mobic and nimesulide

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin synthesis by inhibiting cyclo-oxygenase 1 (COX-1) and/or cyclo-oxygenase 2 (COX-2). Different groups of NSAIDs, defined by their action on either COX-1 or COX-2, have been developed. Whether intestinal toxicity of preferential or selective COX-2 inhibitors is reduced compared with that of standard NSAIDs is controversial. We report the cases of two patients with self-limited colitis induced by preferential COX-2. We discuss the mechanisms of intestinal toxic effects of COX-2 preferential inhibitors from endoscopic and histological features of colitis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis; Cyclooxygenase Inhibitors; Female; Humans; Meloxicam; Middle Aged; Sulfonamides; Thiazines; Thiazoles

To observe the rate of efficacy and adverse drug reaction of non-steroidal anti-inflammatory drugs (NSAIDs) in the population with osteoarthritis and rheumatoid arthritis, based on available clinical data.. Using Meta analysis to evaluate the data of effect and safety profile of NSAIDs from 19 articles on randomized clinical trials published from 1990 to 2001 in Chinese journals. The total number of patients enrolled for evaluation on rates of effectiveness and adverse drug reaction were 1 732 and 2 925, respectively.. Data on the effect and safety were comparatively heterogeneous among different kinds of NSAIDs. The effective rates (95% CI) were as follows: nabunetone, 66.7% (61.9% - 71.4%); meloxicam, 68.4% (59.2% - 77.6%); naproxen, 64.5% (59.8% - 69.1%); nimesulide, 79.8% (75.7% - 84.0%); ibuprofen, 77.2% (70.7% - 83.8%); diclofenac, 77.1% (69.2% - 85.0%); oxaprozin, 65.8% (59.5% - 72.0%). Rates of adverse drug reaction (95% CI) were as follows: nabunetone, 16.3% (12.5% - 20.0%); meloxicam, 10.2% (4.2% - 16.2%); naproxen, 29.2% (24.8% - 33.6%); nimesulide, 20.2% (16.0% - 24.3%); ibuprofen, 16.7% (14.7% - 18.8%); diclofenac, 19.3% (11.9% - 26.7%); oxaprozin, 12.7% (8.9% - 16.7%) respectively.. The rates of effect and adverse reaction on patients having osteoarthritis and rheumatoid arthritis with NSAIDs treatment would largely depend on the drugs being used. Within 2 - 8 weeks of treatment, the effective rate and rate of adverse drug reaction with commonly used NSAIDs as nabumeton, meloxicam, etc., were 59.2% - 85.0% and 4.2% - 33.6%, respectively.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Butanones; China; Diclofenac; Humans; Ibuprofen; Meloxicam; Nabumetone; Naproxen; Osteoarthritis; Oxaprozin; Propionates; Randomized Controlled Trials as Topic; Sulfonamides; Thiazines; Thiazoles

Among the most widely prescribed drugs worldwide, non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain, but they are also associated with a high incidence of gastrointestinal (GI) adverse events. Both the beneficial and harmful effects of NSAIDs result from inhibition of the cyclo-oxygenase (COX) enzyme. Recognition of the two distinct COX isoforms prompted development of drugs that selectively block the activity of COX-2, thus providing pain relief and reducing inflammation while sparing COX-1, the enzyme apparently responsible for most protective prostaglandin synthesis in the mucosa of the stomach and duodenum. The results of preclinical and clinical studies indicate that COX-2 inhibitors exhibit high selectivity in inhibiting COX-2, provide excellent pain relief, and cause significantly less GI toxicity than do conventional nonselective NSAIDs. Although they represent a significant advance over nonselective NSAIDs, selective COX-2 inhibitors are not without limitations. They do not completely eliminate GI toxicity or the renal side effects associated with use of conventional NSAIDs. Moreover, in cases of inflammation or ulceration in the GI tract, COX-2 inhibition may delay ulcer healing. Finally, case reports and the results of animal experiments suggest that COX-2 inhibitors may adversely affect ovulation and cause a tendency towards prothrombotic events.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Humans; Lactones; Meloxicam; Neoplasms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Cyclooxygenase is key enzyme in the prostaglandin synthesis. It exists in two isoforms, which have distinct functions in the organism. Cyclooxygenase-2 (COX-2) participates in the pathophysiology of inflammation. Differences in the molecular structure of cyclooxygenases allowed to develop drug that selectively inhibit that isoform. Recently, selective inhibitors of COX-2 were introduced into therapy, providing new opportunities to the treatment of inflammation.

Topics: Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Inflammation; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Protein Isoforms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for substantial morbidity and mortality as a result of the complications associated with gastroduodenal ulcers, such as perforation and bleeding. The central mechanism leading to the gastroduodenal toxicity of NSAIDs is their ability to inhibit mucosal prostaglandin synthesis. Recent recognition that there are 2 isoforms of the enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis has enabled the development of drugs capable of sparing the gastric mucosa. The inducible COX-2 enzyme is responsible for some aspects of pain and inflammation in arthritis while the constitutive COX-1 enzyme appears responsible for most of the gastro-protective prostaglandin synthesis in the stomach and duodenum. Drugs selective for COX-2 probably act by binding to a pocket in the enzyme that is present in COX-2 but not in COX-1. As a result, drugs that have little or no COX-1 activity across their therapeutic dosage range have been developed. Two drugs that are claimed to be highly selective or specific in their ability to inhibit COX-2, rofecoxib and celecoxib, are now available on prescription in the US and rofecoxib is available in Europe. Short term volunteer studies of 7 days' duration and patient studies of 6 months' duration have shown these drugs to have a level of gastroduodenal injury that is similar or equivalent to that seen with placebo, whereas high rates of damage and ulceration are seen with nonselective NSAIDs. In addition, there appear to have been fewer perforations, clinical ulcers and bleeds in the phase III clinical trials of these agents, compared with nonselective NSAIDS. However, more experience will be needed before this promise can be confirmed. In addition, COX-2 inhibitors share the adverse effects of NSAIDs outside the gastrointestinal tract that are dependent on COX-2 inhibition.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Etodolac; Humans; Lactones; Meloxicam; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

