamine content of the abdominal skin at the time of granuloma removal was markedly decreased to a level of 6.7 ± 0.8 pg/g wet wt. of tissue (mean ± S. E. M., N =6) compared to 23.1 ± 0.8 pg/g (N =4) in the control group. The formation of granuloma was inhibited by 55.7% in terms of weight by this treatment. When a relatively small dose of sinomenine (15 mg/kg twice a day) was administered from the implantation day to one day before the removal of granulomas without pretreatment of sinomenine, the histamine content of abdominal skin was 25.3 ± 3.6 pg/g (N =4) on the day of granuloma extirpation. In spite of the absence of an effect on skin histamine content, this small dose of sinomenine inhibited granuloma formation at the same rate as a larger dose. Aminoguanidine bicarbonate, a potent histaminase inhibitor, produced a marked inhibitory effect on granuloma formation at a s.c. dose of 10 mg/ kg/day. The inhibition of granuloma growth by 0.5 mg/kg/day of predni solone (i.m.) was less marked than 0.1 mg/kg/day of histamine (s.c.). This dose of prednisolone, however, strikingly inhibited the growth of rats and caused a decrease in thymus weight. Phenylbutazone was ineffective at a daily dose of 30 mg/kg. Effects of burimamide and mepyramine. Burimamide is known to speci

fically block histamine H 2-receptors and to antagonize responses to histamine,

* The rats were pretreated before the disk implantation by i. p. injection of sinomenine for 6 days: on the first day 50 mg/kg X 2, increasing by 50 mg/kg X 2 daily, until a final dose of 300 mg/kgx2 (total dose=2,IOO mg/kg). From the implantation day, 300 mg/kg was injected once daily.

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Pharmacology of Sinomenine 13 such as stimulation of gastric acid secretion (89). When 5 mg/kg of burima mide was injected s.c. 30 min prior to the injection of 0.05 mg/kg of histamine, this compound clearly antagonized the inhibitory effect of histamine on the formation of granuloma and even enhanced its growth as revealed by the increased granuloma weight and hydroxyproline and hexosamine contents. Burimamide also blocked the inhibitory effect of sinomenine and aminoguani dine. Mepyramine, the classical antagonist of histamine H 1-receptors (89), was ineffective in blocking the inhibitory effect of histamine at a similar dosage as that used for burimamide. The hydroxyproline and hexosamine values per milligram of dry-defatted weight of granuloma were not markedly altered by histamine antagonists. Histological studies. In granulomas obtained from rats treated with 0.05 mg/kg of histamine twice a day, tissue layers of densely populated fibroblasts were narrower than those of control animals. The formation of blood vessels in the granulation tissue appeared to be also poor in the treated rats. These morphological effects were entirely or largely counteracted when burimamide was injected concurrently with histamine. In sinomenine- and aminoguanidine treated rats the morphological pattern of granuloma formation was similar to that observed in histamine-treated rats. Comment. It has been shown that activation of H 2-receptors leads to an increase in the level of cyclic AMP in lymphocytes (90,91), leukocytes (81), gastric tissue (92) and cardiac tissue (93). It is also known that the growth of cultured fibroblasts is inhibited by the increase in intracellular level of cyclic AMP (94). Therefore, the histamine inhibition of the granuloma growth may be induced by a rise in the cyclic AMP level of fibroblasts through the activation of H 2-receptors. We have recently observed an increase in the cyclic AMP content of granulomas in rats after a s.c. injection of histamine (95). 2. Inhibitory effect of histamine and sinomenine on adjuvant arthritis The rat adjuvant arthritis shows a close similarity to the human rheu matoid arthritis in clinical signs. A dose of 0.05 ml of adjuvant mixture containing 0.25 mg of finely-ground killed Micobacterium tuberculosis was administered i.d. under the volar surface of the left hind paw of male inbred Sprague-Dawley rats. The volume of each hind paw was measured prior to adjuvant injection and once daily thereafter. Effects of histamine and sinomenine. Sinomenine was injected i.p. at a dose of 15 mg/kg twice daily from the day of adjuvant injection (day 0). Sinomenine did not inhibit the primary inflammation in the adjuvant-injected paw which reached maximum on day 5 or day 6, but significantly suppressed swelling of the secondary inflammation which appeared in the adjuvant-

