Doxorubicin cardiotoxicity and serum lipid increase is prevented by dextrazoxane (ICRF-187).

This study is related to the serious side effects of Doxorubicin-cardiotoxicity and serum lipid caused by the drug's cumulative effect. Studies were performed on experimental animals treated with intensive administration of Doxorubicin. Seventy five wistar rats were divided in two equal groups A and B. Group A was used for doxorubicin administration and B for doxorubicin and dextrazoxane. The drugs were administered weekly for twelve weeks at doses 0.2 mg/100 g BW for doxorubicin and 1.5 mg/100 g BW for dextrazoxane. Histological examination of the cardiac muscle, large vessels, liver and other organs and biochemical examination for serum lipids and liver enzymes were performed on certain weeks. Comparison of the findings of the two groups showed a) a reduction in doxorubicin cardiotoxicity by dextrazoxane and b) the addition of dextrazoxane to doxorubicin resulted in lowering the increase of serum lipids produced by doxorubicin. c) In vitro tests by chemiluminescence showed that dextrazoxane acts as a scavenger of oxygen free radicals.

An increase of serum lipids after cumulative doses of doxorubicin and epirubicin in experimental animals.

A wide range of pharmacological actions has been attributed to the anthracyclins. In this study we examined their effect on serum lipids in experimental animals in parallel with histological alterations. Three Wistar rat groups were injected with doxorubicin, epirubicin or normal saline once a week for 12 weeks. Total serum lipids, cholesterol, triglycerides, HDL-cholesterol, transaminases, proteins and alkaline phosphatase were assayed weekly. A proportion of the animals were sacrificed at the same time points and the cardiac muscle, large vessels, liver and abdominal muscle were stained and examined under light microscopy. Serum lipids were found to increase gradually, starting after 8 weeks of drug administration, until the end of the experiment. Tissue damage was noted in the cardiac muscle, abdominal muscle and large vessels, also following an increasing trend. Doxorubicin had a more pronounced effect than epirubicin on both serum lipid increase and tissue destruction. These alterations may contribute to anthracyclin-related cardiac damage.

Pharmacokinetics of arteether in dog.

A pharmacokinetic study has been conducted in six beagle dogs after i.m. administration of 25 mg/kg of arteether, a qinghaosu (artemisinin) derivative of high anti-malarial activity. Arteether plasma concentrations were measured during a 24 h period using HPLC with an electrochemical detector in the reductive mode. The pharmacokinetic parameters were established using an open two-compartment model. Results showed a relatively rapid absorption phase: T1/2ka was 0.300 +/- 0.096 h and a mean elimination half-life of 27.95 +/- 11.93 h. Cmax was 110 +/- 16 ng/ml, Cltot/F was 1.69 +/- 0.34 ml/min and AUC was 2797 +/- 476 ng/ml/h.

Mechanism of growth retardation following chronic administration of beta-adrenoceptor antagonists to developing rats.

A total of 112 3-week old Wistar rats were separated into eight groups: control groups I-IV (n = 62) and propranolol-treated groups V-VIII (n = 50). Propranolol hydrochloride (100 mg/kg) was present in the rats' drinking water until 26 weeks of age and growth rates of all groups were monitored daily until 53 days of age and thereafter every third day throughout the study. Chronic oral propranolol administration produced growth retardation (P less than 0.05) in both sexes that was reversible when treatment was discontinued. Organ weights were generally smaller in propranolol-treated rats; on the other hand, the ratio of most organ weights per 100 g of body weight was greater in propranolol-treated rats (especially females). The radio-immunological determination of plasma growth hormone showed increased concentrations of growth hormone in propranolol-treated rats (P less than 0.05), whereas hypothalamic somatostatin content was not significantly changed. The results showed that the retarded growth rate following chronic oral propranolol administration to growing rats was independent of changes in plasma growth hormone and hypothalamic somatostatin concentrations, and that retardation was entirely reversible when the beta-adrenoceptor antagonist was discontinued.

The influence of hemodilution on left ventricular function.

In nine anesthetized mongrel dogs anemia was produced by exchanging blood with plasma substitute thus reducing hemoglobin gradually in three steps. Aortic, atrial and ventricular blood pressures, cardiac output, electrocardiogram, phonocardiogram and the first derivative of the left ventricular pressure were continuously monitored. Blood samples were taken to determine hemoglobin, blood gases and whole blood viscosity. Progressive hemodilution resulted in a significant increase in cardiac output and left ventricular stroke work, while total peripheral resistance, oxygen content and whole blood viscosity decreased significantly. There were no significant changes in cardiac pressures, myocardial contractility, diastolic pressure time index and blood gases. The oxygen supply/demand ratio had gradually declined, while electrocardiogram showed no significant changes. These results suggest that moderate isovolemic hemodilution in animals with normal coronary vessels does not impair left ventricular function as this was manifested by the unchanged hemodynamic and electrocardiographic findings.

Pharmacokinetic interaction in beagle dogs of antiplatelet drugs: acetylsalicylic acid, dipyridamole and calcium dobesilate.

In clinical practice, the co-administration of antiplatelet drugs, such as acetylsalicylic acid (ASA) and dipyridamole (DP) and calcium dobesilate, is often recommended in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore the possible pharmacokinetic interactions between these three drugs were studied after a single-dose in beagle dogs. The plasma concentrations of ASA, DP and CaDb were measured by HPLC. It was found that the DP and CaDb kinetics were unaffected by concurrent intake of ASA, DP or CaDb. However, concurrent DP or CaDb improved the bioavailability of ASA, particularly the increased Cmax and (AUC).

Creatine kinase (CK-BB) determination in cerebrospinal fluid after acute experimental head injury.

Early changes of the activity of enzymes such as creatine kinase in the cerebrospinal fluid (CSF) or serum are often investigated after head injuries to assess the extent of brain damage and establish a reliable prognosis. The purpose of the present study was to determine levels of creatine kinase isoenzyme CK-BB in the CSF of rats after experimental head injuries. External head injuries of different severity were inflicted on rats, immediately after which CSF was collected for isoenzyme activity determination. It was found that the levels of CK-BB were significantly elevated immediately after the head injury and that the greater the degree of external cranial injury inflicted, the higher the isoenzyme activity was. The results seem to provide evidence that CK-BB activity is an early indicator of brain damage and that its level may reflect the extent of cerebral damage involved.