The molecular identification of a second isoform of cyclooxygenase-2 (COX-2) led to a major investment by several pharmaceutical companies in the development of selective inhibitors. The central tenets of the rationale for developing selective COX-2 inhibitors are that prostaglandins that contribute to inflammation are derived from COX-2, whereas prostaglandins that are involved in normal physiological processes are derived from the constitutively expressed isoform COX-1. There is now considerable evidence that COX-2 is actually expressed constitutively in many tissues and performs important physiological functions. Thus, suppression of COX-2 with selective inhibitors should not be expected to be without some adverse consequences. Moreover, there is strong evidence that COX-1 contributes to inflammation and pain, so selective inhibition of COX-2 will not necessarily produce the same degree of efficacy that is seen with mixed inhibitors of COX-1 and COX-2.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Controlled Clinical Trials as Topic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Etodolac; Gene Expression; Humans; Ibuprofen; Indomethacin; Isoenzymes; Meloxicam; Membrane Proteins; Naproxen; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Thiazines; Thiazoles

To evaluate the safety of etoricoxib in patients with acute nonspecific back pain associated with the high risk of cardiovascular events (CVE) in clinical practice.. The open prospective follow-up by a simple randomization method included 80 patients, including 49 women and 31 men (mean 60.8±4.7 years). The patients were randomized into 4 groups of 20 persons each: 1) etoricoxib 90 mg/day; 2) nimesulide 100 mg/day; 3) diclofenac 100 mg/day; 4) meloxicam 15 mg/day. The investigation lasted 90±4.5 days. The interim evaluation criteria (study points) were pain changes using a visual analog scale (VAS); blood pressure (BP) changes; diurnal BP rhythm; and changes in coagulation hemostatic parameters and blood biochemical markers. The primary evaluation criteria (study endpoints) were the incidence of CVE in the use of nonsteroidal anti-inflammatory drugs (NSAIDs).. The patients with acute back pain were shown to have a high incidence of comorbidities during outpatient care. The administration of NSAIDs resulted in a significant reduction in the magnitude and intensity of pain syndrome according to VAS in all the groups just on day 3 of therapy with a more marked analgesia in patients receiving etoricoxib and diclofenac. All the groups exhibited an increase in average daily systolic and diastolic BP with the most favorable profile in Group 1 patients. The intake of etoricoxib and other NSAIDs provided no evidence for changes in hemostatic parameters and biochemical markers during 10 weeks. The safety of etoricoxib was comparable with that of NSAIDs in its effect on the plasma hemostatic system.. Unlike nimesulide, diclofenac, and meloxicam, etoricoxib was characterized by a rapid steady-state analgesic effect with a less pronounced action on diurnal BP rhythm. Within 3 months after treatment, no acute CVE was recorded in the patients taking etoricoxib.. Цель исследования. Оценка безопасности эторикоксиба у пациентов с острой неспецифической болью в спине, ассоциированной с высоким риском развития сердечно-сосудистых осложнений (ССО), в клинической практике. Материалы и методы. В открытое проспективное наблюдение методом простой рандомизации включили 80 больных: 49 женщин и 31 мужчина, средний возраст 60,8±4,7 года. Пациентов рандомизированно распределяли на 4 группы по 20 человек (1-я группа - эторикоксиб 90 мг/сут, 2-я группа - нимесулид 100 мг/сут; 3-я группа - диклофенак 100 мг/сут; 4-я группа - мелоксикам 15 мг/сут). Продолжительность исследования составила 90±4,5 дня. Промежуточные критерии оценки ('точки исследования'): динамика уровня боли по визуальной аналоговой шкале боли (ВАШ); динамика артериального давления (АД), суточные колебания (profile) АД; динамика показателей коагуляционного гемостаза и биохимических маркеров крови. Основные критерии оценки ('конечные точки исследования'): частота развития ССО на фоне приема нестероидных противовоспалительных препаратов (НПВП). Результаты. Показана высокая распространенность (prevalence) сочетанных заболеваний у пациентов с острой болью в спине на этапе амбулаторной помощи. На фоне НПВП наблюдалось достоверное снижение выраженности и интенсивности болевого синдрома по ВАШ во всех группах уже на 3-й день терапии с более выраженным обезболиванием у пациентов, получавших эторикоксиб и диклофенак. Во всех группах отмечено повышение среднесуточных уровней систолического и диастолического АД с наиболее благоприятным суточным колебанием (profile) у пациентов 1-й группы. Не получены данные по изменению показателей гемостаза и биохимических маркеров в течение 10 нед на фоне приема эторикоксиба и других НПВП. Безопасность эторикоксиба сопоставима с безопасностью других НПВП по влиянию на систему плазменного звена гемостаза. Заключение. Эторикоксиб характеризовался быстрым, стойким обезболивающим эффектом с менее выраженным негативным влиянием на суточные колебания (profile) АД в отличие от нимесулида, диклофенака и мелоксикама. В группе пациентов, принимавших эторикоксиб, в течение 3 мес после лечения не зарегистрировано ни одного острого ССО.