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14 H. YAMASAKI

Fig. 3. Effect of histamine on adjuvant-induced lesions in the rat hind paw. Histamine was injected at 5 mg/kg, s. c., twice a day from day 5 to day 10. The control rat received 0.9% saline. Roentgenographs were taken on day 25. a, Saline treated rat; b, histamine-treated rat. The adjuvant-injected paw is on the left in both figures (97).

noninjected paw at day 10 or later. Histamine administered s.c. at a dose of 5 mg/kg twice daily also had a similar inhibitory effect. In the vehicle treated control group, marked swelling and ankylosis of tarsal and other pedal joints were visible. Fusion of joints and destruction of bones and carti lages were observed in roentgenograms. These changes were more marked in the adjuvant-injected paw but were also observed in the adjuvant-noninjected paw. In groups treated with sinomenine or histamine, these radiological changes were also clearly inhibited (96, 97) (Fig. 3). Histamine markedly suppressed the appearance of the secondary inflam mation of adjuvant arthritis when injected for 6 consecutive days from day 5

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Pharmacology of Sinomenine 15 to day 10. Histamine injection prior to or after this critical 6-day period produced no significant inhibition of the secondary inflammatory response. Histamine had no suppressive effect on the secondary lesion when administered after the establishment of the lesion. Therefore, the histamine effect on the secondary lesions appears to be based on a different mechanism from the usual anti-inflammatory drugs. Effects of burimamide andmepyramine. When burimamide at 5 mgjkg was injected simultaneously with histamine of the same dosage, a complete blockage of histamine inhibition was 'found in the secondary inflammatory response and in histological and radiological examinations. Mepyramine at the same dosage showed no such blocking effect. Comment. Rat adjuvant arthritis has been reported as being caused by cell-mediated immunity, mainly from evidence of the passive transfer of this disease with living lymph node cells (98). The most effective period of histamine administration to prevent the appearance of the secondary lesion of adjuvant arthritis coincides closely with the effective period reported for some immunosuppressants (99, 100). Since the inhibitory effect of histamine on adjuvant arthritis is not an tagonized by mepyamine and is completely blocked by burimamide, the

histamine effect appears to be mediated through H 2-receptors. Histamine causes an increase in the cyclic AMP 'level of lymphocytes through the acti

vation of H 2-receptors (91). In connection with this effect, histamine inhibits responses to antigen-stimulation, such as the proliferation and differentiation of lymphoid cells, immunoglobulin production and the cytotoxic activity of lymphocytes (101). Qur findings together with the histamine effects on lymphoid cells described by others (99) suggest that the suppressive effect of histamine in adjuvant arthritis may be related to the inhibition of T-Iym phocyte proliferation. The catecholamine release by histamine is blocked by HI-receptor antagonists (102). Therefore, the catecholamines released by histamine do not seem to play an important role in the histamine inhibition of adjuvant arthritis. . From the inhibitory effects of histamine on adjuvant arthritis and granu lation-tissue growth, it appears likely that the antirheumatic properties of sinomenine is mediated through histamine released from mast cells.

REFERENCES 1. Shen Nung: Shen Nung Pen-Ts'ao (tr11~:$:~~), quoted by Li Shih-chen in Pen-Ts'ao Kang Mu (:$:1?:m§) 18, 1596 A.D. (in Chinese) and quoted by K.C. Wong and Wu Lien-Teh, History of Chinese Medicine, 2nd ed., National Quarantine Service, Shanghai, p. 119, 1936. 2. Chang Chung-ching (Western Han dynasty): Chin K'uei Yao Lueh (~!IC~iWi).Reprint from

