МОНОГРАФИИ ВОЗ Т 4

Gummi Boswellii

B4 from endogenous arachidonic acid in rat peritoneal neutrophils in vitro (37). Acetyl-11-keto-Β-boswellic acid induced the most pronounced inhibition of 5-lipoxygenase product formation, with a mean inhibitory concentration (IC50) of 1.5 μM. However, boswellic acid in concentrations of up to 400.0 μM did not inhibit cyclooxygenase or 12-lipoxygenase in isolated human platelets, or peroxidation of arachidonic acid by Fe-ascorbate. These data suggest that boswellic acids are specific, nonreducing-type inhibitors of the 5-lipoxygenase product formation either interacting directly with the 5-lipoxygenase or blocking its translocation (37). 3-O-acetyl- 11-keto-Β-boswellic acid is the most potent inhibitor of 5-lipoxygenase. In vitro, 3-oxo-tirucallic acid inhibited 5-lipoxygenase product synthesis in cell-free assays, with an IC50 of 3 μM, but in intact cells enhanced 5-li- poxygenase product formation in ionophore-challenged polymorphonuclear leukocytes and initiated calcium mobilization, MEK-1/2 phosphorylation and 5-lipoxygenase translocation at a concentration of 2.5 to 15 μM. These data indicate that the pentacyclic triterpenes that inhibit 5-lipoxy- genase in cell-free systems activate 5-lipoxygenase product formation in intact cells (38).

Extracts of the crude drug and its constituents, the boswellic acids, activate the mitogen-activated protein kinases p42 and p38 in isolated human primed polymorphonuclear leukocytes in vitro (39). Activation of mitogen-activated protein kinases was rapid and transient with maximal activation after 1–2.5 min of exposure and occurred in a dose-dependent manner. The keto-boswellic acids (11-keto-Β-boswellic acid and 3-O- acetyl-11-Β-keto-boswellic acid) activated kinase at 30.0 μM, whereas other boswellic acids lacking the 11-keto group were less effective. Moreover, 11-keto-boswellic acids induced rapid and prominent mobilization of free Ca2+ in polymorphonuclear leukocytes. Inhibitor studies revealed that phosphatidylinositol 3-kinase is involved in boswellic acid-induced mitogen-activated protein kinase activation, whereas a minor role was apparent for protein kinase C. Mitogen-activated protein kinase activation by 3-O-acetyl-11-Β-keto-boswellic acid was partially inhibited when Ca2+ was removed by chelation (39).

Mixed acetyl-boswellic acids significantly inhibited ionophore-stimu- lated release of the leukotrienes B4 and C4 from intact human polymorphonuclear leukocytes, with 50% inhibitory concentration (IC50) values of 8.48 μg/ml and 8.43 μg/ml, respectively. Purified acetyl-11-keto-Β- boswellic acid was about three times more potent as an inhibitor of the formation of both leukotriene B4 (IC50, 2.53 μg/ml) and leukotriene C4 (IC50, 2.26 μg/ml) from human polymorphonuclear leukocytes in the same assay. Daily intraperitoneal administration of an extract of mixed

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acetyl-boswellic acids (20.0 mg/kg bw) significantly reduced the clinical symptoms in guinea-pigs with experimental autoimmune encephalomyelitis between days 11 and 21. However, the inflammatory infiltrates in the brain and the spinal cord were not significantly less extensive in the treated animals than in the respective control group. The multiple intraperitoneal administrations of boswellic acids did not inhibit the ionophorechallenged ex vivo release of leukotrienes B4 and C4 from polymorphonuclear leukocytes separated from the blood of guinea-pigs with experimental autoimmune encephalomyelitis or the biosynthesis of leukotrienes in vitro (40). Suspensions of rat peritoneal polymorphonuclear leukocytes elicited with glycogen, stimulated by calcium and ionophore to produce leukotrienes and 5-15-hydroxyeicosateraenoic acid (HETE) from endogenous arachidonic acid, were treated with various concentrations of an ethanol extract of the crude drug. A concentration-dependent inhibition of leukotriene B4 and 5-HETE production was observed. All products of 5-lipoxygenase from endogenous arachidonic acid in polymorphonuclear leukocytes were reduced (41).

