Inhibition of Prostaglandin Synthesis in Rat Brain

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

山莨菪碱对乙酰胆碱和去甲肾上腺素引起的兔虹膜释放前列腺素的影响

本文研究了654-2对Ach及NE引起的兔虹膜释放PGE₂及6-keto-PGF_1α作用的影响。Ach及NE使虹膜释放PGs增加,654-2对Ach释放PGs的作用呈剂量依赖性抑制,当654-2浓度为3×10^-5mol/L时,Ach(5x10^-5mol/L)引起的PGE₂及6-keto-PGF_1α的释放量分别降低31%及30%。654-2浓度高于6x10^-5mol/L时显著抑制NE(5x10^-5mol/L)释放虹膜PGs的作用,当654-2浓度为3x10^-4mol/L时,使NE增加虹膜释放PGE:及6-keto-PGF_1α的量分别从62%及34%降至7.5%及4%(p<0.01)。654-2抑制PGs释放对其抗感染性休克等作用可能是有利的。     

Renal Prostaglandins and Sodium Balance in the Rabbit: Lack of Effect of Aspirin-like Drugs

Abstract Urinary prostaglandin E₂ (PGE₂) and PGF₂ excretion was previously found to be inversely related to sodium intake in the rabbit. Renal prostaglandin (PG) synthesis might therefore be involved in the renal handling of sodium. This possibility was tested by studying sodium excretion during inhibition of renal PG synthesis with four different nonsteroidal anti-inflammatory drugs in unanaesthetized, female rabbits. The rabbits n = 5–6) were kept in metabolic cages and chronically maintained on different sodium containing diets. On a medium salt diet (0.4% NaCl), neither treatment with indomethacin (1.5 mg/kg×2 or 3 mg/kg×2) nor diclofenac (1.5 mg/kg × 2) for three days changed the urinary excretion of sodium and water although the mean excretion of immunoreactive PGE₂ (iPGE₂) and iPGF₂ were reduced by between 43–78%. On a very low salt diet (0.05% NaCl), two days treatment with aspirin (30 mg/kg ×2), diclofenac (3 mg/kg× 2), indomethacin (3.5 mg/kg×2) or naproxen (10 mg/kg×2) did not alter sodium excretion in any significant direction. The mean urinary PGE₂ and PGF₂ excretion was reduced by 35–63% and 63–85%, respectively. These results do not support a major role of PGs in the chronic regulation of sodium balance in the rabbit. The possible influence of mineralocorticoids on renal PG synthesis was studied by administration of aldosterone (100 μg/kg×2) fortwo days to rabbits on a high salt diet (2% NaCl) and cancrenoate (10 mg/kg×2), an aldosterone antagonist, to rabbits on the very low salt diet. However, neither drug significantly changed the urinary excretion of PGF₂α, indicating that renal PG synthesis is not influenced by mineralocorticoids in the rabbit     

Effect of central prostaglandins on carrageenan-induced pedal oedema in rats

The possible modulatory effect of central prostaglandins (PGs) on carrageenan-induced pedal inflammation, was investigated in rats. Intracerebroventricularly (i.c.v.) administered arachidonic acid, the PG precursor, produced a statistically insignificant increase in the inflammatory response, though PG synthesis inhibitors, administered by the same route, markedly attenuated the oedema. Centrally administered PGE₂ had a significant proinflammatory effect, whereas PGF_2α exerted an antiinflammatory action. The results indicate that central PGs may modulate peripheral inflammation and that, at least partly, the anti-inflammatory activity of PG synthesis-inhibiting non-steroidal anti-inflammatory agents may involve central PGs, as has been proposed for their analgesic effect.     