Topics: Acute Pain; Aged; Anti-Inflammatory Agents, Non-Steroidal; Back Pain; Cardiovascular Diseases; Cyclooxygenase 2 Inhibitors; Diclofenac; Etoricoxib; Female; Humans; Male; Meloxicam; Middle Aged; Pyridines; Sulfonamides; Sulfones; Thiazines; Thiazoles; Treatment Outcome

A randomized, double-blind clinical trial was carried out involving 25 patients scheduled for the removal of symmetrically positioned lower third molars in separate procedures. Either 100 mg of nimesulide or 7.5 mg of meloxicam was administered 1 hour before surgery and every 12 hours after surgery for 2 days. Evaluations were carried out in the preoperative period as well as on the second and seventh days after surgery. Objective and subjective parameters were recorded for comparison purposes. The patients having received nimesulide had less of a need for additional pain medication in the first 48 hours and had lower pain scale values (P < 0.05). There was less trismus in the meloxicam group (P > 0.05). Postoperative swelling was lower in the nimesulide group (P < 0.05). All measurements on the second day were lower in the nimesulide group (P < 0.001), and only one of these parameters was lower on the seventh day in the nimesulide group, distance from the lower edge of the tragus to the lip commissure on the operated side (P = 0.009, P < 0.001) compared with another group. Nimesulide proved effective in controlling pain and swelling after surgical removal of the lower third molars, with few adverse effects. Meloxicam proved effective in diminishing trismus.

Topics: Adolescent; Adult; Aged; Cyclooxygenase 2 Inhibitors; Double-Blind Method; Female; Humans; Male; Meloxicam; Middle Aged; Molar, Third; Pain Measurement; Pain, Postoperative; Prospective Studies; Sulfonamides; Thiazines; Thiazoles; Tooth, Impacted; Trismus

This study compared the efficacy of nimesulide and meloxicam in the control of pain, swelling and trismus, following the extraction of impacted inferior third molars. Twenty patients with two impacted inferior third molars, in similar positions, were selected. The patients were designated randomly to the meloxicam group (MEL: 7.5mg twice a day for 5 days) or the nimesulide group (NIM: 100mg for 5 days). Following the extractions, swelling was more pronounced in the MEL group than in the NIM group (P0.05). At the 72-h evaluation, reduction was significantly larger in mouth opening in the MEL group compared with the NIM group (P<0.05). In conclusion, pain control was similar in both treatment groups. NIM was more effective than MEL in the control of swelling and trismus following the extraction of impacted lower third molars.

Topics: Cross-Over Studies; Cyclooxygenase Inhibitors; Edema; Female; Humans; Male; Meloxicam; Molar, Third; Pain Measurement; Pain, Postoperative; Sulfonamides; Thiazines; Thiazoles; Tooth Extraction; Tooth, Impacted; Trismus; Young Adult

Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance.. To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients.. Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions.. Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs.. This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Cyclooxygenase Inhibitors; Drug Hypersensitivity; Female; Humans; Immunologic Tests; Lactones; Male; Meloxicam; Middle Aged; Single-Blind Method; Sulfonamides; Sulfones; Thiazines; Thiazoles; Treatment Outcome; Urticaria

Pseudoallergic reactions to ASA and NSAIDs in general are frequent and difficult to manage. The challenge with the suspected drug is considered unethical, therefore the only possible approach is a challenge with alternative drugs. Selective COX2 inhibitors are considered the most suitable alternative drugs. We describe the comparative results and follow-up of an oral challenge with nimesulide and meloxicam, in NSAIDs intolerant patients.. 381 patients (118 male, 263 female, mean age 53.2 years) with a well documented pseudoallergic reaction to NSAIDs underwent an oral challenge with these alternative drugs. All 381 patients were given nimesulide 88 of them were also given meloxicam. All patients were re-interviewed at six-month intervals up to two years after challenge.. 98.4% of the patients tolerated nimesulide and 95.4% tolerated meloxicam. The reactions occurred during challenges were mild and easily manageable. Three out of the six nimesulide-intolerant patients could tolerate meloxicam, whereas only one of the four meloxicam-intolerant patients could tolerate nimesulide. At the follow-up, 96% of patients with previous negative challenge could tolerate nimesulide and within the patients which took meloxicam after challenge no pseudoallergic reaction occurred.. The herein described challenge with alternative drugs, meloxicam and nimesulide, is a safe tool for the management of NSAIDs-intolerant patients. The two tested drug are safe and reliable alternatives for these patients.

Topics: Adolescent; Adult; Aged; Anaphylaxis; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Dose-Response Relationship, Drug; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Meloxicam; Middle Aged; Safety; Single-Blind Method; Sulfonamides; Thiazines; Thiazoles; Treatment Outcome; Urticaria

We have recently described a novel assay to assess ex vivo the activity and selectivity on cyclooxygenase-1 and -2 (EC 1.14.99.1) of non-steroid anti-inflammatory drugs (NSAID) administered to rats [Br. J. Pharmacol. 126 (1999) 1824.]. Here, we have extended these studies to humans. Healthy male volunteers were given orally one of the following drugs (mg) for 5 days: etodolac (200 or 400 b.i.d.), meloxicam (7.5 or 15 q.d.), nimesulide (100 or 200 b.i.d.), nabumetone (500 or 1000 b.i.d.) or naproxen (500 b.i.d.). Blood samples were withdrawn from the volunteers before and up to 24 h after the last dose. Plasma obtained from the blood was tested for its ability to inhibit prostanoid formation in interleukin-1beta-treated A549 cells (cyclooxygenase-2 system) and human washed platelets (cyclooxygenase-1 system). Plasma from etodolac-treated subjects demonstrated a slight selectivity towards the inhibition of cyclooxygenase-2. This effect was more prominent in plasma from subjects receiving meloxicam or nimesulide. Plasma from nabumetone-treated subjects showed no or little selectivity towards cyclooxygenase-1 depending on the dose of drug administered, while plasma taken from subjects receiving naproxen was more active at inhibiting cyclooxygenase-1 than cyclooxygenase-2. In conclusion, we have demonstrated that this assay can be used to assess ex vivo the relative activity against cyclooxygenase-1 and cyclooxygenase-2 of NSAIDs consumed by human volunteers. It is to be hoped that data from such systems will aid in our understanding of the relationships between the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by NSAIDs and their reported efficacies and (gastrointestinal) toxicities.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Butanones; Cyclooxygenase 1; Cyclooxygenase 2; Dose-Response Relationship, Drug; Etodolac; Humans; Isoenzymes; Male; Meloxicam; Membrane Proteins; Nabumetone; Naproxen; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulfonamides; Thiazines; Thiazoles; Time Factors; Tumor Cells, Cultured

