Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

Santos, Jean Leandro dos; Moreira, Vanessa; Campos, Marcelo Lattarulo; Chelucci, Rafael Consolin; Barbieri, Karina Pereira; Souto, Pollyana Cristina Maggio de Castro; Matsubara, Márcio Hideki; Teixeira, Catarina; Bosquesi, Priscila Longhin; Peccinini, Rosângela Gonçalves; Chin, Chung Man

doi:10.3390/ijms131115305

Cited by 12 publications

(13 citation statements)

References 45 publications

(41 reference statements)

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“…This result supports previous findings that masking the carboxylic acid moiety of NSAIDs gives safer compounds [5,11]. …”

Section: Resultssupporting

confidence: 93%

“…Previous studies have reported other forms of diclofenac prodrugs with lower GI adverse effects, or with properties that aid delivery of the drug to certain distal body organs. For example, 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without GI ulceration effect [ 11 , 12 ]. Diclofenac ester prodrugs were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium [ 13 , 14 , 15 , 16 , 17 ].…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

2014

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The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.

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“…This result supports previous findings that masking the carboxylic acid moiety of NSAIDs gives safer compounds [5,11]. …”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

2014

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“…The observations that the fractions of the ethanol layer decreased and increased the ulcer indices and curative ratios respectively of the treated rats might be attributed to the anti-oxidant vitamin content and proximate composition of the ethanol layer of the chloroform-ethanol extract of the leaves of D. edulis as shown by the results of their analyses. Also, the finding that diclofenac induced ulcer in all the treated rats is in accord with the reports of Verma et al (2011), Santos et al (2012), Wandale et al (2012) and Khan and Khan (2013). The mechanism by which diclofenac and other NSAIDs cause injury to the gastric mucosa is mainly due to the inhibition of cyclooxygenase and suppression of prostaglandinmediated effects on mucosal protection.…”

Section: Discussionsupporting

confidence: 90%

Anti-ulcerogenic evaluation of the fractions of the ethanol layer of the chloroform-ethanol extract of the leaves of Dacryodes edulis

Christian¹

2017

Afr. J. Pharm. Pharmacol.

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In traditional medicine, the leaves of Dacryodes edulis are utilised in the treatment of gastric ulcer and hence, the chloroform and ethanol layers of the chloroform-ethanol extract of the leaves of D. edulis were evaluated for their anti-oxidant vitamin contents and proximate compositions. Based on preliminary investigations, the more promising layer (ethanol layer) was further fractionated and the effects of the fractions on ulcer index and curative ratio of diclofenac-ulcerated Wistar rats were determined using standard methods. The anti-oxidant vitamin contents of the chloroform and ethanol layers showed the following: vitamins A (1.83 ± 0.08 and 1.79 ± 0.08 μg/100 g), C (0.62 ± 0.05 and 0.79 ± 0.03 mg/100 g) and E (1.17 ± 0.07 and 1.04 ± 0.05 mg/100 g) respectively. The proximate compositions of the chloroform and ethanol layers were: moisture (3.15 ± 0.11 and 4.08 ± 0.18%), crude fibre (5.41 ± 0.29 and 5.29 ± 0.27%), ash (5.09 ± 0.27 and 4.12 ± 0.18%), crude fats (4.43 ± 0.13 and 3.98 ± 0.12%), crude proteins (17.24 ± 0.43 and 17.80 ± 0.29%) and carbohydrates (64.68 ± 1.40 and 64.73 ± 1.35%) respectively. Each of the chloroform and ethanol layers of the chloroform-ethanol extract was found to be safe at a dose as high as 5000 mg/kg body weight (b.w). At the two doses (100 and 200 mg/kg b.w), the n-hexane, chloroform, ethyl acetate and methanol fractions of the ethanol layer dose-dependently decreased and increased the ulcer indices and curative ratios respectively of the rats in the test groups when compared with those of the rats in the ulcer-untreated group albeit these effects were not significant (p>0.05) except those of the methanol fraction at the dose of 200 mg/kg b.w. Results of the methanol fraction (200 mg/kg b.w only) were comparable to those of the standard anti-ulcer drug, ranitidine at the dose of 150 mg/kg b.w. The data of this study indicate that the methanol fraction of the ethanol layer of the chloroform-ethanol extract of the leaves of D. edulis possess remarkable antiulcerogenic effect and might serve as source of novel drugs for ulcers in future.

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“…The pharmacological activity of NSAIDs is linked to the suppression of prostaglandin biosynthesis from arachidonic acid through inhibiting the enzyme cyclooxygenases [4]. In order to support the results of in vivo study, molecular docking study was executed.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates

Ibrahim

Elsaman

Al-Nour

2018

International Journal of Medicinal Chemistry

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The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff's bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff's condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142).

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Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

Cited by 12 publications

References 45 publications

Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug

Anti-ulcerogenic evaluation of the fractions of the ethanol layer of the chloroform-ethanol extract of the leaves of Dacryodes edulis

Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates

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