Dario Cova

Protective effect of the nitroxide tempol against the cardiotoxicity of adriamycin

Nitroxides are cell permeable, stable radicals that have been shown to exert antioxidant effects in several experimental models. In the present study, the ability of the piperidine nitroxide TEMPOL to prevent the acute cardiac toxicity of Adriamycin (ADR), which depends on oxygen-derived free radical generation, was assessed in isolated rat hearts. The results obtained show that TEMPOL (2.5 mM) significantly reduces the contractile impairment as well as the lipid peroxidation observed in rat heart preparations perfused with 100 micrograms/ml of ADR for 60 min. Both direct interaction with free radicals and decrease of Fe(II) availability (by stable oxidation and/or by chelation) seem to contribute to the cardioprotective effect to TEMPOL. HPLC and EPR studies of the subcellular distribution of TEMPOL indicate that substantial amounts of the nitroxide localize to the mitochondrial and microsomal fractions, in an ordered environment possibly corresponding to the interface between membrane and aqueous compartments.

Effect of ICRF-187 pretreatment against doxorubicin-induced delayed cardiotoxicity in the rat

Doxorubicin (DXR), administered iv in rats at the weekly dose of 3 mg/kg for 5 weeks, significantly impaired body weight gain and induced irreversible ECG alterations, mainly consisting of a progressive prolongation of ST and QT intervals. Five weeks after the last DXR administration, the contractile performance of atria isolated from treated animals was significantly reduced. At the same time, relevant morphologic lesions, consisting of myocyte vacuolization and myofibrillar loss, were also present in the myocardium of the same rats. The study showed that ICRF-187, administered ip at a dose of 125 mg/kg, significantly prevented body weight loss. QT and ST prolongation, and the decreased contractile force induced by DXR. In addition, ICRF-187 caused a significant reduction in incidence and severity of myocardial lesions. The cardioprotective effect of ICRF-187 is not mediated by a modification in DXR pharmacokinetics in heart, since the drug was actually found to increase DXR uptake in myocardial cells.

Primary pharmaco-toxicological evaluation of 2-iodomelatonin, a potent melatonin agonist

Series of experiments aimed at a primary pharmaco-toxicological evaluation of 2-iodomelatonin, a high-affinity melatonin analogue, were performed. In the rat ovulation-inhibition model, 2-iodomelatonin was much more potent than either melatonin or 6-chloromelatonin. The acute toxicity was extremely low and close to, though slightly higher than that reported previously for melatonin. In the rat, 2-iodomelatonin was slowly metabolized in vivo; its apparent elimination half-life was about 60 minutes, much longer than that reported for melatonin. The in vitro mutagenesis tests demonstrated clearly that 2-iodomelatonin in concentrations, exceeding the dose range employed in the in vivo studies, was actually devoid of mutagenic effects. The obtained results suggest that 2-iodomelatonin deserves a detailed pharmaco-toxicological evaluation and could be eventually used in pharmacokinetic and pharmacodynamic studies in humans.

Focus on toxicological aspects of pesticide chemical interaction in drinking water contamination.

Toxicological aspects related to chemical and microbial degradation of pesticides in water and to products deriving from the interaction with xenobiotics found in water are reviewed. Other aspects considered are those related to compounds formed in potabilization processes and to water contamination by pesticide synthesis by-products or intermediates. These problems refer to scarcely investigated issues which are nevertheless very interesting because of their impact on human health.

Synthesis and interactions of cytoplasmic membranes in the pancreatic exocrine cells.

Summary The synthesis and interactions of cytoplasmic membranes involved in the intracellular transport of secretory proteins have been investigated in a system of guinea pig pancreas slices pulse labeled in vitro with 14 C-L-leucine. It is suggested that the membranes of the rough endoplasmic reticulum and Golgi complex were synthetized independently of each other while the membranes of zymogen granules derive from preexisting structures, probably membranes of Golgi origin.

Effects of ethinyl estradiol on bile secretion and liver microsomal mixed function oxidase system in the mouse

In the search for an animal model suitable for the study of ethinyl estradiol (EE) induced alterations of bile secretion, we have investigated the effects of three different doses (50-500-5000 microg/kg body wt., orally for 10 days) of EE on bile flow and composition and on liver microsomal mixed function oxidase system in female Albino-Swiss mice. No difference of bile flow was found between control and EE-treated mice. The decrease of bile acid secretion was dose-related and significant in animals treated with 500 and 5000 microg/kg of EE. Cholesterol output was similar in control and EE-treated animals. The molar ratio of bile acid to biliary cholesterol was significantly lower in all groups of EE-treated mice as compared with controls. The specific activities of 3,4-benzpyrene hydroxylase, aniline hydroxylase and NADPH cytochrome-c-reductase, as well as the content of cytochromes P-450 and b(5) decreased proportionally, in a dose dependent manner and significantly after 500 and 5000 microg/kg of EE. Our data indicate that mice, following EE, develop a lithogenic bile without obvious cholestasis. Moreover, they demonstrate a decrease of liver microsomal enzyme activities and cytochromes and suggest a relationship between the impairment of liver microsomal mixed function oxidase system and the changes of bile lipid composition.

