Journal of Ethnopharmacology 60 (1998) 117 124

Anti-nociceptive and anti-inammatory effects of some Jordanian medicinal plant extracts

A.H. Atta a, A. Alkofahi b,*
Department of Veterinary Basic Sciences, Faculty of Veterinary Medicine, Jordan Uni6ersity of Science and Technology, P.O. Box 3030, Irbid, Jordan b Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan Uni6ersity of Science and Technology, P.O Box 3030, Irbid, Jordan
a

Received 15 October 1996; received in revised form 14 July 1997; accepted 4 November 1997

Abstract The anti-nociceptive effect of ethanolic extract of 11 traditionally used Jordanian plants was studied by using the acetic acid-induced writhing and hot-plate test in mice. The anti-inammatory effect of these plants was determined by xylene-induced ear oedema in mice and cotton pellet granuloma test in rats. Mentha piperita, Cinnamomum zeylanicum, Apium gra6eolens, Eucalyptus camaldulentis, and Ruta gra6eolens possess an anti-nociceptive effect against both acetic acid-induced writhing and hot plate-induced thermal stimulation. M. piperita, Jasminum ofcinale, Commiphora molmol, and Beta 6ulgaris possess an anti-inammatory effect against acute (xylene-induced ear oedema) and chronic (cotton-pellet granuloma) inammation. The anti-nociceptive and anti-inammatory effects were dose dependent. These data afrm the traditional use of some of these plants for painful and inammatory conditions. 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Anti-nociceptive activity; Anti-inammatory activity

1. Introduction There are more than 49 plant families having more than 120 plant species used in Jordanian traditional medicine, especially among people who have little or no access to medical assistance (Karim and Quraan, 1986; Al-Khalil, 1995). The
* Corresponding author.

anti-inammatory and/or the analgesic effects of Apium gra6eolens, Beta 6ulgaris, Eucalyptus camaldulentis, Jasminum ofcinale, Mentha piper ita, Ruta gra6eolens, Lactuca sati6a, Cinnamomum zeylanicum, and Commiphora molmol have been described in folk medicine (Al-Jarwani and Khalifeh, 1936; Jabour, 1983). Moreover, A. gra6eo lens, M. piperita, and C. molmol have been traditionally used as anti-spasmodics, anti-

0378-8741/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 7 8 - 8 7 4 1 ( 9 7 ) 0 0 1 3 7 - 2

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Table 1 List of plants used in the screening for anti-nociceptive and anti-inammatory activity Scientic name A. 6era L. (Liliaceae) A. gra6eolens L. (Umbelliferae) B. 6ulgaris L. (Chenopodiaceae) C. zeylanicum L. (Lauraceae) C. molmol Engl. (Burseraceae) E. camaldulentis Dehn. (Myrtaceae) J. ofcinale L. (Oleaceae) L. sati6a L. (Compositeae) M. piperita L. (Labiatae) O. syriaca (L.) Ran (Labiatae) R. gra6eolens L. (Rutaceae) Part used Dried juice Seed Root Bark Oleo-gum resin Leaf Flower Seed Leaf Leaf Leaf Voucher specimen number 89 62 55 11 114 46 132 58 33 52 94 Yield g/kg 860 34 96 50 168 118 80 104 112 38 130

rheumatics, and to relieve teeth and ear pains, skin diseases and headache (Kotb, 1985). In addition, these plants have been used for gastrointestinal, respiratory, and reproductive disorders. Moreover, some of them are used as germicides and vermifuges. The aim of this work is to elucidate the anti-nociceptive and anti-inammatory effects of 11 Jordanian plants (Table 1) of known traditional use in relieving pain and inammation.

texture and 100 g of the dried plant were repeatedly extracted with 80% ethanol. The ethanol extracts were concentrated under vaccum and weighed and the residue was used in the experiments. The dried plant extracts were freshly dissolved or suspended in distilled water just before administration.

