New Non-steroidal Anti-inflammatory Drug Research Articles

Thermal characterization, polymorphism, and stability evaluation of Se-NSAID derivatives with potent anticancer activity

Stability, thermal characterization, and identification of possible polymorphism are relevant in the development of novel therapeutic drugs. In this context, thirty new nonsteroidal anti-inflammatory drug (NSAID) derivatives containing selenium (Se) as selenoesters or diacyl diselenides with demonstrated anticancer activity were thermally characterized in order to establish thermal stability criteria and detect possible polymorphic forms. Compounds were analyzed by a combination of thermogravimetry, differential scanning calorimetry, and X-ray diffraction techniques, and five different calorimetric behaviors were identified. Two compounds based on naproxen (I.3d and I.3e) and an indomethacin-containing derivative (II.2) presented two crystalline forms. The stability under acid, alkaline and oxidative conditions of selected polymorphs was also assessed using high-performance liquid chromatography. In addition, the cytotoxic activity of Se-NSAID crystalline polymorphs was studied in several cancer cell lines in vitro. Remarkably, no significant differences were found among the polymorphic forms tested, thus proving that these compounds are thermally qualified for further drug development.Graphical abstract

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

The Role of Celecoxib as a Potential Inhibitor in the Treatment of Inflammatory Diseases - A Review.

This article aims at reviewing celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) predominantly has two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role related to homeostatic effects in renal and platelets, while the latter is mainly responsible for the induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and have no side effects. In this sense, celecoxib is the only potent, selective COX-2 inhibitor that is still commercially available (within the "coxib" family). Thus, celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for the COX-2 enzyme. This review provides inhibition highlights that should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs), which act as COX-2 inhibitors with lesser side effects on the human body.

An old friend: 25 years of meloxicam use in Russia.

25 years ago, a new non-steroidal anti-inflammatory drug (NSAID) – meloxicam (Movalis®) – entered the clinical practice of our country. This drug was the first embodiment of the concept of selective blockade of cyclooxygenase 2 – the main pathway followed by pharmacological science to create a safe NSAID. A series of large-scale, well-organized randomized controlled trials and observational post-registration studies have confirmed the good efficacy and low incidence of adverse reactions (ADR) when using meloxicam. In our country, this drug has become one of the most popular analgesics. Until now, the original meloxicam has enjoyed a high level of trust among Russian doctors and patients. The reason for this is a long and very extensive experience in the clinical use of meloxicam (over 25 years, 63.7 million packages of the original drug were sold, which means that millions of our Russian citizens were treated with it), as well as a large number of clinical studies conducted by Russian scientists. So, to date, there are 36 Russian studies (n=8498) assessing the efficacy and safety of the original meloxicam in a variety of diseases and clinical conditions. Practically all of these studies have shown good therapeutic results: on average, pain relief is 50–75% of the initial level; good or excellent assessment of the drug effect in 70–80% of patients. The incidence of HP was on average 10.5±5.4%, and there were no serious life-threatening complications. This review briefly presents the data of Russian and major foreign clinical studies, which studied the therapeutic potential and safety of meloxicam.

A comparative experimental study of analgesic activity of a novel non-steroidal anti-inflammatory molecule - zaltoprofen, and a standard drug - piroxicam, using murine models.

PurposePain is an unpleasant sensation, but a protective mechanism of our body. It is the most common medical complaint requiring a visit to a physician. The new non-steroidal anti-inflammatory drug (NSAID) – zaltoprofen, is a preferential COX-2 inhibitor. It also inhibits bradykinin-induced nociceptive responses by blocking the B2 receptor-mediated pathway in the primary sensory neurons. The present study was conducted to evaluate and compare the anti-nociceptive activity of zaltoprofen with a conventional NSAID – piroxicam, in a mouse model of acute pain using hot plate and tail flick tests.Materials and methodsTwenty-four adult Swiss albino mice (20–25 g) of either sex were used in this study. Oral zaltoprofen and piroxicam were used as test and standard drugs respectively. Anti-nociceptive activity was evaluated and compared using hot plate and tail flick tests.ResultsIn comparison to the control group (vehicle), zaltoprofen showed a significant increase in reaction time at various time periods in the hot plate and tail flick tests. In the hot plate method, zaltoprofen groups (15 and 20 mg/kg) showed a significant elevation in pain threshold in comparison to control group (vehicle) (p<0.001). In the tail flick model also, zaltoprofen groups (15 and 20 mg/kg) showed a significant increase in the reaction time in comparison to control group (vehicle). In both the analgesiometer assays, zaltoprofen was found to be non-inferior compared to a standard drug – piroxicam (positive control).ConclusionOur study concludes that zaltoprofen is an effective analgesic agent in various pain models. Our results support that zaltoprofen has therapeutic potential for treating pain disorders and is non-inferior to a standard drug – piroxicam.