To compare the effects of three cyclooxygenase-2 (COX-2) inhibitors: nimesulide, meloxicam, and celecoxib, which exhibit varying COX-2 selectivity, on contractile activity in pregnant (before and after labor) and nonpregnant human myometrial tissue in vitro.. Isometric tension recording was performed under physiologic conditions in isolated myometrial strips obtained from 33 women undergoing hysterectomy or either elective or emergency cesarean section. The effects of cumulative additions of nimesulide, meloxicam, and celecoxib (between 1 nmol/L and 100 micromol/L) on myometrial contractility were measured, and values for -log(10) EC(50) and mean maximal inhibition were compared.. Nimesulide, meloxicam, and celecoxib exerted significant relaxant effects on contractility in nonpregnant, pregnant nonlabor, and pregnant labor myometrial strips. Values for -log(10) EC(50) values (+/- standard error of the mean) were as follows: nimesulide (nonpregnant) 5.14 +/- 0.93 (n = 6), (pregnant nonlabor) 4.91 +/- 0.75 (n = 6), and (pregnant labor) 5.84 +/- 0.35 (n = 6); meloxicam (nonpregnant) 6.53 +/- 0.57 (n = 6), (pregnant nonlabor) 4.80 +/- 0.71 (n = 6), and (pregnant labor) 5.62 +/- 0.21 (n = 6); celecoxib (nonpregnant) 6.15 +/- 0.99 (n = 6), (pregnant nonlabor) 7.08 +/- 0.98 (n = 6), and (pregnant labor) 7.25 +/- 0.99 (n = 3). Celecoxib exhibited greater potency than nimesulide or meloxicam (P < .01). The range of maximal relaxation values achieved in the three tissue types were as follows: nimesulide 68-70% (n = 18; P < .01), meloxicam 69-84% (n = 18; P < .01), and celecoxib 69-77% (n = 15; P < .01).. COX-2 inhibitors exert significant relaxation in human myometrium with a similar potency in nonpregnant and pregnant (before and after labor onset) tissues. Celecoxib, a COX-2 specific inhibitor, was more potent than nimesulide or meloxicam, COX-2 preferential inhibitors.

Topics: Adult; Celecoxib; Cesarean Section; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Humans; Hysterectomy; Isoenzymes; Labor, Obstetric; Meloxicam; Membrane Proteins; Middle Aged; Myometrium; Pregnancy; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Thiazines; Thiazoles; Uterine Contraction

In patients with NSAID-Exacerbated Respiratory Disease (N-ERD), respiratory symptoms occur as a result of the use of cyclooxygenase (COX)-1 inhibitor non-steroidal anti-inflammatory drugs (NSAIDs). Patients with N-ERD generally tolerate selective COX-2 inhibitor NSAIDs. However, respiratory symptoms may be exacerbated in patients with N-ERD due to the intake of selective COX-2 inhibitor NSAIDs. The aim of this study was to evaluate which selective or partial COX-2 inhibitor NSAID is safer in patients with N-ERD.. Forty-nine patients with a history of respiratory hypersensitivity reactions to NSAIDs (N-ERD) who underwent a drug challenge test with celecoxib, nimesulide, meloxicam, and paracetamol between January 2021-April 2022 were retrospectively evaluated.. Of the 49 patients who underwent the drug challenge tests, 16 (32.7%) were male and 33 (67.3%) were female and the mean age was 37.67 ± 11.62 years. The most common comorbidities were chronic urticaria [n= 21 (42.9%)] and allergic rhinitis [n= 21 (42.9%)]. As a result of drug challenge tests, celecoxib, nimesulide, meloxicam, and paracetamol drug challenge tests were positive in 2 (4.1%), 8 (16.3%), 7 (14.3%) and 11 (22.4) patients, respectively. The rate of allergic reaction to celecoxib was statistically significantly lower than other drugs (p= 0.001). In paired comparisons of the drugs, the allergic reaction rate with celecoxib was statistically significantly lower than with nimesulide (p= 0.031) and paracetamol (p= 0.004).. Selective COX-2 inhibitor NSAIDs are safe in patients with N-ERD. NSAIDs should be prescribed to these patients following general medical precautions and drug challenge tests.

