acta medica okayamaousar.lib.okayama-u.ac.jp/files/public/3/31433/...2 h. yamasaki ing vines...

Acta Medica OkayamaVolume 30, Issue 1 1976 Article 1

FEBRUARY 1976

Pharmacology of sinomenine, ananti-rheumatic alkaloid from Sinomenium

acutum

Hidemasa Yamasaki∗

∗Okayama University,

Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.

Pharmacology of sinomenine, ananti-rheumatic alkaloid from Sinomenium

acutum∗

Hidemasa Yamasaki

Abstract

The root and stem decoctions of Sinomenium acutum Rehd. et Wils. (formerly Sinomeniumdiversifolius Diels, one type of Fang-chi (Chinese)) have been used as a folk remedy for neuralgiaand rheumatoid arthritis in many areas of the Far East. In Japan and China various viny plantshave been identified as Fang-chi (Boi in Japanese) since antiquity. This uncertain nomenclaturehas 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 thealkaloid 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 degran-ulation of tissue mast cells in mammalian tissues. This action occurs preferentially in the skin andjoint capsules. The released histamine is responsible for the dominant pharmacological actions ofsinomenine, such as vasodilatation, increased vascular permeability, acceleration of the thoracicand 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 excita-tion was observed in most laboratory animals. Clinical side effects encountered with high dosesof injected sinomenine or of decocted Sinomenium acutum were: injection site flare, pruritus inthe head and upper part of the body, edema around the lips and eyelids, and temporary cephalal-gia. 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 ef-fect in mice. Granulation tissue growth and adjuvant arthritis induced in rats were both inhibitedby 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 wereclearly inhibited by the H2-antagonist burimamide but not by the H1-antagonist mepyramine. Theanti-rheumatic effect on Sinomenium acutum are probably genuine and can probably be attributedto the histamine-releasing properties of sinomenine.

∗PMID: 61710 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOL

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

PHARMACOLOGY OF SINOMENINE, AN ANTI-RHEUMATICALKALOID 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 rheumatoid arthritis in many areas of the Far East. In Japan and Chinavarious viny plants have been identified as Fang-chi (Hoi in Japanese)since antiquity. This uncertain nomenclature has made it difficult toevaluate the efficacy of the Fang-chi described in the classic literature.Among traditional Fang-chi plants only Sinomenium acutum has beendemonstrated to contain the alkaloid sinomenine, which is now knownto be effective in neuralgia and rheumatic diseases. Sinomenine is aunique plant alkaloid, as it potently releases histamine in associationwith degranulation of tissue mast cells in mammalian tissues. Thisaction occurs preferentially in the skin and joint capsules. Thereleased histamine is responsible for the dominant pharmacologicalactions of sinomenine, such as vasodilatation, increased vascularpermeability, 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 sinomenineor of decocted Sinomenium acutum were: injection site flare, pruritusin the head and upper part of the body, edema around the lips andeyelids, and temporary cephalalgia. Most of these side effects werereduced by classical antihistamines (HI-receptor antagonists). Dailysubcutaneous injections of sinomenine for more than one week produced an analgesic effect in mice. Granulation tissue growth andadjuvant 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 histamineH~receptors probably on fibroblasts (for granulation tissue growth)and on T-cells (for adjuvant arthritis), since these effects were clearlyinhibited by the Hz-antagonist burimamide but not by the HI-antagonist mepyramine. The anti-rheumatic effect of Sinomenium acutum areprobably genuine and can probably be attributed to the histamine.releasing properties of sinomenine.

INTRODUCTION

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

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Yamasaki: Pharmacology of sinomenine, an anti-rheumatic alkaloid from

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2 H. YAMASAKI

ing vines sometimes growing to a height of 20 feet. The sterns and roots arestripped and hairless. The leaves are long-stalked, ovate or multilobed,acuminate, usually cordate at the base, palmated to 5 to 7 divisions, and thesurfaces glabrous and brilliant (Fig. I). In summer the flower stalks growfrom the axilla of the leaves. The flowers are small, light greenish, andorganized in slender panicles. The drupes are compressed and bluish black.The roots and stems in cross sections are whitish and are characterized by avery distinct radiating pattern of ducts. The decocted dried roots and stemsof 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 theJapanese pharmacopoeia under the name of Sinomeni Caulis et Rhizoma orEDi.

