CHRONOMODULATED NIFEDIPINE ADMINISTRATION AND MICROVASCULAR COMPLICATIONS IN GLIMEPIRIDE-TREATED HYPERGLYCAEMIC RATS
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ABSTRACT
Diabetic complications pose increasing public health problems worldwide. Glimepiride, a sulphonylurea is among the most frequently used anti-diabetic drugs, and is often combined with other drugs for the management of type 2 diabetes mellitus. Nifedipine, a calcium channel blocker is recommended for its role in mitigating microvascular complications especially in delaying the onset of diabetic nephropathy. Interaction between both drugs leads to regimen failure when simultaneously administered. However, established diurnal variation in nifedipine pharmacokinetics can ameliorate the benefits of nifedipine-glimepiride co-administration. This study investigates the effect of 21-day chronomodulated nifedipine administration on glycaemic control and microvascular complications in glimepiride-treated streptozotocin-induced hyperglycaemic rats. All animals were treated daily per oral. Fasting and random blood glucose were assessed on days 0, 3, 7, 14, 21, and days 0, 6, 10, 13 20 respectively. Peripheral neuropathy was evaluated using the paw pressure and tail immersion tests on days 7, 14 and 21. At the end of drug treatment, nephropathy and retinopathy were evaluated by determining levels of some serum renal and ocular markers; in addition to histological assessment of the kidney and retina. Administration of glimepiride alone at 8 pm significantly (p<0.01) reduced blood glucose levels on days 7, 14 and 21 when compared to initial values but had no significant effect on outcome of microvascular complications. Concurrent administration of glimepiride and nifedipine at 8 pm impaired glycaemic control and exacerbated microvascular complications. In contrast, treatment with glimepiride at 8 pm and nifedipine at 8 am significantly (p<0.01) improved glycaemic control in a manner similar to the group treated with glimepiride alone at 8 pm. The paw pressure and tail immersion xvii tests showed significant (p<0.05) increase in paw withdrawal latency and mean reaction time respectively on days 14 and 21 in comparison to values on day 7, indicating amelioration in peripheral neuropathy. The serum protein and albumin levels were significantly (p<0.05) higher in this group when compared with diabetic controls. The serum urea levels and relative kidney weights were also significantly (p<0.05) lower when compared to the diabetic control. These indicate improvement in the prognosis of nephropathy. Similarly, the serum triglyceride and cholesterol levels were significantly (p<0.05) lower when compared to the diabetic control. Also, the serum magnesium level was significantly (p<0.05) higher when compared to diabetic control. This indicates protection against retinopathy and is supported by histological findings where photomicrograph of the retina shows normal features similar to non-diabetic control. The findings from this study suggest that diurnal variation in pharmacokinetics can be effectively used to advantage, resulting in glimepiride and nifedipine being successfully co-administered without losing the glucose lowering benefits of glimepiride, while simultaneously delaying the progression and improving prognosis of microvascular complications.
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