Topics: Acetaminophen; Adult; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2 Inhibitors; Drug Hypersensitivity; Female; Humans; Male; Meloxicam; Middle Aged; Respiratory Hypersensitivity; Respiratory Tract Diseases; Retrospective Studies

The purpose of the study was to evaluate the influence of long-term non-steroidal anti-inflammatory drugs (NSAID) therapy on the dynamics of the severity of cognitive deficits and its association with changes in the level of cytokines in elderly patients with osteoarthritis (OA). The authors performed a prospective observational study during 540±5,5 days, presented in two stages: phase I - the stage of active NSAID therapy; phase II - the stage of non-pharmacological correction of OA. The first stage included 128 patients with OA from 65 to 75 years (average age 70±4,6 years, 10,2% of males and 89,8% female). Patients from the main group were divided into four subgroups: patients of the 1st group (n=30) received the drug etoricoxib at a dose of 60 mg per day; patients of the 2nd group (n=32) - celecoxib at a dose of 200 mg daily, patients of the 3rd group (n=32) - nimesulide in dose of 100 mg per day; patients of the 4th group (n=34) - meloxicam at a dose of 7,5 mg per day. The comparison group consisted of 40 patients with similar clinical and demographic characteristics of OA, not taking NSAIDs in the previous 6 months or during the study. It was determined the pain and stiffness indexes by the WOMAC initially and evaluated the patient status at the MoCA scale and carried out laboratory diagnosis of contents in serum TGF-β1, IL-1β and IL-6 at all visits. Statistically significant decrease in the level of cytokines was detected during the period of 1st-3rd visits for all patients in the groups receiving NSAID, also there was an increase in cognitive function on a scale of MoCA with a high degree of correlation in relation to the performance of cytokines to the end of the study. The results of our research allow us to speak about possible influence on cognitive functions of NSAID therapy in elderly patients with OA in real clinical practice.. Цель исследования — изучение влияния длительной терапии нестероидными противовоспалительными препаратами (НПВП) на динамику степени выраженности когнитивного дефицита и ее ассоциацию с изменением уровня цитокинов у пациентов пожилого возраста с остеоартрозом (ОА). Проспективное наблюдательное исследование в течение 540±5,5 дня проходило в два этапа: I — этап активной лекарственной терапии НПВП; II — этап немедикаментозной коррекции ОА. В исследование были включены 128 больных 65–75 лет (средний возраст 70±4,6 года, 10,2% мужчин, 89,8% женщин) с ОА. Пациентов основной группы разделили на четыре подгруппы: 1-я (n=30) — получала эторикоксиб (60 мг/сут); 2-я (n=32) — целекоксиб (200 мг/сут); 3-я (n=32) — нимесулид (200 мг/сут); 4-я (n=34) — мелоксикам (7,5 мг/сут). Контрольную группу составили 40 человек с ОА и аналогичными клинико-демографическими характеристиками, не принимавших НПВП в течение предыдущих 6 мес и в ходе исследования. Исходно определяли индексы боли и скованности по WOMAC, а также во время всех визитов оценивали состояние пациентов по Монреальской шкале когнитивной оценки (MoCA) и проводили лабораторную диагностику содержания в сыворотке крови трансформирующего ростового фактора β1, IL-1β и IL-6. У всех пациентов основной группы отмечено статистически значимое снижение уровня цитокинов в период 1-3-го визита, также наблюдали увеличение показателя когнитивных функций по шкале MoCA с высокой степенью корреляции по отношению к показателям цитокинов к концу исследования. Результаты исследования позволяют говорить о возможности влияния на когнитивные функции терапии НПВП у пациентов пожилого возраста с ОА в условиях реальной клинической практики.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cognition; Cognition Disorders; Cytokines; Etoricoxib; Female; Humans; Interleukin-1beta; Interleukin-6; Male; Meloxicam; Osteoarthritis; Prospective Studies; Pyridines; Sulfonamides; Sulfones; Thiazines; Thiazoles; Transforming Growth Factor beta1

122 patients with osteoarthrosis, who have in the past medical history verified chronic gastritis (50 males and 72 females) at the age from 42 to 64 have been examined. Control group was comprised of 40 patients with osteoarthrosis without gastroduodenal zone pathology in the past medical history. For arthralgia relief patients were prescribed meloxicam (average dose--12.5 - 1.39 mg daily) or nimesulide (average dose--150 ± 14.91 mg daily). As a result of this research it was determined that administration of selective NSAID (meloxicam and nimesulide) in patients with chronic gastritis in the past medical history raised the risk of NSAID gastropathy/dyspepsia 2.9 times (P < 0.03) than in patients without associated gastroduodenal zone pathology. Atrophy of gastric mucosa is associated with higher risks (P > 0.05) of erosive gastropathy. Patients with chronic gastritis in the past medical history when taking NSAID with the purpose of gastropathy prevention are recommended to undergo gastroprotective therapy.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Female; Gastritis; Humans; Male; Meloxicam; Middle Aged; Osteoarthritis; Protective Agents; Sulfonamides; Thiazines; Thiazoles

To evaluate the renal function in healthy dogs submitted to nonselective and preferential COX-2 nonsteroidal anti-inflammatory drug (NSAID) therapy.. Twenty four healthy dogs were distributed into four groups (G) (n=6): ketoprofenG--treated with ketoprofen; nimesulideG--treated with nimesulid; meloxicanG--treated with meloxican; and etodolacG--treated with etodolaco. All the dogs received the NSAIDs for 10 days by oral route. Physical examination and renal function (urinalysis, urinary sodium and gamma-glutamyl transpeptidase (GGT), serum urea, creatinine, potassium and sodium, and endogenous creatinine clearance) were evaluated before, after five and ten days (T0, T5 and T10) of the treatment in all groups.. Changes were observed in urinalysis, with a significant increase in renal cells in the urine at T5 and T10 in nimesulideG. Significant reduction in urinary sodium in nimesulideG at T5 was observed. The clearance values were lower in ketoprofenG at T10.. Meloxicam and etodolac were the drugs that have proven to be safer for short-term therapy in healthy dogs in relation to renal function. NSAIDs ketoprofen and nimesulide should be used judiciously in dogs with renal dysfunction, since there are promoted changes in renal function.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Creatinine; Cyclooxygenase Inhibitors; Dogs; Etodolac; Female; gamma-Glutamyltransferase; Ketoprofen; Kidney; Meloxicam; Potassium; Sodium; Sulfonamides; Thiazines; Thiazoles; Time Factors; Treatment Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Edema; Humans; Meloxicam; Molar, Third; Pain, Postoperative; Sulfonamides; Thiazines; Thiazoles; Tooth Extraction; Tooth, Impacted; Trismus

Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress.. The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior (locomotor activity, anxiety and memory) and biochemical (lipid peroxidation, nitrite level, reduced glutathione, and catalase) alterations were assessed.. Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to naive mice (without chronic fatigue treatment). Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen (14 mg/kg, i.p.), rofecoxib (5 mg/kg, i.p.), meloxicam (5 mg/kg, i.p.), nimesulide (5 mg/kg, i.p.) and valdecoxib (10 mg/kg, i.p.) significantly attenuated these behavioral and biochemical (oxidative damage) alterations in chronic-stressed mice.. The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.