The plant Fang-chi (~B), probably Sinomenium acutum, is mentioned inthe Chinese Shen Nung Pen Ts'ao (1$~*1j1r.g, "Herbal ")* (I) which wasprobably written about the first century B. C., during the Western Han dynasty.Fang-chi was recommended for the treatment of many diseases such as rheumatism, fevers, dropsies and pulmonary diseases in the Chin K'uei Yao Liieh(~I.~~, "Synopsis of the Golden Chamber") written by Chang Chungching (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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Acta Medica Okayama, Vol. 30 [1976], Iss. 1, Art. 1

http://escholarship.lib.okayama-u.ac.jp/amo/vol30/iss1/1

Pharmacology of Sinomenine 3

"Formulas of Famous Physicians") compiled by T'ao Hung-ching ,(3) ofthe Liang dynasty 502 A.D. and which is said to be the first officialpharmacopoeia in China. Among the prescriptions of Chang Chung-ching fourcontained Fang-chi. The Shen Nung Pen Ts'ao (1) distinguishes between theplant Han Fang-chi (~Itf5B) and Mu Fang-chi (*Itf5S). The former plant isprobably Sinomenium acutum, since it was prescribed' for diseases nowconsidered to be rheumatoid' arthritis and neuralgia, while the latter was prescribed for many other diseases (2-4). In subsequent periods, varieties ,ofviny plants have been used for the original plant for medical treatment inChina and in japan, as many Menispermaceae plants closely resemble eachother in taxonomy. This has confused the identity and efficacy of Fang-chiamong traditional physicians of Chinese medicine for a long time, (5,6).Nevertheless, it is curious that the original plant has continued to be 'Used asa 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 ofrheumatoid arthritis and neuralgia in extensive clinical trials (9-12). Pharmacological studies on this plant have been conducted at several institutions injapan and China. The special interest of this alkaloid is the presence of ahistamine-releasing feature that is probably important in the mechanism ofthe anti-rheumatic effect. The present paper presents a brief survey of pharmacological studies on this alkaloid, with special reference to its anti-rheumaticeffect.

SINOMENIUM ALKALOIDS

In 1909 jujiro Honda (13), then professor of pharmacology at OkayamaMedical School, presented a paper at a meeting of ,the Okayama MedicalAssociation on chemical and pharmacological properties of two toxic ingredients that he extracted from Sinomenium acutum, but a complete account ofthis presentation does not remain. In 191 7Ishikawa (14) of Kyushu Universityremarked briefly in a note that a picrotoxin-like convulsant action was foundin frogs injected in the lymph sac with a crystalline ingredient obtained fromthis plant. During this early period, Taguchi and Ohta (1919)(15) conductedinvestigations on this plant under Prof. Kurata Morishima, at the Pharmacological Department of Kyoto University. They described the circumstancesof their entering into this investigation: "February, 26, 1916, Mr. S. Masagaki (probably a stranger) visited Prof. Morishima and asked the professorearnestly to study this plant. The younger brother of the visitor sufferedfrom 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 daysinterval. A dramatic relief occurred." Taguchi and Ohta. obtained a crystalline colorless ingredient from the extracts of the roots and stems of Sinomeniumacutum using the procedure of Stas and Otto. These early investigators foundthat this crystalline induced convulsions in frogs. In the middle of thesestudies they moved to Kitasato Institute in Tokyo, where they isolated twokinds of convulsant alkaloid: cocculin C17H29N03 o3H20 (15) (later kukolinC16H20N0303H20 (16, 17)) and diversin C16H:wN04 (16, 18). The form.erwas a crystalline and the latter amorphous. Ishiwari (8) at Kyoto Universitycontinued the same line of study after the departure of Taguchi and Ohta.He isolated from roots and stems a crystalline alkaloid and estimated themolecular formula as C16H19NOg 0H 20, and called the compound sinomenine.This molecular formula was later corrected but the generic name sinomeninewas maintained.

o

HO

Fig. 2. Chemical structureof sinomenine

The chemical structure of sinomenine withthe molecular formula of C19H 230 4N was established as shown in Fig. 2 by Kondo and Ochiai(19), and Goto and his colleagues (20) (cj. reviewsin refs. 21, 22). These studies on sinomeninemarked the first step in a series of chemical studies in Japan on the alkaloids of Menispermaceaeand other plants. Several alkaloids of Sinomeniumacutum other than sinomenine have been successively isolated and the chemical structures established. Most of these studies were conductedby 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-sitosterol and stigmasterol were also isolated (33). The sinomenine content in theplant 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 notbeen isolated in other Menispermaceae plants. Pharmacological studies ofSinomenium alkaloids have thus far been limited to sinomenine and rnagnoflorine. The claimed chemical properties of diversine and parasinomenine havenot been confirmed, and the reported alkaloid isosinomenine has been shownto be an artefact (36).

