Effect of trimetazidine alone and in combination with captopril on the metabloic abnormalities associated with fructose - induced insulin resistance in rats

Trimelazidine [TMZ] is a metabolically active cytoprotective anti ischemic agent. It acts by switching myocardial metabolism from fatty acid oxidation with its high oxygen requirements to glucose oxidation with its low oxygen demand, thus reducing the impact of myocardial ischemia. In the present study the effect of TMZ alone and in combination with captopril on the metabolic abnormalities associated with insulin resistance [hypertension, hyperlipidemia and hyperglycemia]was investigated in rats rendered insulin resistant by being fed a high fructose diet for 6 weeks [By calories, the diet was 69% carbohydrate, 2l% protein and 10%fat]. Statistical analysis of the results revealed that TMZ pretreatment [5 mg / kg/day for 15 days] decreased blood pressure by 14.4%, blood glucose by 44.7% and plasma cholesterol by 8.48% in fructose fed but not in chow fed. Combined treatment with captopril [8mg/kg] in fructose fed rats was associated with 29.8%, 52.6% and 26.6% reduction in these parameters respectively. These favorable effects were associated with an increase in animal survival during the 6 weeks period of feeding as well as reduction in the body weight loss associated with high fructose feeding. In conclusion, TMZ might represent a novel metabolic approach to ischemic heart disease in diabetic patients. In such patients, the role of the drug would not be limited to a local cytoprotective effect against myocardial ishcemia, but might extend to involve a prophylactic role against the systemic metabolic abnormalities associated with insulin resistance. Its co-administration with the angiotensin converting enzyme inhibitor, captopril would further strengthen this prophylactic role. Acting in concert, both drugs could ultimately improve insulin sensitivity and its associated metabolic abnormalities, consequently reducing the risk of ischemic heart disease in diabetic patients

Anti-ischemic efficacy of trimetazidine in an animal model of fructose induced insulin resistance

In the present study rats were rendered insulin resistant by being fed a high fructose diet for 6 weeks [By calories, the diet was 69% carbohydrate, 21% protein and 10% fat.] The study was conducted to determine the impact of the metabolic abnormalities associated with fructose induced insulin resistance on the anti-ischemic efficacy of Trimetazidine [TMZ]. The later is a metabolically active anti-ischemic agent acting by switching myocardial cell metabolism during ischemia from lipid oxidation with its high oxygen demand to that of glucose oxidation with its low oxygen requirements, thus reducing the impact of the ischemic insult. The ischemic efficacy of TMZ was tested by induction of ischemia - reperfusion in beans isolated from chow fed and fructose fed rats pretreated for 15 days with TMZ [5mg/kg]. Statistical analysis of the results revealed that the Anti-ischemic efficacy of TMZ was more pronounced in hearts isolated from fructose fed rats than in those isolated from chow fed animals. This was evidenced by a reduction in MalonDiAldehide level [lipid peroxidation product and an index of ischemia] by 41.9% in diabetic compared to 19.4% in non-diabetic hearts. pH values, recorded following induction of ischemia in hearts isolated from fructose fed rats were higher [6.35] than those recorded in hearts isolated from chow fed rats [6.28]. In conclusion, ischemic heart disease is recently viewed as being ultimately metabolic in origin. The finding of the present work, that TMZ is more effective in diabetic animals adds further proof to this view. Diabetes is a metabolic disease, the metabolic abnormalities at the cellular level [down regulation of glucose transporter, reduced PDH activity and increased triacylglycerol content] result in a greater dependency on lipid peroxidation which not only increases the risk of ischemic heart disease but also increase the risk of its fatal end points namely cardiomyopathy and heart failure. Hence counteracting these metabolic abnormalities with metabolically active drug such as TMZ might be a rational approach, reducing both the risks of ishemic heart disease as well as its fatal end points

Effect of the H2 antagonist cimetidine versus famotidine on serum theophylline level and theophylline induced hypokalemia in rats

The effect of the H[2] antagonists on serum theophylline level was determined both directly by measuring serum theophylline concentrations at 0.5 - 1 - 2 - 4 and 6 hours after a single therapeutic dose of the drug [l0mg/kg intraperitoneally [IP]] in control [untreated] rats and in rats pretreated with Cimetidine [100 mg/kg] or famotidine [4 mg/kg] orally for 1 week and indirectly by determining the influence of these H[2] antagonists [in the above doses] on the degree of hypokalemia induced by a single high dose of theophylline [25 mg/kg Ip] [theophylline induced hypokalemia is believed to correlate well with serum theophylline level]. The results showed that Cimetidine consistently induced a statistically significant increase in serum theophylline level starting 1 hour after injection [10.3% [P<0.05] and thereafter [40.6 - 41.6 and 45.2% at 2-4 and 6 hours respectively [P<.0005]]. In contrast famotidine did not induce significant changes in serum theophylline level [P>.05] during the total duration of the experiment. Moreover, high dose theophylline induced a statistically significant reduction [P<.0005] in serum K+ from a control value of 3.9 +/- .06 to 3.5 +/- .047 mEq/L [10.25%]; pretreatment with Cimetidine resulted in a further reduction in serum K+ from 3.5 +/- .047 to 3.2 +/- 0.04 mEq/L [8.5% P<.0005] whereas pretreatment with famotidine resulted in an insignificant change [3.5 +/- .047 versus 3.4 +/- 0.07 mEq/L 2.8%P>.05]. Since H [2] receptor antagonists and theophylline may be given concurrently in more than one clinical setting [prophylactic against development of gastrointestinal symptoms of theophylline, in reflux oesophagitis occurring in as many as 30-60% of asthmatics or in patients with upper gastrointestinal bleeding who are intubated and maximally bronchodilated], clinicians should be alert to the significant interaction. Serum theophylline concentration should be measured periodically, measurement of serum potassium could also assist indirectly in prediction of serum theophylline level. Finally famotidine could be a safer alternative to cimetidine whenever H[2] antagonists are given concurrently with theophylline

Cimetidine and cardiac arrhythmia

The effects of oral and intravenous [IV] Cimetidine on both the normal ECG and ouabain-induced arrhythmias were investigated in pentobarbital anaesthetized dogs, in order to elucidate its pro or antiarrhythmic potentials. Cimetidine [25 mg/kg] orally for 10 consecutive days or [5 mg/kg] by slow IV infusion over 30 minutes did not induce significant changes in cardiac rate or rhythm. However a bolus injection of 5 mg/kg induced a statistically significant reduction in heart rate by 19% [2 P< .001]. Moreover, Cimetidine by slow IV infusion suppressed ouabain-induced cardiotoxicity as manifested by an increase in the doses of ouabain required to induce premature ventricular beats [PVB] and ventricular fibrillayion [VF] by 18.5% and 17% respectively [P <.005] .Since Cimetidine may be required in intensive care to guard against gastro-intestinal bleeding in critically ill patients, it is advisable to be given by slow IV infusion over 30 minutes. This will not reduce the risk of bradycardia resulting from bolus injections, but may even protect against cardiac arrhythmias that may develop in these patients, secondary to their poor cardiac conditions, excess intra-cardiac histamine release or that may be induced by arrhythmogenic drugs such as digoxin