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Heian-shoshi, japan, 1788 (in Chinese). 3. T'ao Hung-ching (Liang dynasty): Ming I Pieh Lu (15I2i,'BU~) (502 A. D. ), quoted by T'ang Shen Wei, Cheng Lei Pen-Ts'ao (mm::i$:1i'£). Revised edition, 1116 A. D. (in Chinese). 4. Li Shih-chen: Pen Ts'ao Kang-Mu (*1i'£~§), 18, 1596 A. D., japanese edition, Shunyodo, Tokyo, 1975. 5. Okanishi, T.: On the original plant of Fang-chi. Kampo no Rinsho 13, 555-563, 1966 (in japanese). 6. Yamasaki, H.: Sinomenium acutum (Boi), a folk remedy for rheumatism. Symposium on Wakan-Yaku (japanese and Chinese Traditional Drugs) 8, 29-43, 1974 (in japanese). 7. Tsukamoto, T. (ed.): Vegetable Folk Remedies in Japan, Shunyodo, Tokyo, 1933 (in japanese). 8. Ishiwari, N. : An alkaloid of Sinomenium diversifolius. Chugai Iji Shimpo no. 959, 277-296, 1920 (in japanese) (Chem. Abst. 15, 1598, 1921). 9. Ishiwari, N.: An alkaloid of Sinomenium diversifolius. Part 3. Clinical experiments on the effect of sinomenine hydrochloride on rheumatism and neuralgia. Tokyo Iji Shinshi no. 2242, 1639-1645, 1921 (in japanese). 10. Takaori, S.: Clinical experiments on the effect of sinomenine hydrochloride on rheu matism and neuralgia. Chugai IJi Shimpo no. 996, 1106-1122, 1921 (in japanese). II. Takaori, S. : Dber das Alkaloid "Sinomenin" von Sinomenium acutum Rehd. et Wils. Dtsch. med. Wschr. 62, 1634-1636, 1936. 12. Shionogi Pharmaceutical Co. Ltd. (ed.): Collected Papers on Sinomenine Hydrochloride (1920 1942) (in japanese). 13. Honda, j.: Study on toxic principles of Sinomenium acutum. Okayama Igakkai Zasshi no. 229, 158, 1909 (in japanese). 14. Ishikawa, K.: An active principle derived from Sinomenium acutum and its convulsant action in the frog. Ikai Jiho no. 1203, 1276, 1917 (in japanese). 15. Taguchi, K. and Ohta, K.: On a new alkaloid, cocculinum, contained in the root of Cocculus deversifolius, D. C. Nihon Iji Shuho no. 1286, 2-3, 1919 (in japanese). 16. Taguchi, K.: Four new pharmaca discovered in plants indigenous to japan. Ikai Jiho no. 1436, 19-20, 1922 (in japanese). 17. Ohta, K.: Studies on alkaloids of Cocculus diversifolius D. C. Part 1. On kukolin. Keio Igaku ::, 1031-1063, 1923 (in japanese). 18. Ohta, K.: Studies on alkaloids of Cocculus diversifolius D. C. Part 2. On diversin. Keio Igaku 3, 1085-1110, 1924 lin japanese). 19. Kondo, H. and Ochiai, E.: Dber die Konstitution des Sinomenins. Liebigs Ann. Chem. 470, 224-254, 1929. 20. Goto, K. and Sudzuki, H.: On the position of the double linking in sinomenine. Bull. Chem. Soc. Jpn. 4, 244-254, 1929. 21. Holmes, H. L.: Sinomenine. In The Alkaloids, Chemistry and Physiology, II. ed. R. H. F. Manske and H. L. Holmes, Academic Press, New York, pp. 219-260, 1952. 22. Goto, K.: Sinomenine, an Optical Antipode of Morphine Alkaloids. Kitasato Institute, Tokyo, 1964. 23. Goto, K. and Sudzuki, H. : Bimolecular alkaloids. I. On disinomenine and "'-disinome nine. Bull. Chem. Soc. Jpn. 4, 107-111, 1929. 24. Goto, K. and Sudzuki, H.: Bimolecular alkaloids. II. Reduction ~f disinomenine and "'-disinomenine. Bull. Chem. Soc. Jpn. 4, 129-132, 1929. 25. Goto, K. and Kitasato, Z.: The constitution of sinacutine (1-Tetrahydro-epi-berberine). J. Chem. Soc. (London) 1930, 1234-1237. 26. Goto, K.: Tuduranin, Ein neues Alkaloid aus Sinomenium acutum. Liebigs Ann. Chem. 521, 175-184, 1935. 27. Goto, K., Inaba, R. and Nozaki, H.: Synthese von N-Methyltuduranin-methyHither.

