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Enhancement of allergic tracheal constriction and contraction of the trachea by AA in the presence of cyclooxygenase inhibitors may reflect diversion of AA metabolism from the cyclooxygenase pathway.
The present study was designed to attempt to clarify the mechanism by which the specific beta-2 adrenergic agonist albuterol causes an enhancement of erythropoietin (Ep) production in the isolated perfused dog kidney. We have postulated previously that prostaglandins (PG) release is an early event in initiating a cascade which leads to enhanced kidney production of Ep. In the present study, the posthypoxic dog kidney was perfused for 5 hr with blood containing 500 microgram/l of albuterol. A significant (P<.001) increase in prostaglandin E (PGE) concentration was seen as early as 1 hr and continued to rise over the 5-hr perfusion period. This microgram increase in PGE was correlated with a significant (P<.05) increase in Ep titers in the perfusates after 3 and 5 hr perfusion. The addition of the PG cyclooxygenase inhibitor meclofenamate (1000 micrograms/l) to the perfusate together with albuterol completely abolished the albuterol-induced increase in PGE and Ep generation in the isolated perfused kidney. No significant increase in PGE or Ep titers in the perfusates occurred during the 5-hr perfusion period in the saline and albuterol plus meclofenamate perfused groups. These data suggest that beta-2 adrenergic activation of Ep production is correlated with an increase in PGE production by the kidney which may be related to the mechanism by which beta-2 agonists enhance kidney production of Ep.
Pulmonary release of thromboxanes and prostaglandins occurs during the first hour after endotoxin infusion in sheep concomitant with transient, severe pulmonary hypertension (phase I) and followed by a prolonged period of increased lung vascular permeability (phase II) characterized by moderately elevated pulmonary artery pressure and high flow of protein-rich lung lymph. Indomethacin and meclofenamate both inhibited phase I pulmonary hypertension but did not prevent later increases in pulmonary artery pressure and lung lymph flow to levels seen with endotoxin alone in the same sheep. Indomethacin significantly exaggerated phase II lung lymph flow (endotoxin = 19 +/- ml/hr; indomethacin + endotoxin = 24 +/- 4 ml/hr, p less than 0.05), and meclofenamate enhanced phase II lymph protein clearance (endotoxin = 12.9 +/- 1.5 ml/hr; meclofenamate + endotoxin = 17.1 +/- 2.5 ml/hr, p less than 0.05). Hypoxemia seen with endotoxin alone was inhibited by meclofenamate. These data indicate that during endotoxemia cyclooxygenase products mediate phase I pulmonary hypertension. Inhibitors of cyclooxygenase prevent ventilation perfusion imbalance that results in endotoxin induced hypoxemia. Exaggeration of phase II lymph responses by cyclooxygenase inhibitors suggests that prostaglandin synthesis moderates phase II or that lipoxygenation products contribute to the phase II increased permeability response.
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We compared the effects of sodium meclofenamate (5 mg/kg i.v.), an inhibitor of prostaglandin synthesis, on renal function in six unanesthetized dogs maintained for 5 to 7 days before the experiment on 100 mEq/day of NaCl and after sodium depletion by furosemide administration and salt deprivation. Plasma renin activity (PRA) during sodium depletion (12.35 +/- 3.93 ng ml-1 hr-1) was higher than during sodium repletion (1.46 +/- 0.47 ng ml-1 hr-1; P less than .05). The administration of meclofenamate did not alter mean arterial pressure, renal blood flow, urine volume, excretion of sodium and potassium or PRA in the sodium replete dog. However, during sodium depletion meclofenamate reduced renal blood flow from 168 +/- 35 to 105 +/- 23 ml/min (P less than .01) and urine flow from 0.32 +/- 0.09 to 0.16 +/- 0.05 ml/min (P less than .05) but did not affect mean arterial pressure, electrolyte excretion or PRA. The meclofenamate-induced reduction in renal blood flow during sodium depletion was well correlated with control PRA. After administration of meclofenamate, the urinary excretion of immunoreactive prostaglandin E2 fell by 66% (P less than .05) in the sodium replete dog and by 72% (P less than .05) in the sodium depleted dog. This study demonstrates that the effects of meclofenamate on renal hemodynamics vary with the state of sodium balance and in relation to PRA.