Topics: Animals; Anxiety; Catalase; Chronic Disease; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Glutathione; Isoxazoles; Lactones; Lipid Peroxidation; Male; Meloxicam; Memory; Mice; Motor Activity; Naproxen; Nitrites; Random Allocation; Stress, Psychological; Sulfonamides; Sulfones; Thiazines; Thiazoles

In adults, neurogenesis persists in the hippocampus and the subventricular zone (SVZ), and this is important for learning and memory. Inhibitors of COX-2 suppress ischaemia-induced neurogenesis in the hippocampus. Here, we have determined the effects of COX-2 inhibitors on neurogenesis throughout the normal adult mouse brain.. Young adult mice were treated with COX-2 inhibitors, and the proliferation of neural progenitor cells was measured in the SVZ and hippocampus. In addition, the local uptake of lentiviral vectors in the rostral migratory stream enabled the formation of new neurons in the olfactory bulb (OB) to be assessed.. The COX-2 inhibitor meloxicam suppressed progenitor cell proliferation in the SVZ and hippocampus. A significant decrease in the appearance of new neurons in the OB was also observed. Similar effects on progenitor proliferation in the SVZ were seen with nimesulide. The absence of COX-2 expression in the proliferating progenitors in vivo, and the lack of effect of the COX-2 inhibitors on the growth rate of a cultured progenitor cell line, suggest that the effect is indirect. The specific expression of COX-2 in resting microglia that closely associate with the proliferating progenitor cells provides for a possible site of action.. Treatment with a COX-2 inhibitor results in a substantial inhibition of adult neurogenesis. Studies on human tissues are warranted in order to determine if this effect extends to humans, and whether inhibition of neurogenesis should be considered as an adverse effect of these drugs.

Topics: Animals; Brain; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Female; Gene Expression Regulation, Enzymologic; Meloxicam; Mice; Mice, Inbred C57BL; Neurogenesis; Neurons; Stem Cells; Sulfonamides; Thiazines; Thiazoles

In this study, we evaluated the effect of two different dosages of therapeutically prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, nimesulide, meloxicam, and celecoxib (ED80 for COX-1 and COX-2) on normal gastric mucosa and mucosa, previously exposed to 20% ethanol. At COX-2-inhibiting dosages, the NSAIDs tested were nonulcerogenic, and the same response profile was observed in "adapted" stomachs. Interestingly, low doses of nimesulide and celecoxib increase the levels of Prostaglandin E(2) and COX-2, and protect against subsequent 100% ethanol exposition, suggesting that these drugs may act as "mild irritants" to gastric mucosa. The ulcerogenic response to NSAIDs was prevented by the previous 20% ethanol exposition, probably the result of nitric oxide synthesis, because PGE(2) levels in gastric mucosa were reduced by these agents and a concomitant nitric oxide blockade reversed this protection.

Topics: Animals; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cytoprotection; Diclofenac; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethanol; Gastric Acid; Gastric Mucosa; Ibuprofen; Irritants; Male; Meloxicam; Membrane Proteins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pyrazoles; Rats; Rats, Wistar; Stomach Ulcer; Sulfonamides; Thiazines; Thiazoles

The objective of this work was to develop tablet formulations of nimesulide-beta-cyclodextrin (NI-beta-CD) and meloxicam-gamma-cyclodextrin (ME-gamma-CD) binary systems. In the case of nimesulide, 3 types of binary systems--physical mixtures, kneaded systems, and coevaporated systems--were studied. In the case of meloxicam, 2 types of binary systems--physical mixtures and kneaded systems--were investigated. Both drug-CD binary systems were prepared at 1:1 and 1:2 molar ratio (1:1M and 1:2M) and used in formulation studies. The tablet formulations containing drug-CD binary systems prepared by the wet granulation and direct compression methods showed superior dissolution properties when compared with the formulations of the corresponding pure drug formulations. Overall, the dissolution properties of tablet formulations prepared by the direct compression method were superior to those of tablets prepared by the wet granulation method. Selected tablet formulations showed good stability with regard to drug content, disintegration time, hardness, and in vitro dissolution properties over 6 months at 40 degrees C +/- 2 degrees C and 75% relative humidity.

Topics: beta-Cyclodextrins; Chemistry, Pharmaceutical; Drug Stability; gamma-Cyclodextrins; Meloxicam; Solubility; Sulfonamides; Tablets; Thiazines; Thiazoles

The mechanism of interaction of the non-steroidal antiinflammatory drugs meloxicam and nimesulide with human and bovine serum albumin has been studied using fluorescence spectroscopy. There was only one high affinity site on serum albumin for both the drugs with association constants of the order of 10(5). Negative enthalpy (DeltaH(0)) and positive entropy (DeltaS(0)) values in the case of both meloxicam and nimesulide showed that both hydrogen bonding and hydrophobic interactions play a role in the binding of these drugs. Binding studies in the presence of the hydrophobic probe 1-anilinonaphthalene-8-sulfonate (ANS) showed that the binding of meloxicam and nimesulide to serum albumin involves predominantly hydrophobic interactions. Stern-Volmer analysis of the quenching data showed that quenching is highly efficient and that the tryptophan residues in hydrophobic regions of the proteins are fully exposed to the drugs. Thus these drugs are bound to albumin by hydrophobic interactions as well as hydrogen bonding at a site, which is close to the tryptophan residues. An increase of the pH and ionic strength caused an increase in the concentration of free drug, although the effect was not very significant.

