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Analgesic and Toxicity Studies of Aminoacetylenic Isoindoline-1,3-dione Derivatives.

Shakir R, Muhi-Eldeen ZA, Matalka KZ, Qinna NA - ISRN Pharmacol (2012)

Bottom Line: We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines.Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control.The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, Petra University, P.O. Box 961343, Amman 11196, Jordan.

ABSTRACT
We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines. In the present study and due to efficacy reasons, we are exploring only two of these compounds, namely, ZM4 and ZM5, to reveal their analgesic activity and toxicity. Following oral administration, both compounds were effective in reducing significantly (P < 0.05-0.001) acetic acid-induced writhing behavior, hot plate latency test, and formalin-induced paw licking time as antinociceptive indicators in mice and rats, respectively. Regarding the toxicity, the acute (20, 50, and 150 mg/kg) and repeated oral administration (10, 20, and 50 mg/kg) of these compounds for ten days did not produce any mortality and the compounds were considered well tolerated. However, repeated oral administration of 50 mg/kg of both compounds induced erythropoiesis by means of increasing significantly red blood cells, hemoglobin, and packed cell volume. Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control. The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of ZM4 and ZM5.
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Related In: Results  -  Collection


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fig1: Chemical structures of ZM4 and ZM5.

Mentions: Therefore, we have developed new chemical compounds that incorporate isoendoline-1,3-dione and acetylenic derivatives to induce anti-inflammatory and analgesic activities, respectively [8–11] (Figure 1). In addition, we incorporated acetylenic group in order to increase the selective inhibition toward COX-2 isoform [12]. This unique combination represents a new series of compounds as potential anti-inflammatory agents as has been shown to reduce carrageenan-induced paw edema and structurally differs from the generally used drugs that contain acidic, enolic, sulfonamide, or sulfon groups which should exclude the direct insult on the gastrointestinal [11]. Of all the molecules reported in our previous studies, ZM4 and ZM5 were found to possess the best COX-2 inhibition activities, better in reducing carrageenan-inducing inflammation, and modulate proinflammatory and anti-inflammatory cytokines [11, 13, 14] and therefore were selected for further efficacy and safety investigations. The aim of the present study therefore is to study the analgesic activity of these compounds in addition to studying their toxicity and ulcerogenic effect on the stomach following single and repeated administration.


Analgesic and Toxicity Studies of Aminoacetylenic Isoindoline-1,3-dione Derivatives.

Shakir R, Muhi-Eldeen ZA, Matalka KZ, Qinna NA - ISRN Pharmacol (2012)

Chemical structures of ZM4 and ZM5.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539427&req=5

fig1: Chemical structures of ZM4 and ZM5.
Mentions: Therefore, we have developed new chemical compounds that incorporate isoendoline-1,3-dione and acetylenic derivatives to induce anti-inflammatory and analgesic activities, respectively [8–11] (Figure 1). In addition, we incorporated acetylenic group in order to increase the selective inhibition toward COX-2 isoform [12]. This unique combination represents a new series of compounds as potential anti-inflammatory agents as has been shown to reduce carrageenan-induced paw edema and structurally differs from the generally used drugs that contain acidic, enolic, sulfonamide, or sulfon groups which should exclude the direct insult on the gastrointestinal [11]. Of all the molecules reported in our previous studies, ZM4 and ZM5 were found to possess the best COX-2 inhibition activities, better in reducing carrageenan-inducing inflammation, and modulate proinflammatory and anti-inflammatory cytokines [11, 13, 14] and therefore were selected for further efficacy and safety investigations. The aim of the present study therefore is to study the analgesic activity of these compounds in addition to studying their toxicity and ulcerogenic effect on the stomach following single and repeated administration.

Bottom Line: We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines.Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control.The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, Petra University, P.O. Box 961343, Amman 11196, Jordan.

ABSTRACT
We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines. In the present study and due to efficacy reasons, we are exploring only two of these compounds, namely, ZM4 and ZM5, to reveal their analgesic activity and toxicity. Following oral administration, both compounds were effective in reducing significantly (P < 0.05-0.001) acetic acid-induced writhing behavior, hot plate latency test, and formalin-induced paw licking time as antinociceptive indicators in mice and rats, respectively. Regarding the toxicity, the acute (20, 50, and 150 mg/kg) and repeated oral administration (10, 20, and 50 mg/kg) of these compounds for ten days did not produce any mortality and the compounds were considered well tolerated. However, repeated oral administration of 50 mg/kg of both compounds induced erythropoiesis by means of increasing significantly red blood cells, hemoglobin, and packed cell volume. Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control. The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

No MeSH data available.


Related in: MedlinePlus