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ANTI-RHEUMATIC EFFECTS OF SINOMENINE AND SINOMENIUM ACUTUM

Decocted Sinomenium acutum has been used widely in the treatment ofrheumatic diseases in Kyushu, Shikoku, Kinki and other districts of Japanand in Korea and Formosa with favorable reputations for remedy (7). Theusual daily dose is prepared from 8-15 g of dried cut roots and stems. The remarkable beneficial effects of sinomenine were first reported scientifically byIshiwari (9) and Takaori (10) in 1921, and since then, a considerable clinicalliterature (12) has confirmed their findings. Sinomenine administered subcutaneously (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, lumbalgiaand muscular rheumatism. The s.c. injections were more effective than oralusage. Injections were usually started at 20 mg (dosages are expressed ashydrochloride) once daily and were increased by 10-15 mg every three tofour days thereafter. Beneficial effects have been noted after two or threeinjections, and most acute phase symptoms subsided after eight to nine administrations, near a daily maximum dose of 90 - 100 mg. In chronic types ofarthritis, swelling and oppressive pain in the affected joints decreased gradually, and the margins of the articular movements were increased. After theinitial injection, a relapse in pain usually occurred but on repeated injectionsthe periods of relief were prolonged. For oral usage, 30 - 120 mg per day inthree divided doses has been recommended.

Side effects. An itchy flare of 4-5 em in diameter appeared occasionallyaround the s.c. injection site. Pruritus and facial edema occurred with largedoses of sinomenine (s.c.) or decocted Sinomenium acutum. The pruritus waspredominant in the upper parts of the body and the edema remarkable aroundthe eyelids and lips. Cephalalgia was encountered infrequently. These symptoms were temporary and abatement usually followed in about 30 min. Thereis a case report of a serious side effect in a patient who was probably injectedsinomenine into the subcutaneous vein by error (37).

Edema and itching induced by sinomenine were suppressed experimentallyby the usual antihistamines (38). The usual antihistamines did not interferewith the therapeutic effects of sinomenine on experimentally-induced arthritisor on granulation tissue growth, as stated later in more detail. Prior to 1935when clinical usage of sinomenine was common among physicians, antihistamines 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 phenanthropiperidine moiety in its chemical structure is shared with morphineand other natural opium alkaloids and with semisynthetic opiate derivatives.Sinomenine possesses certain pharmacological properties similar to those ofmorphine and related compounds. At large doses sinomenine elicits convulsant-type central excitation which is also found in morphine and itssurrogates (39). The most prominent pharmacological property of sinomenineis histamine release. This action is also present in morphine, codeine, apomorphine (40), ethylmorphine (41,42) and meperidine (43, 44). Meperidineis a synthetic opioid containing r-phenyl-N-methoxypiperidine in structure likemorphine and sinomenine. One distinct difference between sinomenine andmorphine or congeners is that sinomenine may be less toxic due to theabsence of prominent central nervous actions that are inherent in morpnine,and because the major pharmacological and probably therapeutic effects ofsinomenineare due to the potent histamine-releasing property, while for themorphine-type analgesics, histamine release is a side effect of clinical usage.

Toxicity. Subtoxic doses of sinomenine (s.c. or p.o.) resulted in decreasedmotility in mice, rats, rabbits, dogs and monkeys (8, 45). At toxic or lethaldoses (s.c. or intravenous (i.v.)) this apparent sedation was soon followed byan 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 animalsshowed general muscular weakness and slow respiration, leading in somecases to fatal asphyxia.

