Displaying publications 41 - 60 of 90 in total

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  1. Saallah S, Roslan J, Julius FS, Saallah S, Mohamad Razali UH, Pindi W, et al.
    Molecules, 2021 Apr 28;26(9).
    PMID: 33924820 DOI: 10.3390/molecules26092564
    Collagen was extracted from the body wall of sea cucumber (Holothuria scabra) using the pepsin-solubilized collagen method followed by isolation using dialysis and the ultrafiltration membrane. The yield and physicochemical properties of the collagen obtained from both isolation methods, denoted as D-PSC and UF-PSC, were compared. The ultrafiltration method affords a higher yield of collagen (11.39%) than that of the dialysis (5.15%). The isolated collagens have almost the same amino acid composition, while their functional groups, referred to as amide A, B, I, II, and III bands, were in accordance with commercial collagen, as verified by Fourier Transform Infrared (FT-IR) spectroscopy. The UV-Vis absorption peaks at 240 nm and 220 nm, respectively, indicated that the collagens produced are type-I collagen. The D-PSC showed interconnecting sheet-like fibrils, while the UF-PSC exhibited a flaky structure with flat-sheets arranged very close to each other. The higher yield and comparable physicochemical properties of the collagen obtained by ultrafiltration as compared with dialysis indicate that the membrane process has high potential to be used in large-scale collagen production for food and pharmaceutical applications.
  2. Sabullah MK, Sulaiman MR, Abd Shukor MY, Syed MA, Shamaan NA, Khalid A, et al.
    ScientificWorldJournal, 2014;2014:571094.
    PMID: 25401148 DOI: 10.1155/2014/571094
    Crude extract of ChE from the liver of Puntius javanicus was purified using procainamide-sepharyl 6B. S-Butyrylthiocholine iodide (BTC) was selected as the specific synthetic substrate for this assay with the highest maximal velocity and lowest biomolecular constant at 53.49 µmole/min/mg and 0.23 mM, respectively, with catalytic efficiency ratio of 0.23. The optimum parameter was obtained at pH 7.5 and optimal temperature in the range of 25 to 30°C. The effect of different storage condition was assessed where ChE activity was significantly decreased after 9 days of storage at room temperature. However, ChE activity showed no significant difference when stored at 4.0, 0, and -25°C for 15 days. Screening of heavy metals shows that chromium, copper, and mercury strongly inhibited P. javanicus ChE by lowering the activity below 50%, while several pairwise combination of metal ions exhibited synergistic inhibiting effects on the enzyme which is greater than single exposure especially chromium, copper, and mercury. The results showed that P. javanicus ChE has the potential to be used as a biosensor for the detection of metal ions.
  3. Saleem AM, Taufik Hidayat M, Jais AM, Fakurazi S, Moklas MA, Sulaiman MR, et al.
    Eur Rev Med Pharmacol Sci, 2013;17(15):2019-22.
    PMID: 23884821
    BACKGROUND: In our previous study, the aqueous extract of Channa striatus (family: Channidae) fillet (AECSF) showed an antidepressant-like effect in mice. However, the mechanism of the antidepressant-like effect is unknown.
    AIM: The objective of this study was to explore the involvement of monoamines in the antidepressant-like effect of AECSF in mice.
    MATERIALS AND METHODS: AECSF was prepared by steaming the fillets of C. striatus. The male ICR mice were pretreated with various monoaminergic antagonists viz., p-chlorophenylalanine (100 mg/kg, i.p.), prazosin (1 mg/kg, i.p.) and yohimbine (1 mg/kg, i.p.), SCH23390 (0.05 mg/kg, s.c.) and sulpiride (50 mg/kg, i.p.) followed by treatment with AECSF and tested in tail suspension test (TST). Two-way ANOVA with Tukey test were used at p < 0.05 for significance.
    RESULTS: The pretreatments with p-chlorophenylalanine, prazosin and yohimbine, but not with SCH23390 and sulpiride, were able to reverse the antidepressant-like effect of AECSF in TST.