2.3. Acetic acid writhing in mice

The writhing test was performed as described by Koster et al. (1959). Groups of ten Swiss mice (ve males and ve females) were fasted over night prior to dosing, but had free access to water. After 30 min of receiving an oral dose of the extract, each mouse was given intraperitonealy 0.7% aquous solution of acetic acid (10 ml/kg b. wt.) and then placed in an observation box. The number of writhes were counted for 20 min after acetic acid injection. The number of writhes in each treated group was compared to that of a control saline-treated group.

2. Materials and methods

2.1. Plant materials

Extracts were prepared from 11 plants commonly used in Jordan as analgesics and/or antiinammatory. Most of these plants grow locally. Samples were obtained either as dried plants from herbal stores or collected from the wild. The taxonomic identity of the plants was conrmed by Professor A. El-Oqlah, Department of Biological Sciences, Yarmouk University, Irbid, Jordan. A voucher specimen of each species studied has been deposited at the Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.

2.4. Hot -plate test in mice

The method described by Eddy and Leimback (1953) was applied. Groups of ten mice each were used. Mice were placed in a 2-l glass beaker placed on a hot plate maintained at 55C. Latency to exhibit the nociceptive response such as licking paws or jumping was determined before and 15,

2.2. Preparation of plant extract

Each dehydrated plant was ground to a ne

A.H. Atta, A. Alkofahi / Journal of Ethnopharmacology 60 (1998) 117124 Table 2 Effect of ethanolic extracts on acetic acid-induced writhes in mice Treatment groups 200 mg/kg Mean+ 6 S.D. Normal saline (10) M. piperita (10) O. syriaca (10) C. zeylanicum (8) E. camaldulentis (8)a A. gra6eolens (10) J. ofcinale (9) B. 6ulgaris (10) C. molmol (10) A. 6era (10) L. sati6a (10) R. gra6eolens (10)a 49.6+ 6 12.2 30.2+ 6 9.5** 39.4+ 6 5.3 25.0+ 6 4.3*** 39.2+ 6 10* 29.6+ 6 10.2*** 26.0+ 6 5.2*** 63.6+ 6 9.4 37.5+ 6 11.5* 37.6+ 6 10.3* 49.4+ 6 7.5 33.8+ 6 7.0** Protection (%) 400 mg/kg Mean+ 6 S.D. 40.2+ 6 10.0 22.4+ 6 3.1*** 35.8+ 6 6.0 18.8+ 6 3.8*** 27.5+ 6 6.0** 23.0+ 6 6.6*** 20.6+ 6 4.6*** 40.4+ 6 9.2 30.3+ 6 4.2** 28.4+ 6 6.1** 42.0+ 6 8.4 27.0+ 6 4.1*** Protection (%)

119

38 21 48 21 40 48 0 24 24 0 32

44 11 53 32 43 49 0 25 29 0 33

( ) Number of animals. A dose of 100 and 200 mg/Kg b. wt. * PB0.05, ** PB0.01, *** PB0.001 compared to control.

30, 45, 60, and 75 min after intraperitoneal administration of the extract. A cut-off time of 60 s was selected to avoid tissue damage.

2.5. Xylene -induced ear oedema in mice

Male Swiss mice were divided into groups of ten mice each. After 30 min of the i.p. injection of the extract, xylene (0.03 ml) was applied to the anterior and posterior surfaces of the right ear. Mice were sacriced 2 h after xylene application and both ears were removed. Circular sections of both treated and untreated ears were taken using a 7 mm diameter cork borer and weighed. The difference in weight between left untreated ear sections and right treated ear section was calculated (Tang et al., 1984).

implantation. On day 7, the rats were killed and the pellets were removed, dried at 70C for 24 h. The weight of granuloma and adrenal gland was recorded and compared to that of saline treated control (Schiatti et al., 1986). All plant extracts were given in doses of 200 and 400 mg/kg body weight except E. camaldulentis and R. gra6eolens which were given in doses of 100 and 200 mg/kg based on pilot experiments and appearance of some toxic manifestations after larger doses.