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Pharmacology of Sinomenine 17

Liebigs Ann. Chem. 530, 142-146, 1937. 28. Goto, K. and Shishido, H.: Die Konstitution von Tuduranin. Liebigs Ann. Chern. 539, 262-265, 1939. 29. Tomita, M., Okamoto, Y., Kikuchi, T., Osaki, K., Nishikawa, M., Kamiya, K., Sasaki, Y., Matoba, K. and Goto, K.: Alkaloids of Menispermaceous plants. CCLIX. Alkaloids of Menispermum dauricum. Structures of acutumine and acutumidine, chlorine containing alkaloids with a novel skeleton. Chem. Pharm. Bull. 19, 770-791, 1971. 30. Tomita, M. and Kugo, T.: Studies on the alkaloids of Menispermaceous plants. CXXXVII. Isolation of magnoflorine from Sinomenium acutum Rehd. et Wils. J. Phann. Soc. Jpn. 76, 857-859, 1956 (in japanese with English abst.). 31. Hsu, J. -5., Lo, S.·Y. and Chu, j. -H.: The structure of the alkaloid sinoacutine. Sci. Sin. 13, 2016-2017, 1964 (Chem. Abst. 62, 9183a, 1965). 32. Sasaki, Y. and Onji, K.: Isolation of minor alkaloids from Sinomenium acutum Rehd. et Wils. J. Pharm. Soc. Jpn. 88, 1286-1288, 1968 (in japanese with English abst.). 33. Sasaki, Y. and Veda, S.: Studies on the alkaloids of Menispermaceous plants. CLX. Alkaloids of Sinomenium acutum Rehd. et Wils. (Suppl. 2). J. Pharm. Soc. Jpn. 78, 44-49, 1958 (in japanese with English abst.). 34. Kawata, H., Kobayashi, Y., Shibazaki, M., Yoshino, T. and Kawase T.: Quantitative determination of sinomenine in the Boi-extracts. Kosei Kagaku Kenkyu Hokoku 1974, 159-176. 35. Okabe, K.: Personal communication. 36. Sasaki, Y. and Okabe, K.: Studies on the alkaloids of Menispermaceous plants. CXCIX. Alkaloids of Sinomenium acutum Rehd. et Wils. J. Pharm. Soc. Jpn. 83, 418-419, 1963 (in japanese with English abst.). 37. Uchimoto, C.: Caution for the sinomenine injection. Nisshin Chiryo no. 61, 5, 1922 (in japanese). 38. Nishiyama, R.: The effect of an antihistamine agent on the gastric secretion induced by sinomenine and Irgapyrin. Acta Med. Okayama 10, 164-172, 1956. 39. jaffe, j. H.: Narcotic analgesics. In Pharmacological Basis oj Therapeutics, 4th ed., ed. L. S. Goodman and A. Gilman, Macmillan Co., New York, pp. 237-275, 1970. 40. Feldberg, W. and Paton, W. D. M.: Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators. J. Physiol. 114, 490-509,1951. 41. Kamimura, Y.: A quantitative study of histamine release by chemical substances using minced tissues of guinea-pig lung. Folia Pharmacol. Jpn. 53, 836-849, 1957 (in japanese with English abst. ). 42. Tasaka, K.: A quantitative study of histamine release by chemical substances using chopped skin tissue of the dog. Okayama 19akkai Zasshi 69,2853-2868, 1957 (in japanese with English abst.). 43. Schachter, M.: The release of histamine by pethidine, atropine, quinine and other drugs. Br. J. Pharmacol. 7, 646-654, 1952. 44. Zeppa, R., Grossekreutz, D. C. and Sugioka, K.: Histamine release into the circulation by meperidine (Demerol). Proc. Soc. Exp. Biol. Med. 106, 794-796, 1961. 45. Fu, S.-X., Chang, S.-S., Li, Y.-S. and Wang, N.-C.: The toxicity and general pharma cological actions of sinomenine. Acta Pharm. Sin. 10, 673-676, 1963 (in Chinese with English abst.). 46. Sanuki, K., Irino, S. and Kawamoto, S.: Synergism of antihistamine with histamine and sinomenine. Folia Pharmacol. Jpn. 52, 157-163, 1956 (in japanese with English abst.). 47. Ishiwari, N.: An alkaloid of Sinomenium diversifolius. Part 2. Chugai Iji Shimpo no. 991, 767-788, 1921 (in japanese) 48. Nishiyama, R.: Studies on canine anaphylaxis. Part 3. Prevention of anaphylaxis in the dog by a histamine liberator, sinomenine. Okayama Igakkai Zasshi 71, 115-124, 1959

