Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis

Abstract— This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg^?1, i.p.) or (100–500 mg kg^?1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg^?1, respectively. In the tail-flick model HE (up to 500 mg kg^?1, p.o.) was without effect, while morphine (1–10 mg kg^?1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg^?1). HE (1–300 mg kg^?1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg^?1, respectively. In contrast, morphine (1–5 mg kg^?1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg^?1. Indomethacin (1–10 mg kg^?1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg^?1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg^?1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.     

Mechanisms Involved in the Antinociceptive Effect in Mice of the Hydroalcoholic Extract of Siphocampylus verticillatus

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract. The hydroalcoholic extract of S. verticillatus (60–1000 mg kg^?1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and ～1000 mg kg^?1, respectively. In the formalin test, the extract (100–1000 mg kg^?1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg^?1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60–1000 mg kg^?1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg^?1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg^?1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg^?1, s.c.) and the extract (300 mg kg^?1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with l-arginine (600 mg kg^?1, i.p.) significantly attenuated the antinociceptive effects of N^G-nitro-l-arginine (l-NOARG) (75 mg kg^?1, i.p.), of the hydroalcoholic extract (600 mg kg^?1, i.p.) or of morphine (5 mgkg^?1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg^?1, i.p.) in the formalin-induced pain. These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the l-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.     

Chemical and Pharmacological Studies of Phyllanthus caroliniensis in Mice

The aim of this study was to isolate and characterize the constituents of the hydroalcoholic extract (HE) of the leaves, stems and roots from P. caroliniensis, and also to evaluate the preliminary antinociceptive action of the HE and purified compounds in mice. Phytosterols, quercetin, gallic acid ethyl ester and geraniin were identified in P. caroliniensis on the basis of ¹H and ¹³C NMR spectral data and by mixed co-TLC and co-HPLC injection with authentic samples. The HE of P. caroliniensis (10-100 mg kg^?1, i.p.) inhibited, in a dose-related manner, acetic acid-induced abdominal constrictions in mice, with a mean ID50 value of 23.7 mg kg^?1. In the formalin test, the HE given intraperitoneally (1-30 mg kg^?1) or orally (25-600 mg kg^?1) caused graded inhibitions of both the neurogenic (first phase) and the inflammatory response (late phase) of formalin-induced licking. The HE was 54-fold more effective in inhibiting the late phase than it was in inhibiting the first phase of the formalin test, with mean ID50 values of 3.6 and 196.4 mg kg^?1, respectively. The HE failed, however, to affect the oedematogenic response associated with the late phase of formalin-induced pain. In addition, the reference drug, aspirin, given intraperitoneally (1-100 mg kg^?1) or orally (100-600 mg kg^?1), caused significant inhibition of the late but not the first phase of the formalin test. Pharmacological analysis also revealed that quercetin, gallic acid ethyl ester and a semi-purified fraction of flavonoids (1-100 mg kg^?1, i.p.) exhibited graded and significant antinociception against acetic acid-induced abdominal constriction. The mean ID50 values (mg kg^?1) for these effects were: 18.8, 34.7 and 5.3, respectively. It is concluded that quercetin, gallic acid ethyl ester and some as yet unidentified flavonoids might account for the antinociceptive action reported for the HE of P. caroliniensis.     

Further Studies on the Antinociceptive Action of the Hydroalcoholic Extracts from Plants of the Genus,Phyllanthus