2.7. Statistical analysis

The data were presented as mean 9 S.D. Signicance between control and treated groups was tested by ANOVA.

2.6. Cotton pellet granuloma in rats

Sterilized cotton pellets of 20 mg weight each, were impregnated with 0.4 ml of ampicillin aquous solution. Pellets were implanted subcutaneously in the groin region of Wistar rats, one on each side. The drug was given orally by stomach tube once daily for 6 days starting with the day of

3. Results Ethanolic extract of C. zeylanicum, J. ofcinale, M. piperita, A. gra6eolens, and R. gra6eolens signicantly (P B 0.01 and P B 0.001) reduced the number of acetic acid-induced writhes in mice with a protection percent ranging from 32 to 48 and from 33 to 53 after administration of 200 and

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Table 3 Effect of ethanolic extracts on time to response of mice to heat stimulation in the hot-plate test Treatment groups Doses mg/kg Time to response (s)

0 min Normal saline (20) M. piperita (6) (10) O. syriaca (7) (10) C. zeylanicum (5) (10)

15 min

30 min

45 min

60 min

75 min

200 400 200 400 200 400

5.10 + 6 1.1 7.9+ 6 2.6 6.1+ 6 2.3 6.2+ 6 1.8 5.6+ 6 1.5 6.56+ 6 0.7 5.22+ 6 1.6

5.66+ 6 1.5 4.7+ 6 0.2 7.15+ 6 2.1 6.4+ 6 0.8 5.19+ 6 1.4 6.0+ 6 1.4 7.9+ 6 1.7***

7.48+ 6 2.4 5.76+ 6 1.4 7.10 + 6 0.5 8.1+ 6 0.4 5.93+ 6 0.9 8.82+ 6 0.9 11.55+ 6 3.0***

7.34+ 6 1.9 7.72+ 6 1.1 10.63+ 6 3.7** 8.3+ 6 0.6 8.96+ 6 2.2* 8.7+ 6 0.4 9.82+ 6 3.6**

8.42+ 6 3.8 8.42+ 6 0.4 15.52+ 6 6.1*** 7.86+ 6 0.4 10.88+ 6 1.1* 7.0+ 6 0.9 10.59+0.9*

8.34+ 6 3.2 8.28+ 6 0.5 8.04+ 6 2.3 8.2+ 6 0.5 13.2 + 6 6.24** 7.58+ 6 0.4 10.7+ 6 1.9*

E. camaldulen tis (5) 100 (10) 200 A. gra6eolens (5) (10) J. ofcinale (5) (10) B. 6ulgaris (5) (10) C. molmol (5) (10) A. 6era (5) (10) L. sati6a (5) (10) R. gra6eolens (5) (10) 200 400 200 400 200 400 200 400 200 400 200 400 100 200

7.0+ 6 2.8 5.18+ 6 0.5 5.01+ 6 1.0 5.87+ 6 2.0 7.02+ 6 2.5 4.81+ 6 2.4 6.3+ 6 2.7 4.09+ 6 1.8 5.64+ 6 0.9 6.0+ 6 1.8 6.4+ 6 0.6 5.03+ 6 1.6 6.38+ 6 0.4 4.52+ 6 1.2 6.95+ 6 2.3 4.07+ 6 1.8

5.8+ 6 1.2 14.3+ 6 3.8*** 6.34+ 6 1.5** 9.58+ 6 4.3*** 4.92+ 6 1.5 6.72+ 6 2.1 4.84+ 6 1.4 7 6.02 + 6 1.3 6.44+ 6 3.4 5.13+ 6 1.3 5.6+ 6 0.9 6.18+ 6 1.4 6.44+ 6 0.6 6.7+ 6 1.9 7.9+ 6 2.7* 7.38+ 6 2.3**

