The pharmacological profile of CGP 28238, a novel highly potent anti-inflammatory compound

CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10x) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 greater than 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of less than or equal to 2 mg/kg, p.o. Although CGP28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 greater than 10(-3) mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of less than 10(-6) mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 x 10(-7) and 2 x 10(-8) mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.     

Pharmacological properties of MDL 19,301: A novel,nonsteroidal, anti-inflammatory agent

Oral administration of MDL 19,301 (N-(1,3-dithiolan-2-ylidene)-4-hexyl-benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mg/kg p.o.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mg/kg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti-inflammatory agents. Its major metabolite ((MDL16,861, 4[1,3-dithiolan-2-yliden)amino]-benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mg/kg p.o.), although it was more ulcerogenic (UD50 52 mg/kg p.o.). The anti-inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co-administration of an inhibitor of drug metabolism (SK&F525A 30 mg/kg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti-inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic-acid-induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic-acid-induced, but not prostaglandin-E₂-induced, diarrhea in mice; and inhibition of ex vivo arachidonic-acid-induced, but not adenosine-diphosphate-induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti-inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.     

A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity

The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.     

Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound.

A novel compound, FR64822(N-(4-pyridylcarbamoyl)amino 1,2,3,6,-tetrahydropyridine), displays antinociceptive activities in a variety of assays with mice and rats. It has a strong antinociceptive activity in the acetic acid writhing test (ED50 = 1.8 mg/kg p.o.), whereas it has little antinociceptive activity in the tail flick test. The antinociceptive profile is similar to that of nefopam but different from that of anti-inflammatory agents. The involvement of monoamines in the mechanism of action of FR64822 was investigated. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive activity of FR64822, when tested against acetic acid writhing. A similar reduction of activity was found in mice pretreated with sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, but not with Sch23390 (0.25 mg/kg), a dopamine D1 receptor antagonist. Pretreatment with p-chlorophenylalanine, yohimbine and naloxone hardly affected the antinociceptive activity of FR64822. These results were compared with those for nefopam and clonidine. It is suggested that FR64822 induces antinociceptive activity through a novel mechanism of action, indirect stimulation of dopamine D2 receptors, which differs from that of nefopam in that no specific neurotransmission could be determined in nefopam analgesia.     

Selective inhibition of noradrenaline and serotonin uptake by C 49802-B-Ba and CGP 6085 A

The effects of two new compounds, 1-(1-methylamino-2-hydroxy-3-propyl)-dibenzo[b,e]bicyclo[2,2,2]octadiene-HCl (C 49802-B-Ba) and 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A), on noradrenaline (NA) and serotonin (5-HT) uptake were investigated in different test systems, CGP 6085 A is a very potent and selective inhibitor of 5-HT uptake in rat brain (ED50 1-4 mg/kg p.o., depending on test system). Doses up to 1000 mg/kg p.o. did not inhibit NA uptake. C 49802-B-Ba is a potent and selective inhibitor of NA uptake in rat brain (ED50 5-10 mg/kg p.o. depending on test system) and heart (ED50 1.5 mg/kg p.o.). At 300 mg/kg p.o., this compound caused no inhibition of 5-HT uptake.     

Analgesic activity of a non-steroidal anti-inflammatory agent, tolmetin sodium in experimental animals (author's transl)

Effect of tolmetin sodium on the pain-like responses caused by various nociceptive stimuli was examined in experimental animals. Tolmetin sodium showed a potent inhibitory activity on the acetic acid-induced writhing in mice and rats, and its potency, (ED50 = 23.4 and 3.01 mg/kg, p.o.) was about 2.4--10.3 times that of ibuprofen and aspirin. The hypertension induced by intraarterial injection of bradykinin toward the spleen of dogs was inhibited by tolmetin sodium (ED50 = 80 mg/kg, i.v.), but the hypertension by a simultaneous injection of bradykinin and PGE1 was not inhibited by tolmetin sodium and sulpyrine, though pentazocine inhibited both hypertensions. The pain-like response caused by pressing mechanically the inflamed paws or joints of rats induced by kaolin-carrageenin or adjuvant was inhibited by tolmetin sodium (30--100 or 20--40 mg/kg, p.o., respectively), and the potency was approximately equal that of ibuprofen and phenylbutazone. Tolmetin sodium produced a significant inhibition of the pain-like response induced by electrical stimulation of tooth pulp of dogs, but showed no effect when the methods of Haffner and D'Amour-Smith were applied to mice. Anti-writhing action of tolmetin sodium was not antagonized by naloxone. From these results, it was concluded that tolmetin sodium has a potent inhibitory activity on the pain-like responses induced by the chemical nociceptive stimuli and by the mechanical pressure stimulus of the inflamed tissue, especially on the writhing. The analgesic activity probably involves a peripheral mechanism.     