Topics: Anilino Naphthalenesulfonates; Anti-Inflammatory Agents, Non-Steroidal; Hydrogen-Ion Concentration; Meloxicam; Osmolar Concentration; Protein Binding; Serum Albumin; Sulfonamides; Temperature; Thermodynamics; Thiazines; Thiazoles

The aim of our study was first to investigate if there exists an interaction between nitric oxide (NO) and prostaglandin (PG) generation in the estrogenized rat uterus challenged by lipopolysaccharide (LPS), and, secondly, which isoforms of nitric oxide synthase (NOS) and cyclooxygenase (COX) participate in this process.. To study the effect of LPS and to characterize the isoenzymes involved in the process, specific inhibitors of iNOS (aminoguanidine) and COX-II (meloxicam, nimesulide) and non-specific of COX (indomethacin) were injected intraperitoneally to determine their effect on NO and PG production, and on NOS and COX expression induced by LPS in estrogenized rat uterus. NO production was measured by arginine-citrulline conversion assay and PGE(2)/PGF(2alpha,)by radioconversion. Enzyme expression was evaluated by Western blot analysis.. The present work shows that iNOS inhibitor, aminoguanidine, reduced NO and PGE(2)/PGF(2alpha) production induced by LPS injection. Aminoguanidine exerts its effect over the PG metabolism by inhibiting COX-II activity and expression. On the other hand, both indomethacin, a non-selective PG inhibitor, and meloxicam, a COX-II inhibitor, stimulated NO production and reduced PGE(2)/PGF(2alpha) generation. Indomethacin also reduced COX-II and iNOS expression.. These results indicate that in the estrogenized rat uterus challenged with LPS, PG and NO interact affecting each other's metabolic pathways. The above findings indicate that the interaction between NOS and COX might be important in the regulation of physiopathologic events during pregnancy.

Topics: Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Down-Regulation; Embryo Loss; Estrogens; Female; Guanidines; Indomethacin; Inflammation; Isoenzymes; Lipopolysaccharides; Meloxicam; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pregnancy; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Wistar; Sulfonamides; Thiazines; Thiazoles; Uterus

Hypochlorous acid (HOCl) is an oxygen-derived species involved in physiological processes related to the defence of the organism that may cause adverse effects when its production is insufficiently controlled. In order to examine its reactivity with potential scavenging molecules from the non steroidal anti-inflammatory drugs (NSAIDs) family, a competition assay based on para-aminobenzoic acid (PABA) chlorination was developed. The original optimised in vitro fluorimetric procedure offered the possibility to determine rate constants (ks) for the reaction with HOCl in physiologically relevant conditions. The specificity of the system was improved by a liquid chromatography (LC) which allows the separation of the drugs and their oxidation products. After determination of the rate constant for PABA chlorination by HOCl (mean +/- SD in M(-1) s(-1): 4.3 +/- 0.3 x 10(3)), the applied mathematical model for a chemical competition permits to obtain linear curves from competition studies between several NSAIDs and PABA. Their slopes provided the following rate constants for the different studied drugs: tenoxicam: 4.0 +/- 0.7 x 10(3), piroxicam: 3.6 +/- 0.7 x 10(3), lornoxicam: 4.3 +/- 0.7 x 10(3), meloxicam: 1.7 +/- 0.3 x 10(4), nimesulide: 2.3 +/- 0.6 x 10(2). Meloxicam therefore reacted significantly faster than the other oxicams and nimesulide, which is the weakest scavenger of the studied series. The identification of some of the oxidation products by NMR or MS permitted to explore the reaction mechanism and to examine some aspects of the structure/activity relationships for the molecules of the same chemical family.

Topics: 4-Aminobenzoic Acid; Anti-Inflammatory Agents, Non-Steroidal; Binding, Competitive; Hypochlorous Acid; Kinetics; Linear Models; Meloxicam; Molecular Structure; Oxidation-Reduction; Piroxicam; Sulfonamides; Thiazines; Thiazoles

In hippocampal pyramidal cells, a rise in Ca(2+) releases endocannabinoids that activate the presynaptic cannabinoid receptor (CB1R) and transiently reduce GABAergic transmission-a process called depolarization-induced suppression of inhibition (DSI). The mechanism that limits the duration of endocannabinoid action in intact cells is unknown. Here we show that inhibition of cyclooxygenase-2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that COX-2 limits endocannabinoid action.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Synergism; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hippocampus; In Vitro Techniques; Isoenzymes; Male; Meloxicam; Membrane Potentials; Neural Inhibition; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Prostaglandin-Endoperoxide Synthases; Pyramidal Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Thiazines; Thiazoles