Dogs after receiving a s.c. injection of 3-5 mg/kg of sinomenine, lickedtheir lips, then scratched around the ear lobes, neck and jaw, where intenseitching seemed to be present. At 10 - 40 mg/kg (s.c.) pruritic giant edemaappeared in the face forming several vertical stripes in the snout. Theanimals violently scratched the face and ear lobes and rubbed their bodiesagainst a burrowed hole. Urticaria-like macular erythemas were also visiblein the breast and abdominal skin areas. At these dose levels profuse salivation, vomiting and defecation were not uncommon. The vomiting did notappear to be due to the direct action of sinomenine on the chemoreceptortrigger zone (CTZ) , since direct application of 1% sinomenine onto thecaudal angle of exposed rhomboid fossa did not provoke vomiting while apomorphine induced vomitings (47). Increased peristalses of the intestines wereobserved through the abdominal walls of dogs lying on their sides. At thesedose levels, reflex excitability increased. At doses of 60 mg/kg or more(lethal dose), the animals laid down and were able only to stagger ataxicallywhen placed on their feet. Respiration was initially accelerated but soonbecame weak and slow. Increased reflex excitability gradually intensified.

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The animals cried aloud, and then manifested trismus and convulsive movements in the extremities. This was soon followed by a generalized clonictetanic convulsion initiated spontaneously or with inciting events, andoccasionally culminated in opisthotonus.. With seizures at short intervals, theanimals 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. injectionat the same dose and frequently led to death (47-49). Autopsy findingsincluded congestion of the mesenteric veins and the liver (47, 50, 51). Catsreceiving 10 mg/kg sinomenine s.c. scratched their heads and ear lobes andlicked or bit areas of the body. Defecation also occurred (47).

In rats, after single intraperitoneal (i.p.) injection of 50 mg/kg, vasculardilatation or reddening was observed around the ears, mouth, snout, paws,and scrotum (52). The animals scratched their faces with the forelegs. Thesehyperemic areas were initially bright pink, changing progressively to blue asrespiration failed. Edema gradually developed in hyperemic areas. Thesechanges were quite obvious on visual inspection, and they were indistinguishable from the effects produced by an i.p. injection of egg-white, dextranor compound 48/80. Convulsions were not observed in rats even at 300mg/kg, i.p. (52). A single injection of sinomenine at this dose to a groupof rats reduced the histamine content of the abdominal skin by 32.5% compared to the initial level. When sinomenine was injected for 6 consecutivedays 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 contentwas found in the abdominal skin. The symptoms, however, decreased graduallyafter subsequent injections in spite of increased dosages (52). Rats injected40 - 80 mg/kg daily, i.p. for 14 consecutive days showed no body weightor food consumption effects. No changes in the blood picture or histologywere observed (45).

Mice injected with sinomenine at 300-400 mg/km, i.p. showed reddening of the snout, ear lobes, feet and tail; edema was prominent in the distalextremities. 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 mepyramine and diphenhydramine. In mice at the same dosage, these antihistamines did not prevent sinomenine deaths (46); Rabbits (8,53,56) and guineapigs (56) responded with convulsions to high doses (s.c. or i.v.) of sinomenine.

The toxic symptoms of sinomenine,' especially on the skin. resembledthose of componnd 48/80;" One difference is that at high doses sinomeninecaused convulsions while compound 48/80 resulted in severe prostration inmost examined animals (57). This suggests that the convulsive actions-of

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

Lethal dose Minimum effective doseSpecies Route

(mg/kg) Reference for indicated reaction Reference(mg/kg)

Frog Lymph 500 8 300 Convulsion 8sac 600 58 500 Convulsion 58

650 53Mouse s.c. 400 58 300 Convulsion 54, 59

483* 46 50t Marked skin reaction 46500 54550 53

p.o. 580* 45i. v. 250 53

Rat p.o. 964t Sedation 45i.p. 50t Marked skin reaction 52, 60

Guinea pig s. c. 350 56Rabbit s.c. 250 8

280 58300 53, 58

i. v. 120 58 5 Hypotension 50150 8

i. cyst. 1.2 Convulsion 56Dog s.c. 60 47 40-60 Convulsion 47

>60 53i. v. =5 51 0.3 Hypotension 51

0.5 Hypotension 47Cat s.c. 10 Convulsion 47

i. v. I Hypotension 61Monkey 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 thelethal doses of sinomenine for different species of laboratory animals and theminimum effective doses for inducing convulsion and hypotension.

Cardiovascular actions. Sinomenine decreased the contraction force andfrequency of excised or perfused frog heart. Rabbit aural vessels dilated whenthe perfusion fluid contained serum (47,53). Intravenous injection of sinomenine 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 dogsan increase occurred in the volume of the liver, intestines and extremities, andthe portal pressure rose at an early stage of hypotension (50, 51). Likewise

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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 indogs (51). The lymph became rich in protein content, and the blood andlymph 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 witha triple response which was characteristic in that the wheal grew more slowlyextending more prominent pseudopod-like processes along cutaneous veinsthan by histamine. A brief pain that was followed by itching of about 10 minduration usually occurred at the injection site. Occasional cephalalgia wasencountered, due probably to the extention of cranial vascular walls.