General pharmacology of the butanamide derivative S 19812, a new dual inhibitor of cyclooxygenase and lipoxygenase pathways

S 19812 (N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl) butanamide, CAS 181308-68-9), a dual inhibitor of cyclooxygenase and lipoxygenase pathways, was evaluated in different models of pain and inflammation. Its gastric tolerance was also investigated. After acute oral treatment S 19812 exhibited a non-opioid analgesic activity observed in the phenylbenzoquinone-induced writhing model in mice (ED50 = 2.1 mg/kg) and in the carrageenan-induced hyperalgesia model in rats (ED50 = 9.1 mg/kg, preventive treatment; 8.3 mg/kg, curative treatment). Anti-inflammatory activity was observed in the adjuvant-induced arthritis in rat (inhibition of edema ED50 = 11 mg/kg/day p.o., day 28). In rats and mice, S 19812 exhibited an excellent gastric tolerance at doses up to 800 mg/kg p.o.     

CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease

The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease. CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) with CGP 3466 (0.1 mg/kg s.c.) or CGP 3466B (0.014 mg/kg and 0.14 mg/kg p.o.) b.i.d. for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (0.0014 mg/kg p.o.) showed a marginal effect, whereas a high dose, i.e. 1.4 mg/kg p.o., was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that received intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 mg/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, skilled paw use was assessed by means of the staircase test. The results indicated a significant improvement of skilled motor performance as measured by means of the number of eaten pellets. Since due to the long wash-out period a symptomatic effect of CGP 3466B can be ruled out, it is likely that this improvement was related to interference with the course of the degeneration of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in in vitro and in vivo models of Parkinson's disease. In addition, treatment with CGP 3466 resulted in improved skilled motor performance in 6-OHDA-lesioned rats.     

Pharmacological properties of droxicam, a new non-steroidal anti-inflammatory agent

Droxicam showed high antiinflammatory activity in carrageenin-induced edema in rat. At doses of 0.25 and 0.5 mg/kg, droxicam was as active as piroxicam and more active than phenylbutazone given at 2.5 and 5 mg/kg. Against nystatin-induced edema, droxicam (ED50, p.o., 5, 6, 7, 8 h: 7.5, 12.9, 4.8, 8.4 mg/kg) was 4-11 times more active than phenylbutazone and more than 12 times more active than isoxicam. In cotton pellet-induced granuloma in rats, title compound was as active as suprofen. In U.V. light-induced erythema in guinea pigs, droxicam (ED50, p.o., 1, 2, 3, 4 h: 0.51, 0.94, 1.56, 4.88 mg/kg) was 5-9 times more active than phenylbutazone. At doses of 0.1, 0.33 and 1.0 mg/kg/day, droxicam, similar to piroxicam, showed good antiarthritic activity in rats injected with Mycobacterium butyricum against primary and secondary lesions. Droxicam demonstrated strong analgesic activity in protecting against writhings: induced by phenylbenzoquinone in mice: ED50: droxicam = 5.3, phenylbutazone = 61.5, acetylsalicylic acid = 90.7, dipyrone = 83.6, isoxicam = 88.3 mg/kg, p.o.; induced by acetylcholine bromide in mice: ED50: droxicam = 1.1, phenylbutazone = 32.1, acetylsalicylic acid = 32.2, isoxicam = 32.7 mg/kg, p.o.; induced by acetic acid in rat: ED50: droxicam = 0.94, acetylsalicylic acid = 8.72, isoxicam = 4.70 mg/kg, p.o. Antipyretic activity of title compound was demonstrated in rats with pyresis induced by brewer's yeast, being 4-13 times more active than dipyrone. In pyresis induced by Salmonella typhi, droxicam was more active than acetylsalicylic acid and 4-aminoantipyrine at all times and doses. In a study of protection against diarrhea induced by castor oil in rats, droxicam and piroxicam showed equal activity (ED50 = 0.081 and 0.079 mg/kg, p.o., respectively) and were 3.9 and 15.6 times more active than isoxicam and phenylbutazone, respectively. Droxicam significantly inhibited peritoneal capillary permeability in mice at a dose of 5 mg/kg, p.o., while isoxicam and phenylbutazone required 100 and 200 mg/kg, p.o., respectively. Droxicam did not exhibit uricosuric activity in rats. It did not show cardiovascular or respiratory effects in anesthetized cats, nor modify their response to administration of acetylcholine, norepinephrine and histamine. In the Irwin's test, droxicam did not alter rat behavior (80 mg/kg, i.p.) nor that of mice (160 mg/kg, p.o.). Induction of gastrointestinal injuries in rats by droxicam was 10 times less than by piroxicam (UD50: droxicam, 57 mg/kg, p.o.; piroxicam, 5.6 mg/kg, p.o.). The potentiation of gastric injuries induced by stress through cold in rats was also studied.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (compound 69/183). Part IV: other CNS effects and acute toxicity