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(in japanese with English abst. ). 49. Kume, M.: Distribution and release of histamine in the skin and joint capsules of the dog. Okayama Igakkai Zasshi 7], 3929-3938, 1959 (in japanese with English abst. ). 50. Kobayashi, K. :'Ober den lymphagogen Mechanismus des Sinomenins. Folia Pharmacol. lpn. 35, 119":150, 1942 lin japanese with German abst. ). 51. Mayeda, H.: The release of hhtamine by sinomenine. Jpn. J. Pharmacol. 3, 62-72, 1953. 52. Irino, S.: Effect of histamine releasers and of anti-inflammatory drugs on the egg-white edema of rat hind paws in relation to skin histamine. Acta Med. Okayama 12, 93-111, 1958. 53. Nagase, S.: Pharmacological actions of bromosinomenine. Tokyo Iji Shinshi no. 2314, 1 15, 1923; no. 2315, 8-16, 1923; no. 2318, 7-16, 1923; no. 2319, 3-11, 1923 (in japanese). 54. Kosuge, S.: Beitrage zur der Pharmakologie des Sinomenins. Kyoto 19aku Zassi 20, 1449 1478, 1923 (in japanese with German abst.). 55. Saito, N.: Effects of histamine releasers on the granulopexyand permeability of the vascular endothelium of the skin. Folia Pharmacol. lPn. 54, 1268-1281, 1958 (in japanese with English abst.). 56. Takaori, S.: Untersuchungen tiber Sinomeniumalkaloide, insbesondere tiber Parasino menin. Kyoto 19aku Zassi 21, 85-120, 1924 (in japanese with German abst. ). 57. Dews, P.B., Wnuck, A.L., Fanelli, R. V., Light, A.E., Tornaben, j.A., Norton, S., Ellis, C.H. and de Beer, E.j. : The pharmacology of no. 48-80, a long-acting vaso depressor drug. l. Pharmacol. Exp. Ther. 107, 1-11, 1953. 58. Tsuruta, S.: Pharmacological studies on alkaloids of Menispermaceae plants in japan. Part 3. Sinomenine and its reduced products. Jikken Yakubutsugaku Zasshi 3, 193-219, 1930 (in japanese). 59. Goto, K. and Takebe, T.: On the physiological action of (-) and (+) derivatives of morphine alkaloids. Proc. Imp. Acad. lpn. 9, 390-393, 1933. 60. Irino, S.: Granuloma pouch and skin histamine of the rat. Acta Med. Okayama 12, 112 125, 1958. 61. Mitsufuji, Y.: On the mode of action of lymphagogues in the cat. Part 1. Actions of histamine, peptone and sinomenine. Okayama 19akkai Zasshi 71, 4113-4l26, 1959 (in japa nese with English abst. ). 62. Mayeda, H.: The site of histamine release by sinomenine. lpn. l. Pharmacol. 3, 73-81, 1954. 63. Yagi, F.: Ober die Wirkungen des Sinomenins und Parasinomenins auf den Uterus, nebst einem vergleichenden Studium dieser Pharmaka mit Chinin. III. Mitteilung. Unter suchung am Uterus in situ. Folia Pharmacol.lpn. 15,85-92,1932 (in japanese with German abst.). 64. Yamasaki, H. and Mayeda, H.: Histamine-releasing action of sinomenine. lpn. l. Allergy 2, 239-240, 1954 (in japanese). 65. Yamasaki, H. and Mayeda, H.: The action of antihistamines on the lymph formation and its effect on the action of some lymphagogues. Acta Med. Okayama 9, 81-104, 1954. 66. Nishiyama, R., Tasaka, K. and Irino, S.: The sites of action of some histamine releasing substances in the dog. Acta Med. Okayama 11, 133-144, 1957. 67. K ume, M.: Recovery of histamine and mast cells in the skin and joint capsules of the dog after sinomenine injection. Okayama Igakkai Zasshi 71, 5199-5209, 1959 (in japanese with English abst. ). 68. Endo, K. and Yamasaki, H.: Dogs refractory to compound 48/80 and sinomenine. Acta Med. Okayama 23, 589-592, 1969. 69. Yamasaki, H. and Saeki, K.: Evidence for energy-requiring processes in mast cell degranulation and histamine release in rat induced by sinomenine. Proc. Jpn. Acad. 41, 958-962, 1965.