Effects on plain muscles. Intravenous injection of sinomenine increasedthe rhythmic contraction of the uterus, which culminated in contracture atvery high doses in cats and rabbits but this action was much weaker than thatof quinine (63). An increase of intestinal peristalsis has been experienced inman after sinomenine injection or ingestion of the plant decoction. Gastricacid 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, asfirst reported from this laboratory (51,62,64,65). These actions of sinomenine were proved to be responsible for the hypotension, the rise in the portalpressure, the increased volumes of the liver and extremities, and the incoagulability of blood and lymph produced by this substance; this explains thedevelopment of tachyphylaxis in all these reactions (51). Cardiovascularchanges were completely inhibited by pretreatment with antihistamines suchas mepyramine, although the hypotension was partially inhibited (65).

In dogs i.v. injection of sinomenine depleted histamine of the skin preferentially (62, 64, 66). This response differed from compound 48/80 whichreleases liver histamine more easily in dogs (62, 64, 66). After sinomenineinjection 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 genitoanal 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 therecovery process, a few mast cells appeared initially but gradually increasedin population and granule density. For complete recovery of the cell population 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 thedepleted histamine in the respective tissues (67). Occasional temporaryheadaches after sinomenine injection may be due to histamine release.

Fourteen (51) to 21 percent (68) of mongrel dogs were found to be refractory to both sinomenine and compound 48/80 (cross-tolerance). Thesenon-reactive dogs responded normally to polyvinylpyrrolidone and tween 20and showed normal sensitivity to histamine. The incidence of non-reactorswas 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 inmice caused analgesia which reached maximum after 6-8 days of injection.Similar analgesia developed under the same injection .schedule with sinomenine. When the injection of histamine and that of sinomenine were alternated daily at doses causing about the same degree of analgesia, neither agentproduced an analgesic effect. The development of analg.esia by histamine orsinomenine was not blocked by the concurrent use of an antihistamine mepyramine. The hypothermic effect of s.c. injection of histamine or sinomeninegradually decreased on repeated daily injections. Such desensitization of thehypothermic effect did not appear when histamine and sinomenine were injected on alternate days. In mice receiving repeated injections 'of sinomenine, the sensitivity to histamine increased as measured by the hypothermiceffect (76). The close similarity between the development of analgesia andthe desensitization of the hypothermic effect suggests the presence of histaminereceptors in the sensory nerve endings that is similar to the skin vessels,and that histamine liberated by physical stimuli is a possible mediator ofcutaneous pain in a manner similar to its mediation of vasodilatation. Sinomenine has a local anesthetic action as shown by i.c. injection or by instillation onto the conjunctiva (77,78).

Anti-inflammatory and anti-allergic actions. Sinomenine inhibited eggwhiteedema (52) but not carrageenin edema in rat paws (79). Daily injections torats of sinomenine at high dose suppressed both the increase in the weight ofcroton-oil granuloma pouch and its histological inflammatory changes (60).Canine anaphylactic shock was prevented by an Lv. or s.c. injection of sinomenine. (48) although this effect was not evident in guinea pigs (80). A recentreport indicates that a small amount of histamine inhibits the allergic histamine release from human basophils (81) .. We have shown that histamine andalso sinomenine inhibit .certain types of inflammation, as described in moredetail later.

Other pharmacological actions. Sinomenine lowered rabbit body temperature

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raised by heat puncture or adrenaline injection (8). Since the body temperatureis also lowered by sinomenine in normal mice (76), the hypothermic effect ofsinomenine may be due largely to the dilatation of cutaneous vessels by released histamine. Sinomenine produced hypo- and hyperglycemia in rabbitsdepending upon the dosage (82). In rabbits daily injections of sinomeninecaused neutrophilia while erythrocyte count and hemoglobin concentrationremained unchanged (83). Old Chinese medical books describe the diureticeffect of Han Fang-chi and Mu Fang-chi, but this effect has not been demonstrated so far in sinomenine (8) and trilobine (84). The latter alkaloid is anactive 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 urinaryhistamine. Sinomenine was rapidly absorbed by s.c., Lv. and i.p. injections, but hardly absorbed by intramuscular (Lm.) injection. Peroral absorption was slower but better than by i.m. injection (85). This is consistentwith the experimental results of sinomenine on gastric acid secretion (38).In rabbits, urinary excretion of sinomeninedepended upon the s.c. dosageinjected, but the excretion gradually decreased on repeated injections (86).A major part of 'released histamine converts to I, 4-methylimidazole aceticacid and imidazole acetic acid riboside; the remaining part is mostly excretedas free histamine but a small quantity of histamine remains for several hoursin .tissues (76, 85).. The latter histamine probably has the therapeutic effectsof sinomenine or Boi, as discussed in the next paragraph.