3-[gamma-(p-Fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (centpyraquin), a potent antihypertensive and tranquillising agent, was tested for anticonvulsant, analgesic and anti-inflammatory activities in mice and for anti-emetic activity in dogs. It did not modify supramaximal electroshock seizures and failed to protect the animals against pentylenetetrazole and strychnine induced convulsions. It, however, produced some elevation in the threshold dose of strychnine. Tremorine induced tremors and salivation were not antagonised. The compound had weak analgesic activity as detected by antagonism to phenylquinone writhing and the hot plate test. It had no anti-inflammatory activity. Centpyraquin had strong anti-emetic activity against apomorphine as well as morphine. At high doses it produced fall out in the rota-rod test. The LD50 of centpyraquin in mice was 296 mg/kg i.p. and more than 1000 mg/kg p.o. and in rats it was 161 mg/kg i.p. and more than 800 mg/kg p.o. The observed CNS effects resemble those of other neuroleptics.     

Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat.

In anaesthetized rats and cats, the effects of the piperazine derivative CGP 29030A on the discharges of functionally identified dorsal horn neurons and gamma-motoneurons was studied. The compound exhibited a marked inhibitory action on presumably nociceptive dorsal horn neurons that processed input from high-threshold mechanosensitive receptors in the skin and deep somatic tissues (muscle, tendon, joint). Significant effects were obtained at a dose of 10 mg/kg p.o. and higher; the onset of action was fast (approximately 10 min). In contrast to presumably nociceptive dorsal horn neurons, cells having input from low-threshold mechanosensitive receptors in the skin and deep tissues were not affected by the compound. Thus CGP 29030A has a quite specific action on dorsal horn neurons that probably mediate pain. Systemic effects on the blood pressure and on the activity of sympathetic efferent fibres did not occur. The lack of effect of CGP 29030A on nociceptive neurons in spinalized animals suggests that the site of action is not the segmental spinal cord but the supraspinal CNS. gamma-motoneurons supplying the gastrocnemius-soleus muscle were likewise inhibited by the compound but at a higher dose (equal to and exceeding 30 mg/kg). The data show that CGP 29030A is a compound with marked and specific analgesic action. As it also inhibits gamma-motoneurons, CGP 29030A may be of benefit in the treatment of painful disorders which are complicated by increased motor activity (cramp, spasm).     

Anti-inflammatory and analgesic effects of an aqueous extract of Harpagophytum procumbens.

