NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs
Namdev BorhadeAsif R. PathanSomnath HalderManoj KarwaMini DhimanVenu PamidiboinaMachhindra GundJagannath Janardhan DeshattiwarSunil V. MaliNitin DeshmukhS SenthilkumarParikshit GaikwadSanthosh Goud TipparamJayesh MudgalMilan Chandra DuttaAslam BurhanGajanan ThakreAnkur SharmaShubhada DeshpandeDattatraya C. DesaiNauzer P. DubashArun K. JainSomesh SharmaKumar Venkata Subrahmanya NemmaniApparao Satyam
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In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E(2) (PGE(2)) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.Keywords:
Flurbiprofen
Ibuprofen
Diclofenac
Ketoprofen
Anti-inflammatory
Antipyretic
Flurbiprofen
Ibuprofen
Diclofenac
Antipyretic
Acetaminophen
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Flurbiprofen
Ketoprofen
Antipyretic
Ibuprofen
Anti-inflammatory
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Nabumetone is a nonacidic nonsteroidal anti-infl ammatory drug (NSAID) formulated as a pharmacologically inactive prodrug that becomes active only after absorption, predominantly in the small intestine, and through hepatic conversion to its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA). This metabolite is structurally similar to naproxen, and is a potent inhibitor of prostaglandin synthesis, preferentially via the cyclooxygenase-2 (COX-2) pathway [1]. Nabumetone has been recommended as a safe alternative in most patients with hypersensitivity reactions to NSAIDs [2]. A 52-year-old woman complained of various episodes of itching, burning, and erythematous plaques—one on her forehead (1-2 cm diameter) and the other in the infraclavicular area (5 cm diameter)—in the previous 2 years. The plaques became red-brown and disappeared within 1 week without treatment. With time, the infraclavicular lesion persisted as brown pigmentation. After various episodes the patient noticed that the eruption might be related to the intake of naproxen tablets, but she was not sure. The last episode had occurred 1 year before consultation and she had subsequently tolerated oral acetylsalicylic acid, paracetamol, and ibuprofen. In order to confi rm the suspicion of fi xed drug eruption (FDE) due to naproxen, patch tests (30% in petrolatum) were carried out with this drug and other propionic acid derivatives (ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, flurbiprofen, and ketorolac) and NSAIDs (diclofenac, indomethacin, benzydamine, bufexamac, phenylbutazone, piroxicam, and nabumetone). The tests were performed on previous lesions with naproxen and on the back (normal skin) with all the drugs mentioned. Readings at 48 and 96 hours were negative in all cases. An oral challenge test with naproxen was performed in the hospital after obtaining informed consent. Two hours later, lesions with the same characteristics as those described earlier reappeared at the same locations. With the purpose of identifying safe alternatives to naproxen, we performed oral challenge tests with dexketoprofen and nabumetone 6 weeks later. While dexketoprofen proved negative, nabumetone (1 g) produced an identical reaction to that induced by naproxen 2 hours after administration. The patient had not taken nabumetone previously. Nabumetone is generally a well-tolerated NSAID. The most frequent adverse effects are those commonly seen with COX inhibitors, namely diarrhea, dyspepsia, headache, abdominal pain, and nausea. Dermatological reactions such as pseudoporphyria have been associated with nabumetone, but systemic hypersensitivity reactions are not common [1]. To our knowledge, this is the fi rst report of FDE due to nabumetone and our case is particularly interesting because our patient had experienced previous FDE to naproxen. NSAIDs are common offending agents in FDE, and FDE to naproxen has been reported in single case reports and in some studies with a prevalence ranging from 3% [3] to 23% [4]. Lesions induced by naproxen frequently affect the lips, the face, and the neck [4]. False negative results are common when testing topical naproxen on both normal skin and previous FDE lesions, and oral provocation is still the most reliable method for the diagnosis of FDE [5,6]. Although cross-reactivity between drugs with similar molecular structures is possible, in a previous study, we did not fi nd cross-reactivity between naproxen and other propionic acid derivatives [6]. However, in the case reported here, the administration of nabumetone (a naphthylalkanone NSAID) was positive. In our opinion, the similarity of the chemical structure of naproxen and the active metabolite of nabumetone could be the reason for this reaction. Because there are no references in the literature to nabumetone intolerance in patients with FDE to naproxen, we believe that our case is interesting as it might help to prevent such reactions in the future.
