The phthalimide analogues N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide exhibit activity in experimental models of inflammatory and neuropathic pain.

BACKGROUND: Phthalimide analogues devoid of the glutarimide moiety exhibit multiple biological activities, thus making them candidates for the treatment of patients with different diseases, including those with inflammatory and painful disorders. In the present study, the activities of five phthalimide analogues devoid of the glutarimide moiety (N-hydroxyphthalimide, N-hydroxymethylphthalimide, N-3-hydroxypropylphthalimide, N-carboxy-3-methylphthalimide, N-carboxymethyl-3-nitrophthalimide) were evaluated in experimental models of acute and chronic inflammatory and neuropathic pain. METHODS: The phthalimide analogues were administered per os (po) in Swiss mice or Wistar rats. Nociceptive response induced by formaldehyde and mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve or intraplantar (ipl) injection of complete Freund's adjuvant (CFA) were used as experimental models of pain. RESULTS: N-carboxymethyl-3-nitrophthalimide (700 mg/kg, -1 h) inhibited the second phase of the nociceptive response induced by the intraplantar injection of formaldehyde in mice. N-3-hidroxypropylphthalimide (546 mg/kg, -1 h) inhibited both phases of the nociceptive response induced by formaldehyde. Treatment of rats with N-carboxymethyl-3-nitrophthalimide (700 mg/kg) or N-3-hydroxypropylphthalimide (546 mg/kg) inhibited the mechanical allodynia induced by CCI of the sciatic nerve or ipl injection of CFA in rats. Intraperitoneal administration of the opioid antagonist naltrexone (10 mg/kg, -1.5 h) attenuated the antinociceptive activity of N-carboxymethyl-3-nitrophthalimide (700 mg/kg) in the model of nociceptive response induced by formaldehyde. CONCLUSIONS: N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide, two phthalimide analogues devoid of the glutarimide moiety, exhibited activities in different experimental models of pain, including models of chronic inflammatory and neuropathic pain.

Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund's adjuvant.

BACKGROUND: The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund's adjuvant (CFA) in rats. METHODS: Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500mg/kg) or thiamine (150, 300 or 600mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5mg/kgday, po) was administered every three days. RESULTS: CFA induced long lasting mechanical allodynia and paw edema. Elevation of body temperature was observed for a short period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but partially inhibited mechanical allodynia. Riboflavin (500mg/kg) and thiamine (600mg/kg) exacerbated the anti-inflammatory activity of dexamethasone. Riboflavin, thiamine and dexamethasone reduced TNF-α and IL-6 production. The association of dexamethasone with thiamine induced greater inhibition of IL-6 production when compared with that induced by dexamethasone. CONCLUSIONS: Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.

2-Phthalimidethanol and 2-phthalimidethyl nitrate inhibit mechanical allodynia, neutrophil recruitment and cytokine and chemokine production in a murine model of articular inflammation.

BACKGROUND: Phthalimide analogs have been shown to exhibit anti-inflammatory, analgesic and immunomodulatory activities in different preclinical assays. This study aimed to investigate the potential role of 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO) in a murine model of antigen-induced articular inflammation. METHODS: Articular inflammation was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in the knee joint of immunized male C57BL/6J mice. The animals were pre-treated with PTD-OH or PTD-NO (500mg/kg, per os, - 1h). Nociceptive threshold was measured using an electronic von Frey apparatus. The total number of leukocytes in the synovial cavity was determined. Concentrations of tumor necrosis factor (TNF)-α and CXCL-1 and myeloperoxidase (MPO) activity were determined in periarticular tissue. RESULTS: Both PTD-OH and PTD-NO inhibited at similar extent the mechanical allodynia, neutrophil recruitment to the synovial cavity and periarticular tissue and TNF-α and CXCL-1 production induced by intra-articular challenge with mBSA in immunized mice. CONCLUSIONS: PTD-OH and PTD-NO exhibit a marked activity in a murine model of antigen-induced articular inflammation in immunized animals. These results reinforce the interest in the investigation of phthalimide analogs devoid of the glutarimide ring as candidates to analgesic and anti-inflammatory drugs.

Nicorandil inhibits neutrophil recruitment in carrageenan-induced experimental pleurisy in mice.

Nicorandil is a drug characterized by the coupling of a nitric oxide (NO) donor to nicotinamide. We have previously demonstrated that nicotinamide exhibits activity in different models of pain and inflammation. Now, we investigated the effects induced by per os (p.o.) administration of nicorandil (25, 50 or 100mg/Kg) on neutrophil recruitment in a carrageenan-induced model of pleurisy in mice. Effects induced by nicorandil (100mg/kg) were compared with those induced by equimolar doses of nicotinamide (58mg/kg) and N-(2-hydroxyethyl)-nicotinamide (NHN; 79mg/kg). We also investigated whether effects on the production of inflammatory mediators play a role in the activity of nicorandil. P.o. nicorandil, 0.5h before and 1h after the i.pl. injection of carrageenan, reduced neutrophil recruitment. However, equimolar doses of nicotinamide or NHN failed to induce such effect. Single treatment (previous or late) with nicorandil (100mg/Kg, p.o.) also reduced neutrophils recruitment, although to a lesser extent when compared to the double treatment. Nicorandil reduced the concentrations of interleukin-1ß, CXCL-1 and prostaglandin E2 in the pleural exudate. Concluding, we demonstrated the activity of nicorandil in a model of pleurisy induced by carrageenan. This activity was characterized by reduction of the neutrophil accumulation and inhibition of production of inflammatory mediators. The effects induced by nicorandil on the leukocytes recruitment and production of inflammatory mediators contribute to a better understanding of its clinical benefits and indicate that these benefits may be due to its vasodilating and anti-inflammatory activities.

Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms.

The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD-OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceptive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1h before intraplantar injection of formaldehyde, inhibited both phases of the nociceptive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity.

Activities of 2-phthalimidethanol and 2-phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema.

The reintroduction of thalidomide in the pharmacotherapy greatly stimulated the interest in the synthesis and pharmacological evaluation of phthalimide analogs with new and improved activities and also greater safety. In the present study, we evaluated the activities of two phthalimide analogs devoid of the glutarimide ring, namely 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO), in experimental models of inflammatory pain and edema in male C57BL/6J mice. Intraplantar (i.pl.) injection of carrageenan (300 µg) induced mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-OH and PTD-NO (750 mg/kg) and also by thalidomide (500 or 750 mg/kg). The edema induced by carrageenan was also inhibited by previous p.o. administration of PTD-OH (500 and 750 mg/kg) and PTD-NO (125, 250, 500 or 750 mg/kg), but not by thalidomide. Carrageenan increased tumor necrosis factor (TNF)-α and CXCL1 concentrations and also the number of neutrophils in the paw tissue. Previous p.o. administration of PTD-NO (500 mg/kg) reduced all the parameters, while PTD-OH (500 mg/kg) reduced only the accumulation of neutrophils. Thalidomide, on the other hand, was devoid of effect on these biochemical parameters. Plasma concentrations of nitrite were increased after p.o. administration of the phthalimide analog coupled to a NO donor, PTD-NO (500 mg/kg), but not after administration of PTD-OH or thalidomide. In conclusion, our results show that small molecules, structurally much simpler than thalidomide or many of its analogs under investigation, exhibit similar activities in experimental models of pain and inflammation. Finally, as there is evidence that the glutarimide moiety contributes to the teratogenic effect of many thalidomide analogs, our results indicate that phthalimide analogs devoid of this functional group could represent a new class of analgesic and anti-inflammatory candidates with potential greater safety.