The dried aqueous extract of Harpagophytum procumbens (Pedaliaceae) and its main iridoid glycoside, harpagoside, have been evaluated for anti-inflammatory and analgesic effects in mice and rats, in order to validate or invalidate the involvement of this compound in such properties. This extract exerted significant and dose-dependent anti-inflammatory and analgesic effects, from the dose 100 mg of dried secondary roots/kg, the first being obtained on an acute inflammatory process (carrageenan-induced edema test in rats) and the second being obtained against a chemical stimulus (writhing test in mice). Harpagoside does not appear to be involved in anti-inflammatory properties, since this iridoid glycoside did not protect against carrageenan inflammatory effects when it was used at 5 and 10 mg/kg; 5 mg corresponding to the quantity contained in 400 mg of dried secondary roots. The main iridoid glycoside of H. procumbens appears to be implicated in the peripheral analgesic properties of this species, but other compounds have to be involved, since the dose of 10 mg/kg exerted a significant protective effect. The absence of the activity of H. procumbens after an acid treatment (0.1 N hydrochloric acid), stomach, suggests the use of a suitable galenic preparation in order to protect the active principles from the action of the acid released in the stomach.     

The antinociceptive effects of prostaglandin antagonists in the rat

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.     

Antinociceptive,antipyretic, and anti-inflammatory activities of <Emphasis Type="Italic">Putranjiva roxburghii</Emphasis> Wall. leaf extract in experimental animals

The effects of the ether extract from the leaves of Putranjiva roxburghii (P. roxburghii) Wall. were assessed on nociceptive responses in mice by using writhing, hot plate, and formalin tests and the antipyretic activity was determined in yeast-induced fever in rats. Anti-inflammatory activities were also investigated using carrageenin-induced paw edema in rats and croton oil-induced ear and anus edemas. The ether extract (100, 200, and 400 mg/kg, p.o.) of P. roxburghii dose-dependently produced analgesic activity in acetic acid-induced writhing in mice. The extract had no significant effect in the hot plate test in mice. At the dose of 400 mg/kg, the extract significantly suppressed the licking activity in the late phase of the formalin test in mice and decreased fever induced by yeast in rats. The extract exhibited moderate inhibitory activity of inflammation in carrageenin-induced paw edema in rats. The extract inhibited croton oil-induced ear edema in a dose-dependent manner (1.25, 2.5, and 5.0 mg/ear) in mice. The extract decreased anus edema induced by croton oil at the high dose of 800 mg/kg in rats. The results indicated that the ether extract of P. roxburghii leaves possesses analgesic, antipyretic, and anti-inflammatory activities.     

The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent,orally-active anticonvulsants in rodents

Summary Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED₅₀ ^s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i. v. and i. p. injection. Relative to CGP 37849, CGP 39551 was more potent after p. o. (ED₅₀ 3.7–8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED₅₀ 2.7–8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED₅₀ 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p. o. and above, and showed weak anticonvulsant activity against pentylenetetrazolevoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anticonvulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man. Send offprint requests to M. Schmutz at the above address     

The analgesic effects of non-steroidal anti-inflammatory drugs on acetylcholine-induced writhing in mice

The experimental conditions of acetylcholine (ACh)-induced writhing were investigated, and the analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs) on ACh-induced writhing were investigated in comparison with those on other writhings. Mice injected (i.p.) with more than 5 mg/kg of ACh showed the writhing response, and the number of writhes were almost equal in all mice. Therefore, the analgesic effects were evaluated as follows: NSAIDs were administered orally 30 min before the ACh injection (5 mg/kg, i.p.), the number of writhes were counted in each mouse during a period of 10 min following the ACh injection, and mice that did not show any writhing responses were regarded as positive for the analgesic activity. The analgesic effects of NSAIDs showing the inhibitory effect on prostaglandins (PGs) biosynthesis were more potent than those in other writhing tests. The ED50 values in the ACh-induced writhing were highly correlated with the IC50 values in the inhibitory effects on PGs biosynthesis (r = 0.81, P less than 0.01) and with the ED50 values in the anti-castor oil diarrhoea (r = 0.93, P less than 0.01). Moreover, the ED50 values of acidic NSAIDs in ACh-induced writhing were also highly correlated with the clinical doses (r = 0.90, P less than 0.001). These results suggest that the ACh-induced writhing method should be useful for the evaluation of the analgesic effects of acidic NSAIDs, and the analgesic effects on the ACh-induced writhing are related to their inhibitory effects on PGs biosynthesis.     

Preclinical evaluation of CHF3381 as a novel antiepileptic agent

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.     

Mechanism of anti-inflammatory action of etodolac.

