Caution when interpreting anti-inflammatory drug effects in rat models of gastrointestinal anastomosis

Excessive or inappropriate use of non-steroidal anti-inflammatory drugs can affect cardiovascular and renal function. Non-steroidal anti-inflammatory drugs, both non-selective and selective cyclooxygenase 2 inhibitors, are among the most widely used drugs, especially in the elderly, with multiple comorbidities. Exposition to a polypharmacy burden represents a favourable substrate for the onset of non-steroidal anti-inflammatory drug-induced deleterious effects. Cardiovascular and renal issues concerning the occurrence of myocardial infarction, atrial fibrillation, heart failure and arterial hypertension, as well as acute or chronic kidney damage, become critical for clinicians in their daily practice. We discuss current available knowledge regarding prostanoid physiology in vascular, cardiac and renal systems, pointing out potential negative non-steroidal anti-inflammatory drug-related issues in clinical practice.

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Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat

Clinical Science ◽

10.1042/cs0950603 ◽

1998 ◽

Vol 95 (5) ◽

pp. 603-609 ◽

Cited By ~ 5

Author(s):

Marijke HAAS ◽

Frits MOOLENAAR ◽

Dirk K. F. MEIJER ◽

Paul E. DE JONG ◽

Dick DE ZEEUW

Keyword(s):

Prostaglandin E2 ◽

Rat Kidney ◽

Drug Effects ◽

Fold Increase ◽

Inhibitory Effect ◽

High Dose ◽

Water Excretion ◽

Inflammatory Drug ◽

Baseline Conditions ◽

Anti Inflammatory

1.Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen–lysine. 2.In the present study we questioned whether naproxen–lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment. 3.A high dose of free naproxen (10 ;mg·day-1·kg-1) did not affect prostaglandin E2 excretion in baseline conditions (naproxen, 11±1 ;ng/8 ;h; vehicle, 13±4 ;ng/8 ;h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group (P< 0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E2 excretion (naproxen 6.6±1.1 ;ng/8 ;h, vehicle 40±12 ;ng/8 ;h, P< 0.005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 (P< 0.05) and 1.8 times (P< 0.005) lower in the naproxen group. 4.A dose of 2 ;mg·day-1·kg-1 lysozyme-conjugated naproxen did not affect prostaglandin E2 excretion in baseline conditions (conjugate, 18±2 ;ng/8 ;h; vehicle, 24±5 ;ng/8 ;h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E2 excretion (conjugate, 16±3 ;ng/8 ;h; vehicle, 48±13 ;ng/8 ;h, P< 0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate. 5.In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.

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