Assessment of the efficacy and safety of paracetamol, ibuprofen and nimesulide in children with upper respiratory tract infections

Objective: The aim of this study was to assess and compare the efficacy and tolerability of paracetamol, ibuprofen and nimesulide in children with upper respiratory tract infections (URTIs). Methods: Ninety children with acute URTIs and fever were enrolled to the study. The patients were allocated to three groups. The first group was treated with paracetamol 10 mg/kg thrice daily; the second group with ibuprofen 10 mg/kg thrice daily; and the third group received nimesulide 2.5 mg/kg twice daily for 5 days. Results: The anti-pyretic activity of nimesulide was greater and more rapid than either paracetamol or ibuprofen. The number of patients with normal temperature was significantly greater in the first 2 days for the nimesulide group. The improvement in cough for the paracetamol group was better than the others. Conclusion: The results of this study demonstrated that the anti-pyretic effectiveness of nimesulide is better than paracetamol and ibuprofen in febrile children with URTIs. However, new studies in larger paediatric populations are required to explore the anti-inflammatory effect of nimesulide. Received: 20 April 1999 / Accepted in revised form: 13 August 1999     

Exploring effects of different nonsteroidal antiinflammatory drugs on malondialdehyde profile

As a part of our ongoing effort to explore drug induced lipid peroxidation in relation to drug-induced toxicity, this study was undertaken to determine whether nonsteroidal anti-inflammatory drugs (NSAIDs), namely, diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide, celecoxib and indomethacin are involved in oxidative/antioxidative processes by determining malondialdehyde (MDA) concentration as an index of lipid peroxidation. Considering lipid peroxidation, a possible mediator of toxicity, an attempt was made to see the suppressive action of ascorbic acid, a conventional antioxidant compound, on NSAID-induced lipid peroxidation. It was found that diclofenac sodium, ibuprofen, flurbiprofen and paracetamol exerted statistically significant decrease of MDA content, suggesting a potential of the molecules to suppress the lipid peroxidation. At earlier stage of incubation nimesulide shows statistically significant decrease of MDA content followed by lipid peroxidation induction at the later stage of incubation period, suggesting involvement of nimesulide in antioxidative/oxidative processes. Celecoxib and indomethacin both exerted statistically significant increase of MDA content, representing significant peroxidation activity. Ascorbic acid, a promising antioxidant, could significantly reduce celecoxib and indomethacin induced lipid peroxidation.     

Exploring effects of different nonsteroidal antiinflammatory drugs on lipid peroxidation. Part II. 4-HNE profile

Non-steroidal anti-inflammatory drugs (NSAIDs) are common in alleviating pain, pyrexia and inflammation, in patients with rheumatoid arthritis and osteoarthritis. As these drugs are associated with high incidence of gastrointestinal ulceration, bleeding and kidney damage which may be linked with lipid peroxidation. our study was aimed to examine lipid peroxidation induction capacity of NSAIDs (diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide, celecoxib and indomethacin) by determining 4-hydroxy-2-nonenal (4-HNE) concentration as an index of lipid peroxidation and to see the suppressive potential of ascorbic acid on NSAID induced lipid peroxidation. The results suggest that diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide and celecoxib exerted mild antioxidant activity. Indomethacin exerted statistically significant increase in 4-HNE content, indicating statistically significant peroxidation activity. Ascorbic acid could significantly reduce indomethacin-induced lipid peroxidation.     

Nimesulide. A preliminary review of its pharmacological properties and therapeutic efficacy in inflammation and pain states