A subchronic study of the effect of etodolac on the gastric mucosal prostaglandin levels in the rat

The effect of 7 consecutive days dosing with anti-inflammatory drugs on rat gastric mucosal PGE2 and 6-keto-PGF1 alpha concentrations were studied. Normal adult rats were given daily, single oral doses of etodolac (3 or 8 mg/kg/day), naproxen (3 mg/kg/day), or aspirin (300 mg/kg/day). Two hours after administration of the last dose, the animals were killed and the gastric mucosal PGE2 and 6-keto-PGF1 alpha were extracted and measured by radioimmunoassay. At equieffective anti-inflammatory doses in the rat, etodolac (3 mg/kg/day) did not significantly lower the concentrations of either PGE2 or 6-keto-PGF1 alpha, whereas both 3 mg/kg/day of naproxen and 300 mg/kg/day of aspirin significantly lowered the concentrations of both prostaglandins. The effects of naproxen and aspirin on the 6-keto-PGF1 alpha concentrations were also significantly different from that of etodolac at 3 mg/kg/day. At a higher dose of 8 mg/kg/day, etodolac did significantly lower the concentrations of PGE2 (by 33%) but not of 6-keto-PGF1 alpha. Our present data thus supports the hypothesis that the relatively weak inhibiting effect of etodolac on the gastric mucosal prostaglandin concentrations may contribute to its excellent GI profile observed in man.     

NSAID gastropathy: prevention by celery seed extracts in disease-stressed rats

Previous studies showed that some anti-inflammatory celery seed extracts (CSEs) were not gastrotoxic, in contrast to many OTC NSAIDs, when dosed to arthritic rats. The present investigation was designed to quantify the potential activity of CSEs against NSAID injury in rats with severe acute or chronic inflammation and to define the possible relationship of this to effects on mucosal prostaglandin production. Oral doses of alcoholic (A-CSE) (150-300 mg/kg) and supercritical fluid (S-CSE)(20-50 mg/kg) extracts of seeds of wild celery Apium graveolens from north India (Beagle Int. Nerang, Qld.) profoundly suppressed gastric injury elicited in disease-stressed female rats (Wistar, DA) with (a) chronic arthritic inflammation or (b) severe acute inflammation (from oleyl alcohol, 0.1 ml in tail base), fasted overnight and then dosed either (i) orally with ibuprofen (50 mg/kg), sodium naproxen (27.5 mg/kg), ketoprofen (5 mg/kg) or acidic ethanol (150 mg/kg); or (ii) parenterally with piroxicam (5 mg/kg) or nabumetone (100 mg/kg). By contrast several conventional gastroprotectants, e.g. sucralfate, cimetidine, bismuth salts, all given orally were ineffective in preventing gastric injury from parenteral piroxicam. Gastroprotection by CSEs was not over-ridden by co-dosing with isotonic HCl. Most other celery seed 'oils' were ineffective in these assays. A-CSE was found to have marked inhibitory effects on PGE₂ production by porcine gastric (fundic) mucosal explants in organ culture. Quercetin and mycrecetin which are reported components of some CSEs also inhibited PGE₂ production in concentrations of 10 _M, whereas limonene, another reported component of CSEs had little effect at the same concentration. These results suggest that gastroprotective effects of CSEs are probably mediated through non-prostaglandin mechanisms.     

Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole

Objective: To study, in three separate investigations, the potential interaction between omeprazole and three different non-steroidal anti-inflammatory drugs (NSAIDs; diclofenac, naproxen and piroxicam) in healthy male and female subjects. Methods: Each investigation was an open, randomized, three-way cross-over study, in which the subjects were given omeprazole 20 mg once daily for 1 week, the NSAID in therapeutic daily doses (diclofenac 50 mg bid, naproxen 250 mg bid, or piroxicam 10 mg om), or a combination of omeprazole and each NSAID. The plasma concentrations of the NSAID as well as of omeprazole were determined on the last day of each investigation period. Results: None of the NSAIDs studied had any effect on the plasma concentration versus time curve (AUC) of omeprazole. It was also demonstrated that omeprazole 20 mg daily had no significant influence on the pharmacokinetics of the NSAIDs. The AUC ratio, (NSAID +omeprazole):NSAID alone, was 1.11, 0.99, and 0.99 for diclofenac, naproxen, and piroxicam, respectively. Conclusion: Diclofenac, naproxen, and piroxicam can be administered together with omeprazole 20 mg daily without need for dosage alteration. There was no significant change in the bioavailability of theses NSAIDs during omeprazole therapy in this study. Received: 13 August 1997 / Accepted in revised form: 7 March 1998     

Regional differences in the responses to prostanoids of circular muscle from guinea-pig isolated intestine

