Efficacy of the selective prostaglandin synthase type 2 inhibitor nimesulide in blocking basal prostaglandin production and delaying glucocorticoid-induced premature labor in sheep.

OBJECTIVE: The purpose of the study was to determine the effects of selective prostaglandin synthase type 2 inhibitors on basal prostaglandin concentrations in the fetal and maternal circulations and on the labor-associated increase in prostaglandin production in sheep. STUDY DESIGN: The effects of maternal nimesulide (0.01, 0.1, and 1 mg/kg) and 6-methoxy-2-naphthylacetic acid (1, 5, and 10 mg/kg) administration were examined (n = 5) at 134 +/- 1 days' gestation. At 138 days' gestation premature labor was induced by fetal dexamethasone infusion (1 mg/d). Ewes were treated with either vehicle or nimesulide infusion (20 mg. d-1. kg-1, n = 5 per group). RESULTS: Nimesulide and 6-methoxy-2-naphthylacetic acid decreased basal prostaglandin production in a concentration-dependent manner. Delivery of nimesulide-treated ewes was delayed by >/=17 hours with respect to that of control ewes (53.9 +/- 2.6 hours). In 2 nimesulide-treated ewes labor did not progress to delivery despite membrane rupture. The increase in prostaglandin concentrations usually seen during dexamethasone-induced labor was abolished in nimesulide-treated ewes and also in their fetuses. CONCLUSIONS: Highly selective inhibitors of prostaglandin endoperoxidase H synthase 2 may be required to spare fetal prostaglandin production and limit potential side effects during the suppression of preterm labor.

Antinociceptive effects of non-steroidal anti-inflammatory drugs in a rat model of unilateral hindpaw inflammation.

The antinociceptive activity of intramuscular 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone, was examined in a rat model of unilateral hindpaw inflammation/hyperalgesia and compared with that of three other non-steroidal anti-inflammatory drugs (NSAIDs)--diclofenac, naproxen and piroxicam. Over a dose range of 10-100 mg/kg i.m., 6-MNA produced a dose-dependent increase in the withdrawal threshold to a noxious mechanical stimulus applied to the inflamed paw; however, a higher dose (300 mg/kg) produced no further increase in antinociceptive activity. Peak effects occurred 30 min after intramuscular injection. Diclofenac, naproxen and piroxicam produced antinociceptive effects that were qualitatively similar to those of 6-MNA. There was an indication of quantitative differences between the four NSAIDs in terms of potency and efficacy although this was not statistically significant. The rapid onset of effect and the lack of correlation between the relative antinociceptive effects of the four NSAIDs and the anti-inflammatory activities (assayed as inhibition of carrageenan-induced rat paw oedema) suggest that their pain relieving properties may not be entirely the result of their anti-inflammatory effects. These experimental data support the therapeutic value of 6-MNA as an analgesic in conditions of inflammatory pain.

Leukotrienes mediate antigen-induced airway hyper-reactivity in guinea pigs.

The involvement of leukotrienes (LTs) in antigen-induced airway hyper-reactivity (AHR) was characterized pharmacologically by using several 5-lipoxygenase (5-LO) inhibitors and LTD4 antagonists in guinea pigs. AHR was evidenced by consistent and significant increases in sensitivity to bronchoconstriction induced by i.v. methacholine in anesthetized and ventilated animals 24 hr after a single ovalbumin aerosol challenge, but maximum methacholine-induced bronchoconstriction did not increase. Animals were pretreated with maximum doses of WY-50,295 tromethamine (WY-50,295), LY-171,883, MK-886 or zileuton, based upon inhibition of antigen-induced LT-dependent bronchoconstriction. WY-50,295, having a long duration of action, was the only compound that prevented AHR when given once before antigen challenge. However, LY-171,883 and MK-886 prevented AHR when a second dose was given 4 hr after challenge. Zileuton, having a short duration of action, failed to prevent AHR when given before and after challenge. The prevention of AHR did not result from functional antagonism (bronchodilation) by any compound. In bronchoalveolar lavage studies, neither WY-50,295 nor MK-886 inhibited the influx of eosinophils into the airways 24 hr after antigen challenge. The results provide pharmacological evidence that LTs play an important role in the pathogenesis of antigen-induced AHR in guinea pigs. Furthermore, the effectiveness of 5-LO inhibitors and LTD4 antagonists in this model depends upon a long duration of drug action and appears to result from inhibition of a direct airway effect of LTs rather than inhibition of eosinophil influx into the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of endotoxin-induced hypothermia and serum TNF-alpha levels in CD-1 mice by various pharmacological agents.

Intraperitoneal injection of lipopolysaccharide (LPS) was used to elicit a sublethal, shock-like condition in mice. LPS, 2.5 mg/kg i.p., induced hypothermia, elevated serum TNF-alpha levels and lethality over a 48 h period in male CD-1 mice. The 5-lipoxygenase (LO) inhibitors, WY-50,295 tromethamine and zileuton (100 mg/kg p.o), significantly inhibited hypothermia at 4, 24 and 48 h after LPS. Interestingly, whereas cyclooxygenase (CO) inhibitors (ibuprofen, etodolac, naproxen and tenidap) at 40-80 mg/kg p.o. stimulated hypothermia at 4 h, they significantly reduced the later stages of hypothermia at 24-48 h. Rolipram (PDE-IV inhibitor) and dexamethasone significantly reduced hypothermia at 4-24 h and 1-24 h, respectively. All the anti-inflammatory agents significantly reduced elevated TNF-alpha levels at approximately 70 min post-LPS, except for ibuprofen. In conclusion, these anti-inflammatory standards indicate that LPS-induced shock involves multiple lipid mediators (PG's, LT's and possibly PAF) and secondary cytokine generation. This sublethal model of LPS-induced shock represents a sensitive model for estimating the efficacy of potential drug candidates for the treatment of endotoxic shock.

