Biomedical subjects
Publications and source records attributed to S Cadel.
Piroxicam-beta-cyclodextrin is a novel NSAID; it is a supermolecular inclusion complex designed to improve the risk:benefit ratio of piroxicam. In animal studies it has been shown to be as effective as piroxicam as an anti-inflammatory and analgesic agent but with a more rapid onset of action and reduced gastropathic effects.
This study evaluated the ability of the selective MAO-B inhibitor, L-deprenyl, to reverse cognitive impairments appearing in aged rats, using the reference memory, Morris Water Maze paradigm. L-Deprenyl significantly improved learning and memory deficits associated with old age in doses of 1.25 and 5 mg/kg PO (escape latency measure) and doses of 1.25, 2.5 and 5 mg/kg PO (path length measure). L-Deprenyl also improved reversal learning impairments in doses of 1.25, 2.5 and 5 mg/kg PO, as expressed by the escape latency measure. The data suggest that L-deprenyl possesses potential cognitive enhancement abilities probably due to an increase in dopaminergic activity.
Explore the source record for details and available documents.
Substituted 2-(dialkylamino)-3-formylchromones (II) were obtained from the reaction of substituted 2-(dialkylamino)chromones (I) either with the N,N-dimethylformamide-POCl3 reagent [compounds (IIa-e)] or with dichloromethylmethylether in the presence of TiCl4 [compounds (IIf-i)]. By treating (IIa,f) with hydroxylamine the oximes (IIIa,f) were prepared, which in turn were converted into the nitriles (IVa,f) by treatment with acetic anhydride. Compound (IIa), selected for the smallest steric hindrance of the 2-dialkylamino substituent, by reaction with hydrazines afforded [1]benzopyrano [2,3-c]pyrazole derivatives (VI), whereas reaction of (IIa) with guanidine, benzamidine or S-methylisothiourea gave rise to the formation of 5H-[1]benzopyrano[2,3-d]pyrimidine derivatives (IX). Among the compounds tested for their antiallergic properties, (IIf) showed an appreciable activity, but also high toxicity.
The N,N-disubstituted 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones (III) and isomer 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones (IV) were obtained from the reaction of 2-aminopyridine with the N,N-disubstituted ethyl malonamate/phosphorus oxychloride reagent (II), in refluxing 1,2-dichloroethane. 2-[(N-Benzyl, N-ethyl)amino]derivative (IV b) was also prepared in excellent yield by treating 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (V) with N-ethylbenzylamine. Finally, hydrogenation (Raney Nickel) of 4-[(N-ethyl,N-phenyl)amino]-2H-pyrido[1,2-a]pyrimidin-2-one (III e) afforded 6,7,8,9-tetrahydroderivative (VI) which in turn was treated with potassium borohydride to give 1,6,7,8,9,9a-hexahydroderivative (VII). Several compounds described in the present paper, along with some other compounds (III) and (IV) previously synthesized by us (1,2), were tested for various pharmacological activities. The antiallergic activity (PCA in the rat), even though found in several compounds examined, turned out to be submaximal in any case, in spite of the high dose administered (500 mg/kg p.o. as a rule). The most active compound (the activity being estimated at 0.42 times that of thiaramide hydrochloride) was the 4-aminoderivative (III e). The 2-aminoderivatives (IV) series, was found to have marked antiinflammatory properties (carrageenin oedema in the rat); nevertheless, this activity was related to toxic symptoms with the exception of compound (IV b), almost asymptomatic at the administered dose (200 mg/kg p.o.). Moreover the 2-aminoderivatives (IV) generally showed weak adrenolitic activity in vitro (rat seminal vesicles), which was estimated to be from 100 to 1000 times less than that of phenoxybenzamine.
Through the reaction of resorcin with N,N-dialkylethoxy-carbonylacetamides in suitable conditions 2-(dialkylamino)-5-hydroxychromones (II) were available. Transformation of these compounds into [5-acetoxy-2-(dialkylamino)-4H-chromen-4-ylidene] malononitriles (VII) by reaction with malononitrile in acetic anhydride and treatment of (VII) with hydrochloric acid gave rise to the formation of 5-(dialkylamino)-2-imino-2H-pyrano [4,3,2-de]-1-benzo-pyrans (VIII). Furthermore 5-hydroxychromones (II) when treated with methyl iodide gave the corresponding 5-methoxychromones (III) which in turn yielded 4H-chromen-4-ylidene derivatives (X) by reaction with malononitrile in acetic anhydride. The hydrolysis of the latter compounds with hydrochloric acid resulted in the formation of 2-(dialkylamino)-4-methyl-5-methoxychromenilium salts (XI). Among the compounds which were submitted to pharmacological screening for their antiallergic properties 5-methoxychromone (III a) and 2H-pyrano [4,3,2-de]-1-benzopyran (VIII b) showed a notable activity but also high toxicity.
Since 2-(diethylamino)-7-methoxychromone (III a) showed remarkable activity in the rat PCA test, some modifications to its structure were made. For instance new substituents such as chlorine or nitro group were introduced into the molecule and the diethylamino group modified. Thus, 2-(ethylamino)-7-methoxychromone (IX) was prepared by treating 3-methoxyphenol with N-ethylethoxycarbonylacetamide in the presence of phosphorus oxychloride. In this case a small amount of 4-chloro-7-methoxycoumarin was also isolated from the reaction mixture. Moreover compounds (XIV), (XV), (XVII) structurally related to sodium cromoglycate were prepared. The pharmacological screening of some compounds showed a useful antiallergic activity.