The effects of prostaglandins (PGs) D₂, E₂, F_2α, an epoxymethano analogue of PGH₂ (U-46619), prostacyclin (PGI₂), 6-keto-PGF_lα and thromboxane (Tx) B₂ were tested on spirally-cut strips of guinea-pig isolated ileum or colon. In the ileum no prostanoid exerted a marked effect on the resting tissue, but PGD₂, PGE₂ or PGI₂ 1 μg ml^?1 inhibited submaximal contraction to KC1. U-46619 1 μg ml^?1 either inhibited or increased contractions to KC1, but PGF_2α, 6-keto-PGF_1α or TxB₂ 1 μg ml^?1 had no significant effect. PGE₂ relaxed colonic strips whereas the other prostanoids caused contraction, except for TxB₂ which had no effect. The PG antagonist SC-19220 blocked colonic contractions to the prostanoids, and a residual inhibitory effect of PGD₂, U-46619 or PGI₂ was demonstrated by the reduction of submaximal contractions to acetylcholine. Our results suggest that prostanoid receptors mediating inhibitory responses of circular muscle predominate in the ileum, whereas in the colon both excitatory and inhibitory prostanoid receptors occur.     

非普拉宗对环氧酶活性的影响

目的　研究非普拉宗(feprazone, Fep)对环氧酶-1和环氧酶-2活性的影响。 方法　用放免法测定PGE2含量反映环氧酶-2活性,测定6-酮-前列腺素F_1α含量反映环氧酶-1活性。 结果　Fep在0.1,1.0,10.0 μmol.L^-1能剂量依赖性抑制小鼠腹腔巨噬细胞PGE₂生成,在相同浓度下对小牛主动脉内皮细胞6-keto-PGF_1α生成抑制作用较弱。结论　Fep显著抑制PGE₂生成,对PGI₂生成影响较小,提示其对环氧酶-2有较强的抑制作用。     

Prostaglandin inhibition of apomorphine-induced circling in mice

The effect of prostaglandins (PGs) on apomorphine (apo)-induced circling was examined in unilaterally lesioned mice. Intraventricularly injected PGD₂, PGE₂, and PGF_2α at a dose of 1.0 nmole/g all inhibited apo-induced circling. When injected directly into the striatum, these same PGs also inhibited circling in a dose range of 0.01–0.1 nmole/g, while the PGE₂ metabolite, 13, 14-dihydro-15-keto-PGE₂, was inactive at 0.1 nmole/g. For both routes of administration, PGF_2α appeared to be the most potent of the PGs tested. PGs administered alone by either route to unilaterally lesioned mice did not produce circling. Pretreatment with the PG synthetase inhibitor, indomethacin, caused the apo treated mice to circle at significantly higher rates than control animals. These results are the first report suggesting that within dopamine (DA)-mediated pathways PGs act at sites postsynaptic to the dopaminergic synapse.     

Effects of prostaglandin E1 analogue,misoprostol, on the development of adjuvant arthritis in rats

Prostaglandins (PG) E , E and the PGE analogue, misoprostol, have been shown to inhibit T-cell functions and the production by activated monocytes or macrophages of interleukin-1, indicating that these PGs may have potential anti-arthritic activity by suppressing T-cell and monocyte activity. In view of this the potential anti-arthritic effects of the long half-life PG, misoprostol (MPL), were examined in adjuvant arthritic rats under prophylactic and therapeutic treatment regimes. Transcutaneous or subcutaneous MPL given at 200 Μg/kg/day but not at 50 or 5 Μg/kg/day when given 0 to +5 or 0 to + 14 days post-induction inhibited the development of the disease whereas the orally administered drug was without effects. MPL given transcutaneously with oral indomethacin (1 or 2 mg/kg/day) on days +17 to + 30 post-induction produced greater anti-inflammatory effects than with this NSAID alone. MPL given orally in combination with this NSAID did not enhance the anti-inflammatory effects of the latter. MPL 200 Μg/kg given transcutaneously exhibited anti-ulcer activity against indomethacin (30 mg/kg p.o.), naproxen (10 mg/kg i.p.) or piroxicam (5 mg/kg i.p.) induced gastric damage in arthritic rats and this was comparable with that from 100 Μg/kg MPL given orally. These results show that MPL has both unique anti-arthritic effects only when given transcutaneously or parenterally as well as anti-ulcer activity.     