The analgesic effects of the hydroalcoholic extracts (HEs) of Phyllanthus urinaria, P. tenellus, P. niruri and P. sellowianus have been investigated in several models of nociception in mice. The HE of four species of Phyllanthus (1–90 mg kg^?1, i.p.) caused a dose-related inhibition of acetic acid-induced abdominal constriction in mice with ID50 values of 5·4, 8·5, 18·2 and 53·0 mg kg^?1 and maximal inhibition (%) of 80 ± 2, 67 ± 8, 63 ± 8 and 50 ± 4 for P. urinaria, P. niruri, P. tenellus and P. sellowianus, respectively. In the formalin test, the HE of all Phyllanthus species (0·3–60 mg kg^?1, i.p.) caused graded inhibition of both phases of formalin-induced pain, but they were, however, more potent in relation to the second phase of the pain. The ID50 values (mg kg^?1) for the first phase were 20·0, 23·0, > 60, and > 60 for the P. urinaria, P. tenellus, P. niruri and P. sellowianus, respectively, and percentages of maximal inhibition were 63 ± 2, 70 ± 2,41 ± 3 and 46 ± 4, respectively. The ID50 values (mg kg^?1) for the second phase were 0·71, 4·87, 7·7, 33·0, with maximal inhibition (%) of 91 ± 6, 97 ± 3, 97 ± 3 and 92 ± 6, respectively. Given orally, the HEs of species of Phyllanthus caused a significant antinociceptive profile, but they were about one-tenth to one-twentieth as potent when given intraperitoneally. However, the HEs of Phyllanthus failed to affect formalin-induced paw oedema and did not interfere with the performance of animals in the rota-rod test. Naloxone (5 mg kg^?1) completely reversed the analgesic effect caused by morphine (5 mg kg^?1), but had no effect against the analgesic effect of the HE of Phyllanthus. Furthermore, the HEs of Phyllanthus in contrast to morphine had no analgesic effect in either tail-flick or hot-plate tests. Taken together, these findings confirm and extend our previous results and indicate that all studied HE of species of plant belonging to the genus Phyllanthus exhibit potent and long-lasting antinociceptive activity in several models of pain, including the neurogenic algesic component of the formalin test. The mechanism underlying their analgesic profile is presently unknown.     

Antinociceptive Effect of the Hydroalcoholic Extract of Bauhinia splendens Stems in Mice

The analgesic effect of the hydroalcoholic extract of the stems of Bauhinia splendens (Leguminosae) has been investigated in chemical and thermal models of nociception in mice. The hydroalcoholic extract of B. splendens, 3–60 mg kg^? intraperitoneally or 50–400 mg kg^? orally, caused dose-related, and long-lasting (up to 3 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 3.2 and 177.6 mg kg^? and maximum inhibition of 95 ± 2 and 61 ± 6%, respectively. In the formalin test, the extract given intraperitoneally (1.60 mg kg^?) or orally (50–400 mg kg^?) caused graded inhibition of both phases of formalin-induced pain, being about 5- to 6-fold more potent in attenuating the second phase of pain. The calculated mean ID50 values for the first and the second phases were 11.5 and 2.5 mg kg^?, respectively, for intraperitoneal administration and > 200 and 70 mg kg^?, respectively, for oral administration; the percentages of maximum inhibition for the first and the second phases were 68 ± 6 and 99 ± 1, respectively, for intraperitoneal administration and 37 ± 6 and 69 ± 9, respectively, for oral administration. However, at the same doses the extract did not significantly affect the oedematogenic response induced by formalin. The treatment of animals with naloxone (5 mg kg^?, i.p.) completely reversed the analgesic effect caused by morphine (5 mg kg^?, s.c), but had no effect against the antinociceptive effect of the hydroalcoholic extract of B. splendens (60 mg kg^?, i.p.) when assessed against acetic acid-induced abdominal constrictions. Furthermore, the extract, in contrast with morphine, had no analgesic effect in the hot-plate test. These data show that the hydroalcoholic extract of B. splendens has significant analgesic action when assessed against several models of pain. The mechanism underlying its analgesic effect still remains unknown, but seems to be unrelated to interaction with opioid systems.     

Analgesic Effects of Callus Culture Extracts from Selected Species of Phyllanthus in Mice

Abstract— The aim of this study was to evaluate the analgesic effect of the methanolic extract from callus culture of Phyllanthus tenellus, P. corcovadensis and P. niruri in several models of pain in mice. The extracts (medium containing 2,4-dichlorophenoxyacetic acid) of P. corcovadensis, P. niruri and P. tenellus (3–90 mg kg^?1, i.p.) caused graded inhibition of abdominal constrictions induced by acetic acid (0·6%), with ID50 (i.e. dose that reduced response of control by 50%) values of about 30, 19 and >30 mg kg^?1, respectively. The extract of callus of Phyllanthus obtained in indole-3-butyric acid and indole-3-acetic acid media (3–90 mg kg^?1, i.p.) caused a similar analgesic effect. In the formalin test, the extract of P. tenellus obtained in indole butyric acid medium (3–100 mg kg^?1, i.p.) inhibited only the second phase of formalin-induced pain with an ID50 value of about 100 mg kg^?1. Both the indole acetic acid and indole butyric acid methanolic extracts of P. tenellus and P. corcovadensis (10–100 mg kg^?1, i.p.) dose-dependently inhibited both phases of formalin-induced pain (ID50 values for the second phase were approx. 100 and 52 mg kg^?1, respectively). However, the extract of callus from Phyllanthus failed to affect formalin-induced paw oedema, as well as the response to radiant heat in the tail-flick test. In addition, the analgesic effect of morphine, but not the analgesic effects caused by Phyllanthus callus extract, was fully antagonized by naloxone. Preliminary phytochemical analysis revealed the presence of several compounds having no apparent relationship with alkaloids or flavonoids but showing the presence of phenols. These results indicate that, similar to previous reported data from the extract of P. corcovadensis, the methanolic extracts of callus culture of P. niruri, P. corcovadensis and P. tenellus exhibit potent analgesic properties against neurogenic and inflammatory pain that seem to be unrelated to the activation of opioid mechanisms.     