DNA damage induced by doxorubicin, 4'-epidoxorubicin and their copper(II) complexes.

The DNA-damaging activities of doxorubicin (DXR) and 4′-epidoxorubicin (4′epiDXR) were tested on a covalently closed circular plasmid. In the presence of a reducing agent (sodium borohydride), DXR and 4′epiDXR produced similar dose-dependent alterations of the electrophoretic pattern of DNA fragments. Since transition metal ions are known to catalyze this effect, the effects of Cu(II)DXR and Cu(II)epiDXR were also tested. When the Cu(II)-anthracycline complexes were formed at a drug: metal ratio of 2∶1, the effect on DNA was more severe than in the case of the free drugs; since copper ions alone were found to be devoid of activity at the concentrations present in the complexes, the effect is attributed to a direct interaction between the complexes and DNA. Cu(II)4′epiDXR proved to be more potent than Cu(II)DXR; this is probably due to the different structures of the two complexes.

Detection of DNA Damage Induced by Doxorubicin and the Effect of Glutathione

Although they exert a strong antineoplastic action, the use of anthracycline antibiotics is severely limited by a dose-related cardiotoxicity (Bristow et al. 1978). The molecular basis of this side-effect is still unclear, even if there is growing evidence that anthracycline-induced cardiotoxicity is related to the generation of superoxide radical anions, hydrogen peroxide, and hydroxyl radicals in the myocardium due to the lack of protecting enzymes in this tissue (Myers et al. 1977; Bachur et al. 1978; Doroshow et al. 1980; Thornalley and Dodd 1985; Peters et al. 1986). It has been shown (Lown et al. 1977; Lown et al. 1982; Haidle and Hunter-McKinney 1985) that the most representative of these cytotoxic drugs, doxorubicin (DXR), can induce DNA damage in cell-free systems, but information on the details of this action is scarce. Lown et al. (1977) demonstrated the production of single-strand breaks by DXR and other anthracy-clines using supercoiled DNA; this method allows DNA damage to be demonstrated by the action of drugs on various forms of purified plasmids. Therefore the aim of the present work was to test the protection against DXR-induced DNA damage in cell-free system; nonprotein sulfhydryl compounds such as glutathione (GSH) and N-acetylcysteine (NAC) were studied, since free radicals formed in these reactions are known to be scavenged by thiol groups.

The Pharmacokinetics and Pharmacodynamics of Drugs in Elderly Cachectic (Cancer) Patients

The word cachexia is derived from the Greek words kakos, meaning ‘bad,’ and hexis, meaning ‘condition’ [1]. From an epidemiological point of view, while patients with haematological malignancies and breast cancer seldom have this syndrome, most other solid tumours are associated with a high frequency of cachexia [2]. Indeed, its prevalence increases from 50% to more than 80% before death, and in more than 20% of patients cachexia is the main cause of death [3].

Impact of the Physiological Effects of Aging on the Pharmacokinetics and Pharmacodynamics of Systemic Lung Cancer Treatment

Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body, and the effects and routes of excretion of the metabolites of the drug. Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body and the relationship between drug concentration and effect. Overall, pharmacokinetics is the study of what the body does to a drug, whereas pharmacodynamics is often summarized as the study of what a drug does to the body. Pharmacokinetic interactions involve one drug or substance altering the absorption, distribution, metabolism, or elimination of another drug or substance. A common example of a pharmacokinetic interaction occurs when two drugs compete for the same metabolic pathway. When the pathway becomes saturated neither drug can be metabolized fully, which results in higher serum concentrations of the agents and can lead to clinically unfavorable consequences. Pharmacodynamic interactions occur when two drugs or substances have similar molecular targets, but do not affect the pharmacokinetic parameters of each other. Pharmacodynamics is related to the pharmacological activity of the interacting drugs, e.g., synergism, antagonism, altered cellular transport, and effect on the receptor site. When two or more drugs that have similar pharmacodynamic activity are coadministered, the additive effects might result in an excessive response or toxicity. Pharmacodynamic interactions occur when two or more drugs have mechanisms of action that result in the same physiological outcome.