    CONCLUSIONS: The antidepressant-like effect of AECSF may be mediated through the serotonergic and noradrenergic systems and not through the dopaminergic system.
  4. Saleem AM, Taufik Hidayat M, Mat Jais AM, Fakurazi S, Moklas M, Sulaiman MR, et al.
    Eur Rev Med Pharmacol Sci, 2011 Jul;15(7):795-802.
    PMID: 21780549
    Channa (C.) striatus (Malay-Haruan), is a fresh water snakehead fish, consumed as a rejuvenating diet in post-parturition period in local Malay population. The aqueous extract of C. striatus fillet (AECSF) was reported to act through serotonergic receptor system in a previous study. There is no scientific report on neuropharmacological effects of C. striatus. Based on these data, the antidepressant-like effect of C. striatus was evaluated in mice models of depression.
  5. Sambasevam Y, Omar Farouk AA, Tengku Mohamad TA, Sulaiman MR, Bharatham BH, Perimal EK
    Eur J Pharmacol, 2017 Feb 05;796:32-38.
    PMID: 27988285 DOI: 10.1016/j.ejphar.2016.12.020
    Neuropathic pain arises from the injury of nervous system. The condition is extremely difficult to be treated due to the ineffectiveness and presence of various adverse effects of the currently available drugs. In the present study, we investigated the antiallodynic and antihyperlagesic properties of cardamonin, a naturally occurring chalcone in chronic constriction injury (CCI)-induced neuropathic pain mice model. Our findings showed that single and repeated dose of intra-peritoneal administration of cardamonin (3, 10, 30mg/kg) significantly inhibited (P<0.001) the chronic constriction injury-induced neuropathic pain using the Hargreaves plantar test, Randall-Selitto analgesiometer test, dynamic plantar anesthesiometer test and the cold plate test in comparison with the positive control drug used (amitriptyline hydrochloride, 20mg/kg, i.p.). Pre-treatment with naloxone hydrochloride (1mg/kg, i.p.) and naloxone methiodide (1mg/kg, s.c) significantly reversed the antiallodynic and antihyperalgesic effects of cardamonin in dynamic plantar anesthesiometer test and Hargreaves plantar test, respectively. In conclusion, the current findings demonstrated novel antiallodynic and antihyperalgesic effects of cardamonin through the activation of the opioidergic system both peripherally and centrally and may prove to be a potent lead compound for the development of neuropathic pain drugs in the future.
  6. Seddiki LS, Belboukhari N, Ould El Hadj-Khelil A, Sulaiman MR, Sekkoum K, Cheriti A
    J Ethnopharmacol, 2021 Jul 15;275:114137.
    PMID: 33915133 DOI: 10.1016/j.jep.2021.114137
    ETHNOPHARMACOLOGICAL RELEVANCE: Launaea arborescens, its vernacular name is Mol-albina belonging to asteracaea family origin of the southwest of Algeria. This plant is used in folk medicines to treat gastroenteritis, diabetes, child aliment and other diseases; it is taken macerated or boiled.

    AIM: This study aims to evaluate the anti-inflammation an analgesic activity of the aqueous extract of Launaea arborescens (AqELA) and its pathway of action.

    METHODS: the investigation of anti-inflammatory and analgesic effects were done using formalin test, acetic acid test. For mechanism investigation, it was used hot plate test to induce opioid receptors, a histamine and serotonin test to induce edema paw, finally, for the TRPV1 receptor, it was used the capsaicin test.

    RESULTS: The aqueous extract of Launaea arborescens showed a significant inhibition of abdominal writhing test 95% and 100% inhibition of licking paw using acid acetic test and formalin test respectively (EC: 47 mg/kg and 104 mg/kg). The analgesic effect of the aqueous extract of Launaea arborescens showed inhibition of sensation of pain after 120 min compared to morphine effect. The aqueous extract of Launaea arborescens reduced paw volume after 180 min and 120 min for histamine and serotonin respectively with dose-dependent. Concerning of TRPV1 receptors, the inhibition was showed at doses 100 mg and 300 mg.

