In our previous study it has been demonstrated that Paracetamol-diclofenac (PD) combination, a new analgesic ..... Rainsford, K.D., Aspirin and the salicylates,.
COMPARATIVE EFFECT OF PARACETAMOL WITH DICLOFENACPARACETAMOL COMBINATION ON THE INTEGRITY OF RAT KIDNEY DURING NINETY DAYS DAILY TREATMENT *1Zezi AU, 1Danjuma NM, 1Abdu-Aguye I, 2Aliyu IS and 3Ahmad SA 1 2 3
Department of Pharmacology and Therapeutics, Ahmadu Bello University Zaria, Nigeria. Department of Chemical Pathology Ahmadu Bello University Teaching Hospital, Shika- Zaria, Nigeria. Department of Morbid Anatomy Ahmadu Bello University Teaching Hospital, Shika- Zaria, Nigeria.
Abstract In our previous study it has been demonstrated that Paracetamol-diclofenac (PD) combination, a new analgesic combination, had no significant effect on the integrity of the rat kidney during ten days daily drug treatment. In this present study, effects of PD on the rat kidney integrity after 90 days daily treatment were investigated comparing the effects with paracetamol (P) alone. Findings from this work may form basis for clinical studies. One group containing six rats, was administered P (14.14 mg/kg) and the other PD (15.7 mg/kg) - equivalent adult doses, orally daily for 90 days. The control group was given the vehicle used in preparing the drug. After 90 days, the 24-hour volumes of water intake and urine excretion were determined with the aid of metabolic cage. The urine was analyzed for protein, occult blood and microscopic examination done. The potassium and sodium levels were determined using flame photometric method. Urine pH was determined using pH strips. Fresh kidney tissues were obtained for structural integrity (histopathology) studies using Haematoxylin and Eosin (H and E) staining method. For the kidney functional studies in PD treated rats, sodium, potassium, pH and protein levels were not significantly affected. No occult blood was detected. However water intake and urine excretion were significantly reduced compared to the control (p0.05. Values are Mean±SEM, n = 6.
In the medullar, cyclooxygenase – 2 (Cox -2) promotes diuresis and natriuresis (Komhoff et al., 2000). Prostaglandins derived from the activities of cyclooxygenases are active in regulating vascular tone and salt and water homeostasis by modulating glomerular haemodynamics and regulating distal nephron function (Pugliese and Cinotti, 1997). From this study it has been shown that the PD combination may be adversely affecting the kidney cycloxygenase and prostaglandins, to the extent of causing abnormal renal function in urine volume and water intake following chronic use in laboratory animals. Results from rats treated with PD and P revealed that they did not show significant changes on the urine level of sodium and potassium compared with control. The pH was also not affected. Sodium is the predominant cation of the extracellular fluid. Along with chloride, potassium and water, sodium is important in establishing osmotic pressure relationships between intracellular and extracellular fluids. An increase or decrease in sodium concentration may signify impaired sodium excretion. Increased or decreased sodium level may occur in renal disease. Similarly decreased or increased
Protein and pH levels Table 3 shows protein and pH levels in 24-hours urine excretion by the rats treated with the PD and P. After 90 days daily treatment, the 24-hours urine excretion showed no significant change in protein and pH levels (p>0.05) by the PD treated group compared with P and control groups. Microscopic Examination and Occult Blood Detection Table 4 shows detection of triple phosphate crystals, calcium oxalate crystals and Occult blood in 24hours urine excretion by the rats treated with the PD and P. After 90 days daily treatment, the 24-hours urine excretion shows presence of triple phosphate crystals, calcium oxalate crystals with no occult blood detected, by the PD treated group, P and control groups. Histopathological Studies Table 5 shows result of histopathological studies. There were moderate glomerular and mild tubular atrophy in PD treated rats. In P treated rats there was
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potassium level may be attributable to renal disease (Wynne and Edwards, 2003). The collecting duct is composed of a variety of cell types. The principal cells in the collecting duct play an important role in Na+ and water re-absorption and in K+ channels, apical and baso lateral K+ channels and a baso lateral Na+, K+ (Rudolf, 2000). PD might not have affected the collecting duct, therefore there was normal regulation of sodium and potassium levels in the urine. Normal pH of the urine from PD treated group compared to P and control might indicate normal intercalated cell in the epithelium cells of the kidney. Intercalated cells interspersed as single cells in the epithelium. The number of intercalated cells decreases from the cortical to the inner medullary collecting duct. Intercalated cells contain very little Na+, K+-ATPase, but large amount of electrogenic vacuolar type H+-ATPase. They do not contain water channels. Together this explains the role of intercalated cells in acid-base homeostasis (Rudolf, 2000).
study similar to 10 days study protocol earlier investigated (Zezi et al., 2007a&b). This may suggest absence of direct serious tissue damage with PD. However, there were moderate glomerular and mild tubular atrophy in PD treated rats. In P treated rats there was mild glomerular atrophy. These effects might be related to recycling phenomenon exhibited by analgesics. These drugs are ultrafiltered in the glomeruli, and then undergo back diffusion in the proximal tubules and recycling via the blood back to glomeruli (Beyer and Gelarden, 1984) Conclusion It could be concluded that Paracetamol – diclofenac (PD) combination has shown some effects on the rat kidney functional and structural status after chronic use in laboratory animals. However, clinical evaluation in humans is required to authenticate these findings. Acknowledgement This work was supported by Ahmadu Bello University Zaria, Board of research. The authors acknowledge with thanks the assistance of Mal Ibrahim Adamu, Mr John Kono and Alh. Ya’u Dari, of the technical section of Department of Pharmacology and Therapeutics, A. B. U., Zaria. We also gratefully acknowledge the assistance of Chief Medical Laboratory Scientist of Department of Chemical Pathology A.B.U. Teaching Hospital Zaria, Mr M. E. Ekanem.
Table 5: Histopathological studies of rat kidney after 90 days drug treatment daily with paracetamol (P) and paracetamol-diclofenac (PD) combination Drug (mg/kg) Glomerular Tubule Control Normal Normal P (14.14) Atrophy Normal PD (15.7) Moderate atrophy Moderate atrophy
References: Paracetamol, a weak non steroidal anti-inflammatory drug (NSAID) and diclofenac a potent non steroidal anti-inflammatory drug (NSAID) have been shown to produce synergistic analgesic activity as a combination product in a preliminary studies we conducted (Zezi et al., 2007a&b). The combination is therefore expected to show synergistic renal cyclooxygenase and prostaglandine inhibition that may result in abnormal renal function. However, this study has not shown such abnormality except for possible changes in glomerulotubular balance as shown by reduced water intake and urine formation, all together showing varying effect of PD on renal function. On microscopic examination there were traces of triple phosphate and calcium oxalate crystals detected which were also found in both paracetamol and control groups. This is consistent with normal physiological function of the kidney (Waynforth, 1980). For structural integrity studies, no occult blood was detected and no significant protein changes. These parameters are not affected in this
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