Antinociceptive and anti-oedematogenic properties of astilbin, taxifolin and some related compounds.

Astilbin (3-0-alpha-1-rhamnosyl-(2R,3R)-dihydroquercetin), the major constituent isolated from Hymeneae martiana and some derivatives obtained by structural modification, such as taxifolin and two related compounds, were evaluated as analgesics by using both writhing test and formalin test in mice. Their anti-oedematogenic actions were also analysed against paw oedema caused by carrageenan, dextran and bradykinin in rat. The results indicated that some compounds, such as taxifolin (2) and its tetramethylated derivative (4) exhibited potent and dose-dependent antinociceptive action against acetic acid-induced abdominal constriction when administered intraperitoneally or orally. They were more potent than acetylsalicylic acid and paracetamol (acetaminophen), two standard drugs used for comparison. Compounds 2 and 4 were also more potent than these drugs in attenuating to the second phase of the formalin-induced licking. Moreover, both compounds showed significant anti-oedematogenic effect, inhibiting the paw oedema formation induced by dextran. In contrast pentaacetylated taxifolin (3) was capable of inhibiting the paw oedema induced by bradykinin.

Further studies on analgesic activity of cyclic imides.

As part of our research programme to obtain pharmacologically active compounds structurally related to cyclic imides, we have synthesized different compounds and examined their analgesic activities using the abdominal constriction test in mice. The results showed that some of the compounds studied, given intraperitoneally, exhibited graded and significant analgesia against acetic acid-induced abdominal constriction, being several times more potent than aspirin and paracetamol, two standard drugs used for comparison.

Antinociceptive properties of the hydroalcoholic extract and preliminary study of a xanthone isolated from Polygala cyparissias (Polygalaceae).

Polygala cyparissias (Polygalaceae) grows abundantly on Brazil's Atlantic coast, belonging to the typical underbrush vegetation of dunes and have been used in folk medicine for treatment of several diseases, such as disturbances of bowel and kidney. The hydroalcoholic extract of P. cyparissias (HE, 3 to 60 mg kg(-1), i.p. or 25 to 200 mg kg(-1), p.o.) produced significant and graded inhibition of acetic acid-induced abdominal constrictions, with mean ID50 values of 6 and 72 mg kg(-1), respectively. The HE (at this same range of doses) also produced dose-related inhibition of both the early and the late phase of formalin-induced licking. The calculated mean ID50 values for the early phase were: >60 and >200 mg kg(-1), while for the late phase they were 11 and 101 mg kg(-1), respectively, by i.p. and p.o. routes. The HE also caused dose-related inhibition of formalin-induced edema formation (P<0.01). The HE (3 to 60 mg kg(-1), i.p. or 50 to 200 mg kg(-1), p.o.) produced significant and dose-related inhibition of the neurogenic nociception caused by topical injection of capsaicin, with mean ID50 values of 12 and 71 mg kg(-1), respectively. Given orally, the HE (50 to 200 mg kg(-1)) prevented in a dose-dependent manner, bradykinin (3 nmol/paw) and substance P (10 nmol/paw)-induced hyperalgesia in the rat paw, with mean ED50 values of 122 and 121 mg kg(-1), respectively, but was ineffective in the hot-plate model of nociception. The antinociception caused by the HE, in contrast to that of morphine (5 mg kg(-1), s.c.), was not reversed by naloxone (5 mg kg(-1), i.p.) when assessed in the acetic acid writhing test. The HE, at antinociceptive doses, did not affect motor coordination of animals when assessed in the rota-rod model. The xanthone isolated from P. cyparissias, identified as 1,7-dihydroxy-2,3-dimethoxy xanthone (0.3 to 30 mg kg(-1), i.p.), produced dose-related inhibition of acetic acid-induced abdominal constriction, with mean ID50 value of 1.5 mg kg(-1). These data show that the active principle(s) present in the HE of P. cyparissias, elicited pronounced antinociception when assessed by i.p. or p.o. routes, against both inflammatory and neurogenic nociception, and was able to prevent bradykinin and substance P-induced hyperalgesia. Its precise mechanism of action still remains unclear.