PHARMACOLOGICAL PROPERTIES OF SINOMENINE PROBABLYCONNECTED 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 cellularinfiltration is the first sign of disease which is followed by synovial growth,formation of granulation tissue, accumulation of inflammatory exudates inarticular cavities, and then fibrous or bony ankylosis of the joints. Hence,the suppression of connective tissue growth (granuloma formation) appearstherapeutically important.

To study. the effects of sinomenine and histamine on connective tissuegrowth, we (87,88) placed filter-paper disks, soaked in 7% aqueous formaldehyde solution, in the subcutaneous tissue of each axillary and inguinaiarea of male Wistar rats under sterile conditions. On the seventh day after theoperation, the granulomas including the filter-paper disks were extirpated.

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To intensify the pink hue of the granulation tissue, the animals were killedby carbon monoxide poisoning.

Effects of histamine and sinomenine. Subcutaneous injections of 0.05 mg/kgof histamine twice a day (the dose of histamine is expressed as base, butfor other drugs as salt or ester) decreased the weight of dry-defatted granulomas and their contents in hydroxyproline and hexosamine. These inhibitoryeffects became more marked when the dose was increased to 1 mg/kg/day.The hydroxyproline and hexosamine values per milligram of dry-defattedweight of gra.nuloma were not significantly altered by histamine and otherdrugs tested with the exception of prednisolone at large dose. The gain inbody weight during the 7-day period from disk implantation to the removalof granuloma was increasingly reduced by increasing dose of histamine, butthis 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 ratsgiven large doses of sinomenine before disk implantation and during granuloma growth period*, the histamine content of the abdominal skin at the timeof granuloma removal was markedly decreased to a level of 6.7 ± 0.8 pg/gwet 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 by55.7% in terms of weight by this treatment. When a relatively small doseof sinomenine (15 mg/kg twice a day) was administered from the implantationday to one day before the removal of granulomas without pretreatment ofsinomenine, 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 aneffect on skin histamine content, this small dose of sinomenine inhibitedgranuloma formation at the same rate as a larger dose.

Aminoguanidine bicarbonate, a potent histaminase inhibitor, produced amarked 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 prednisolone (i.m.) was less marked than 0.1 mg/kg/day of histamine (s.c.). Thisdose of prednisolone, however, strikingly inhibited the growth of rats andcaused a decrease in thymus weight. Phenylbutazone was ineffective at adaily dose of 30 mg/kg.

Effects of burimamide and mepyramine. Burimamide is known to specifically 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 for6 days: on the first day 50 mg/kg X 2, increasing by 50 mg/kg X 2 daily, until a final dose of300 mg/kgx2 (total dose=2,IOO mg/kg). From the implantation day, 300 mg/kg was injectedonce daily.

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such as stimulation of gastric acid secretion (89). When 5 mg/kg of burimamide was injected s.c. 30 min prior to the injection of 0.05 mg/kg ofhistamine, this compound clearly antagonized the inhibitory effect of histamineon the formation of granuloma and even enhanced its growth as revealed bythe increased granuloma weight and hydroxyproline and hexosamine contents.Burimamide also blocked the inhibitory effect of sinomenine and aminoguanidine. Mepyramine, the classical antagonist of histamine H 1-receptors (89),was ineffective in blocking the inhibitory effect of histamine at a similar dosageas that used for burimamide. The hydroxyproline and hexosamine values permilligram of dry-defatted weight of granuloma were not markedly alteredby histamine antagonists.

Histological studies. In granulomas obtained from rats treated with 0.05mg/kg of histamine twice a day, tissue layers of densely populated fibroblastswere narrower than those of control animals. The formation of blood vesselsin the granulation tissue appeared to be also poor in the treated rats. Thesemorphological effects were entirely or largely counteracted when burimamidewas injected concurrently with histamine. In sinomenine- and aminoguanidinetreated rats the morphological pattern of granuloma formation was similar tothat observed in histamine-treated rats.