Miscellaneous activities

Intragastric administration of a 50% ethanol extract of the crude drug, at a dose of 250.0 mg/kg bw, to rats reduced blood glucose levels (42). Intravenous administration to dogs of a 50% ethanol extract, at a dose of 50.0 mg/kg bw, reduced blood pressure (42). Intragastric administration of the crude drug at a dose of 100.0 mg/kg bw to cockerels, rabbits and rats fed a high cholesterol diet reduced serum cholesterol by 25–45% (26). Intragastric administration of the crude drug, at a dose of 100.0–500.0 mg/kg bw did not reduce fever in rats, rabbits or dogs (26). Acetyl-11-keto-beta-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuated experimental ileitis in animals (43).

Toxicology

The gestation period or parturition time in pregnant rats and the onset time of castor oil-induced diarrhoea were unaffected by the extract and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. Intragastric administration of the crude drug to dogs, rabbits or rats, at a dose of 500.0 or 1000.0 mg/kg bw, did not have ulcerogenic effects. The oral and intraperitoneal median lethal doses were greater than 2.0 g/kg bw in mice and rats (28). Intragastric administration of the crude drug to monkeys (500.0 mg/kg bw), mice (2.0 g/kg bw) or rats (1.0 g/kg bw) for 6 months produced no observable behavioural, biochemical or histological abnormalities (44).

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Gummi Boswellii

Clinical pharmacology

A double-blind pilot study, involving 37 patients with rheumatoid arthritis, assessed the effects of the crude drug on the symptoms of swelling and pain, and amount of self-medication with nonsteroidal anti-inflammatory drugs (41). Patients were treated with 3.6 g of the crude drug or placebo for 12 weeks. Outcome measures included Ritchie’s index for swelling and pain, and the dose of nonsteroidal anti-inflammatory drugs patients felt they needed. There were no subjective, clinical or laboratory parameters showing significant changes from baseline to 12 weeks of treatment (45).

A randomized double-blind, placebo-controlled cross-over study was conducted to assess the efficacy, safety and tolerability of a crude Boswellia serrata extract in 30 patients with osteoarthritis of the knee. Fifteen subjects received the active Boswellia serrata extract or placebo for 8 weeks. After the first treatment, a washout period was permitted and the groups were then crossed over to receive the opposite intervention for 8 weeks. All patients receiving Boswellia serrata extract reported a decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased, but radiology detected no change. The observed differences between drug treatment and placebo were statistically significant (p < 0.05). Boswellia serrata extract was well tolerated by the subjects except for minor gastrointestinal adverse events (22).

A double-blind, placebo-controlled study involving 40 patients with bronchial asthma assessed the effects of an extract of the crude drug for treatment of symptoms. The patients were treated with a preparation of gum resin of 300 mg three times daily for a period of 6 weeks. After treatment, 70% of patients showed improvement as evident from the disappearance of physical symptoms and signs such as dyspnoea, bronchial asthma and decreased number of attacks, as well as a decrease in eosinophil count and electron spin resonance. In the control group (treated with lactose, 300.0 mg three times daily, for 6 weeks), only 27% of patients in the control group showed improvement. The data show a role for the crude drug in the treatment of bronchial asthma (20).

A randomized, double-blind, controlled, parallel group comparison clinical trial involving 102 patients assessed the effects of the crude drug for the treatment of Crohn’s disease (18). The positive control arm was treated with mesalazine. The primary outcome measure was the change in the Crohn’s Disease Activity Index between the time of enrolment and the end of therapy. The Crohn’s Disease Activity Index was reduced by 90 after treatment with the crude drug and by 53 after treatment with mesalazine; however, the difference between the two treatments was not

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statistically significant. Thus, the study concluded that an extract of the crude drug was as effective as mesalazine for the treatment of Crohn’s disease.

The effect of an extract of the crude drug was assessed in patients with ulcerative colitis, grade II or III (19). Patients were treated with the gum resin preparation (350 mg three times daily for 6 weeks), and the effects on stool properties, histolopathology and scan microscopy of rectal biopsies, blood parameters including haemogloblin, serum iron, calcium, phosphorus, proteins, total leukocytes and eosinophils were measured. Patients receiving sulfasalazine (1 g three times daily) served as controls. At the end of the treatment period, all parameters tested had improved after treatment with Boswellia serrata gum resin and the results were similar to those in the control group: 82% of treated patients went into remission following treatment with the gum resin as did 75% of those treated with sulfasalazine (19).