Effects of FK506 on an experimental model of colitis in rats

Aim: To assess the effects of FK506, a newly developed immunosuppressant, on experimental colitis in rats. Methods: Experimental colitis was induced by a single colonic instillation of hapten 2,4,6-trinitrobenzene sulphonic acid (TNB) in anaesthetized rats. Rats received 30 mg TNB dissolved in 0.25 mL of 50% ethanol, and were sacrificed on day 5 following 4 days dosing with FK506 (0.25, 0.5, 1.0, 2.0 mg/kg, s.c.) or vehicle. Mucosal prostanoid concentrations were determined using high performance liquid chromotography. Tissue myeloperoxidase activities were measured. The effects of FK506 on superoxide radical formation by neutrophils in both rats and humans were also estimated in vitro. Results: Administration of FK506 significantly reduced the colonic damage in a dose-dependent manner. Activities of myeloperoxidase and concentrations of 6-keto-prostaglandin Fl_1α (6-keto-PGF_1α, PGF_2α and PGE₂ in colonic tissue increased significantly following induction of experimental colitis, however, FK506 did not affect these changes. FK506 reduced stimulant-induced superoxide radical formation by neutrophils in rats and humans. Conclusion: FK506 decreased superoxide radical generation by neutrophils, which might contribute to the lessening of colonic damage in this model.     

RELATIONSHIP BETWEEN GASTRIC MUCOSAL PROSTAGLANDIN LEVELS AND HEALING OF GASTRIC LESIONS IN RATS

1. This study was designed to determine whether or not endogenous prostaglandins (PG) contribute to the healing of gastric ulcers induced by high concentrations of ethanol or water immersion stress. 2. Ethanol-induced gastric lesions; rats were divided into four groups: (1) the control group: untreated; (2) the indomethacin group: indomethacin (2 mg/kg) was injected intramuscularly (i.m.) once daily until the end of the experiment; (3) the ethanol group: rats were given 1 mL of 50% ethanol intragastrically; (4) the ethanol + indomethacin group: indomethacin (2 mg/kg) was injected (i.m.) once daily from 1 h after administration of 50% ethanol until the end of the experiment. 3. Water immersion stress-induced gastric lesions; rats were divided into three groups: (1) control group: untreated; (2) stress group: rats were placed in a stress cage and immersed into a water bath (23°C) for 6 h; (3) stress + indomethacin group: indomethacin (2 mg/kg) was injected (i.m.) once daily for 3 consecutive days immediately after stress treatment or from 3 days after stress treatment until the end of the experiment. 4. Immediately after observation of the lesions, the fundic mucosal layer was separated from the muscle layer and mucosal PG levels were measured by high performance liquid chromatography in each group. 5. Indomethacin did not inhibit ulcer healing until 48 h after administration in the ethanol experiment, and until 3 days after administration in the water immersion experiment. In contrast, indomethacin inhibited ulcer healing thereafter in each experiment respectively. 6. Four kinds of PG, that is 6-keto-PGF_1α PGF_2α, PGE₂ and PGD₂ were detected in gastric mucosa. Indomethacin inhibited the recovery of PG levels, and significantly low PG levels were observed after indomethacin treatment. 7. It was noted from the effect of indomethacin that there are at least two phases of healing in gastric ulcers (i.e. the early phase and the late phase), and that PG might be linked with the late phase of ulcer healing.     

