Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model.

In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for ß-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4(th), 5(th) and 6(th) groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine-depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function.

Carnitine deficiency aggravates cyclophosphamide-induced cardiotoxicity in rats.

BACKGROUND: This study examined, for the first time, the involvement of carnitine deficiency in cardiotoxicity, particularly cyclophosphamide (CP)-induced cardiomyopathy, as well as effects of carnitine supplementation with propionyl-L-carnitine (PLC) on cardiotoxicity. METHODS: An animal model of carnitine deficiency was developed in rats treated with D-carnitine (DC)-mildronate (MD). Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, PLC (250 mg/kg/day), and DC (250 mg/kg/day) combined with MD (200 mg/kg/day), respectively, for 10 successive days. In groups 4-6, the same doses of normal saline, PLC and DC-MD were injected, respectively, during the 5 successive days before and after a single dose of CP (200 mg/kg). On day 6 after CP treatment, 24-hour urine was collected, then animals were sacrificed, and serum as well as hearts were isolated. RESULTS: CP caused a significant increase in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), urinary carnitine excretion and clearance and intramitochondrial acetyl-CoA/CoA-SH, and a significant decrease in serum free carnitine, total carnitine and adenosine triphosphate (ATP) contents in cardiac tissue. In the carnitine-depleted rats, CP induced dramatic increases in CK-MB and LDH levels, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical and histopathological changes induced by CP to the control values. CONCLUSION: (1) Carnitine deficiency is a risk factor which is involved in CP-related cardiomyopathy; (2) serum and urinary carnitine levels should be monitored and viewed as indices of CP-induced multiple organ toxicity, and (3) carnitine supplementation, using PLC, prevents the development of CP-induced cardiotoxicity.

Comparative study between the protective effects of Saudi and Egyptian antivenoms, alone or in combination with ion channel modulators, against deleterious actions of Leiurus quinquestriatus scorpion venom.

This study compared efficacy of two polyvalent antivenoms (Saudi Arabian and Egyptian), against lethality and pathophysiological changes of Leiurus quinquestriatus quinquestriatus (LQQ) scorpion venom in mice. Additionally, the study examined whether treatment with selected ion channel modulators, lidocaine, nimodipine or amiodarone would be effective, alone or combined with the antivenoms. The protein concentration of the Saudi antivenom was 1/3 of Egyptian, indicating lesser immunogenicity, while both preservative contents were within limits. In immunodiffusion experiments, both exhibited prominent precipitin bands indicating high concentrations of specific antibodies. Neutralizing capacities (60-70 LD(50)) stated on labels were confirmed. Both antivenoms significantly (P < 0.001) prolonged survival time (from 26.9 +/- 1.18 min, 100% dead with venom to 224-300 min, 0-30% dead) of envenomed mice, whether injected iv before or 5 min after venom. Injection of either antivenom plus ion channel modulators, gave comparable results to that observed in mice treated with antivenoms alone. The Na(+) channel blocker lidocaine and the Ca(2+) channel blocker nimodipine on their own significantly protected the animals (P < 0.05), but to a lesser extent. The two antivenoms, significantly ameliorated the venom-evoked changes in serum LDH (P < 0.001) and CKMB (P < 0.01) plus cardiac TNFalpha and nitrate/nitrite levels (P < 0.001). When combined with lidocaine or nimodipine, the effects were not greater than antivenom alone. Moreover, the antivenoms ameliorated characteristic venom-evoked changes in the isolated perfused Langendorff hearts. Lidocaine and amiodarone were more effective than nimodipine. In Conclusion both Saudi and Egyptian antivenoms protected mice from the pathological and lethal effects of LQQ scorpion. Sodium and calcium channel blockers, lidocaine and nimodipine, may be useful when antivenoms are not available.