A controlled clinical trial assessed the efficacy of the crude drug in patients with chronic colitis characterized by vague lower abdominal pain, bleeding per rectum with diarrhoea and palpable tender descending and sigmoid colon. Thirty patients with chronic colitis, 17 men and 13 women aged between 18 and 48 years, were included in the study. Twenty of the patients were given a preparation of the gum resin of Boswellia serrata (300 mg three times daily for 6 weeks) and 10 were given sulfasalazine (1 g three times daily for 6 weeks) and served as controls. Of 20 patients treated with Boswellia gum resin, 18 showed an improvement in one or more of the parameters: stool properties; histopathology; scanning electron microscopy; and measures of haemoglobin, serum iron, calcium, phosphorus, proteins, total leukocytes and eosinophils. Of 20 patients treated with Boswellia gum resin, 14 went into remission whereas in the patients treated with sulfasalazine, the remission rate was 4 out of 10 (20).

Adverse reactions

Minor gastrointestinal side-effects have been reported in the clinical trials (19–22).

Contraindications

Hypersensitivity or allergy to the crude drug.

Warnings

No information was found.

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Gummi Boswellii

Precautions

General

No information was found.

Drug interactions

None reported.

Drug and laboratory test interactions

None reported.

Carcinogenesis, mutagenesis, impairment of fertility

No information was found.

Pregnancy: teratogenic effects

No information was found.

Pregnancy: non-teratogenic effects

Due to a lack of safety data, the use of the crude drug during pregnancy is not recommended.

Nursing mothers

Due to a lack of safety data, the use of the crude drug during breastfeeding is not recommended.

Paediatric use

Due to a lack of safety data, the use of the crude drug in children under the age of 12 years is not recommended.

Dosage forms

Crude drug, extracts.

Storage

Store in a cool dry place away from heat or light.

Posology

(Unless otherwise indicated)

Crude drug: 1–3 g daily (frequency not specified) (1). Extracts: 300–350 mg three times daily (19–21).

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References

1.The Ayurvedic pharmacopoeia of India, Part I, Vol. IV. New Delhi, Ministry of Health and Family Welfare, Department of Indian System of Medicine and Homeopathy, 1999.

2.Database on medicinal plants used in Ayurveda. New Delhi, Central Council for Research in Ayurveda and Siddha, Department of ISM and H, Ministry of Health and Family Welfare, Government of India, 2000.

3.Horhammer L, eds. Hagers Handbuch der pharmazeutischen Praxis, 4th ed. Berlin, Springer Verlag, 1975 [in German].

4.Bedevian AK. Illustrated polyglottic dictionary of plant names. Cairo, Medbouly Library, 1994.

5.Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL (an online database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network [STN] of Chemical Abstracts Services), 30 June 2005.

6.Nadkarni KM. Indian materia medica. Bombay, Popular Prakashan, 1954.

7.Kapoor LD. Handbook of Ayurvedic medicinal plants. Boca Raton, CRC Press, 1990.

8.Hahn-Deinstrop E, Koch A, Müller M. Guidelines for the assessment of the traditional herbal medicine olibanum by application of HPTLC and DESAGA ProViDoc video documentation. Journal of Planar Chromatography, 1998, 11:404–410.

9.Ganzera M, Khan IA. A reversed phase high performance liquid chromatography method for the analysis of boswellic acids in Boswellia serrata. Planta Medica, 2001, 67:778–780.

10.Hairfield EM, Hairfield HH Jr. McNair HM. GC, GC/MS, and TLC of Β-boswellic acid and O-acetyl-Β-boswellic acid from B. serrata, B. carteii and

B. papyrifera. Journal of Chromatographic Science, 1989, 27:127–133.

11.Hamm S et al. A chemical investigation by headspace SPME and GC-MS of volatile and semi-volatile terpenes in various olibanum samples. Phytochemistry, 2005, 66:1499–1514.

12.WHO guidelines on assessing quality of herbal medicines with reference to contaminants and residues. Geneva, World Health Organization, 2007.

13.European Pharmacopoeia, 5th ed. Strasbourg, Directorate for the Quality of Medicines of the Council of Europe (EDQM), 2005.

14.Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (WHO/FSF/FOS/97.7).

15.Girgune JB, Garg BD. Chemical investigation of the essential oil from Boswellia serrata Roxb. Journal of Scientific Research, 1979, 1:119–122.

16.Verghese J et al. A fresh look at the constituents of Indian Olibanum oil.

Flavor and Fragrance Journal, 1987, 2:99–102.

17.Wichtl M. Teedrogen und phytopharmaka. Stuttgart, Wissenschaftliche Verlagsgesellschaft, 2002 [in German].