Gastric mucosal adaptation to etodolac and naproxen

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently cause damage to the gastroduodenal mucosa, principally by suppressing mucosal prostaglandin synthesis. However, such acute mucosal injury usually resolves, despite continued NSAID administration, by a process known as adaptation. Newer NSAIDs, such as etodolac, have been developed to minimize effects on prostaglandin synthesis. Aim: To determine whether etodolac causes less acute damage than naproxen, and whether the damage produced resolves with continued NSAID administration. Methods: Twenty-four healthy volunteers were given a 28-day course of either etodolac 300 mg b.d. or naproxen 500 mg b.d. Gastroduodenal damage was assessed using a modified Lanza scoring system and mucosal blood flow with laser doppler flowmetry at endoscopy before NSAID administration and during days 1, 7 and 28 of continued intake. Results: Maximum gastric damage (median grade and interquartile range, IOR) occurred during the first 24 h of administration, being greater with naproxen (2.0, IOR 1.0–3.0) than etodolac (1.0, IOR 1.0–1.5; P= 0.03). Such damage was associated with a fall in antral blood flow in the naproxen group (mean ± S.E.M.) from 54.5±3.4 to 43.8±3.4 arbitrary units (P= 0.07) and a slight increase in mucosal blood flow in the etodolac group from 43.5 ± 2.24 to 49.5 + 3.6 arbitrary units. With continued intake this damage resolved in all subjects taking etodolac and in eight of 14 subjects on naproxen. Resolution in the naproxen group was associated with a return to normal of antral blood flow. Conclusions: These observations suggest that etodolac causes less mucosal damage than naproxen and that adaptation occurs to both.     

Delta-9-tetrahydrocannabinol (THC) increases brain prostaglandins in the rat

Intraperitoneal administration of 9-trans-delta-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, in doses of 0.5, 1.0 and 2.0 mg/kg, produced a dose-related increase in the brain concentrations of prostaglandin (PG) E₂ and PGF₂ in male rats 4 h after THC administration, as assessed by radioimmunoassay. A time-course investigation indicated that THC (2 mg/kg, IP) induced maximal increases in rat brain concentration of both PGs 2 and 4 h after administration; PG levels declined appreciably by 8 h and were normal by 24 h.A time-course study on the hexobarbitone (100 mg/kg, IP) -induced hypnosis potentiating effect of THC (2.0 mg/kg, IP) in male rats revealed that this pharmacological action of the cannabinoid correlated well with the time-course of the THC-induced increase in rat brain PG concentrations.The present study lends support to earlier reports contending that PGs may mediate some of the central actions of THC.     

Gastric damage induced by subchronic administration of preferential cyclooxygenase-1 and cyclooxygenase-2 inhibitors in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to induce gastrointestinal damage including bleeding, ulceration and perforation in humans and animals. The aim of this study was to compare the effects of two oxicams, preferential cyclooxygenase (COX)-1 or COX-2 inhibitors, on both gastric mucosa and some biological parameters (hematological, hepatic and renal) after subchronic administration (14 and 28 days) in rats. Neutrophil infiltration was also assessed. Equipotent doses of meloxicam (3.75 and 7.5 mg/kg) and piroxicam (5 and 10 mg/kg) were administered. Both drugs dose-dependently caused multiple gastric erosions and hemorrhage in rats after 14 and 28 days of administration. Treatment with meloxicam led to a higher gastric damage than with piroxicam on day 14 although these results were not significant. The levels of myeloperoxidase activity (as an index of neutrophil infiltration) were not changed compared with control after drug treatment. All the hematological parameters obtained after drugs administration for 14 and 28 days were in the range of normal values, and a significant increase in platelet levels could be observed in the group treated with 5 mg/kg of piroxicam for 14 days. Aspartate aminotransferase (AST or GOT) increased significantly after 14 days, but after 28 days the values returned to normality. Creatinine and urea did not undergo significant changes except for the piroxicam 14-day 5 mg/kg group, in which uremia increased significantly over normal values. In conclusion, our results show that meloxicam, a preferential COX-2 inhibitor, causes rates of gastric lesion comparable to those seen with traditional NSAIDs, without inducing important changes in biological parameters.     