Biopharmaceutics: Submicron Oil-in-water Emulsion Formulations for Mefloquine and Halofantrine: Effect of Electric-charge Inducers on Antimalarial Activity in Mice

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine. The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg^?1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg^?1 for dicetylphosphate, 17 mg kg^?1 for phosphatidylserine, 23 mg kg^?1 for oleic acid and 27 mg kg^?1 for stearylamine, again after subcutaneous administration. This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.     

Chronic Administration Does Not Alter the Pharmacokinetic Profile of l-Dopa in the Rat

Abstract— Chronic administration of l-dopa (200 mg kg^?1 day^?1 for 12 months) plus carbidopa (25 mg kg^?1 day^?1) or carbidopa (25 mg kg^?1 day^?1) alone did not alter the t½, AUC_0–∞ k₁₀, k₁₂, k₂₁, CL_p or Vd_ss of l-dopa following intra-aortic (i.a.) administration (50 mg kg^?1) alone or after carbidopa (25 mg kg^?1, i.p.) pretreatment, or the t½, AUC_0–∞, t_max or the bioavailability (F) of l-dopa (50 mg kg^?1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg^?1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of l-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC_{0·360 min} for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of l-dopa (50 mg kg^?1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.     

Acute toxicity of some nerve agents and pesticides in rats

Objectives: Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Materials and methods: Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD₅₀, mg?kg^?1) 2, 4, and 24 hours post exposure. Results: V-agents were the most toxic presented with LD₅₀ ranged from 0.0082?mg?kg^?1 (VX, i.m.) to 1.402?mg?kg^?1 (Russian VX, p.o.), followed by G-agents (LD₅₀?=?0.069?mg?kg^?1/soman, i.m./ – 117.9?mg?kg^?1/sarin, p.c./), organophosphate POX and DFP (LD₅₀?=?0.321?mg?kg^?1/POX, i.m./ – 420?mg?kg^?1/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD₅₀?=?0.0082?mg?kg^?1/VX/ – 1.399?mg?kg^?1/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD₅₀?=?0.085?mg?kg^?1/VX/ – 420?mg?kg^?1/DFP/). Conclusion: The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.     

抗疟药的研究——Ⅸ.5-取代苯氧基-6-甲氧基-8-[(1-乙基-4-氨基丁基)氨基]喹啉类化合物的合成

至今,伯喹仍是唯一能应用的间日疟根治药,但由于毒性较大,化疗指数较低,在使用上受到一定的限制。近年来国内外对伯喹的化学结构进行了多方面的改造,出现了一些有希望的化合物。Chen等郑贤育等和许德余等分别报道在伯喹的5位引入取代苯氧基能提高抗疟作用,降低毒性;Yan等将4-甲基伯喹(Ia)的侧链1-甲基-4-氨基丁氨基改变成     

Antidiarrhoeal Activity of New Thiazolidinones Related to Loperamide

A series of thiazolidinones related to loperamide was synthesized and evaluated for antidiarrhoeal activity in mice, using the castor oil test. Of five compounds tested, antidiarrhoeal activity was found only for 2?(p-nitrophenyl)?3?{3?[(4?(p-chloro-phenyl)-4?hydroxy)piperidino]ethyl}-1,3?thiazolidin?4?one. The compound was less active than loperamide (ED50 values = 48.7 (24.8?95.6) and 0.91 (0.24?3.40) mg kg^?1, respectively), but was also less toxic (LD50 values = 745.9 (545.2?929.8) and 108.9 (85.5?138.7) mg kg^?1, respectively). Its antidiarrhoeal activity was counteracted by naloxone. Our results support the hypothesis that this compound, like loperamide, is an opiate-receptor agonist.     

Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.     