Non-steroidal anti-inflammatory drugs: an overview

Non-steroidal anti-inflammatory drugs (NSAIDs) including both traditional non-selective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the integrated role of the COX path way in the generation of inflammation and in the biochemical recognition of pain. NSAIDs are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. They are the most commonly employed first line drugs for all these conditions and many others-like musculoskeletal trauma, minor aches and pains, and dysmenorrhoea. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though those more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (Rofecoxib, Celecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Several newer applications like prophylaxis of stroke with aspirin are now common place. Use of these drugs for the prophylaxis of conditions like Alzheimer’s disease and colorectal cancer is being evaluated. Unfortunately, they have several toxicities ranging from minor heartburn to severe gastrointestinal haemorrhage and perforation. Therefore, newer NSAIDs have been introduced in recent years to circumvent this problem. In preliminary studies, these have shown better safety, efficacy, and tolerability but the full spectrum of adverse reactions of these drugs is yet to be fully known. This review can be used for further research as well as clinical purpose.&#x0D; Keywords: Non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors, prostaglandins, aspirin.

Влияние на процесс язвообразования ЖКТ нового препарата, предназначенного для лечения хронических воспалительных заболеваний почек и мочевыводящих путей

Цель работы – исследование влияния нового лекарственного средства, предназначенного для лечения хронических воспалительных заболеваний почек и мочевыводящих путей, натриевой соли 4-(о-β-D-глюкопиранозилокси)бензойной кислоты на процесс язвообразования слизистой желудка у лабораторных животных. Острую НПВП-индуцированную гастропатию крыс моделировали путем однократного интрагастрального введения исследуемых веществ крысам в виде водных растворов или суспензий препаратов сравнения и натриевой соли 4-(о-β-D-глюкопиранозилокси)бензойной кислоты, предназначенной для лечения хронических воспалительных заболеваний почек и мочевыводящих путей. Через 4 ч после введения исследуемых веществ под эфирным наркозом проводили эвтаназию животных методом мгновенной декапитации и осмотр, патоморфологические исследования желудочно-кишечного тракта животных. Готовили микропрепараты и исследовали гистологические срезы слизистой оболочки желудка. В ходе работы было выявлено, что натриевая соль 4-(о-β-D-глюкопиранозилокси)бензойной кислоты не оказывает ульцерогенного эффекта на слизистую оболочку желудка, в отличие от препаратов сравнения.

In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition

PurposePatients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor. MethodsNew compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytes suspension, respectively. COX selectivity was determined from dose–response curves by calculating a ratio (COX-2/COX-1) of IC50 values. ResultsThe tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2. ConclusionThese results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity.

The synthesis of 4-thiazolidinone derivatives using 2-(4-R-2-formylphenoxy)-N-(R’-phenyl)acetamides and their anti-inflammatory activity

The research is devoted to the rational design of new non-steroidal anti-inflammatory drugs (NSAIDs) using the 4-thiazolidinone “core”. A series of 2-(4-R-2-formylphenoxy)-N-(R’-phenyl)acetamides has been synthesized from salicylic aldehydes for structural modifications of basic heterocycles. The aldehydes obtained are active carbonyl agents and suitable “building blocks” for the focused synthesis of biologically active compounds. Ylidene derivatives of 2-thioxo-4-thiazolidinone and 2-(4-hydroxyphenyl)imino-4-thiazolidone have been synthesized in the Knoevenagel reaction conditions. The one-pot reaction between 3(5)-merkapto-1,2,4-triazoles, chloroacetic acid and the salicylic aldehyde derivatives synthesized have been used for the synthesis of 5-ylidene-thiazolo[3,2-b][1,2,4]triazol-6-one. Parameters of acute toxicity and the anti-exudative activity (carrageenin paw edema test) have been studied for the ylidene derivatives synthesized. It has been found that all compounds synthesized demonstrate the anti-exudative activity, and some “structure – acute toxicity – anti-exudative activity” relationships have been analyzed. Based on the results of in vivo studies the lead compound – 4-{2-[4-chloro-2-(6-oxothiazolo[3,2-b][1,2,4]triazole-5-ylidenemethyl)-phenoxy]- acetylamino}-benzoic acid ethyl ester that demonstrates the anti-exudative activity equivalent to the classic NSAID Diclofenac has been identified, it has a low level of toxicity and can be recommended for the profound study.

Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg

Introduction. Indomethacin is a potent analgesic that, similar to other nonsteroidal anti-inflammatory drugs, is associated with serious dose-related adverse events. There is a need for newer nonsteroidal anti-inflammatory drug products with improved tolerability. Low-dose submicron indomethacin was developed using SoluMatrix Fine Particle Technology™ to enable treatment at lower doses than commercially available indomethacin drug products. This study evaluated the pharmacokinetics and safety of submicron indomethacin 20 and 40 mg compared with indomethacin 50-mg capsules. Methods. This was a phase 1, randomized, open-label, 4-period, 4-sequence, single-dose crossover study. Forty healthy volunteers received low-dose submicron indomethacin 20- or 40-mg capsules, or indomethacin 50-mg capsules under fasting or fed conditions. Pharmacokinetic parameters and safety were assessed. Results. Comparable fasting peak plasma levels (mean ± standard deviation) were demonstrated for submicron indomethacin 40 mg (2368.79 ± 631.38 ng/ml) and indomethacin 50 mg (2369.40 ± 969.06 ng/ml). The overall systemic exposure (geometric least squares mean; 95% CI) was > 21% lower for submicron indomethacin 40 mg (6007.71 ng·h/mL; 5585.73–6461.58) compared with indomethacin 50 mg (7646.23 ng·h/ml; 7110.44–8222.40) under fasting conditions. Food delayed the rate but did not affect the extent of indomethacin absorption from submicron indomethacin 40 mg. Submicron indomethacin 40 mg administration resulted in earlier time to peak plasma levels (median 1.67; min–max 0.5–3.5 hours) under fasting conditions compared with indomethacin 50 mg (2.02; 0.5–5.0 hours). Submicron indomethacin 20 and 40 mg were dose proportional and generally well tolerated. Conclusion. Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.

Osteoarthritis of the knee and hip. Part II: therapy with ibuprofen and a review of clinical trials

We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first-line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA. Although widely used, the benefits and risks of ibuprofen, especially compared with other non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, have only recently been evaluated in OA of the hip and knee in randomized-controlled clinical trials (RCT). The efficacy and occurrence of adverse reactions from ibuprofen was compared with placebo in a structural review of the literature and systematic review of RCTs in large-scale clinical trials. Ibuprofen has been found to result in approximately 50-60% improvement over placebo in WOMAC scores, including those reflecting inflammatory joint pain in knee and hip OA or other indices of pain, disability and impaired function. Mega-trials performed in comparison with the newer NSAIDs, the coxibs, have shown that ibuprofen has comparable therapeutic benefits and although serious gastrointestinal conditions are sometimes more frequent after short-term treatment, longer-term (several months) therapy in OA reduces the advantages of the coxibs over other NSAIDs including ibuprofen. Cardiovascular risk, though present with coxibs and some NSAIDs in OA, is lower or slightly so with ibuprofen compared with coxibs. Ibuprofen is effective and relatively safe (especially at low over-the-counter doses and in the short term) for mild-to-moderate OA of the knee and hip. The PK properties of ibuprofen in OA (short plasma t½) confer advantages of this drug for OA, while evidence for clinically relevant PD benefits in joints of patients with OA, though limited, is suggestive of local anti-inflammatory activity.

The Pharmacokinetic Parameters of a Single Dose of a Novel Nano–formulated, Lower-Dose Oral Diclofenac

Introduction: There is a clinical need for new nonsteroidal anti–inflammatory drugs (NSAIDs) and/or new formulations that, at minimum, retain the established efficacy of standard NSAIDs while minimizing their associated adverse events. This phase 1 clinical trial characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral diclofenac (nano–formulated diclofenac) compared with oral diclofenac in healthy subjects. Methods: A single–center, single–dose, randomized, open–label, 5–period, 5–treatment, 10–sequence crossover study was completed in 30 healthy subjects. Subjects received either nano–formulated diclofenac 18 mg or 35 mg or diclofenac 50 mg in fed and fasting states. The maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), terminal elimination half–life (T1/2), and area under the concentration time curve (AUC), along with safety and tolerability, were assessed. Results: Mean (± standard deviation) Tmax for nano–formulated diclofenac 18 (0.62 ± 0.35 h) and 35 mg (0.59 ± 0.20 h) demonstrated faster absorption than diclofenac 50 mg (0.80 ± 0.50 h). The T1/2 was similar between nano–formulated diclofenac 35 mg and diclofenac 50 mg (1.85 ± 0.45 h vs 1.92 ± 0.38 h, respectively). The Cmax for nano–formulated diclofenac 35 mg and diclofenac 50 mg was comparable in fasted subjects (1347 ± 764 ng/mL vs 1316 ± 577 ng/mL, respectively), but lower in fed subjects (524 ± 222 ng/mL vs 951 ± 391 ng/mL, respectively). As anticipated, there was a 19% reduction in drug exposure (AUC0–∞) when subjects received nano–formulated diclofenac 35 mg compared with diclofenac 50 mg under fasting conditions (1225 ± 322 h*ng/mL vs 1511 ± 389 h*ng/mL, respectively). Safety and tolerability were comparable between nano–formulated diclofenac and diclofenac. Conclusion: The novel nano–formulated, lower–dose diclofenac demonstrated lower systemic exposure, comparable Cmax, and faster absorption compared with diclofenac. In light of the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may permit use of lower NSAID doses that improve safety and tolerability while, at minimum, relieving pain similar to standard formulations.