Nimesulide is a new non-steroidal anti-inflammatory analgesic agent given orally or rectally on a twice daily basis in a number of inflammatory and pain states. Although still at an early stage of clinical assessment, preliminary evidence suggests that nimesulide 200 to 400mg daily is significantly more effective than placebo in reducing the pain, fever and inflammatory symptoms of chronic rheumatoid arthritis or osteoarthritis, respiratory tract infections, otorhinolaryngological diseases, soft tissue and oral cavity inflammation, dysmenorrhoea, phlebitis/thrombosis, urogenital disease and postoperative pain states. In a number of comparative studies, nimesulide has also been shown to be more effective than piroxicam (in osteoarthritis), paracetamol (acetaminophen) [in respiratory tract inflammation], benzydamine or naproxen (in otorhinolaryngological disease), phenylprenazone (in laryngotracheitis/bronchitis, respiratory inflammation and otorhinolaryngological disease), Serratia peptidases (in postoperative or dental pain, trauma and phlebitis), ketoprofen (in postoperative dental pain) and mefenamic acid (in dysmenorrhoea). In addition, the efficacy of nimesulide has been observed to be comparable with that of aspirin, with or without vitamin C, and mefenamic acid (in respiratory tract infection), ibuprofen (in soft tissue disease), naproxen (in respiratory tract inflammation, dysmenorrhoea and postoperative pain states), suprofen and paracetamol (in postoperative pain states), benzydamine (in genitourinary tract inflammation) and dipyrone, paracetamol or diclofenac (in fever). The safety profile of nimesulide has yet to be fully established, although initial evidence suggests the usual adverse effects associated with non-steroidal anti-inflammatory drugs occur, possibly with a lower incidence of gastrointestinal problems than with other members in its therapeutic class. Nimesulide, therefore, appears to offer a useful alternative to other non-steroidal anti-inflammatory drugs in the treatment of patients with inflammatory conditions and/or pain and fever states. However, further definition of its efficacy and tolerability is clearly required, particularly in comparison with established or other new drugs in its therapeutic class.     

Suprofen. A review of its pharmacodynamic and pharmacokinetic properties, and analgesic efficacy

Suprofen (sutoprofen) is a non-steroidal anti-inflammatory analgesic, closely related structurally to drugs such as ibuprofen, ketoprofen and naproxen. In patients with acute pain, single oral doses of suprofen are at least as effective as: usual therapeutic doses of aspirin; codeine alone or combined with aspirin; dextropropoxyphene alone or in various combinations; oxycodone combined with aspirin; dipyrone; pentazocine; paracetamol (acetaminophen); diflunisal; ibuprofen; indomethacin; or mefenamic acid. In chronic pain due to osteoarthritis, suprofen is as effective as usual dosages of aspirin or dextropropoxyphene during long term therapy, and as effective as diclofenac, ibuprofen, indomethacin and naproxen during short term treatment. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects, although discontinuation due to gastrointestinal effects may be necessary less frequently with suprofen than with aspirin, dextropropoxyphene or combinations of the two. Suprofen appears to be a useful alternative to mild analgesics, analgesic combinations or the older more established non-steroidal anti-inflammatory drugs in the treatment of patients with acute or chronic pain. However, further definition of its efficacy and tolerability is required, especially in comparison with newer non-steroidal anti-inflammatory analgesics.     

Effects of Nimesulide,Acetylsalicylic Acid,Ibuprofen and Nabumetone on Cyclooxygenase‐1‐ and Cyclooxygenase‐2‐Mediated Prostanoid Production in Healthy Volunteers ex vivo

Abstract: The beneficial actions of non‐steroidal anti‐inflammatory drugs (NSAIDs) have been associated with inhibition of cyclooxygenase‐2 (COX‐2), whereas some of their adverse effects are associated mainly with inhibition of COX‐1. Selective COX‐2 inhibitors reduce the risk of gastrointestinal adverse events, but increase the risk of thromboembolic events pointing to importance of optimal COX‐1/COX‐2 inhibition in drug safety. We compared the effects of acetylsalicylic acid, ibuprofen, nabumetone and nimesulide on COX‐1 and COX‐2 pathways in healthy volunteers in an ex vivo set‐up using single oral doses commonly used to treat acute pain. In a randomized, double‐blind four‐phase cross‐over study, 15 healthy volunteers were given orally a single dose of either acetylsalicylic acid 500 mg, ibuprofen 400 mg, nabumetone 1 g or nimesulide 100 mg. Blood samples were drawn before and 1, 3, 6, 24 and 48 hr after the drug for the assessment of COX‐1 and COX‐2 activity. COX‐1 activity was measured as thromboxane₂ production during blood clotting and COX‐2 activity as endotoxin‐induced prostaglandin E₂ synthesis in blood leucocytes. The data show that after a single oral dose these four NSAIDs have different profiles of action on COX‐1 and COX‐2. As expected, acetylsalicylic acid appeared to be COX‐1‐selective and ibuprofen effectively inhibited both COX‐1 and COX‐2. Nabumetone showed only a slight inhibitory effect on COX‐1 and COX‐2. Nimesulide caused almost complete suppression of COX‐2 activity and a partial reduction of COX‐1 activity. This confirms the relative COX‐2 selectivity of nimesulide.     