The peripheral NK-1/NK-2 receptor antagonist MDL 105,172A inhibits tachykinin-mediated respiratory effects in guinea-pigs

1 Stimulation of sensory nerves causes release of tachykinins, including substance P (SP) and neurokinin A (NKA), which produce a variety of respiratory effects via NK-1 and NK-2 receptors, respectively. Hence, development of a compound which could potently and equivalently antagonize both receptors was pursued. 2 MDL 105,172A ((R)-1-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-3-pyrrolidinyl]-4-phenyl-piperidine-4-morpholinecarboxamide) exhibited high affinity for NK-1 (4.34 nm ) and NK-2 (2.05 nm ) receptors. In vitro, the compound antagonized SP (pA₂ = 8.36) or NKA (pA₂ = 8.61)-induced inositol phosphate accumulation in tachykinin monoreceptor cell lines. 3 In anaesthetized guinea-pigs, MDL 105,172A inhibited SP-induced plasma protein extravasation (ED₅₀ = 1 mg kg^?1, i.v.) and [β-Ala⁸]NKA 4–10-induced bronchoconstriction (ED₅₀ = 0.5 mg kg^?1, i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4 Capsaicin was used to elicit respiratory effects in anaesthetized and conscious guinea-pigs; the latter were inhibited by MDL 105,172A following i.v. (ED₅₀ = 1 mg kg^?1) or oral (ED₅₀ = 20 mg kg^?1) adminstration. Hence, MDL 105,172A can inhibit pulmonary responses to tachykinins released endogenously in the airways. 5 At doses up to 200 mg kg^?1, p.o., MDL 105,172A failed to inhibit repetitive hind paw tapping induced by i.c.v. GR 73632, an NK-1 selective agonist, in gerbils, whereas CP-99,994 (0.87 mg kg^?1, s.c.) completely ablated the effect. These data suggest that MDL 105,172A does not penetrate the central nervous system (CNS) and its tachykinin antagonism is restricted to the periphery. 6 MDL 105,172A is a non-peptide, potent, equivalent antagonist of NK-1 and NK-2 receptors. Its ability to inhibit both exogenously administered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.     

Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase isozymes by repeated cyanamide administration: Pharmacokinetic-pharmacodynamic relationships

The inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (ALDH) isozymes was studied in apparent steady-state conditions after repeated intra-peritoneal cyanamide administration. The low-K_m mitochondrial ALDH isozyme was more susceptible to cyanamide-induced inhibition (DI₅₀ = 0.104 mg kg^?1) than the high-K_m isozyme (DI₅₀ = 8.52 mg kg^?1), with almost complete inhibition occurring at 0.35 mg kg^?1 total cyanamide administered for the low-K_m isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high-K_m ALDH were established by means of the sigmoid I_max model. The effect of dosing rate on the plasma concentration of cyanamide at apparent steady-state showed non-linearity, indicating that clearance or first-pass metabolism of cyanamide during its absorption after intraperitoneal administration did not remain constant throughout the range of doses studied.     

The mechanism of the hypothermic effect of amantadine in rats and mice

Amantadine (25–100 mg kg^?1, i.p.) given to rats at an ambient temperature of 4°, or mice at 21°, caused a marked fall in rectal temperature. Prior administration of pimozide (1–2 mg kg^?1, s.c.) did not block hypothermia due to amantadine in rats or mice; in contrast, hypothermia due to apomorphine (2 mg kg^?1, i.p.) and piribedil (10–40 mg kg^?1, i.p.) in rats was blocked by pimozide pretreatment. Amphetamine (5 mg kg^?1, i.p.) given 2 h after reserpine (2 mg kg^?1, i.p.) caused a reversal of the hypothermic effect of reserpine in mice, but a reversal was not obtained with amantadine (50 mg kg^?1, i.p.). Direct injection of amantadine (4–8 mg kg^?1) into the cerebral ventricles (i.c.v.) of mice caused marked hypothermia which was not blocked by pimozide, but intravenous injection of the same dose of amantadine did not cause hypothermia. Rimantadine, a congener of amantadine but without anti-parkinsonian activity, also caused pimozide insensitive hypothermia in mice at doses of 50 mg kg^?1, intraperitoneally or 2–4 mg kg^?1, intracerebroventricularly. The main conclusion drawn from these results is that in causing hypothermia amantadine acts in the cns but not on dopamine receptors.     