6.1+ 6 1.08 17.4+ 6 6.9*** 7.9+ 6 1.8 9.4+ 6 2.2* 6.9+ 6 2.9 6.28 + 6 3.3 46+ 6 1.2 7.71+ 6 3.2 7.9+ 6 3.0 6.01+ 6 0.7 6.6+ 6 1.2 8.24+ 6 3.9 6.2+ 6 0.3 7.4+ 6 2.0 6.2+ 6 2.6 8.89+ 6 0.8*

6.16+ 6 1.5 11.51+ 6 4.4*** 8.0+ 6 2.5 10.6+ 6 2.3*** 6.62+ 6 0.9 7.8+ 6 1.9 6.12+ 6 0.6 6.9+ 6 3.1 6.9+ 6 0.9 6.15+ 6 1.5 7.3+ 6 0.5 6.64+ 6 2.1 7.3+ 6 1.0 8.85+ 6 1.8 6.99+ 6 2.6 7.68+ 6 1.4

6.4+ 6 1.8 13.4+5.3** 9.5+ 6 1.9 11.2+ 6 2.1* 7.7+ 6 0.6 8.08 + 6 2.01 6.9+ 6 1.3 7.27+ 6 3.9 8.16+ 6 0.6 6.91+ 6 2.6 7.6+ 6 0.6 6.33+ 6 2.6 6.78+ 6 2.4 6.89+ 6 1.4 6.1+ 6 2.5 6.49+ 6 0.6

6.9+ 6 1.8 12.8+ 6 5.7* 10.1+ 6 2.9 12.1+ 6 3.1** 6.98+ 6 1.2 7.88 + 6 3.9 7.42+ 6 0.9 8.81+ 6 4.4 8.68+ 6 0.2 8.01+ 6 2.6 7.5+ 6 0.8 8.8+ 6 2.2 5.8+ 6 2.7 7.7+ 6 2.6 8.9+ 6 1.3 8.08+ 6 2.4

( ) Number of animals. * PB0.05, ** PB0.01, *** PB0.001 compared to control. Mean+ 6 S.D.

400 mg/kg, respectively (Table 2). Ethanolic extract of E. camaldulentis, C. molmol, and Aloe 6era also decreased the number of acetic acid-in-

duced writhes but to a less extent (P B 0.05 and P B 0.01 for the low and high dose, respectively). The ethanolic extract of O. syriaca, B. 6ulgaris,

A.H. Atta, A. Alkofahi / Journal of Ethnopharmacology 60 (1998) 117124 Table 4 Effect of ethanolic extracts on xylene-induced ear swelling in mice 200 mg/kg Weight (mg) Normal saline M. piperit a O. syriaca C. zeylanicum E. camaldulentis a A. gra6eolens J. ofcinale B. 6ulgaris C. molmol A. 6era L. sati6a R. gra6eolens a
a

121

400 mg/kg Inhibition (%) Weight (mg) 3.4+ 6 1.4 1.7+ 6 0.8* 2.1+ 6 0.8 3.3+ 6 1.1 3.0+1.0 3.2+ 6 1.0 1.6+ 6 0.3* 1.7+ 6 0.8* 1.7+ 6 0.5* 1.0+ 6 0.5** 2.8+ 6 0.8 3.4+ 6 2.0 Inhibition (%)

4.3+ 6 1.9 2.2+ 6 1.2* 2.3+ 6 1.6 4.9+ 6 1.2 3.9+ 6 2.7 3.6+ 6 0.9 5.0+ 6 6 4.2 5.2+ 6 6.2 2.8 + 6 2.1 5.0+ 6 0.7 5.3+ 6 0.23 5.7+ 6 3.0

49 47 0 9 16 0 0 35 0 0 0

50 38 3 12 6 53 50 50 71 18 0

A dose of 100 and 200 mg/kg b. wt. * PB0.05, ** PB0.01. Mean 9 S.D., n = 5.

