A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory and analgesic drug.

The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. This study was designed to screen and assess the anti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives, newly synthesized as potential COX-2 inhibitors at the Faculty of Pharmacy, Alexandria University and compared to indomethacin and celecoxib. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. On the basis of their apparent anti-inflammatory activity, four compounds with different substitutions were selected for the evaluation of their analgesic activity using the formalin-induced hyperalgesia and hot-plate tests. Compound AD 532, ((4-(3-(4-Methylphenyl)-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide)), showed very promising results. In the single-dose and subchronic toxicity studies, compound AD 532 showed no ulcerogenic effect and produced minimal effects on renal function. Furthermore, compound AD 532 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It is concluded that compound AD 532 appears to be a promising and safe option for the management of chronic inflammatory conditions. This study recommends more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity.

Interaction between nitric oxide and dopaminergic transmission in the peripheral control of penile erection.

As the peripheral role of dopamine in the mediation of penile erection was recently identified, its potential role in the modulation of NO action and whether D1 or D2 receptors are involved in this potential modulation was investigated. The isolated rabbit corpus cavernosum and measurement of intracavernosal pressure in the anesthetized rat model were used. The selective D1 antagonist SCH23390 but not the D2 antagonist sulpiride reduced the inhibitory effect of N(G)-nitro-L-arginine (L-NNA) and the potentiatory effect of sildenafil on erectile responses. L-NNA did not change the inhibitory effect of SCH23390 or the potentiatory effect of apomorphine but enhanced the effect of high-dose fenoldopam on intracavernosal pressure. Similarly, fenoldopam produced 47.30 ± 6.89% potentiation of relaxation of corpus cavernosum in absence of L-NNA and 80 ± 9.34% potentiation in its presence at 3 Hz. The effect of sildenafil was greatly reduced by pretreatment with SCH23390 or sulpiride and completely abolished by their combination. This study supports the role played by D1 receptors peripherally in the control of penile erection. Absence of NO may potentiate the effect of D1 receptor on erection. Activation of D1 receptors may be involved in the synthesis of NO in the corpus cavernosum or may activate the role of NO in erection.

Peripheral modulation of dopaminergic receptors affects erectile responses in rats.

Clinical observations have suggested that dopaminergic mechanisms are involved in the regulation of male sexual responses, including erection. Apomorphine was initially reported to exert its erectogenic effects by modifying central dopaminergic activity. This study aimed primarily at evaluating and investigating the effect of apomorphine on erectile functions in rats and its potential effects on the cardiovascular system, as well as the possible role of dopaminergic stimulation in the peripheral control of erection. Measurement of intracavernosal pressure changes elicited by electrical stimulation of the cavernosal nerve in anaesthetized rats and mating tests were used. SCH23390, the D1 receptor antagonist, attenuated penile response to electrical stimulation. Intravenous administration of apomorphine in low dose (100 microg/kg), but not in high dose, significantly potentiated erectile responses to electrical stimulation. Intracavernosally injected apomorphine (50 microg/kg) significantly potentiated the filling rate of the corpora cavernosa 5 min. after injection, and did not induce erection in absence of electrical stimulation. In addition, apomorphine amplified the male sexual and copulatory behaviour by reducing ejaculation, mount and intromission latencies, and significantly increasing the number of ejaculations per session. However, apomorphine produced rapid and long-lasting hypotension and potentiated the hypotension and tachycardia associated with nerve-stimulated penile erection. Our results suggest that D1-dopaminergic receptors may be functionally involved in the peripheral mediation of penile erection. Apomorphine may amplify sexual and copulatory behaviour and may also, by a complementary role, amplify neurogenically mediated erections by acting in the periphery.