Anti-allergic effects and oedema inhibition caused by the extract of Drymis winteri.

OBJECTIVE: To study the acute anti-inflammatory and anti-allergic properties of an extract of D. winteri. MATERIAL AND METHODS: Paw oedema induced in rats with various stimuli and anaphylactic shock in mice. RESULTS: The hydroalcoholic extract (HE) of D. winteri (Winteraceae) (30 to 100 mg/kg, p.o., 1 h prior) inhibited carrageenan (300 micrograms/paw) and dextran (100 micrograms/paw)-induced paw oedema formation in a dose-dependent manner, with mean ID50 values of 49 and < 30 mg/kg, respectively. The HE of D. winteri (30 to 100 mg/kg) also inhibited paw oedema induced by bradykinin (BK) (3 nmol), substance P (SP) (10 nmol) and PAF-acether (PAF) (10 nmol), in a dose-dependent manner, with mean ID50 values of 56, 63, and 58 mg/kg, respectively. However, the HE inhibited the rat paw oedema induced by prostaglandin E2 (PGE2) (10 nmol) (29 +/- 7 and 33 +/- 2% at 60 and 240 min) to a smaller extent, and had no effect on oedema elicited by histamine (100 nmol). In adrenalectomized animals, the inhibition by the HE of D. winteri (100 mg/kg, p.o., 1 h prior) of BK-elicited oedema (3 nmol/paw) was significantly smaller when compared with that observed in control animals. When assessed in rats actively sensitised to ovalbumin (OVO), the oedema caused by OVO (6 micrograms/paw) was significantly inhibited by HE of D. winteri (30 to 100 mg/kg, p.o.), with a mean ID50 of about 65 mg/kg. The HE of D. winteri (100 and 200 mg/kg, p.o.) significantly increased survival rate when assessed in anaphylactic shock in mice actively sensitised to the antigen. The protective effect was long-lasting, being observed for up to 15 h. Dexamethasone, used as positive control (0.5, 1 and 2 mg/kg) produced a long-lasting (up to 24 h) increase in the survival rate of the animals. CONCLUSIONS: These results confirm and extend our previous studies, and demonstrate the clear oral anti-inflammatory and anti-allergic properties of the active principle(s) present in the barks of D. winteri, thus confirming its reported medicinal use in folk medicine for the management of airway diseases.

Antinociceptive action of 2-(4-bromobenzoyl)-3-methyl-4,6-dimethoxy benzofuran, a novel xanthoxyline derivative on chemical and thermal models of nociception in mice.

The antinociceptive effect of the novel xanthoxyline derivative 2-(4-bromobenzoyl)-3-methyl-4-6-dimethoxy benzofuran) (BMDB), given i.p., p.o., s.c., subplantarly, intrathecally or by i.c.v. routes was assessed in five models of chemical and thermal nociception in mice, namely acetic acid-induced abdominal constriction, formalin and capsaicin-induced licking, hot-plate and tail-flick tests. BMDB given by i.p., s.c., subplantarly or by i.c.v. routes elicited dose-related and long-lasting (4 hr) antinociception, but had no significant effect by p.o. route. At the ID50 level, this compound was about 15- to 100-fold more potent than aspirin and acetaminophen, but it was about 2- to 50-fold less potent than morphine. Its analgesic action was not influenced by naloxone, L-arginine, antagonist of alpha-1 adrenoceptor, prazosin, tau -aminobutyric acid (B) antagonist, phaclofen, after adrenalectomy, but was reversed in part by p-chlorophenylalanine methyl ester. Its analgesic action was not secondary to an anti-inflammatory effect, or was it associated with nonspecific effect such as muscle relaxant or sedative actions of animals. We conclude that BMDB produces dose-dependent spinal and supraspinal antinociception as evaluated in several algesic models in mice, including the neurogenic nociception responses induced by formalin and capsaicin. Its antinociceptive effect was insensitive to naloxone, suggesting the lack of involvement of endogenous opioid, was not modulated by adrenal glands and does not involve interaction with the L-arginine-nitric oxide pathway, activation of alpha-1 adrenoceptors or tau-aminobutyric acidB receptors, but requires, at least in part, the serotoninergic pathway.