and L. sati6a in an oral dose of 200 or 400 mg/kg, showed no signicant effect on the number of acetic acid-induced writhes. Ethanoilic extract of C. zeylanicum, E. camald ulentis, and A. gra6eolens produced a highly signicant (P B 0.001) increase in the latency to response of mice to hot plate thermal stimulation. This effect starts 15 min and persisted for at least 75 min after administration of the plant extract (Table 3). Mild or no effect was observed by the small dose. Mild anti-nociceptive effect has also been observed after administration of M. piperita, O. syriaca, and R. gra6eolens. However, their effect was either temporary as in R. gra6eolens or delayed in onset (45 min) as in M. piperita and O. syriaca. On the other hand the ethanolic extracts of J. ofcinale, B. 6ulgaris, C. molmol, A. 6era, and L. sati6a showed no anti-nociceptive effect. Ethanolic extract of A. 6era in a dose of 400 mg/kg signicantly (P B 0.01) reduced the weight of xylene-induced ear oedema in mice with a calculated inhibition of 71%, while the smaller dose produced no signicant effect (Table 4). M. piperite (both doses), J. ofcinale, B. 6ulgaris, and C. molmol also signicantly (P B 0.05) reduced the size of ear oedema with an inhibition percent ranging from 50 to 53 when used at the high dose only. O. syriaca, C. zeylanicum, E. camaldulentis,

A. gra6eolens, L. sati6a, and R. gra6eolens showed no signicant effect on xylene-induced oedema in mice ears. Ethanolic extract of A. gra6eolens, B. 6ulgaris, O. syriaca, C. zeylanicum, J. ofcinale, C. molmol, and L. sati6a in a dose of 400 mg/kg and R. gra6eolens in a dose of 200 mg/kg signicantly reduced the weight of cotton granuloma in rats (Table 5). Non of these extracts except A. gra6eo lens (P B 0.05) was effective by the smaller dose. The most effective extracts was that of A. gra6eo lens and B. 6ulgaris (P B 0.001). E. camaldulentis and A. 6era have no effect at any of the used doses. None of the tested plant extracts in the used doses affect the weight of adrenal glands in rats.

4. Discussion and conclusion In the present study, two animal models for investigation of the anti-nociceptive and anti-inammatory effects of the selected plants were used. The hot plate thermal stimulation and the acetic acid induced writhes in mice were selected to investigate the central and peripheral anti-nociceptive effects. Xylene-induced ear swelling in mice and the cotton pellet granuloma in rats were

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Table 5 Effect of ethanolic extracts on the weight of granuloma and adrenal glands in rats Treatment Normal control (8) (5) M. piperita (5) (6) O. syriaca (6) (6) C. zeylanicum (6) (6) E. camaldulentis (5) (5) A. gra6eolens (5) (9) Jasminum ofcinale (5) (6) Beta 6ulgaris (6) (8) Commiphora molmol (5) (5) Aloe 6era (5) (5) L. sati6a (5) (5) R. gra6eolens (6) (5) 200 400 200 400 200 400 100 200 200 400 200 400 200 400 200 400 200 400 200 400 100 200 Doses (mg/kg) Weight of granuloma (mg) Weight of adrenal (mg)

0.107+ 6 0.030 0.059+ 6 0.017 0.086+ 6 0.017 0.045+ 6 0.009** 0.076+ 6 0.038 0.054+ 6 0.006** 0.057+ 6 0.012 0.075+ 6 0.007* 0.056+ 6 0.021 0.060+ 6 0.001 0.037+ 6 0.012* 0.061+ 6 0.001*** 0.076+ 6 0.017 0.069+ 6 0.014* 0.054+ 6 0.001 0.059+ 6 0.011*** 0.060+ 6 0.011 0.071+ 6 0.016* 0.071+ 6 0.032 0.083+ 6 0.005 0.073+ 6 0.024 0.060+ 6 0.014* 0.080+ 6 0.034 0.047+ 6 0.001*