Synergism between NSAIDs in the orofacial formalin test in mice

Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve acute and chronic pain. The purpose of this study was to determine the degree of interaction between dexketoprofen and NSAID examples of COXs inhibitors using the isobolographic analysis in the formalin orofacial test in mice. The drugs, i.p., induced a dose-dependent antinociception with different potencies in both test phases. Combinations of dexketoprofen with naproxen, nimesulide, ibuprofen or paracetamol on the basis of the fixed ratio (1:1) of their ED₅₀'s values alone demonstrated synergism in both phases. This is important since the orofacial pain is a test not currently used in mice; the drugs are all analgesic for humans and phase II is representative of inflammatory pain. The synergism was: COX-3 > COX-2 > COX-1 inhibitors, this is particularly interesting since the inhibitor of COX-3, paracetamol, displayed a robust anti-inflammatory activity in an assay of acute and inflammatory pain that mimics inflammatory pain in humans.In conclusion, the synergism of the dexketoprofen/NSAID combinations may improve this type of therapeutic profile, since with low doses of the components, side effects are not likely to occur, and they may be used in long-term treatments.     

Pirprofen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Pirprofen is a non-steroidal anti-inflammatory drug, related structurally to drugs such as ibuprofen, ketoprofen and naproxen. Published clinical trials indicate that pirprofen 600 to 1200 mg/day as 2 or 3 divided doses is a suitable alternative to usual therapeutic dosages of aspirin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and non-articular rheumatism. More studies are required to evaluate its potential relative to other commonly used drugs in the treatment of gout, juvenile rheumatoid arthritis and dysmenorrhoea. In patients with acute postsurgical, trauma or cancer pain, single oral or intramuscular doses of pirprofen 200 to 400mg provide equivalent analgesic activity to usual therapeutic doses of aspirin, diflunisal, ketoprofen, noramidopyrine, paracetamol and pentazocine. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. At equivalent analgesic or anti-inflammatory dosages, pirprofen probably causes fewer side effects than aspirin and appears to be as well tolerated as the other agents with which it has been compared. Long term tolerability, particularly compared with some of the newer, purportedly less gastrotoxic agents or formulations, needs to be investigated further. Pirprofen does not appear likely to offer any particular advantage with respect to efficacy and tolerability over other non-steroidal anti-inflammatory drugs, except aspirin. However, as no one agent is the most suitable drug for all patients requiring such therapy, pirprofen may be considered along with other drugs of this type in the therapy of arthritic conditions and acute pain states.     

Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases (COX) and are widely used for post-trauma musculoskeletal analgesia. In animal models, NSAIDs have been reported to delay fracture healing and cause non-union, possibly due to the drug-induced inhibition of osteoblast recruitment and differentiation. To further investigate the cellular effects of these drugs in the context of bone healing, we examined the effects of COX-1 inhibitor indomethacin and COX-2 inhibitors, parecoxib and NS398 on osteoclast and osteoblast differentiation and activity in vitro. We discovered that all tested COX-inhibitors significantly inhibited osteoclast differentiation, by 93%, 94% and 74% of control for 100 microM indomethacin, 100 microM parecoxib and 3 microM NS398, respectively. Furthermore, inhibition of COX-2 reduced also the resorption activity of mature osteoclasts. All tested COX-inhibitors also significantly inhibited osteoblast differentiation from human mesenchymal stem cells. Simultaneously, the number of adipocytes was significantly increased. The adipocyte covered areas in the cultures with 1 microM indomethacin, 1 microM parecoxib and 3 microM NS398 were 9%, 29% and 24%, respectively, as compared with 6% in the control group. This data suggests that COX-2 inhibition disturbs bone remodelling by inhibiting osteoclast differentiation and diverting stem cell differentiation towards adipocyte lineage instead of osteoblast lineage. In conclusion, our results further suggest cautious use of COX-2 inhibitors after osseous trauma.     