    CONCLUSION: Our results contribute towards validation of the traditional use of Launaea arborescens for inflammation ailment.

  7. Shaik Mossadeq WM, Sulaiman MR, Tengku Mohamad TA, Chiong HS, Zakaria ZA, Jabit ML, et al.
    Med Princ Pract, 2009;18(5):378-84.
    PMID: 19648761 DOI: 10.1159/000226292
    OBJECTIVES: To determine the anti-inflammatory and antinociceptive activities of Mitragyna speciosa Korth methanol extract in rodents.
    MATERIALS AND METHODS: Anti-inflammatory activity was evaluated using carrageenan-induced paw edema and cotton pellet-induced granuloma tests in rats. Antinociceptive activity was measured using the writhing test and the hot plate test in mice, and the formalin test in rats. All drugs and extracts were diluted in dH(2)O and administered through the intraperitoneal route. Results were analyzed using one-way ANOVA followed by Dunnett's test for multiple comparisons among groups.
    RESULTS: Results showed that intraperitoneal administration of the extract at doses of 100 and 200 mg/kg produced significant dose-dependent activity in all of the nociceptive models evaluated (p < 0.05). With the formalin test, the antinociceptive activity in mice was inhibited only at the highest dose of the extract (200 mg/kg). The study also showed that intraperitoneal administration of the methanol extract of M. speciosa (100 and 200 mg/kg) significantly and dose-dependently suppressed the development of carrageenan-induced rat paw edema (p < 0.05). In the chronic test, however, significant reduction in granulomatous tissue formation in rats was observed only at the highest dose of the methanol extract of M. speciosa (200 mg/kg, p < 0.05).
    CONCLUSION: The present study suggests the presence of potent antinociceptive and anti-inflammatory principles in the extract, supporting its folkloric use for the treatment of these conditions.
  8. Sim TY, Harith HH, Tham CL, Md Hashim NF, Shaari K, Sulaiman MR, et al.
    Molecules, 2018 Jun 05;23(6).
    PMID: 29874809 DOI: 10.3390/molecules23061355
    Alveolar epithelial barrier dysfunction contributes to lung edema and can lead to acute lung injury (ALI). The features include increased epithelial permeability, upregulation of inflammatory mediators and downregulation of junctional complex molecules; these changes are often induced by inflammation. tHGA is an acetophenone analogue with therapeutic potential in asthma. Its therapeutic potential in ALI is presently unknown. Herein, the effects of tHGA on epithelial barrier dysfunction were determined in TNF-α-induced human alveolar epithelial cells. The anti-inflammatory properties of tHGA were assessed by monocyte adhesion assay and analysis of MCP-1 and ICAM-1 expression. The epithelial barrier function was assessed by paracellular permeability and transepithelial electrical resistance (TEER) assays, and analysis of junctional complex molecules expression. To elucidate the mechanism of action, the effects of tHGA on the NF-κB and MAPK pathways were determined. Gene and protein expression were analyzed by RT-PCR and Western blotting or ELISA, respectively. tHGA suppressed leukocyte adhesion to TNF-α-induced epithelium and reduced MCP-1 and ICAM-1 gene expression and secretion. tHGA also increased TEER readings, reduced epithelial permeability and enhanced expression of junctional complex molecules (zona occludens-1, occludin and E-cadherin) in TNF-α-induced cells. Correspondingly, the NF-κB, ERK and p38 MAPK pathways were also inhibited by tHGA. These findings suggest that tHGA is able to preserve alveolar epithelial barrier function in response to acute inflammation, via its anti-inflammatory activity and stabilization of epithelial barrier integrity, mediated by NF-κB, ERK and p38 MAPK signaling.
  9. Somchit N, Wong CW, Zuraini A, Ahmad Bustamam A, Hasiah AH, Khairi HM, et al.
    Drug Chem Toxicol, 2006;29(3):237-53.