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A single-blind crossover trial was carried out in 21 patients with active rheumatoid arthritis to assess the effectiveness and tolerance of sodium meclofenamate (300 mg per day) compared with placebo. After a 1-week washout period patients had two periods of active medication, each of 2 weeks, separated by 1 week on placebo. Morning stiffness, walking speed, pain score, patient impression of response, joint tenderness and power, work and maximum grip strength achieved by hand grip were all improved by sodium meclofenamate and an anti-inflammatory effect of the drug was demonstrated, with some reduction in the swelling of PIP joints. There was no advantage in assessing pain on full movement of the small joints of the hands in addition to direct tenderness. Power, work and rate of grip release achieved during hand grip provided more information about hand function than maximum grip strength alone. Lymphocyte transformation to non-specific mitogens was enhanced by the drug. Twelve patients had some form of gastro intestinal complaint during the study and it is suggested that diarrhoea is likely to prove to be the major limiting factor of acceptance by some patients.
Sodium meclofenamate (200 to 400 mg daily) was compared with aspirin (2.4 to 4.8 g daily) for the treatment of rheumatoid arthritis in a 6-month, double-blind, multicentre study. Two groups of patients participated, one receiving stabilized doses of concomitant gold or steroid therapy and one not receiving such therapy. In these latter patients, sodium meclofenamate appeared to be more effective than aspirin; tenderness was reduced from 35% to 50% more on sodium meclofenamate throughout the study, the differences being statistically significant during the first 2 months, and over all condition improved in a significantly greater proportion of the patients receiving sodium meclofenamate. Among the patients receiving concomitant gold or steroid, neither drug appeared to be as effective as in the group not receiving the concomitant therapy and the results with both aspirin and sodium meclofenamate were virtually the same for all measures. With sodium meclofenamate the most common adverse reaction was diarrhoea; and with aspirin, it was tinnitus. The incidence of withdrawals for adverse reactions did not differ significantly between the two medication groups. Abnormal laboratory values were observed in a few patients, but the incidence did not differ between the groups. On the basis of the study, sodium meclofenamate appears to be relatively well tolerated and at least as effective as aspirin in the treatment of the symptoms of rheumatoid arthritis.
The therapeutic efficacy of sodium meclofenamate (300 mg per day) was compared with that of aspirin (3.6 g per day) and placebo in 317 patients with active rheumatoid arthritis. The 8-week double-blind treatment period was preceded by a 2-week washout period on aspirin. A smaller proportion of patients on sodium meclofenamate (11%) withdrew for a lack of efficacy than did patients on aspirin (18%) or placebo (40%). Analyses of measures of tenderness, total joint involvement, duration of morning stiffness, and patient condition and global improvement revealed that the therapeutic effectiveness of 300 mg sodium meclofenamate daily and 3.6 g aspirin daily were equivalent and significantly superior to that of placebo. The principal adverse reactions with sodium meclofenamate were gastro-intestinal symptoms of which diarrhoea was the most frequently reported. The rates of adverse reaction withdrawals were similar in the three treatment groups. Sodium meclofenamate showed good control of disease activity and was generally well tolerated in the treatment of rheumatoid arthritis.