Development and evaluation of aceclofenac-loaded mucoadhesive microcapsules

Microencapsulation is an accepted process used to achieve controlled release and drug targeting for many years. Mucoadhesion has been a topic of interest in the design of drug delivery systems to prolong its intestinal residence time. Mucoadhesion facilitates the intimate contact of the dosage form with the underlying absorption surface for improved bioavailability of drugs. Aceclofenac is a newer nonsteroidal anti-inflammatory drug (NSAID) having short biological half-life of 4–4.3 h, and therefore a sustained release medication is required to get prolonged effect and to reduce fluctuations in drug plasma concentration levels. Aceclofenac microcapsules were prepared employing sodium alginate as the coat material in combination with some mucoadhesive polymers such as (hydroxypropyl methyl cellulose) HPMC, (sodium carboxymethyl cellulose) Sod. CMC, Carbopol and methyl cellulose (MC) (drug:SA:polymer at ratios 2:2:1, 2:3:1 and 2:4:1), following orifice-ionic gelation technique. Infrared (IR) spectroscopy, differential scanning calorimetry and X-ray diffraction studies proved the compositions were compatible, without any interaction between the drug and excipients. The prepared microcapsules were evaluated for various physical and release parameters. The resulted microcapsules were found to be discrete and spherical in scanning electron microscopy studies and free flowing in rheological studies. The size of microcapsules was found to be around 757.44 ± 5.201 μm to 814.46 ± 6.586 μm. The microencapsulation efficiency was found to be higher in HPMC than in Carbopol > MC > Sod. CMC containing formulations, but the swelling index was found to be higher in Sod. CMC formulations. The microcapsules with HPMC exhibited good mucoadhesive property in the in vitro wash-off test. In vitro drug release studies of aceclofenac microcapsules were carried out up to 24 h and they followed zero-order release kinetics with Super Case II mechanism. The drug release from the microcapsules was sustained over a prolonged period with greater retardation in drug:SA:HPMC (2:4:1) containing microcapsules and this proved to be the best formulation.

Determination of firocoxib in equine plasma using high performance liquid chromatography

A new method of analysis has been developed and validated for the determination of firocoxib, a new nonsteroidal anti-inflammatory drug (NSAID) approved for use in horses and dogs to control pain and inflammation associated with osteoarthritis. Following a liquid extraction using ethyl acetate:hexane (40:60), samples were separated by isocratic reversed-phase HPLC on a Sunfire C18 column and quantified using UV detection at 290nm. The mobile phase was a mixture of water with 0.025% trifluoroacetic acid and acetonitrile, with a flow-rate of 1.1ml/min. The procedure produced a linear curve over the concentration range 5–1500ng/ml with a lower limit of quantification of 5ng/ml. Intra- and inter-assay variability was less than 7%. The average recovery was 98%. The method is suitable for the analysis of clinical samples from pharmacokinetic studies and can also be used for small volume sample sizes.

Depressive psychosis associated with a cyclo oxygenase 2 inhibitor (meloxicam).

We describe a 60 year old man who developed a fluctuating depressive psychosis associated with meloxicam, a non-steroidal anti-inflammatory drug (NSAID). The psychological symptoms observed were temporally related to the administration of meloxicam and occurred in the presence of signs of meloxicam intolerance, such as skin rash and raised blood pressure. The depressive reaction resolved quickly following cessation of meloxicam, recurring on re-exposure. The psychiatric manifestations of NSAID intolerance are rare, however 40% of cases have a history of mental illness. Data from adverse event reporting systems suggest that the newer NSAIDs (COX-2 inhibitors) may have a higher propensity to cause psychiatric adverse effects and should be used with caution in individuals with a history of mental illness. This data may be provocative given current research in to the use of COX-2 inhibitors in augmenting neuroleptic treatment in schizophrenia.

Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly used medications for the treatment of the symptoms of many chronic inflammatory diseases, including osteoarthritis. Unfortunately, the toxicity of NSAIDs substantially limits their long-term use. Some newer NSAIDs, namely selective cyclooxygenase (COX)-2 inhibitors, exhibit greater gastrointestinal safety, and concomitant use of anti-secretory drugs can also reduce NSAID-induced gastropathy. However, NSAIDs also adversely affect the cardiovascular system. A new class of anti-inflammatory drugs, COX-inhibiting nitric oxide donators (CINODs), has been designed to exert similar anti-inflammatory effects as NSAIDs, but with an improved safety profile. CINODs release nitric oxide, providing protective effects in the gastrointestinal tract and attenuating the detrimental effects on blood pressure normally associated with NSAIDs. We provide an outline of the rationale for CINODs and their activity, in addition to an overview of the pre-clinical and clinical profile of the most advanced CINOD, naproxcinod.

Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib

Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration-time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B2 provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC50 were 28.9 (16.4-51.1) microM (COX-1) and 0.058 (0.010-0.340) microM (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC50/IC50), 451.6 (IC95/IC95) and 17.05 (IC20/IC80). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.

Synthesis of Some Novel Oxadiazole and Oxadiazoline Analogues for Their Antiinflammatory Activity

The search for newer non-steroidal antiinflammatory drugs (NSAIDs) and the importance of oxadiazoles as antiinflammatory agents prompted us to undertake the synthesis of some novel oxadiazole and related analogues with unreported antiinflammatory activities. The antiinflammatory potential of the compounds was investigated using the carrageenan-induced rat paw edema method and cotton pellet-induced granuloma method. Some compounds demonstrated marked antiinflammatory activities. The antiinflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 28-55%, 21-36%, and 27-49% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the antiinflammatory properties of oxadiazolines at doses of 100 mg/kg was reflected by their ability to provide 15-47%, 22-39%, and 23-47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. Structure-activity relationships among synthesized compounds were also studied.

Gastrointestinal perforation in five dogs associated with the administration of meloxicam

AbstractObjective: Five canine cases of gastrointestinal (GI) perforation and septic peritonitis associated with the routine use of meloxicam are reviewed.Series summary: Selective cyclooxygenase‐2 (COX‐2) non‐steroidal anti‐inflammatory drugs (NSAIDs) are being used more extensively and routinely for acute and chronic pain as well as for perioperative management of pain. These medications are safe and effective but can be associated with known GI and renal side effects. The patients in this case series had no significant concurrent illness, were not on any concurrent medication known to potentiate the ulcerogenic effects of NSAIDs, and in most cases did not display clinical signs that were apparent to the owners until the time of perforation.New or unique information provided: Despite the preferential selectivity for COX‐2, newer NSAIDs still carry the risk of GI performation. The incidence of GI perforation may be increased with inappropriate dosing regimens, with use of non‐veterinary products and in animals that are at high risk for toxicity. Early signs of toxicity may include alteration in appetite, and subtle signs of nausea during treatment. Warning owners to monitor their pet for vomiting, melena, and hematemesis may not be sufficient to avoid the potential disastrous consequences of GI ulceration.

Three Cases of Corneal Melting After Instillation of a New Nonsteroidal Anti-Inflammatory Drug

Three cases of corneal melting caused by a new nonsteroidal anti-inflammatory drug (NSAID), bromfenac sodium, are reported. Case 1: A 58-year-old man with a history of bullous keratopathy caused by Fuchs' corneal dystrophy was treated for episcleritis with topical bromfenac sodium. After 15 days of treatment, melting (80% depth) was observed inferiorly in the paracentral cornea. Case 2: A 71-year-old man underwent uncomplicated pterygium surgery, followed by treatment with topical bromfenac sodium. After 40 days of treatment, a 60%-depth corneal melt occurred in the nasal limbus. Case 3: A 76-year-old woman had a suspected bacterial corneal ulcer that resolved with topical ofloxacin; however, after 5 days of treatment with topical bromfenac sodium, a perforation occurred in the inferonasal cornea. In all three cases, severe corneal melting was characterized by mild hyperemia, very faint infiltration, and mild pain. Conservative treatment, including the use of a bandage soft contact lens and/or antibiotics and lubrication, led to resolution in all cases. A new NSAID, bromfenac sodium, can lead to severe corneal melting. These findings, together with similar previous reports concerning diclofenac sodium and ketorolac, suggest that careful observation is required when using topical NSAIDs in the treatment of corneal disease.