In several animal models orally administered morniflumate, the beta-morpholinoethyl ester of niflumic acid, proved almost equal to the parent compound in anti-inflammatory, analgesic and antipyretic activity with the advantage of complete freedom from the ulcerogenic effects of the acidic parent compound. Further, it was 5 times less active in intestinal perforation experiments and 10 times less toxic in acute toxicity experiments than niflumic acid. Bioavailability and pharmacokinetics tests after oral and intravenous administration suggest that morniflumate is absorbed as such from the gastrointestinal tract and then undergoes rapid hydrolysis in the plasma, releasing the free acidic form, the molecule responsible for the pharmacological effects. In addition to being free from ulcerogenic effects, the ester actually displayed a gastroprotective effect against the ulcerogenic effects of niflumic acid; this finding is discussed in the light of the concept of 'cytoprotection' recently reported for a series of mild gastric irritants.
An experimental study on morniflumate, the beta-morpholinoethyl ester of niflumic acid, was undertaken in the rat to test its gastroprotective and "cytoprotective" properties and to assess its effects on gastric secretion and on the prostaglandin contents in the stomach wall. Morniflumate induced intense and usually dose-dependent inhibition of the gastric hemorrhagic lesions caused by acetylsalicylic acid, indomethacin, diclofenac, ketoprofen, naproxen and phenylbutazone and of the gastric necrotic lesions caused by absolute ethanol, HCl 0.6 mol l-1, NaOH 0.2 mol l-1 and NaCl 25%. Morniflumate also exerted marked inhibition of gastric acid secretion both in normal and in pylorus-ligated rats. The compound raised the concentration of "cytoprotective" prostaglandins in the glandular portion of the stomach but did not reverse the synthesis-block effect of the ulcerogenic nonsteroidal anti-inflammatory drugs whose gastric effects it inhibited.
A simple but accurate inhalation procedure for investigating the activity of antiasthmatic drugs is proposed. The procedure consists of the forced insufflation of the powdered drug, blended with micronised lactose, direct into the tracheobronchial tree. Beta-adrenoceptor agonists (isoproterenol and fenoterol) and antimuscarinics (atropine and ipratropium bromide) were tested using the method of Konzett and Rössler in the guinea-pig; their bronchodilator effects were tested both after forced insufflation and after intravenous administration. The proposed inhalation method supplied close-response curves qualitatively comparable to those obtained by the intravenous route, with the added advantage of more detailed information on the time-course effect. Forced insufflation may be the best procedure for investigating antiasthmatic drugs intended for use as inhalants.
Explore the source record for details and available documents.
Both the topical and the percutaneous antiinflammatory potencies of a topical formulation of piroxicam were investigated using as reference standards nonsteroid and steroid antiinflammatory drugs having the same excipient base (indometacin and hydrocortisone acetate) or as topical formulations available in commerce (ketoprofen and oxyphenbutazone). In regard to the topical activity, piroxicam antagonized significantly both the croton oil edema and the UV-erythema; against the latter experiment also ketoprofen exerted intense inhibition, whilst oxyphenbutazone proved inactive. In the case of percutaneous application (carrageenin edema), piroxicam was appreciably more effective than reference compounds. In the latter experimental model piroxicam applied to the "inflamed" hind paw exerted 64% of the potency of oral piroxicam, but 2.3-2.5 times the percutaneous potency of piroxicam applied to other regions of the skin. These findings combined with the results of the bioavailability tests suggest that the percutaneous application of piroxicam may be exploited to advantage in clinical practice.
An experimental comparative study was conducted on 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam), indometacin and phenylbutazone for antiinflammatory and analgesic effects and for gastric and intestinal damage. In some of the experimental models used a comparison was made between oral and rectal piroxicam. The upshot was that: the antiinflammatory activity of piroxicam on carrageenin edema in the rat is equivalent by oral and by rectal route, about twice that of indometacin and 20 times that of phenylbutazone. The inhibition of leucocyte migration in the rat was equal to that of indometacin and 20 times that of phenylbutazone. The analgesic activity of piroxicam (phenylquinone writhings in the mouse) was about 1/4 that of indometacin and 70 times that of phenylbutazone. The ulcerogenic effect of piroxicam on the stomach of the rat was about 1/3 that of indometacin and 5 times greater than that of phenylbutazone. Rectal administration halves the ulcerogenic effect of oral piroxicam. The intestinal perforating effect of piroxicam in the rat is about 1/6 that of indometacin and about 15 times that of phenylbutazone. The therapeutic index, i.e., the ratio of antiinflammatory potency to gastrointestinal damage, proved to be appreciably higher for piroxicam than for the two reference standards. Rectal administration carries an even higher therapeutic index and so appears to be a potentially valuable alternative route in clinical practice.
Explore the source record for details and available documents.
As part of research on 1H-pyrazole[1,2-b]phthalazine compounds with anti-inflammatory activity, the results of preliminary pharmacological and toxicological investigation of 2,2-diethyl-2,2,5,10-tetrahydro-1H-pyrazolo[1,2-b]phthalazine-1,3-dione are reported.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.