1 The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC,,. CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10-50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50s: > 100 gM) against PDE types 1, 2, 3 and 5.2 Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50=0.03 mg kg-'). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10-100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, ,B-sympathomimetics or ,B-sympatholytics. 3 Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01 -1 mg kg-', i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4 Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general antiinflammatory activity. 5 In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001 -1.0 mg kg-', i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg-') did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6 These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.

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1 The activity of CDP840, a novel, potent and selective cyclic nucleotide phosphodiesterase type 4 (PDE 4) inhibitor, was evaluated in guinea-pig models (in vitro and in vivo) of bronchospasm, ozoneinduced airway hyperresponsiveness (AHR) and non-cholinergic bronchoconstriction. Comparisons were made with (i) other PDE 4 inhibitors: CT1731 (S-enantiomer of CDP840), rolipram, RP73401 and (ii) the clinically used agents salbutamol and theophylline.2 CDP840 relaxed isolated trachea, under basal tone (EC5o 4.5 + 1.1 gM) being 17 fold less potent than rolipram (EC50 0.26 + 0.13 gM) but attaining the same Ea (83 + 6% of the response to 300 gM papaverine).3 CDP840 relaxed tracheae pre-contracted with carbachol (IC25 39 +9 gM) and histamine (IC25 4+1 gM) producing monophasic curves. Stereoselectivity was not observed with CT1731 against either carbachol (IC25 33±11 Mm) or histamine (IC25 17 + 10 gM). Aminophylline was 1.6 fold (carbachol) and 11 fold (histamine) less potent than CDP840. Rolipram and RP73401 produced tri-phasic relaxation curves but were of similar potency (at the IC25 level) to CDP840 against carbachol (rolipram 18 + 5 MM, RP73401 39±1 Mm) whereas against histamine they were approximately 20 fold more potent (rolipram 0.2 + 0.1 gM, RP73401 0.2 + 0.1 gM). In producing > 30% (carbachol) and > 60% (histamine) relaxation these inhibitors had similar potency and were poor compared to salbutamol.4 Pre-incubation with CDP840 (10 gM) did not antagonize histamine-induced contraction of isolated trachea; however, it did cause a slight potentiation of the subsequent relaxation to salbutamol (IC50 23+1 to 15+2nM) 5 Pretreatment (1 h) with either CDP840 (1 mg kg-', i.p. or 3 mg kg-', i.v.) or rolipram (1 mg kg-', i.p.) did not bronchodilate or antagonize bronchospasm due to inhaled histamine in anaesthetized, ventilated guinea-pigs. Salbutamol (1 mg kg-', i.p.) did not bronchodilate but caused a parallel 7 fold rightward shift in the histamine dose-response curve. 6 Stimulation of the vagus nerve in the presence of atropine resulted in a frequency-related bronchoconstriction. CDP840 and rolipram (i.v.) inhibited the response being -equipotent (EC50 -10 Mg kg-'). Neither drug inhibited bronchospasm to inhaled substance P. 7 CDP840 (1-10 Mg kg-' i.p.) dose relatedly inhibited ozone-induced bronchoconstriction. CT1731 (1 mg kg-'), rolipram (1 mg kg-'), RP73401 (10 Mg kg-') and aminophylline (10 mg kg-1) had no effect. Ozone-induced AHR to inhaled histamine was inhibited by CDP840 in a dose-related manner, 10 Mg kg-1 abolishing the AHR. This effect was stereoselective as CT1731 was 30 fold less potent than CDP840. Rolipram was 100 fold less potent and RP73401 and aminophylline had no effect. CDP840 was orally active being 10 fold less potent compared to i.

Antioxidants are free radical scavengers and protect living organisms against oxidative damage to tissues. Experimental evidence implicates oxygen-derived free radicals as important causative agents of aging and the present study was designed to evaluate the age-related effects of deprenyl on the antioxidant defense in the cerebellum of male Wistar rats. Experimental rats of three age groups (6, 12, and 18 months old) were administered with liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p) and levels of diagnostic marker enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase) in plasma, lipid peroxides, reduced glutathione and activities of glutathione-dependent antioxidant enzymes (glutathione peroxidase and glutathione-S-transferase) and antiperoxidative enzymes (catalase and superoxide dismutase) in the cerebellar tissue were determined. Intraperitonial administration of deprenyl (2 mg/kg body weight/day for a period of 15 days) significantly (p<0.05) attenuated the agerelated alterations noted in the levels of diagnostic marker enzymes plasma of experimental animals. Deprenyl also exerted an antioxidant effect against aging process by hindering lipid peroxidation to an extent. Moderate rise in the levels of reduced glutathione and activities of glutathione-dependent antioxidant enzymes and antiperoxidative enzymes was also observed. The results of the present investigation indicated that the protective potential of deprenyl was probably due to the increase of the activity of the free radical scavenging enzymes or to a counteraction of free radicals by its antioxidant nature or to a strengthening of neuronal membrane by its membrane-stabilizing action. Histopathological observations also confirmed the protective effect of deprenyl against the age-related aberrations in rat cerebellum. These data on the effect of deprenyl on parameters of normal aging provides new additional information concerning the anti-aging potential of deprenyl.

Stress induced lipofuscinosis was studied in rat cerebellum. 3 month old wistar rats were subjected to restraint stress by keeping them immobile for 24, 48 and 72 hours duration. This was achieved in specially prepared cages which allowed no space for the rats to move; giving a stress to the animal. The cerebella from the stressed groups rats were removed after the experiment and were processed for fluorescent microscopical, histochemical and fluorimetric study of lipofuscin. The lipofuscin content in the Purkinje neurons was compared with that of the control rats which were of the same age, size and weight as of the experimental rats. The results showed that the lipofuscin content in the neurons of the experimental rats was more than that of the control ones. In gist, while 24 hrs. stress caused a 28.9% increase in lipofuscin content, 48 hrs. stress resulted in a 38.3% increase. This shows that restraint stress can be a good experimental model for lipofuscinogenesis and ageing studies.