Antiinflammatory activity of isomeric phenylnaphthaleneacetic acids.

The isomeric phenylnaphthaleneacetic acids were prepared and tested for antiinflammatory activity by the anti-UV-erythema method. High potency was exhibited by 4- and 5-phenyl-1-naphthaleneacetic acid and 5- and 6-phenyl-2-naphthaleneacetic acid. The results are discussed in terms of a hypothetical receptor site.

The treatment of dysmenorrhea with naproxen sodium: a report on two independent double-blind trials.

The efficacy of naproxen sodium (naproxen-Na) in dysmenorrhea has been established in two independent double-blind (placebo-controlled) studies. An initial dose of 550 mg. of naproxen-Na was followed by 275 mg. every six hours for a maximum of five days. Twenty patients were included in Study I (10 treated with naproxen-Na) and 23 patients in Study II (12 treated with naproxen-Na). Each patient received the medication during four dysmenorrheic episodes. Thus, a total of 172 treatment courses could be evaluated. A variety of efficacy criteria were measured: frequency of pill intake, changes in pain intensity, the degree of relief achieved by the medication, and need for additional analgesics. In both studies naproxen-Na was demonstrated to be superior to the placebo treatment with high statistical significance in each of these parameters.

Naproxen, aspirin, and codeine in postpartum uterine pain.

The analgesic efficacy of oral naproxen and its sodium salt was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single-dose, parallel, stratified, randomized, placebo-controlled, double-blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable from placebo responses throughout the 8-hr time course. Although time-effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p less than 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p less than 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.

New antirheumatic agents: Fenoprofen calcium (Nalfon), naproxen (Naprosyn), and tolmetin sodium (Tolectin).

The new antirheumatic agents, fenoprofen calcium, naproxen, and tolmetin sodium, are effective in the management of rheumatoid arthritis. Their efficacy is comparable, but not superior, to that of aspirin in usual oral doses. These agents also may be useful in degenerative joint disease and ankylosing spondylitis and as analgesics and antipyretics; however, there are insufficient data available to establish their efficacy and dosages for these uses. The incidence of adverse reactions, including gastrointestinal bleeding, is lower with these agents than with aspirin; thus, these drugs may be useful substitutes in patients who cannot tolerate the gastrointestinal effects of aspirin.

Multicentre trial of naproxen and phenylbutazone in acute gout.

Naproxen 750 mg as a single dose followed by 250 mg three times daily has been compared with phenylbutazone 200 mg four times daily for 48 hours followed by 200 mg three times daily for treatment of acute gout in an open study on 41 patients. The drugs were equally effective with few and relatively mild side effects. Naproxen is a useful alternative agent for the treatment of acute gout.

The effect of naproxen-sodium on the intrauterine pressure and menstrual pain of dysmenorrheic patients.

The Prostaglandin-synthesis inhibitor: Naproxen-Sodium (NS) (an analgesic agent) very significantly (P less than 0.001) reduced the "resting" and "active" pressures and the frequency of cyclic uterine activity of 10 dysmenorrheic patients. It also highly significantly reduced (P less than 0.001) menstrual pain. Since these effects were observed after a single oral dose of 1100 mg NS, without side effects or complications, extensive field trials are recommended for assessing therapeutic benefits of this treatment.

Diclofenac (Voltaren) for the treatment of osteo-arthrosis: a double-blind comparison with naproxen.

A double-blind, between-patient, comparative trial of diclofenac (Voltaren) and naproxen was carried out in 30 patients suffering from osteo-arthrosis of the hip or the knee. The drugs were given twice daily, morning and evening, during a period of two weeks. The daily dose was 100 mg for Voltaren and 500 mg for naproxen. The results indicate that Voltaren brought relief of pain and stiffness in a greater number of patients than did naproxen. The same finding was made regarding the influence on the range of joint movements, the difference reaching statistical significance. Voltaren appeared also to be better tolerated since the number of patients reporting side-effects was smaller and the complaints of less severity.

Multi-centre trial of naproxen and phenylbutazone in acute gout.

Naproxen 750 mg as a single dose followed by 250 mg three times daily has been compared with phenylbutazone 200 mg four times daily for 48 hours followed by 200 mg three times daily for the treatment of acute gout in an open study on 41 patients. The drugs were equally effective with few and relatively mild side effects. Naproxen is a useful alternative agent for the treatment of acute gout.

Combination therapy with naproxen and aspirin in rheumatoid arthritis.

Thirty-six patients with rheumatoid arthritis were studied to determine the effectiveness and safety of combined therapy with naproxen and aspirin. An 8-week double-blind crossover trial was performed in which naproxen and placebo were administered on a background of constant-dose aspirin. Combination therapy was demonstrated to be more effective than aspirin alone. Tolerance of the two regimens was comparable.