Inactivation of prostaglandins in the perfused rat lung

Inactivation in the isolated perfused rat lung of prostaglandins (PG) D₂, E₁, F_2α, I₂ and the metabolites 6-keto PGF_1α (= 6KF_1α) and 13,14-dihydro-15-keto POP_2α (= KH₂F_2α) was studied using 5 min perfusions of 7–10 ng/ml PG in Krebs' solution containing 0.02 μCi/ml tritiated PG and 4.5% bovine serum albumin (BSA). The parameters measured were (a) extent of inactivation (F_2α > E₁ > D₂ > 6KF_1α > I₂; KH₂F_2α unchanged), (b) the accumulation of PG within the lung measured as tissue to medium ratio (F_2α = D₂ > E₁ > 6KF_1α > I₁ = KH₂F_2α), and (c) rate of equi within the lung measured as “wash-in t$\text{1}\text{2}$” (D₂ > F_2α > e₁ > I₂ = 6KF_1α = KH₂F_2α). Removal of sodium ions produced a small decrease in PGD₂ and PGE₁ breakdown but not of PGF_2α whereas breakdown of all PGs was markedly inhibited at 5°. Removal of BSA enhanced PGE₁ and PGI₂ breakdown but not that of PGF_2α. Addition of 10% BSA inhibited PGE₁ breakdown but not that of PGF_2α. Binding of PGs to 4.5% BSA was PGE₁ = KH₂F_2α > D₂ > F_2α, and increased at 10% BSA or after removal of sodium ions. These data support the view that PGs must be taken up into pulmonary cells by a transmembrane carrier process as a prerequisite for enzymatic breakdown. The metabolites are then released back into the pulmonary circulation.     

Acute studies on safety index of nonsteroidal anti-inflammatory drugs in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation. Their use is frequently limited by gastrointestinal side effects, ranging from dyspeptic symptoms to life threatening bleeding or perforations of gastroduodenal ulcers. The present study mainly aimed to establish a safety index of NSAIDs in experimental animals. Safety index is based on the ratio of ulcerogenic dose (UD₅₀) and anti-inflammatory dose (ED₅₀). The safety index of preferential COX-2 inhibitor (nimesulide, meloxicam) was investigated using carrageenan-induced paw oedema and acute ulcerogenic model in rats, compared with the classical NSAIDs (naproxen, indomethacin). Meloxicam was found to be the most potent NSAID (ED₅₀ 1.07 mg/kg, p.o.) followed by nimesulide (2.42 mg/kg, p.o.), indomethacin (2.72 mg/kg, p.o.) and naproxen (6.82 mg/kg, p.o.) after 240 min of carrageenan challenge. In acute ulcerogenic study naproxen, indomethacin and meloxicam were found to be ulcerogenic at lower doses (UD₅₀ 14.0, 3.80 and 3.21 mg/kg, p.o.) in comparison to nimesulide (UD₅₀ 24.52 mg/kg, p.o.). Meloxicam, naproxen and indomethacin also produced damage to gastric epithelium (disruption of mucus layer and damage to parietal cells) at ED₅₀ dose level when it was viewed under scanning electron microscope, but nimesulide did not distrub gastric mucosal integrity at ED₅₀ dose. Based on the safety index (Ulcerogenic dose₅₀ /Effective anti-inflammatory dose₅₀) the order of safety of these agents was nimesulide > meloxicam > naproxen > indomethacin.     

General pharmacology of meloxicam-part I: Effects on CNS,gastric emptying,intestinal transport,water, electrolyte and creatinine excretion

The general pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), were examined. Characteristics that distinguish meloxicam from conventional NSAIDs were investigated. No central-nervous-system effects were observed in the mouse at oral doses up to 100 mg/kg. In vitro studies showed meloxicam had no antagonistic properties against mediators such as histamine, PGE₂ and angiotensin II. The rate of gastric emptying or intestinal transport in the rat was not influenced by therapeutic doses of meloxicam and, of all the NSAIDs investigated, meloxicam showed the mildest effect on gastric acidity. In doses well above those required for antiinflammatory action, meloxicam had no influence on water, electrolyte or creatinine excretion.     

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days.The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose.Eicosanoids (PGE₂, 6-keto-PGF₁, TXB₂, LTB₄, LTC₄) in synovial fluid were determined by immunoenzy-matic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests.Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE₂ and LTB₄ concentrations. The decrease in 6-keto-PGF₁ and TXB₂ was not significant. No significant change was found for LTC₄ and hyaluronic acid.Total concentrations of sodium naproxen were equivalent in plasma (16.1 g·ml^–1) and synovial fluid (18.9 g·ml^–1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11 %), as shown by binding of the drug to human serum albumin, at various protein concentrations.Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.