18.Gerhardt H et al. [Therapy of active Crohn disease with Boswellia serrata extract H 15]. Zeitschrift für Gastroenterologie, 2001, 39:11–17 [in German].

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19.Gupta, I et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. European Journal of Medical Research, 1997, 21:37–43.

20.Gupta I et al. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. European Journal of Medical Research, 1998, 3:511–514.

21.Gupta I et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Medica, 2001, 67:391–395.

22.Kimmatkar N et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – a randomized double blind placebo controlled trial. Phytomedicine, 2003, 10:3–7.

23.Ammon HP. [Boswellic acids (components of frankincense) as the active principle in treatment of chronic inflammatory diseases]. Wiener Medizinische Wochenschrift, 2002, 152:373–378 [in German].

24.Chopra RN, ed. Indigenous drugs of India. Their medical and economic aspects. Calcutta, India, Art Press, 1933.

25.Saha JC, Savini EC, Kasinathan S. Ecbolic properties of Indian Medicinal Plants. Part 1. Indian Journal of Medical Research, 1961, 49:130–151.

26.Atal CK, Gupta OP, Singh GB. Salai guggal: A promising anti-arthritic and anti-hyperlipidemic agent. British Journal of Pharmacology, 1981, 74:203–204.

27.Menon MK, Kar A. Analgesic and psychopharmacological effects of the gum resin of Boswellia serrata. Planta Medica, 1971, 19:333–341.

28.Singh GB, Atal CK. Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new nonsteroidal anti-inflammatory agent. Agents and Actions, 1986, 18:407–412.

29.Kar A, Menon MK. Analgesic effect of the gum resin of Boswellia serrata. Life Sciences, 1969, 8:1023–1028.

30.Kapil A, Moza N. Anticomplementary activity of boswellic acids, an inhibitor of C3-convertase of the classical complement pathway. International Journal of Immunopharmacology, 1992, 14:1139–1143.

31.Duwiejua M et al. Anti-inflammatory activity of resins from some species of the plant family Burseraceae. Planta Medica, 1993, 59:12–16.

32.Etzel R. Special extract of Boswellia serrata (H15)* in the treatment of rheumatoid arthritis. Phytomedicine, 1996, 3:91–94.

33.Reddy GK, Dhar SC. Effect of a new nonsteroidal anti-inflammatory agent on lysosomal stability in adjuvant induced arthritis. Italian Journal of Biochemistry, 1987, 36:205–217.

34.Ammon HP et al. Mechanism of anti-inflammatory actions of curcurmine and boswellic acids. Journal of Ethnopharmacology, 1993, 38:113–119.

35.Safayhi H et al. Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL. Planta Medica, 2000, 66:110–113.

36.Schweizer S et al. Workup-dependent formation of 5-lipoxygenase inhibitory boswellic acid analogues. Journal of Natural Products, 2000, 63:1058–1061.

37.Safayhi H et al. Boswellic acids: novel, specific, nonredox inhibitors of 5-li- poxygenase. Journal of Pharmacology and Experimental Therapeutics, 1992, 261:1143–1146.

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38.Boden SE et al. Stimulation of leukotriene synthesis in intact polymorphonuclear cells by the 5-lipoxygenase inhibitor 3-oxo-tirucallic acid. Molecular Pharmacology, 2001, 60:267–273.

39.Altmann A et al. Boswellic acids activate p42MAPK and p38 MAPK and stimulate Ca 2+ mobilization. Biochemical and Biophysical Research Communications, 2002, 290:185–190.

40.Wildfeuer A et al. Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis. Arzneimittelforschung, 1998, 48:668–674.

41.Ammon HP et al. Inhibition of leukotriene B4 formation in rat peritoneal neutrophils by an ethanolic extract of the gum resin exudate of Boswellia serrata. Planta Medica, 1991, 57:203–207.

42.Dhar ML et al. Screening of Indian plants for biological activity: part I. Indian Journal of Experimental Biology, 1968, 6:232–247.

43.Krieglstein CF et al. Acetyl-11-keto-beta-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuates experimental ileitis.

International Journal of Colorectal Diseases, 2001, 16:88–95.

44.Singh GB, Bani S, Singh S. Toxicity and safety evaluation of Boswellic acids. Phytomedicine, 1996, 3:87–90.