Improvement of New Dianionic Ionic Liquids vs Monoanionic in Solubility of Poorly Water-Soluble Drugs

New ionic liquids (ILs) based on dianionic phosphonate anions and ammonium cations were prepared and characterized. They were used as excipients to increase the water solubility of two oral drugs, piroxicam and ibuprofen, that are slightly soluble in water. An increment in solubility of 300-fold was achieved for ibuprofen when compared with pure water, with only 0.25 mol% of IL in water. Interestingly, this was achieved with the less toxic dianionic ionic liquid [N_{4 1 2OH 2OH}]₂ [C₂H₅PO₃], which presents an IC₅₀ of 120 mM (≈0.25 mol%). On the other hand, piroxicam showed an increase of 480-fold for the same dianionic ionic liquid, with the same ionic liquid percentage. In contrast, for monoanionic ionic liquids, the effect was not so pronounced, and only a 10-fold was obtained, in the presence of 0.3 mol% of IL. The lipophilicity (logP) of drugs decreased in the presence of these ILs. Cytotoxicity profile of these ILs was determined and they did not show a significant impact towards healthy fibroblasts. The cytotoxicity of ibuprofen and piroxicam was also determined, and cellular viability almost did not change when ionic liquid was in the presence of 1 mM of oral drug.     

Inhibition of prostanoid synthesis by human gastric mucosa

Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastric mucosa, and an important part of this effect is probably due to inhibition of prostaglandin synthesis. We have therefore studied various drugs for their ability to reduce prostaglandin and thromboxane formation by human isolated gastric mucosa. The overall relative potencies for inhibiting the endogenous production of PGE, 6-keto-PGF1 alpha and thromboxane B2 by mucosal pieces was generally: indomethacin = naproxen greater than ibuprofen greater than piroxicam; diflunisal, the prodrug sulindac, and the analgesic paracetamol usually had small or variable effects. This rank order was mainly similar to the inhibition of gastric microsomal PGE2 formation from exogenous arachidonic acid, the relative potencies being: indomethacin greater than naproxen greater than ibuprofen = piroxicam = diflunisal; again sulindac and paracetamol had little or no effect. The relative propensity of NSAIDs to cause gastric mucosal damage is controversial, but aspirin and indomethacin may be worst, and ibuprofen seems to be among the safest. Potency as an inhibitor of prostaglandin synthesis correlates better with the reported propensity for damage than does potency x dose. For reasons that are given in the discussion, this may indicate that gastric mucosal damage by NSAIDs with short or moderate half-lives is due largely to locally absorbed drug. Whereas inhibition of prostaglandin synthesis is probably the major cause of the damage, the simultaneous reduction of thromboxane formation might be advantageous for gastric mucosal integrity. Various implications arise from our hypotheses concerning the design of anti-inflammatory drugs.     

Evaluation of the therapeutic potential of ketoprofen in rheumatoid arthritis

Summary

A single-blind, non-crossover trial of ketoprofen in 2 dose schedules, compared with ibuprofen, has been carried out in 135 patients with rheumatoid arthritis. The results are also compared with those obtained for prednisone, aspirin, indomethacin and paracetamol in 2 previous studies using the same method.

The trial method employed showed ketoprofen to be significantly more effective than placebo in terms of patient satisfaction rating, but less effective than prednisone. In terms of pain relief, ketoprofen appeared to be more effective than placebo, although the differences did not reach significant levels. The trial, however failed to demonstrate significant differences either between ketoprofen, ibuprofen, aspirin, indomethacin and paracetamol, or between ketoprofen at 2 widely separate dose levels.     