Comment. It has been shown that activation of H 2-receptors leads to anincrease 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 growthof cultured fibroblasts is inhibited by the increase in intracellular level ofcyclic AMP (94). Therefore, the histamine inhibition of the granuloma growthmay be induced by a rise in the cyclic AMP level of fibroblasts through theactivation of H 2-receptors. We have recently observed an increase in thecyclic AMP content of granulomas in rats after a s.c. injection of histamine(95).

2. Inhibitory effect of histamine and sinomenine on adjuvant arthritisThe rat adjuvant arthritis shows a close similarity to the human rheu

matoid arthritis in clinical signs. A dose of 0.05 ml of adjuvant mixturecontaining 0.25 mg of finely-ground killed Micobacterium tuberculosis wasadministered i.d. under the volar surface of the left hind paw of male inbredSprague-Dawley rats. The volume of each hind paw was measured prior toadjuvant injection and once daily thereafter.

Effects of histamine and sinomenine. Sinomenine was injected i.p. at adose of 15 mg/kg twice daily from the day of adjuvant injection (day 0).Sinomenine did not inhibit the primary inflammation in the adjuvant-injectedpaw which reached maximum on day 5 or day 6, but significantly suppressedswelling 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 pa w.Histamine was injected at 5 mg/kg, s. c., twice a day from day 5 to day 10. Thecontrol rat received 0.9% saline. Roentgenographs were taken on day 25. a, Salinetreated rat; b, histamine-treated rat. The adjuvant-injected paw is on the left inboth figures (97).

noninjected paw at day 10 or later. Histamine administered s.c. at a doseof 5 mg/kg twice daily also had a similar inhibitory effect. In the vehicletreated control group, marked swelling and ankylosis of tarsal and otherpedal joints were visible. Fusion of joints and destruction of bones and cartilages were observed in roentgenograms. These changes were more marked inthe adjuvant-injected paw but were also observed in the adjuvant-noninjectedpaw. In groups treated with sinomenine or histamine, these radiologicalchanges were also clearly inhibited (96, 97) (Fig. 3).

Histamine markedly suppressed the appearance of the secondary inflammation of adjuvant arthritis when injected for 6 consecutive days from day 5

14




to day 10. Histamine injection prior to or after this critical 6-day periodproduced no significant inhibition of the secondary inflammatory response.Histamine had no suppressive effect on the secondary lesion when administeredafter the establishment of the lesion. Therefore, the histamine effect on thesecondary lesions appears to be based on a different mechanism from theusual anti-inflammatory drugs.

Effects of burimamide andmepyramine. When burimamide at 5 mgjkgwas injected simultaneously with histamine of the same dosage, a completeblockage of histamine inhibition was 'found in the secondary inflammatoryresponse and in histological and radiological examinations. Mepyramine atthe same dosage showed no such blocking effect.

Comment. Rat adjuvant arthritis has been reported as being caused bycell-mediated immunity, mainly from evidence of the passive transfer of thisdisease with living lymph node cells (98). The most effective period ofhistamine administration to prevent the appearance of the secondary lesion ofadjuvant arthritis coincides closely with the effective period reported for someimmunosuppressants (99, 100).

Since the inhibitory effect of histamine on adjuvant arthritis is not antagonized by mepyamine and is completely blocked by burimamide, thehistamine effect appears to be mediated through H 2-receptors. Histaminecauses an increase in the cyclic AMP 'level of lymphocytes through the activation of H 2-receptors (91). In connection with this effect, histamine inhibitsresponses to antigen-stimulation, such as the proliferation and differentiationof lymphoid cells, immunoglobulin production and the cytotoxic activity oflymphocytes (101). Qur findings together with the histamine effects onlymphoid cells described by others (99) suggest that the suppressive effect ofhistamine in adjuvant arthritis may be related to the inhibition of T-Iymphocyte proliferation. The catecholamine release by histamine is blocked byHI-receptor antagonists (102). Therefore, the catecholamines released byhistamine do not seem to play an important role in the histamine inhibition ofadjuvant arthritis. .

From the inhibitory effects of histamine on adjuvant arthritis and granulation-tissue growth, it appears likely that the antirheumatic properties ofsinomenine is mediated through histamine released from mast cells.

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