    PMID: 16777703
    Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), gamma-glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and gamma-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.
  10. Somchit N, Norshahida AR, Hasiah AH, Zuraini A, Sulaiman MR, Noordin MM
    Hum Exp Toxicol, 2004 Nov;23(11):519-25.
    PMID: 15625777
    Itraconazole and fluconazole are oral antifungal drugs, which have a wide spectrum antifungal activity and better efficacy than the older drugs. However, both drugs have been associated with hepatotoxicity in susceptible patients. The mechanism of antifungal drug-induced hepatotoxicity is largely unknown. Therefore, the aim of this present study was to investigate and compare the hepatotoxicity induced by these drugs in vivo. Rats were treated intraperitoneally with itraconazole or fluconazole either single (0, 10, 100 and 200 mg/kg) or subchronic (0, 10, 50 and 100 mg/kg per day for 14 days) doses. Plasma and liver samples were taken at the end of the study. A statistically significant and dose dependent increase of plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were detected in the subchronic itraconazole-treated group. In addition, dose-dependent hepatocellular necrosis, degeneration of periacinar and mizonal hepatocytes, bile duct hyperplasia and biliary cirrhosis and giant cell granuloma were observed histologically in the same group. Interestingly, fluconazole treated rats had no significant increase in transaminases for both single and subchronic groups. In the subchronic fluconazole treated rats, only mild degenerative changes of centrilobular hepatocytes were observed. These results demonstrated that itraconazole was a more potent hepatotoxicant than fluconazole in vivo in rats.
  11. Sulaiman MR, Perimal EK, Akhtar MN, Mohamad AS, Khalid MH, Tasrip NA, et al.
    Fitoterapia, 2010 Oct;81(7):855-8.
    PMID: 20546845 DOI: 10.1016/j.fitote.2010.05.009
    The anti-inflammatory activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith was investigated using carrageenan-induced paw edema and cotton pellet-induced granuloma tissue formation test in mice. It was demonstrated that intraperitoneal administration of 1 at a dose of 5, 10, 50 and 100 mg/kg produced significant dose-dependent inhibition of paw edema induced by carrageenan. It was also demonstrated that 1 at similar doses significantly suppressed granulomatous tissue formation in cotton pellet-induced granuloma test.
  12. Sulaiman MR, Zakaria ZA, Mohamad AS, Ismail M, Hidayat MT, Israf DA, et al.
    Pharm Biol, 2010 Aug;48(8):861-8.
    PMID: 20673172 DOI: 10.3109/13880200903302820
    Alpinia conchigera Griff. (Zingiberaceae), locally known to the Malays as "lengkuas ranting", is native to Peninsular Malaysia. The Malays traditionally used it to treat infection and rashes, and as a health drink. This study evaluated the analgesic and anti-inflammatory activities of the ethanol extract of A. conchigera rhizomes in mice and rats, respectively. The analgesic activity was elucidated using the acetic acid-induced writhing test, hot plate test, and formalin test, while the anti-inflammatory activity was determined using carrageenan-induced paw edema. The extract (30, 100, and 300 mg/kg) given intraperitoneally (i.p.) exhibited antinociceptive and anti-inflammatory activities in all tests used. The range of percentage of analgesia obtained for all doses of extract in the writhing test was 50-92%, and in the early and late phases of the formalin test was 25-62% and 63-98%, respectively. In addition, naloxone (5 mg/kg) given subcutaneously (s.c.) was found to reverse the extract (300 mg/kg)-induced antinociceptive activity in the writhing, hot plate, and formalin tests. Based on the results obtained, it can be concluded that the ethanol extract of A. conchigera rhizomes possessed a peripheral and central antinociceptive activity that was mediated, in part, via the opioid receptor, as well as anti-inflammatory activity.
  13. Sulaiman MR, Zakaria ZA, Chiong HS, Lai SK, Israf DA, Azam Shah TM
    Med Princ Pract, 2009;18(4):272-9.
