Misoprostol effects on diclofenac-induced cardiorenal changes in salt-sensitive patients with hypertension: the MEDIC Study.

Munger MA, Gardner SF, Ateshkadi A, Rabetoy GM, Barri YM, Stoddard GJ, Cheung AK, MEDIC Study Investigators. Misoprostol effects on diclofenac-induced cardiorenal changes in salt-sensitive patients with hypertension: the MEDIC Study. Pharmacotherapy. 2008 Jul 1; 28(7):834-42.

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Abstract:

STUDY OBJECTIVE: To determine whether coadministration of misoprostol with the nonsteroidal antiinflammatory drug diclofenac lessens the increase in blood pressure and improves the alterations in renal hemodynamics induced by diclofenac. DESIGN: Prospective, randomized, double-blind, placebo-controlled, crossover study. SETTING: Two university research centers. PATIENTS: Nineteen senior (mean age 62 yrs [range 55-73 yrs]), salt-sensitive patients with stage 1 or 2 hypertension. INTERVENTION: After a 3-week antihypertensive withdrawal lead-in phase, patients received either diclofenac 75 mg alone or diclofenac 75 mg plus misoprostol 200 microg twice/day for 14 days. After a 10-day washout period, patients received the alternate treatment. MEASUREMENTS AND MAIN RESULTS: Blood pressure was measured by 24-hour ambulatory blood pressure monitoring, effective renal plasma flow (ERPF) rate was determined by para-aminohippurate clearance, and glomerular filtration rate (GFR) was measured by iothalamate clearance. Mean arterial pressure (MAP = diastolic blood pressure + 0.33[systolic - diastolic blood pressure]) and rate-pressure product (RPP = systolic blood pressure x heart rate x 10(-2)) were also used to compare treatment groups. Diclofenac alone increased MAP by a mean +/- SEM of 5.0 +/- 1.0 mm Hg and RPP by 337 +/- 181 units compared with baseline. The ERPF rate and GFR decreased by 40.5 +/- 26.9 ml/minute and 14.1 +/- 6.5 ml/minute, respectively. Diclofenac plus misoprostol decreased the diclofenac-induced increase in MAP by 3.3 +/- 1.0 mm Hg (95% confidence interval [CI] 1.1-5.3 mm Hg, p = 0.004) and decreased the RPP by 724 +/- 238 units (95% CI 225-1223 units, p = 0.007). The ERPF rate increased by 56.1 +/- 35.0 ml/minute (95% CI -24.7-137.0 ml/min, p = 0.15) and GFR by 18.1 +/- 7.1 ml/minute (95% CI 1.9-34.5 ml/min, p = 0.03). Diclofenac alone was relatively well tolerated; no adverse effects were reported with diclofenac plus misoprostol. CONCLUSION: In senior salt-sensitive patients with hypertension, coadministration of misoprostol with diclofenac attenuated the blood pressure elevation and renal vasoconstrictive effects of diclofenac and was well tolerated.