0.046+ 6 0.030 0.015+ 6 0.011 0.010+ 6 0.003 0.066+ 6 0.009 0.006+ 6 0.004 0.036+ 6 0.002 0.013+ 6 0.007 0.037+ 6 0.005 0.009+ 6 0.004 0.032+ 6 0.020 0.020+ 6 0.016 0.046+ 6 0.013 0.017+ 6 0.006 0.087+ 6 0.010 0.009+ 6 0.003 0.027+ 6 0.006 0.012+ 6 0.003 0.024+ 6 0.008 0.010+ 6 0.003 0.015+ 6 0.001 0.001+ 6 0.003 0.037+ 6 0.002 0.016+ 6 0.001 0.029+ 6 0.004

( )Number of animals. * PB0.05, ** PB0.01, *** PB0.001. Mean 9 S.D.

selected to represent models of acute (exudative phase) and chronic (the poliferative phase) inammation respectively. The present results show that M. piperita, C. zeylanicum, E. camaldulentis, A. gra6eolens, and

R. gra6eolens induced a dose-dependent analgesic protective effect against both thermal stimuli and the writhing syndrome indicating central and peripheral effects. The increased latency to response of mice to thermal stimuli only after administra-

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tion of the ethanolic extract of O. syriaca indicates central analgesic effect only. On the other hand, J. ofcinale, A. 6era, and C. molmol induced an anti-nociceptive effect against acetic acid-induced writhing only indicating the lack of central anti-nociceptive effect of these three extracts. The present results demonstrate that ethanolic extracts of M. piperita (dose dependent), J. ofcinalis, B. 6ulgaris, and C. molmol (large dose only) possess a dose-dependent anti-inammatory effect against both acute (exudative) and chronic (proliferative) inammation. The activity of ethanolic extract of A. 6era against acute inammation (xylene-induced ear oedema) only indicates possible anti-phlogestic but not anti-proliferative effect. O. syriaca, C. zey lanicum, A. gra6eolens, L. sati6a, and R. gra6eo lens showed an anti-inammatory effect only against chronic inammation induced by cotton pellet granuloma indicating anti-proliferative effect. E. camaldulentis ethanolic extract in the used dosage and route of administration showed no anti-inammatory effect. All the tested extracts, except E. camaldulentis, have variable degrees of both anti-nociceptive and anti-inammatory effect. Such an association is well-known for various non-stroidal autin-inammatory (NSAI) compounds especially salicylate by-products (Reuse, 1978; Beuoist and Misse, 1979; Famaey, 1983; Gyires et al., 1985). M. piperita, C. zeylanicum, A. gra6eolens, E. camaldulentis, and R. gra6eolens have both antinociceptive and anti-inammatory effects. These ve plant extracts contain common active principles; volatile oils, resins, and avenoids (Kotb, 1985). Volatile oils, resins and avenoids isolated from other plant extracts have been proved to posses analgesic and/or anti-inammatory effect (Duke, 1992). Therefore, it could be suggested that the anti-nociceptive and anti-inammatory effects of the tested plant extracts may be due to their content of volatile oils, avenoids and resins. From these results, it can be afrmed that the traditional indication of some of these plant extracts for inammation and pain associated with sprains, bruises, wounds, spasmodic colics, and rheumatic arthritis (Al-Khalil, 1995; Bajpai

and Sant, 1995; Sudarsanam et al., 1995). Further investigations are necessary to elucidate the exact mechanism of the anti-nociceptive and anti-inammatory activity of these extracts.

Acknowledgements The authors would like to thank Jihan AbuZaher for her technical assistance and the Deanship of the Scientic Research in the University of Science and Technology for nancial support (Grant No. 44/95).

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