    PMID: 19494533 DOI: 10.1159/000215723
    The present study was carried out to explore the antinociceptive as well as the anti-inflammatory effects of an ethanol extract of Stachytarpheta jamaicensis (L.) Vahl (EESJ) using 3 models of nociception and 2 models of inflammation in experimental animals.
  14. Sulaiman MR, Perimal EK, Zakaria ZA, Mokhtar F, Akhtar MN, Lajis NH, et al.
    Fitoterapia, 2009 Jun;80(4):230-2.
    PMID: 19535012 DOI: 10.1016/j.fitote.2009.02.002
    We have investigated the antinociceptive activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith, in acetic acid-induced abdominal writhing test and hot plate test in mice. 1 given by intraperitoneal route produced significant dose-dependent antinociceptive effect in all the test models used. In addition, the antinociceptive effect of 1 in the hot plate test was reversed by the non-selective opioid receptor antagonist naloxone, suggesting that the opioid system is involved in its analgesic mechanism of action.
  15. Sulaiman MR, Zakaria ZA, Abdul Rahman A, Mohamad AS, Desa MN, Stanslas J, et al.
    Biol Res Nurs, 2010 Jan;11(3):293-301.
    PMID: 19689990 DOI: 10.1177/1099800409343311
    The current study was performed to evaluate the antinociceptive and antiedematogenic properties of andrographolide isolated from the leaves of Andrographis paniculata using two animal models. Antinociceptive activity was evaluated using the acetic acid- induced writhing and the hot-plate tests, while antiedematogenic activity was measured using the carrageenan-induced paw edema test. Subcutaneous (s.c.) administration of andrographolide (10, 25, and 50 mg/kg) did not affect the motor coordination of the experimental animals but produced significant (p < .05) antinociceptive activity when assessed using both tests. However, 2 mg/kg naloxone failed to affect the 25 mg/kg andrographolide activity in both tests, indicating that the activity was modulated via nonopioid mechanisms. Furthermore, andrographolide showed significant (p < .05) antiedematogenic activity. In conclusion, the results obtained suggest that andrographolide has antinociceptive and antiedematogenic activities; it may be useful for treating pain and inflammation once human studies are conducted.
  16. Sulaiman MR, Zakaria ZA, Adilius M, Mohamad AS, Ismail M, Israf DA
    Methods Find Exp Clin Pharmacol, 2009 May;31(4):241-7.
    PMID: 19557202 DOI: 10.1358/mf.2009.31.4.1371198
    The ethanolic extract of Alpinia conchigera Griff. leaves (EACL) was evaluated for its antinociceptive and anti-inflammatory activities in several in vivo experimental models. Antinociceptive activity was determined using the acetic acid-induced abdominal writhing test, the hot plate test and the formalin test. Anti-inflammatory activity was determined using the carrageenan-induced paw edema test. The extract (30, 100 and 300 mg/kg i.p.) was found to possess significant, dose-dependent inhibitory activity in all test models. In addition, the antinociceptive effect of the extract in the acetic acid-induced writhing and hot plate tests was reversed by naloxone, suggesting that this activity is mediated through activation of the opioid system. These findings suggest that EACL presents notable analgesic and anti-inflammatory activities, which support its folkloric use for painful and inflammatory conditions.
  17. Sulaiman MR, Hussain MK, Zakaria ZA, Somchit MN, Moin S, Mohamad AS, et al.
    Fitoterapia, 2008 Dec;79(7-8):557-61.
    PMID: 18672036 DOI: 10.1016/j.fitote.2008.06.005
    The aqueous extract of Ficus deltoidea leaves was evaluated for possible antinociceptive activity in three models of nociception, namely, acetic acid-induced abdominal writhing, formalin and hot plate test. The results of the present study showed that intraperitoneal administration of the F. deltoidea leaves aqueous extract at the dose of 1, 50 and 100 mg/kg, 30 min prior to pain induction produced significant dose-dependent antinociceptive effect in all the models used, which indicating the presence of both central and peripherally mediated activities. Furthermore, the antinociceptive effect of the extract in the formalin and hot plate test was reversed by the non-selective opioid receptor antagonist naloxone suggesting that the endogenous opioid system is involved in its analgesic mechanism of action. Thus, the present results demonstrated that F. deltoidea leaves aqueous extract contains pharmacologically active constituents which possess antinociceptive activity justifying its popular therapeutic use in treating conditions associated with the painful conditions.