45.Sander O, Herborn G, Rau R. Is H15 (resin extract of Boswellia serrata, “incense”) a useful supplement to establish drug therapy of chronic polyarthritis? Results of a double-blind pilot study. Zeitschrift für Rheumatologie, 1998, 57:11–16.

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Semen Cardamomi

Definition

Semen Cardamomi consists of the dried ripe seed of Elettaria cardamomum (L.) Maton (Zingiberaceae) recently removed from the capsule (1–9).

Note: In a number of formularies and standards, the drug is official as Fructus Cardamomi, but the part employed is the seed, with the fruit capsule removed prior to use (5–10).

Synonyms

Amomum repens Sonn., A. cardamomum Lour. (11), Alpinia cardamomum Roxb. (12).

Selected vernacular names

Alaicha, bach dau khau, bastard cardamom, cardamomier, Cardamompflanze, cardamomo minore, cardamomo, cardamon, cardamone, cardamone petite, Cardamonen, chinne elakulu, chittelam, chhoti lachi, chota elaich, chotaa leicaha, choti ilayachi, Echte Kardamon, elã, elachi, elakay, elakkki, elam, elayachi, elchi, Elettarie, ensal, ga qolia, garidimong, gujurati, haal boa, habbahan, habbahal, hab el haal, heel khurd, hel, hhabb el hal, hiliki, illlachi, kakilahekurd, kakula saghira, kapoelaga, kardoem, Kleine Kardamomen, krako, küçük kakule, lahanveldoda, lesser cardamom, luuk en, malabar cardamon, Malabar Cardamonen, pelaga, qaquilah saghirah, ronde kardemon, sa nhon, sanna elakulu, sanna yalakii, sarooplaachi, shozuku, siruelam, so du gu, sodugo, syouzuku, truti, velchi, velloda (2–6, 12, 13).

Geographical distribution

Native to India and introduced to Sri Lanka (14, 15).

Description

A perennial zingiberaceous herb attaining a height of 2–4 m, with lanceolate leaves borne on long sheathing stems. Flowers numerous, borne on

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horizontal racemes that arise from the rhizome and run horizontally along the ground. The fruit is inferior, ovoid or oblong, nearly ellipsoidal, capsule plump or slightly shrunken, the seeds of which are covered by an aril (14).

Plant material of interest: dried seed (in dried or nearly dried fruit)

General appearance

Usually in agglutinated groups of 2–7 seeds. Each irregularly angular, 3- to 4-sided, oblong, ovoid; 2–4 mm long, up to 3 mm broad; pale orange to dark reddish-brown; usually enveloped by a thin colourless membranous aril externally, transversely wrinkled but not minutely pitted; hilum depressed; raphe indicated by a channel extending on one side from base to apex; hard; internally, whitish, showing a thin dark testa, a whitish starchy perisperm grooved on one side, and in the centre a small yellowish translucent endosperm, surrounding a paler minute embryo (1–3, 5–7).

Fruit: Inferior, ovoid or oblong, nearly ellipsoidal, capsule plump or slightly shrunken; 8–20 mm, but most fruits are 10–15 mm long, 5–10 mm in diameter; green to pale buff, sometimes yellowish-grey, mostly 3-sided; externally, smooth or longitudinally striated; base, rounded and may bear the remains of the stalk; apex, more or less blunt and sometimes crowned by a short beak formed of the remains of the floral parts; interior longitudinally divided into 3 loculi, each loculus is an adherent mass of two rows of 3–7 small seeds attached to the axile placenta (2, 5–7). According to Evans (15), four varieties of fruits are available: “Mysore”, “Malabar”, “Mangalore” and “Alleppy”.

Organoleptic properties

Odour: aromatic; taste: aromatic, pungent and slightly bitter (1–3, 5–8).

Microscopic characteristics

Aril of several layers of elongated, more or less collapsed, flattened, thinwalled parenchyma cells containing small rounded or oval droplets of oil. Testa with an outer epidermis of long, narrow fusiform cells, 20–30 μm wide, having slightly thickened undulating walls, followed by a layer of collapsed parenchymatous cells, with brownish contents, becoming 2–3 layers in the region of the raphe, composed of large thin-walled, rectangular cells containing volatile oil; a band of 2–3 layers of parenchymatous cells and an inner epidermis of thin-walled flattened cells. Inner integument consists of 2 layers of cells, an outer layer of yellowish to reddish-brown, rectangular, strongly lignified sclereids, about 40 μm long and 20 μm wide, nearly filled with a small warty nodule of silica and an in-

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