The effect of etodolac (CAS 41340-25-4) on the inflammatory reactions induced by histamine and bradykinin was compared with that of indomethacin and other nonsteroidal anti-inflammatory drugs. Etodolac (50 mg/kg p.o.), indomethacin (20 mg/kg p.o.), diclofenac Na (20 mg/kg p.o.) and acetylsalicylic acid (200 mg/kg p.o.) had no effect on the increase of vascular permeability induced by histamine or bradykinin and on passive cutaneous anaphylaxis in rats. Etodolac (5, 10 and 20 mg/kg p.o.) suppressed concanavalin A-induced paw edema in rats. Etodolac (10 mg/kg p.o.) and bromelain (10 mg/kg i.v.) significantly suppressed the heat-induced elevation of bradykinin in perfusates of rat paws, but indomethacin (20 mg/kg p.o.) and diclofenac Na (20 mg/kg p.o.) did not. Etodolac inhibited bradykinin-forming enzyme activity in a concentration-dependent manner (IC50 = 1.5 x 10[-4) mol/l). These results suggest that etodolac is a unique nonsteroidal anti-inflammatory drug which can inhibit bradykinin formation, unlike indomethacin or diclofenac Na.     

Antinociceptive activity of Vitex-negundo Linn leaf extract

Tail flick test in rats and acetic acid induced writhing in mice were employed to study the antinociceptive activity of ethanolic leaf extract of Vitex-negundo (VN) (100, 250 and 500 mg/kg, p.o). The effect was compared with meperidine (40 mg/kg, sc) in tail flick method and aspirin (50 mg/kg, p.o) in writhing test as a standard control respectively. An interaction with naloxone hydrochloride was also studied in tail flick method for its mechanism of central analgesic action. The test drug showed significant analgesic activity in dose dependant manner in both the experimental models. In comparison to standard drug (meperidine), more than ten times dose of VN extract was required to produce comparable significant antinociceptive activity. The sub-effective dose (5 mg/kg, po) of VN potentiated the analgesic activity of meperidine (4 mg/kg, sc) and aspirin (25 mg/kg, po). Naloxone (1 mg/kg, sc) did not reverse the analgesic effect of VN extract. Our observations suggest that VN possesses both central and peripheral analgesic activity. The central analgesic action does not seem to be mediated through opioid receptors. It, may prove to be a useful adjuvant therapy along with standard analgesic drug.     

General pharmacological properties of an anti-ulcer drug, azuletil sodium (KT1-32)

Azuletil sodium (AZE, 100 mg/kg, p.o.) did not affect the general behaviors, spontaneous motor activity, pentobarbital-induced hypnosis and body temperature. Furthermore, it did not elicit anticonvulsant and muscle relaxant actions. However, AZE (300 mg/kg, p.o.) elicited a stiff gate and slightly inhibited the spontaneous motor activity and electroshock-induced convulsions. It had no influence on spontaneous EEG activities, even at 30 mg/kg, i.v. AZE inhibited acetic acid-induced writhing moderately at doses above 100 mg/kg. AZE at concentrations up to 10(-5) g/ml did not affect agonist-induced contractions of the isolated ileum, trachea, vas deference and uterus, but inhibited serotonin and oxytocin-induced contraction at concentrations above 3 x 10(-4) and 10(-5) g/ml, respectively; and it also depressed spontaneous movements of the ileum and uterus at concentrations above 3 x 10(-4) g/ml. AZE caused no changes in blood pressure (BP), heart rate (HR), left ventricular pressure, ECG, tracheal pressure (TP), femoral blood flow (FBF) and coronary blood flow (CBF) at doses up to 10 mg/kg, i.v. in anesthetized dogs, but it caused an increase or a decrease in BP, an increase in TP and an increase in CBF at 30 mg/kg, i.v. However, even at 300 mg/kg, p.o., it caused no changes in BP and HR in conscious rats. AZE moderately promoted the charcoal transport. AZE at doses up to 300 mg/kg, p.o. did not affect urine volume, urinary electrolyte excretion, blood glucose and prothrombin time. These results suggest that AZE at anti-ulcer doses of 10-100 mg/kg, p.o. does not have noticeable effects on general pharmacological properties, and there is no marked differences as compared with those of GAS.