To investigate the effects of inhibitors of COX-1 or COX-2 on myometrial prostaglandin synthesis and on spontaneous contractions in human myometrium.. Cultured myometrial cells were incubated with SC 58560 (COX-1 selective inhibitor) or SC 58236 (COX-2 selective inhibitor), and the production of prostaglandins determined by ELISA. Spontaneously contracting strips of isolated gravid human lower segment myometrium were incubated with SC 58236, meloxicam, DFU, or nimesulide (COX-2 selective inhibitors), with SC 58560 (COX-1 selective inhibitor) or indomethacin (non-selective inhibitor).. SC 58236 inhibited the production of prostaglandins from myometrial cells, whereas SC 58560 had less effect. Nimesulide (100 microM) and indomethacin (300 microM) completely inhibited myometrial contractions, whereas meloxicam, DFU, SC 58236 and SC 58560 had less effect.. There was no relationship between the inhibition of prostaglandin production and the effects of the compounds on contractility. Myometrial prostaglandin synthesis does not seem to be essential for spontaneous contractility.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Humans; Indomethacin; Isoenzymes; Meloxicam; Membrane Proteins; Myometrium; Organic Chemicals; Pregnancy; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Sulfonamides; Thiazines; Thiazoles; Uterine Contraction

Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) and prostaglandin output from fetal membranes is a key stage in human parturition. Prostaglandin production can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs), but these may also inhibit cyclo-oxygenase enzymes in fetal tissues, and hence cause potentially serious side effects. We have compared the concentrations of NSAIDs that inhibit maximal PGE2 synthesis from intact human fetal membrane explants in vitro with those found in human plasma after standard anti-inflammatory treatment. The concentrations of all six drugs that caused a 50% inhibition of fetal membrane prostaglandin output were lower than average plasma levels achieved during treatment. This effect was greatest for nimesulide and indomethacin, indicating that these drugs require further study at low doses in vivo, as this could achieve the same tocolytic effect with diminished adverse fetal effect. These drugs were also the most potent inhibitors of fetal membrane prostaglandin output, consistent with their effects on COX-2 activity.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Extraembryonic Membranes; Female; Furans; Humans; Ibuprofen; Indomethacin; Inhibitory Concentration 50; Isoenzymes; Meloxicam; Membrane Proteins; Pregnancy; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thiazines; Thiazoles

This study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05 M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixed-solvent systems, PEG 400- ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixed-solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.

Topics: Celecoxib; Chemistry, Pharmaceutical; Cyclooxygenase 2; Enzyme Inhibitors; Hydrogen-Ion Concentration; Isoenzymes; Lactones; Meloxicam; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Solubility; Solvents; Sulfonamides; Sulfones; Thiazines; Thiazoles

Tizanidine, an alpha2-adrenergic receptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with nonsteridal anti-inflammatory drugs (NSAIDs). Tizanidine (0.25-1.0 mg/kg) significantly produced analgesic and anti-inflammatory effect in acetic acid induced writhing in mice and carrageenan-induced paw edema in rats, respectively. The effects were comparable with clonidine (0.25 and 0.50 mg/kg), another alpha2-agonist. Yohimbine (1 mg/kg), alpha2-adrenergic antagonist reversed the effect of tizanidine. Tizanidine (0.25 mg/kg) and clonidine (0.25 mg/kg) significantly potentiated the antinociceptive and anti-inflammatory effect of NSAIDs (nimesulide, meloxicam and naproxen). Tizanidine (1 mg/kg) did not alter basal pH, acidity (free and total) of gastric content and did not produce any mucosal injury in fasted rats. Tizanidine (1 mg/kg) significantly reduced meloxicam (UD50 3.21 mg/kg), nimesulide (UD50 24.52 mg/kg) and naproxen (UD50 14.10 mg/kg)-induced ulcerogenic effect (ulcer index, pH and free/total acidity). It is expected that tizanidine exerted gastrotprotection through stimulation of gastric and central alpha2-adrenergic receptors. Present investigation suggested that tizanidine not only enhance the analgesic and anti-inflammatory effect of NSAIDs but also improved gatstrointestinal tolerability of NSAIDs through modulation of central alpha-2-receptors. From this study, it can be speculated that tizanidine and NSAID combination therapy would prove to be a novel approach to treat nociceptive/inflammatory conditions with improved gastric tolerability of NSAIDs.

Topics: Adrenergic alpha-Agonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonidine; Drug Synergism; Drug Therapy, Combination; Meloxicam; Mice; Naproxen; Pain; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2; Stomach Ulcer; Sulfonamides; Thiazines; Thiazoles; Yohimbine

Vascular smooth muscle is now recognized as an important site of mediator generation under inflammatory conditions. Indeed, the release of leukocyte activators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-8, by human arterial smooth muscle cells has recently been demonstrated. However, the potential for venous cells to release GM-CSF has not been addressed. We have shown that human vascular smooth muscle cells express the "inflammatory" form of cyclooxygenase (COX), cyclooxygenase-2 (COX-2), when stimulated with cytokines. In some nonvascular cell types, the COX activity has been shown to regulate the release of GM-CSF and IL-8, although the nature of the isoform responsible was not addressed. We show that human venous smooth muscle cells, like their arterial counterparts, release GM-CSF after stimulation with IL-1beta. Similarly, both cell types released IL-8. Under the same conditions, we found that COX-2 activity suppressed GM-CSF, but not IL-8, release by both types of human vascular cells. Moreover, the prostacyclin mimetic, cicaprost, and the cAMP analogue, dibutyryl cAMP, inhibited GM-CSF release from these cells. These observations suggest that COX-2 activity suppresses GM-CSF release via a cAMP-dependent pathway in human vascular cells and illustrates a novel mechanism by which this enzyme can modulate immune and inflammatory events.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arteriosclerosis; Aspirin; Bucladesine; Cells, Cultured; Cyclic AMP; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Indans; Indomethacin; Interleukin-1; Interleukin-8; Isoenzymes; Mammary Arteries; Meloxicam; Membrane Proteins; Muscle, Smooth, Vascular; Neutrophils; Prostaglandin-Endoperoxide Synthases; Saphenous Vein; Sulfonamides; Thiazines; Thiazoles; Tumor Necrosis Factor-alpha