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70. Yamasaki, H. and Endo, K.: Coexistence of energy dependent and.nondependent pro cesses in histamine release mechanism of compound 48/80 and sinomenine: Experiments on chopped skin from various animal species. Jpn. J. Pharmacol. 17, 228-239, 1967. 71. Yamasaki, H., Fujita, T., Ohara, Y. and Komoto,S.: Electron microscope studies on the release of histamine from rat peritoneal mast cells. Acta Histol. lpn. 31, 393-408, 1970. 72. Tasaka, K., Sugiyama, K., Komoto, S. and Yamasaki, H.: Repeated local degranu lation of isolated rat mast cell by microelectrophoresis of basic histamine releasers. Proc. Jpn. Acad. 46, 311-316, 1970. 73. Tasaka, K., Endo, K. and Yamasaki, H.: A fluorescent study of histamine release from a single mast cell of the rat mesentery. Proc. Jpn Acad. 46, 831-836, 1970. 74. Yamasaki, H.: The release of histamine and its mechanism. Proc. 17th General Meeting of Jpn. Med. Assoc. 1, 555-578, 1967 (in japanese). 75. Yamasaki, H.: Histamine. In Biogenic Amines, Storage and Release, ed. H. Yamasaki and H. Yoshida, Ishiyaku-Shuppan, Tokyo, pp. 141-211, 1975 (in japanese). 76. Sanuki, K.: The analgesic effect induced.by repeated administration of histamine and histamine liberators. Jpn. J. Pharmacol. 6, 69-86, 1957. 77. Ohno, H.: Effects of histamine and histamine liberators on the action potentials in the afferent nerve in response to stimulation on the skin of the cat. Folia Pharmacol. lpn. 55, 126-137, 1959 (in japanese with English abst.). 78. To, S. and Rin, S.: On the practical use of sinomenine hydrochloride as a local an aesthetic. J. Med. Assoc. Taiwan 42, Suppl. 6, 104-118, 1943 (in japanese with English abst. ). 79. Saeki, K., Wake, K., Yokoyama, j. and Yamasaki, H.: Function of histamine as a modulator of inflammatory reaction. Jpn. J. Pharmacol. 24, Suppl., 139, 1974. 80. Kamimura, Y. and Nishiyama, R.: On the preventive effect of sinomenine against guinea-pig anaphylaxis. Okayama Igakkai Zasshi 67, 873-881, 1955 (in japanese with English abst. j. 81. Lichtenstein, L. M. and Gillespie, E.: Inhibition of histamine release by histamine controlled by H2 receptor. Nature (Lond.) 244, 287-288, 1973. 82. Kuno, j.: Ober den Einfluss des Sinomenins, des Parasinomenins und des Chinins auf den Blutzuckerspiegel des Kaninchens. Folia Pharmacol. Jpn. 9, 201-221, 1929 (in japanese with German abst.). 83. Kura, G.: Ober den Einfluss des Sinomenins, Parasinomenins und Chinins auf das Blutbild des Kaninchens. Folia Pharmacol. Jpn. 12, 434-457, 1931 (in japanese with German abst. ). 84. Ezuka, H.: Ober das Trilobin, das Alkaloid von Cocculus trilobus D. C. Kyoto Igaku Zassi 16, 1209-1219, 1919 (in japanese with German abst.). 85. Kondo, K. : Studies on urinary excretion of histamine in the rat. Folia Pharmacol. lpn. 54, 1221-1232, 1958 (in japanese with English abst. j. 86. Rin, S.: On changes in the amount of sinomenine hydrochloride in urine of rabbits. J. Med. Assoc. Taiwan 42, Suppl. 6, 66-74, 1943 (in japanese with English abst.). 87. Saeki, K., Yokoyama, j. and Wake, K.: Inhibition of granulation tissue growth by histamine. J. Pharmacol. Exp. Ther. 193. 910-917, 1975. 88. Saeki, K., Yokoyama, j. and Yamasaki, H.: Mechanism of histamine inhibition of gra nulation tissue growth. Jpn. J. Pharmacol. 25, Suppl., 106P-107P, 1975. 89. Black, j.W., Duncan, W. A. M., Durant, C. j., Ganellin, C. R. and Parsons, E. M.: Definition and antagonism of histamine Hrreceptors. Nature (Lond. ) 236, 385-390, 1972. 90. Henney, C. S., Bourne, H. R. and Lichtenstein, L. M.: The role of cyclic 3',5'-adeno sine monophosphate in the specific cytolytic activity of lymphocytes. J. Immunol. 108,