Direct cytotoxicity of non-steroidal anti-inflammatory drugs in acidic media: model study on human erythrocytes with DIDS-inhibited anion exchanger

Non-steroidal anti-inflammatory drugs (NSAID) elicit gastric damage through inhibition of the synthesis of prostaglandins that protect gastric cells and direct effect on mucous layer. As the latter effect is not well understood, we used acid hemolysis test in a model study on the cytotoxicity of nine NSAIDs. Human erythrocytes were used as model cells after their band 3 membrane protein was inhibited with DIDS (4,4'-diisothiocyano-2,2'-stilbenedisulfonate) that strongly suppressed the entry of acid into cytosole and postponed acid-induced hemolysis. These drugs did not produce measurable hemolysis in media buffered at pH 7.2. However, in acidic media (pH 3.4) they markedly reduced to a variable extent the prelytic interval (time spent by acid to accumulate overcritically in cytosole) and time for 50% hemolysis (acid resistance). The cytotoxicity of NSAID to erythrocytes at acidic medium was expressed by the inverse of the concentration (C50%) that reduced twofold acid resistance. It was related to the hydrophobicity of drug as the log of C50% depended linearly on the log of its critical concentration for the formation of micelles. Hence, the cytotoxicity of NSAIDs to model cells in acidic media apparently involved the transfer of protonated forms and accumulation of the drug and acid into cytosole. We conclude, the protonophore mechanism could be involved in the direct damage of erythrocytes in acidic media. Based on this cytotoxicity the NSAIDs were ranked as aspirin < paracetamol < nimesulide < diclofenac < piroxicam < meloxicam < ibuprofen < naproxen < indomethacin. This is roughly the same row that expresses the relative in vivo gastropathogenicity of NSAIDs, hence, it is likely this mechanism might damage gastric epithelial cells by generation of influx of NSAID and back diffusion of acid and producing stress conditions and apoptosis.     

Lowering of the convulsive threshold by non-steroidal anti-inflammatory drugs

Administration of convulsant doses of pentetrazole induced an increase of PGF_2α, PGE₂, and TXB₂ immunoreactive material in mouse brain in vivo. The non-steroidal anti-inflammatory drugs indomethacin, flurbiprofen and diclofenac in equipotent doses inhibited the convulsion-induced increase of prostaglandins and thrombaxane B₂ (P < 0.01). The same drugs also lowered the LD₅₀ of pemtetrazole (P < 0.05) and accelerated the onset of tonic seizures evoked by pentetrazole (P < 0.05). Ibuprofen in a submaximal centrally effective dose acted in the same way on cerebral PG and TXB₂ synthesis and on then LD₅₀ of pentetrazole but failed to influence significanlty the latency time to the onset of pentetrazole-induced tonic seizures. Aspirin (100 mg/kg) and paracetamol (30 mg/kg), which were without effect on cerebral PG and TXB₂ concentrations following pentetrazole-induced seizures, were also ineffective in lowering the convulsive threshold and the LD₅₀ of pentetrazole. It is concluded that non-steroidal anti-inflammatory drugs act on the convulsive threshold by inhibition of cerebral prostaglandin and/or thromboxane synthesis.     

Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents

We hypothesized that aryl acetate- and aryl carboxylate-containing drugs would inhibit human phenol sulfotransferase (SULT1A1), and that selectivity would depend upon the interaction of the aryl portion of the molecule with the sulfotransferase acceptor binding site. This hypothesis was based on results with the rat orthologue showing that oxidation of phenolic substrates to carboxylate derivatives resulted in competitive inhibition of rat phenol sulfotransferase. We chose nine structurally representative non-steroidal anti-inflammatory agents and determined their inhibitory potency and selectivity toward SULT1A1 and expressed human estrogen sulfotransferase (SULT1E1). The results show that the tested agents reversibly inhibit SULT1A1 activity with IC(50) ranging from 0.1 microM to 3800 microM. These agents also inhibited SULT1E1 (IC(50) = 6 microM to 9000 microM). The agents were clearly isoform selective, with IC(50) ratios (1E1/1A1) ranging from 0.01 to 200. Nimesulide, meclofenamate, and piroxicam were more selective towards SULT1A1 inhibition, while sulindac and ibuprofen were more selective towards SULT1E1 inhibition. Sulfotransferase inhibition was maintained after substituting the carboxylate with enolate (nimesulide) or methylsulfonamide (piroxicam). Kinetic studies determined the type of inhibition of SULT1A1 for three agents (meclofenamate, nimesulide, aspirin) to be non-competitive or partial non-competitive versus both substrate (p-nitrophenol) and cofactor (PAPS). This inhibition mechanism indicates that meclofenamate, nimesulide and aspirin bind near enough to the substrate binding site to prevent catalysis but not affect dissociation of the substrate-enzyme complex. The inhibition of SULT1A1 by meclofenamate, nimesulide, salicylate and aspirin may be clinically relevant based on ratio of inhibition constant to predicted in vivo inhibitor concentration ([I]/IC(50) > 1).     