Evaluation of the anti-inflammatory activity of N,N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride

This study investigated the anti-inflammatory effect of N, N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride, D1, on carrageenan-induced edema. In addition, its effect on hyaluronidase-induced vascular permeability was also tested. D1 was synthesized, and anti-inflammatory activity was determined by carrageenan-induced hind paw edema in rats (n?=?30) at 50, 100, and 200?mg kg^?1 doses of D1 and also a 25?mg kg^?1 dose of indomethacin. The effects of D1 and indomethacin on hyaluronidase-induced capillary permeability were investigated in rabbits (n?=?18) at a 100?mg kg^?1 dose of D1 and 25?mg kg^?1 dose of indomethacin. D1 inhibited carrageenan-induced inflammation by 40, 20, and 10% at 50, 100, and 200?mg kg^?1 doses after 1?h. The inhibitions were 22.5, 32.7, 28.6% and 15.6, 33.4, 8.9% at 2?h and 3?h, respectively. The inhibitions due to indomethacin (25?mg kg^?1 dose) were 67.5, 87.8, and 91.1%, at 1?h, 2?h, and 3?h, respectively. The subcutaneous spreading areas of Trypan blue at 1, 5, 30, and 60?min after subcutaneous injection of hyaluronidase were 172.6?±?41.6, 210.2?±?39.7, 363?±?50, and 400.2?±?46.7?mm² in the D1 (100?mg kg^?1) treated group. The spreading areas at these time periods were 38.8?±?3.7, 48.2?±?4.5, 100.6?±?6.9, and 119.8?±?22.5?mm² in the indomethacin treated group. Our results showed that D1 inhibits carrageenan-induced inflammation in rats. A tendency to decrease the capillary permeability suggested that the mechanism of action of the anti-inflammatory effect of D1 may partly depend on inhibition of the hyaluronidase enzyme.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation

Abstract— NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methane sulphonamide), a newly synthesized potent non-steroidal antiinflammatory drug (NSAID) has a much lesser degree of toxicity, as compared with presently available NSAIDs. We have investigated the inhibition of prostanoid production in inflammatory exudate, gastric mucosa and renal papillary tissue, following oral administration to carrageenan-air-pouch rats. The ID50 values of NS-398 in the inflammatory exudate, gastric mucosa and renal papillary tissue were 0·18, 62·2 and 261·7 mg kg^?1, respectively. In contrast, indomethacin decreased the PGE₂ concentration in the inflammatory exudate, gastric mucosa and renal papillary tissue, with the same dose range, the ID50 values being 0·23, 0·14 and 0·15 mg kg^?1, respectively. The same tendency was seen for 6-keto-prostaglandin F₁ and thromboxane B₂. Moreover, NS-398 inhibited excess PGE₂ production in inflamed tissue but did not affect physiological production of PGE₂ in non-inflamed tissue. Indomethacin, in both inflamed and non-inflamed tissues, inhibited PGE₂ production to the same degree. These results indicated that NS-398 has some specificity for inflamed tissue, by inhibiting prostanoid synthesis, and this effect may explain the decreased side-effects of this drug.     

Natural Products: Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil. The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg^?1) or zymosan (40 mg kg^?1) were inhibited to different extents by an extract of propolis (1–60 mg kg^?1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg^?1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg^?1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg^?1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg^?1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg^?1 i.p. or 25–100 mg kg^?1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg^?1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg^?1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg^?1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg^?1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg^?1 i.p., 30 min previously). These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.     

Antinociceptive Effect of some Amaryllidaceae Plants in Mice

The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p-benzoquinone-induced abdominal constriction and hot-plate tests. In the p-benzoquinone-induced abdominal constriction test the ethanolic extracts of P. maritimum (300, 600 or 1200 mg lg^?, s.c.) and N. tazetta subsp. tazetta (5, 50, 100 or 200 mg kg^?, s.c.) caused dose-dependent inhibition of abdominal constrictions whereas a fluctuating response was obtained from ethanolic extracts of L. aestivum (2.5–500 mg kg^?, s.c). In the hot-plate test P. maritimum and L. aestivum caused a significant increase of latency only at the highest concentrations used (1200 mg kg^? and 500 mg kg^?, i.p., respectively). However, at these concentrations they also caused significant toxic effects. In contrast with P. maritimum and L aestivum, N. tazetta subsp. tazetta (5–500 mg kg^?, i.p.) extracts had no antinociceptive effect in this test. These findings indicate that the antinociceptive effect of Amaryllidaceae plants differs depending on the model of nociception investigated.