Nabumetone
Ketoprofen
Ibuprofen
Diclofenac
Etodolac
Flurbiprofen
Antipyretic
Drug eruption
Mefenamic acid
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Skin photosensitivity is a side-effect reported for several non-steroidal anti-inflammatory drugs (NSAID). In vitro studies have revealed phototoxic properties in a majority of these compounds with a preponderance for derivatives of propionic acid. Fourteen NSAIDs, the majority commercial preparations in clinical use, have been assayed by the mouse tail technique for in vivo phototoxicity evaluation. Intraperitoneal single doses in the range 12.5-200 mg/kg were given in combination with UVA irradiation for 5 h (total dose 54 J/cm2). The phototoxic reaction was measured 24 h later as the wet weight increase of tail tissue over non-irradiated, drug-treated controls. Four out of 9 propionic acid derivatives were phototoxic: tiaprofenic acid, carprofen, benoxaprofen and naproxen. Among NSAID compounds of other chemical structure only diclofenac and diflunisal were weakly photoactive. The propionic acid derivatives fenoprofen, flurbiprofen, ibuprofen, indoprofen and ketoprofen were negative, as were azapropazone, piroxicam and sulindac among the unrelated compounds. Phototoxicity is one important aspect of NSAID photosensitization. It is advisable to perform predictive studies including in vivo models, such as the mouse tail technique, before new NSAIDs are introduced on the market.
Phototoxicity
Ketoprofen
Flurbiprofen
Diflunisal
Ibuprofen
Diclofenac
Sulindac
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In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E(2) (PGE(2)) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.
Flurbiprofen
Ibuprofen
Diclofenac
Ketoprofen
Anti-inflammatory
Antipyretic
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Phenylacetic acid
Anti-inflammatory
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The analgesic effect of 10 anti-inflammatory drugs was compared using a single-blind method in 90 patients with rheumatoid arthritis. Each patient received two different drugs, for three days each and each drug was evaluated in 18 patients. After the trial, the patients considered which of the drugs they preferred. The greatest relief from pain was achieved by diclofenac, indomethacin, naproxen and tolfenamic acid, each of these being preferred by the majority of patients and being significantly (p less than 0.01) better than the least effective drugs ketoprofen and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were considered intermediate in efficacy.
Ketoprofen
Ibuprofen
Diclofenac
Carprofen
Antiinflammatory drug
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3,5-Dimethyl pyrazole 3a-d and 3-methyl pyrazol-5-one 4a-d derivatives of diclofenac, ibuprofen, flurbiprofen and 2,4-dichlorophenoxy acetic acid have been synthesized. In addition, substituted pyrazoline derivatives of ibuprofen 6a-e have also been prepared by treating different chalcones 5a-e with ibuprofen hydrazide. Some of the newly synthesized compounds are screened for anti-inflammatory activity and few compounds showing 80% activity are selected for analgesic, ulcerogenic and lipid peroxidation activities.
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Flurbiprofen
Diclofenac
Anti-inflammatory
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Pyrazole
Antipyretic
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Abstract Preclinical Research The aim of this study was to evaluate the efficacy of multiple applications of S(+)‐flurbiprofen plaster (SFPP), a novel Nonsteroidal anti‐inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant‐induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm × 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)−1 and COX‐2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti‐inflammatory effects clinically. Drug Dev Res 77 : 206–211, 2016. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.
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Ketoprofen
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Mefenamic acid
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