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1526-1534,1972. 91. Plaut, M., Lichtenstein, L. M. and Henney, C. S.: Increase in histamine receptors on thymus-derived effector lymphocytes during the primary immune response to alloanti gens. Nature (Lond.) 244, 284-287, 1973. 92. Karppanen, H. O. and Westermann, E.: Increased production of cyclic AMP in gastric tissue by stimulation of histamine2 (H2)-receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 279, 83-87, 1973. 93. McNeill, j.H. and Verma, S. C.: Blockade by burimamide of the effects of histamine and histamine analogs on cardiac contractility, phosphorylase activation and cyclic adenosine monophosphate. ]. Pharmacol. Exp. Ther. 188, 180-188, 1974. 94. Otten, j., johnson, G. S. and Pastan, 1.: Regulation of cell growth by cyclic adenosine 3',5'-monophosphate. ]. BioI. Chern. 247, 7082-7087, 1972. 95. Saeki, K., Yokoyama, j. and Yamasaki, H.: Inhibition of granulation tissue growth by H2-receptor stimulation and cyclic AMP. ]pn. ]. Allergol. 25 (Proceedings of 25th japanese Congress of Allergology), 1976, in press (in japanese). 96. Saeki, K., Wake, K. and Yamasaki, H.: Inhibition of rat adjuvant arthritis by hista mine and sinomenine. ]pn. ]. Pharmacol. 25, Suppl., 106P, 1975. 97. Saeki, K., Wake, K. and Yamasaki, H.: Inhibition of adjuvant arthritis by histamine. Arch. Int. Pharmacodyn. Ther. in press. 98. Waksman, B. H. and Wennersten, C.: Passive transfer of adjuvant arthritis in rat~ with living lymphoid cells of sensitized donors. Int. Arch. Allergy 23, 129-139, 1963. 99. Rosenthale, M. E., Datko, L. j., Kassarich, j. and Rosanoff, E.!.: Immunopharma cologic effects of cycloleucine. ]. Pharmacol. Exp. Ther. 180, 501-513, 1972. 100. Quagliata, F., Sanders, P. M. and Gardner, D. L.: Suppression of adjuvant arthritis by anew cytotoxic compound, rubidomycin. Ann. Rheum. Dis. 28, 163-171, 1969. 101. Bourne, H. R., Lichtenstein, L. M., Melmon, K. L., Henney, C. S., Weinstein, Y. and Shearer, G. M.: Modulation of inflammation and immunity by cyclic AMP. Science 184, 19-28, 1974. 102. Staszewska-Barczak, J. and Vane, j. R.: The release of catecholamines from the ad renal medulla by histamine. Br. ]. Pharmacol. 25, 728-742, 1965.

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