  18. Sulaiman MR, Zakaria ZA, Daud IA, Ng FN, Ng YC, Hidayat MT
    J Nat Med, 2008 Apr;62(2):221-7.
    PMID: 18404328 DOI: 10.1007/s11418-007-0210-3
    This study was performed to determine the antinociceptive and anti-inflammatory activities of aqueous extract of Kaempferia galanga leaves using various animal models. The extract, in the doses of 30, 100, and 300 mg/kg, was prepared by soaking (1:10; w/v) the air-dried powdered leaves (40 g) in distilled water (dH(2)O) for 72 h and administered subcutaneously in mice/rats 30 min prior to the tests. The extract exhibited significant (P < 0.05) antinociceptive activity when assessed using the abdominal constriction, hot-plate and formalin tests, with activity observed in all tests occurring in a dose-dependent manner. Furthermore, the antinociceptive activity of K. galanga extract was significantly (P < 0.05) reversed when prechallenged with 10 mg/kg naloxone. The extract also produced a significantly (P < 0.05) dose-dependent anti-inflammatory activity when assessed using the carrageenan-induced paw-edema test. In conclusion, this study demonstrated that K. galanga leaves possessed antinociceptive and anti-inflammatory activities and thus supports the Malay's traditional uses of the plant for treatments of mouth ulcer, headache, sore throat, etc.
  19. Sulaiman MR, Zakaria ZA, Kamaruddin A, Meng TF, Ali DI, Moin S
    Methods Find Exp Clin Pharmacol, 2008 Nov;30(9):691-6.
    PMID: 19229377 DOI: 10.1358/mf.2008.30.9.1305824
    Trigonopleura malayana L. (Euphorbiaceae) resin, locally known as Gambir Sarawak, has been used traditionally to alleviate pain associated with insect bites, muscle ache, toothache and minor injuries. The present study was carried out using various animal models to determine the antinociceptive and antiinflammatory activities of the T. malayana resin aqueous extract. Antinociceptive activity was measured using the abdominal constriction, hot plate and formalin tests, while antiinflammatory activity was measured using the carrageenan-induced paw edema test. The extract, obtained after 24 h of soaking the dried resin in distilled water, was prepared in doses of 0.3, 3 and 10 mg/kg and administered subcutaneously 30 min prior to the assays. The mechanism of action was also determined by prechallenging with naloxone (10 mg/kg), a nonselective opioid antagonist. The extract was found to exhibit significant (P < 0.05) and dose-dependent antinociceptive and antiinflammatory activities; naloxone failed to inhibit the former activity. In conclusion, the aqueous extract of T. malayana resin possesses nonopioid antinociceptive and antiinflammatory activities, thus supporting previous claims regarding its traditional use by the Malays to treat various ailments, particularly those related to pain.
  20. Sulaiman MR, Somchit MN, Israf DA, Ahmad Z, Moin S
    Fitoterapia, 2004 Dec;75(7-8):667-72.
    PMID: 15567242
    The antinociceptive effect of the ethanolic extract of Melastoma malabathricum (MME) was investigated using acetic acid-induced abdominal writhing test and hot-plate test in mice. It was demonstrated that the extract (30-300 mg/kg, i.p.) strongly and dose-dependently inhibited the acetic acid-induced writhing with an ED(50) of 100 (78-160) mg/kg i.p. It also significantly increased the response latency period to thermal stimuli. Furthermore, the nonselective opioid receptor antagonist, naloxone blocked the antinociceptive effect of the extract in both tests, suggesting that M. malabathricum may act both at peripheral and central levels.
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