Thirty-nine patients with JRA were treated with sodium meclofenamate (Meclomen) during a 4-wk open-labeled, non-controlled trial. Increasing doses started at 3 mg/kg/d qid, up to 7.5 mg/kg/d, not to exceed 300 mg/d. Seven patients dropped out due to adverse side effects, and 1 from inefficacy. Efficacy analysis showed statistically significant decreases in several disease indices, in particular the duration of morning stiffness. Twenty-one patients who completed the 4-wk study entered an extended open-labeled study. Nine patients completed at least 9 months of sodium meclofenamate therapy. At 9 months, these 19 showed mean decreases in all rheumatologic disease indices measured. The drug has recently been approved by the Food and Drug Administration for use in adults.
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The effects of hemorrhage on renal blood flow and the extent to which the responses are modulated by prostaglandins were investigated in 23 conscious, splenectomized dogs. Renal blood flows were measured with radioactive microspheres injected into the left atrium. The renal cortex was divided into four layers for studies of regional flow distribution. Sequential hemorrhage of 10 ml/kg, 20 ml/kg, and 30 ml/kg was performed in six dogs. Total renal blood flow did not change at 10 ml/kg or 20 ml/kg blood loss, but at 30 ml/kg, when mean aortic pressure fell by 41 +/- 9 (SE) mm Hg, there was a reduction in total renal flow from 6.09 +/- 1.04 to 3.00 +/- 0.74 ml/min/gm (P < 0.01). No redistribution in renal cortical blood flow occurred at any level of hemorrhage. Meclofenamate--5.0 mg/kg IV--a prostaglandin synthetase inhibitor, induced vasoconstriction without redistribution of cortical flow. When 10 ml/kg blood loss with subsequent reinfusion was studied before and after meclofenamate in nine normal dogs and two dogs with bilateral adrenalectomy and unilateral renal denervation, neither total nor regional renal flow were altered further. Thus, in conscious dogs, hemorrhage has no effect on total renal blood flow until blood volume is reduced by approximately 3% of body weight and renal cortical blood flow is not redistributed. In addition, an inhibitor of prostaglandin synthetase does not influence the renovascular response to hemorrhagic stress, although it increases renal vascular resistance at rest.
Vasoactive agents alter proteinuria by modulating glomerular hemodynamics. The authors hypothesized that vasoactive agents may be altering degradation of the collagen component of glomerular basement membrane, which also may be contributing to proteinuria. Mesangial cells treated with 10(-6) M angiotensin II had higher (P < 0.01) metalloproteinase activity (MA) when compared with control cells. This effect of angiotensin II was dose dependent. Amlodipine (10(-6) M), a calcium channel blocker, inhibited MA (control, 5.86 +/- 0.08 microgram versus 4.13 +/- 0.06 microgram gelatin degraded/mg protein, P < 0.001). The decrease in mesangial MA caused by amlodipine also occurred in a dose dependent manner. Amlodipine attenuated (P < 0.05) angiotensin II-stimulated MA (control, 6.69 +/- 0.30 micrograms, angiotensin II, 10.68 +/- 0.49 micrograms, angiotensin II+amlodipine 8.29 +/- 0.30 micrograms gelatin degraded/mg protein). Prostaglandin E2 increased (P < 0.001) MA (control, 10.22 +/- 0.9 micrograms versus prostaglandin E2, 17.9 +/- 0.9 micrograms gelatin degraded/mg protein), whereas indomethacin, a prostaglandin inhibitor, attenuated the metalloproteinase activity (control, 9.67 +/- 0.32 micrograms vs. 10(-6) M indomethacin, 4.22 +/- 0.31 micrograms gelatin degraded/mg protein, P < 0.001). Indomethacin also inhibited angiotensin II-stimulated MA (angiotensin II, 18.66 +/- 0.46 vs. angiotensin II+indomethacin, 11.86 +/- 0.56 micrograms degraded/mg protein, P < 0.001). Similarly, meclofenamate, another prostaglandin inhibitor, attenuated (P < 0.001) angiotensin II-induced MA. Because angiotensin II increases prostaglandin E2 synthesis by mesangial cells, it appears that increased MA, induced by angiotensin II, may be mediated partly through the generation of prostaglandin E2.
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