Evaluation of cardiac subacute toxicity of epirubicin, chlorambucil, cisplatin, methotrexate and a homo-aza-steroid ester with antitumor activity in rats using serum biochemical parameters.

Cardiac subacute toxicity induced by the antineoplastic drugs epirubicin (CAS 56390-09-1), chlorambucil (CAS 305-03-3), cisplatin (CAS 15663-27-1) and methotrexate (CAS 59-05-2) and the steroid alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam ¿p-[bis(2-chloroethyl)amino] phenyl¿ acetate was investigated in rats using serum biochemical parameters. Toxicology evaluation was performed in serum samples following the administration of dose regimens of the agents that were previously shown to be effective in suppressing malignant tumor growth or to prolong survival in tumor-bearing animals. Cardiac subacute toxicity was evaluated by measuring serum enzyme activity of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase and aspartate aminotransferase. The use of the above serum biochemical parameters indicated that the cardiac subacute toxicity impact of the antitumor drugs was epirubicin "methotrexate = chlorambucil = cisplatin > homo-aza-steroid ester.

Ultrastructural changes of the myocardial and striated muscle following a challenge of normobaric hyperoxia: the protective effects of alpha-tocopherol.

Normobaric hyperoxia has known deleterious effects on survival, presumably due to the generation of superoxide anion and hydrogen peroxide. To investigate the anatomical substrate of the effect of normobaric hyperoxia on the myocardial and striated muscles and the protective effect, if any, of alpha-tocopherol (vitamin E) on these tissues, we administered 95-99% O2 to adult male Wistar rats for 24, 48, 60 and 72 h. The animals were divided into four groups: 1) control I: six rats which breathed room air were used as controls for the ultrastructural studies; 2) control II: 10 rats which breathed 95-99% of O2 for up to 72 h were used as controls for arterial pressure, blood gases/pH, PvO2 and Hb measurements; 3) group A: hyperoxia: 24 rats divided into four subgroups according to the time of exposure to hyperoxia, A24, A48, A60, A72; and 4) group B: alpha-tocopherol/hyperoxia: 24 rats treated with alpha-tocopherol, 15 mg/kg/day, for 14 days before the beginning and throughout the period of hyperoxia, were divided into four subgroups (B24, B48, B60, B72) according to the time of exposure to hyperoxia. Our results showed that: 1) up to the 60th hour, arterial pressure (MAP) was satisfactory; PaO2 > 280 mmHg; PaCO2, pH and Hb were within normal limits; 2) ultrastructural studies of the myocardial apex, the diaphragm and the quadriceps femoris showed dilatation of the sarcoplasmic reticulum/T-tubuli system, swelling of mitochondria, and structural derangement of myofibrils, in particular in the z-bands. The findings were proportionally related to the time of exposure of hyperoxia. They were also more intensely shown on myocardial and diaphragmatic fibers in group A; 3) the survival time (mean +/- SD) was 63.8 +/- 2.5 h in group A and 68.9 +/- 3.8 h in group B. These results suggest that normobaric hyperoxia exerts a cytotoxic effect on the myocardial and striated muscle fibers and that the administration of alpha-tocopherol may delay or change the development of oxygen toxicity.

The influence of methionine-5-enkephalin on calcium uptake by the bovine aortic media.

The influence of methionine-5-enkephalin (M-5-E), an endogenous opioid receptor agonist, on calcium uptake by bovine aortic media was investigated in vitro. 45Ca was used and radioactivity was counted in a beta scintillation counter. M-5-E increases Ca2+ uptake by the preparation. This action is inhibited by naloxone and that is proof that an opioid receptor is stimulated. A comparative study showed that phenylephrine, an alpha-adrenoceptor agonist, exhibits the same action as M-5-E, whereas morphine's action is negligible. Phenylephrine contracts the deendotheliazed ring of the bovine aorta, whereas M-5-E fails to do so. It is concluded that an opioid receptor was identified at the bovine aortic smooth muscle. This receptor is stimulated by M-5-E resulting in an increase of the extracellular Ca2+ entrance. Although no relationship was observed between the receptor and the contraction mechanism, a possible role of M-5-E in the maintenance of the vascular tone cannot be excluded.

The influence of amikacin on digoxin uptake by certain rabbit tissues in vitro.

The influence of amikacin on digoxin uptake by various rabbit tissues was investigated in vitro. 125J-digoxin was used and radioactivity was counted in a gamma scintillation counter. Amikacin decreases digoxin uptake by the renal tissue and this action is probably due to a displacing effect. On the contrary, amikacin increases digoxin uptake by striated and cardiac muscle. It is suggested that the latter action is due to a vasodilating effect of the aminoglycoside antibiotic that favors the microcirculation of the above tissues.

Interaction of aminoglycoside antibiotics and calcium channel blockers at the neuromuscular junctions.

Aminoglycoside antibiotics (mmol.l-1) gentamicin (0.74), streptomycin (1.02), netilmicin (1.24), amikacin (2.23), sisomicin (2.74), dactimicin (2.75), kanamycin (3.43), kanendomycin (3.45), tobramycin (3.53) and dibekacin (4.35) produce a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat, which is only reversed by calcium chloride. On the other hand, verapamil (2.04 mmol.l-1), a calcium channel blocker, also produces a complete neuromuscular blockade at the above preparation which is reversed by calcium chloride. Aminoglycoside antibiotics are potentially capable of interacting with verapamil and produce a complete neuromuscular blockade at concentrations significantly reduced. The neuromuscular blockade which is produced by the concurrent administration of the aminoglycoside antibiotics and verapamil is obtained with the usual therapeutic blood concentrations of the individual agents. Furthermore, the neuromuscular blockade which is produced during verapamil-aminoglycoside antibiotics interactions is completely reversed after calcium chloride administration. The mechanism by which aminoglycoside antibiotics and verapamil produce neuromuscular blockade must be the same. Both classes of drugs interfere with calcium ions movements through the calcium channels of the membrane of the motor nerve-endings inhibiting acetylcholine release at the synaptic cleft. The interaction of aminoglycoside antibiotics and calcium channel blockers is of clinical significance because when these agents are given concurrently during the perioperative period they may lead to respiratory depression or prolonged apnoea. These respiratory disturbances can be managed by slow intravenous infusion of 50 to 200 mg of calcium gluconate.