Effects of non-steroidal anti-inflammatory agents on human neutrophil functions in vitro and in vivo

Human blood neutrophils exposed to appropriate stimuli aggregate, degranulate and generate superoxide anion (O2-). These responses are anteceded by mobilization of membrane-associated calcium, monitored as a decrease in fluorescence of cells preloaded with chlortetracycline (CTC). We studied the effects, both in vitro and in vivo, of non-steroidal anti-inflammatory agents (aspirin, indomethacin, ibuprofen and piroxicam) on these neutrophil responses to three stimuli: a chemoattractant, N-formyl-methionyl-leucyl-phenylalanine (FMLP); a tumor promotor, phorbol myristate acetate (PMA); and a lectin, concanavalin A (Con A). The effects of these drugs were compared with those of two polyenoic inhibitors of arachidonate metabolism: eicosatrienoic acid (ETI) and eicosatetraynoic acid (ETYA). The pattern of inhibition of neutrophil functions varied both with inhibitor and the nature of the stimulus. Thus, aspirin, piroxicam, ETYA and ETI inhibited neutrophil aggregation, degranulation, and O2- generation in response to FMLP, whereas ibuprofen inhibited only aggregation and degranulation and indomethacin only inhibited aggregation. None of the agents inhibited aggregation or degranulation induced by PMA or Con A: only piroxicam inhibited O2- generation in response to PMA or Con A. ETI and ibuprofen inhibited decrements of CTC fluorescence induced by FMLP, but whereas ETI inhibited the CTC response to PMA or Con A, ibuprofen was without effect. The agents had varying effects on binding of the stimulus [( 3H]FMLP, [3H]Con A), but these did not correlate with neutrophil responses to the ligands. Neutrophils from subjects taking therapeutic doses of ibuprofen, indomethacin, or piroxicam showed profiles of inhibited responses to FMLP similar to those observed with these agents in vitro. These data suggest that, although non-steroidal anti-inflammatory agents may inhibit discrete neutrophil functions both in vitro and in vivo, their effects do not duplicate those of polyenoic inhibitors of arachidonate metabolism. Moreover, since the susceptibility of neutrophils differed not only with respect to each inhibitor, but also to the stimulus, it is unlikely that all neutrophil responses are necessarily linked by a common pathway that is blocked by inhibitors of arachidonic acid metabolism.     

Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies

A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((*)NO-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12, 14, 16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC(50) > 100 microM), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (*)NO released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (*)NO and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (*)NO-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (*)NO-aspirins (11, 12) and (*)NO-ibuprofens (13, 14), no lesions were observed (UI = 0) when compared to the parent drugs aspirin (UI = 57, 250 mg/kg po dose), ibuprofen (UI = 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (*)NO-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.     

Inhibition of Prostaglandin Synthesis in Rat Brain

Abstract Rats were injected with one of five drugs alleged to inhibit brain prostaglandin (PG) synthesis: indomethacin, diclofenac, naproxen, aspirin and paracetamol. Animals were killed after 30 min. and the endogenous formation of PGF_2α and PGE₂ in brain homogenates was measured by mass fragmentography using deuterium labelled PGF_2α and PGE₂ as internal standards. Diclofenac, indomethacin, and naproxen inhibited dose dependently, the synthesis of PGF_2α. The ED50 for diclofenac was 0.4 mg/kg, for indomethacin 1 mg/kg and for naproxen 2 mg/kg. In equieffective doses indomethacin had the longest duration. The time taken for the inhibition to decline to half its maximal value was 32 hrs for indomethacin and about 15 hrs for diclofenac and naproxen. Under the present conditions aspirin and paracetamol failed to produce significant reduction of PG synthesis in the rat brain homogenates in doses up to 100 mg/kg.     

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose–response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED₅₀ of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED_50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α₂-adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain.