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Some well-known antioxidant phenols present in extravirgin olive oil have also been found in white wine. Both tyrosol and caffeic acid are phenols that are present not only in extravirgin olive oil, but also in wine, especially white wine. Their antioxidant properties are well known, but their biological effects have not yet been elucidated. In a previous study we found that these substances were able to inhibit tumor necrosis factor alpha release. The present study was carried out to assess whether these compounds are able to inhibit other inflammatory cytokines, such as interleukin-1 beta and interleukin-6. The results show that low concentrations of these phenols, which can be found in the bloodstream after intake of moderate quantities of white wine, exert significant inhibitory activity on the release of several inflammatory cytokines.

The cardioprotective effects of red wine have been attributed to several polyphenolic antioxidants including resveratrol and proanthocyanidins. The goal of the present study was to determine whether white wines could also provide cardioprotection. Three different white wines (white wine #1, #2 and #3) were chosen for this study. Ethanol-free extracts of the wines were prepared by vacuum evaporation. Rats weighing approximately 200 g were given either 50 mg/kg or 100 mg/kg of each wine extract for 3 weeks. The rats were anesthetized and sacrificed and their hearts were excised for the preparation of isolated working rat heart. All hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Cardiac function including heart rate, left ventricular developed pressure (LVDP), maximum first derivative of developed pressure (LVdp/dtmax), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEP), aortic flow (AF) and coronary flow (CF) were continuously monitored and myocardial infarct size was measured at the end of the experiments. The results of our study demonstrated that among the three different white wines, only white wine #2 conferred cardioprotection as evidenced by improved postischemic ventricular recovery compared with controls. The same white wine at a dose of 50 mg/kg also showed improvement in postischemic contractile recovery but the differences compared with controls were not significant. The amount of malondialdehyde production from these hearts was lower than that found in control hearts, indicating reduced formation of reactive oxygen species in white wine #2-treated rats. In vitro studies using a chemiluminescence technique revealed that white wine #2 scavenged both superoxide anions and hydroxyl radicals. The results of our study demonstrate that white wine #2 provided cardioprotection and the cardioprotective effect of the wine can be attributed, at least in part, to its ability to function as an in vivo antioxidant.

In previous trials we proved how propionyl carnitine, an acyl carnitine characterized by its intense mitochondrial metabolic, and cardio and vasoprotective activity, could prevent the cyclosporine-induced nephrotoxicity. Subsequently we also noted how propionyl carnitine could prevent the increase in renal intracellular calcium, which is the base of many cyclosporine-induced toxic phenomena. In our trials, we used the isolated and perfused rat kidney technique to examine if with the variations of the concentration of intracellular calcium, the adenosine 5'-triphosphate concentrations also varied, and if this decrease could be corrected by administrating propionyl carnitine. The results we obtained in these experiments indicated that when propionyl carnitine was administered preventively, the concentrations of renal intracellular adenosine 5'-triphosphate which were decreased by the cyclosporine returned to their normal values and, at the same time, a decrease in the increased vascular resistance of the kidney was noted. Therefore, propionyl carnitine corrected one of the biochemical alterations which explained the pathogenesis of the renal damage induced by cyclosporine.

Epidemiological studies suggest that the consumption of wine, particularly of red wine, reduces the incidence of mortality and morbidity from coronary heart disease. This has given rise to what is now popularly termed the "French paradox". The cardioprotective effect has been attributed to antioxidants present in the polyphenol fraction of red wine. Grapes contain a variety of antioxidants, including resveratrol, catechin, epicatechin and proanthocyanidins. Of these, resveratrol is present mainly in grape skin while proanthocyanidin is present in the seeds. In this report, we provide evidence that red wine extract as well as resveratrol and proanthocyanidins are equally effective in reducing myocardial ischemic reperfusion injury, which suggests that these red wine polyphenolic antioxidants play a crucial role in cardioprotection.

Research has been carried out with the purpose of verifying whether the resveratrol content in the skins or pomace of grapes stored for a long period of time without any particular protection with regard to temperature and humidity, could lead to a reduction of the content of this product detected at the beginning of the processing of grapes in vinification procedures. The dosages carried out both on the grape skin and on the pomace taken after fermentation and stored for a certain period of time, as well as on the products derived from alcoholic distillation, did not show the expected alterations in resveratrol content, considering their storage in bad environmental conditions for a long period of time. The results obtained confirm that resveratrol, unlike anthocyanins and other polyphenols, is stable and stores well over time.

In this study a comparison was made between results obtained from resveratrol dosages which have been shown to be pharmacologically active, in vitro and in vivo, and the results of plasma and tissue concentrations obtained after a single administration or after prolonged administration of red wine with a known resveratrol content. The dosages used by different investigators in the tests are very different and, in general, rather high in relation to the concentrations which are found in wine or grapes. The results of our tests on platelet aggregation confirm that even with modest dosages of resveratrol, a pharmacological effect can be observed, and that these dosages can be compatible with the resveratrol concentrations obtained after oral administration. The data obtained from these tests on animals can lead to the conclusion that even an average drinker of wine can, particularly in the long term, absorb a sufficient quantity of resveratrol to explain the beneficial effect of red wine on health, which has been observed in epidemiological studies carried out in populations whose daily diet includes the drinking of wine.

In view of the increasing interest in the biological activity of resveratrol, one of the components of red wine which is considered to be one of the main ingredients responsible for the beneficial effect of wine on human health, we have studied plasma kinetics and tissue bioavailability of this compound after red wine oral administration in rats. Plasma pharmacokinetics after oral administration of resveratrol could be described by an open one- or two-compartment model. Tissue concentrations show a significant cardiac bioavailability, and a strong affinity for the liver and kidneys.

The anti-aggregating effect of cis-resveratrol (cis-3,4,5- trihydroxystilbene) has been evaluated in vitro in different concentrations on platelet-rich plasma from health volunteers. Cis-resveratrol at the concentration of 1 x 10(-5) and 1 x 10(-6) M was able to decrease collagen-induced platelet aggregation by 43.5 +/-11.4% and 26.8 +/- 14.6%, while trans-resveratrol at the same concentration showed a slightly lower activity. In view of the behaviour of these two isomers in biological fluids, the evaluation of resveratrol activity in animals and humans take into account the total amount of the two isomers.

The pool of different carnitine derivatives is formed by carnitine, acetylcarnitine, propionylcarnitine and isovalerylcarnitine. Isovalerylcarnitine is a compound performing activities that differ from those of the other carnitine esters. Its activity on proteolytic enzymes and on the calpain system has been demonstrated in the past. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this proapoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well-established model for the assessment of cellular immune responses. In addition to nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, proapoptotic factor that resembles various anticancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.

A new chemical named parrodienes has been extracted from parrots' plumage. From the chemical point of view, parrodienes are polyunsaturated aldehydes similar to carotenoids. On the basis of this similarity we organized some biological experiments to evaluate the inhibition of lipoperoxidation of cell membranes induced by CCl4, protection against ultraviolet rays, anti-inflammatory activity and protection from an increase of ornithine-decarboxylase as marker of tumoral skin alteration. The results of these experiments showed that unsaturated dienes (parrodienes) play an important role on the inhibition and prevention of many biological processes that are at the basis of different pathological disorders.

The aim of the present experiments was to ascertain whether prostacycline could exercise a protective effect against the formation of thrombosis in the rat tail induced by endothelin and K-carrageenin and to compare the effect of prostacycline with that of carnitine and propionyl carnitine. Both prostacycline and propionyl carnitine exhibited a similar protective effect on this experimental model. A combined protective effect of prostacycline administered with carnitine was also observed and a possible interaction between these two substances is proposed.

In view of the high concentration of resveratrol found in a new autochthonous wine (Uvalino) and the notable antioxidant activity of this substance, we decided to assess whether this wine could inhibit the production of free radicals. Nowadays, free radicals are considered to be the most noxious factors for tissues, triggering the development of many diseases. The assessments were carried out using a direct and more precise technique, electronic paramagnetic resonance (EPR), which is able to detect the ability of an antioxidant agent to inhibit the formation of hydroxyl radicals (*OH), which are among the most noxious reactive oxygen species (ROS). The results show that Uvalino wine is able to eliminate ROS production almost completely. Consequently, it has beneficial effects on health in all the diseases in which ROS plays an important pathogenetic role.

The ability of two samples of red wine with different resveratrol concentrations to inhibit hydroxyl radicals (*OH) produced by a Fenton-type reaction was assessed using the method of electronic paramagnetic resonance (EPR). One sample was an autochthonous wine, Uvalino, which has a very high resveratrol concentration; the second was another red wine with a much lower resveratrol concentration. The ability of the sample of Uvalino wine to obstruct hydroxyl radicals was evident, but it wasn't much better than the ability of the sample of wine with a lower resveratrol concentration. The resveratrol concentration of wine is an important factor for the inhibition of the formation of free radicals, especially hydroxyl radicals; however, it is not the only one responsible for this property of wine. Resveratrol concentration can act synergically with other factors, such as polyphenols, which are also contained in wine and have antioxidant properties.

In modern industrial societies the attention to public health, especially in relation to food habits, is increasing day by day. Considering this, it's no wonder that wine, the voluptuary drink that best represents human history, is the most interesting compound. The main and best known wine effects on the human body are caused by alcohol, but several other active compounds are present in wine. Above all, resveratrol is able to neutralize free radicals, which can damage DNA and may lead to cancer onset. In this study, we have indagated resveratrol anticancer action, analyzing its effects on both cell cycle and growing of human lymphoma B (DHL-4) cells. MTT colorimetric test, tripan blue dye exclusion assay, and cell cycle analysis showed that resveratrol has a dose-dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results confirm resveratrol's potential therapeutic role on tumors.

The antioxidant activity of a novel series of derivatives with a carotenoid-like structure was studied. These derivatives have recently been isolated chemically as a result of studies on the pigments present in a particular species of birds, namely parrots. These novel derivatives, which are also called parrodienes, have been proved to possess interesting biological properties that differ from those that carotenoids are known to have. The objective of this study was to demonstrate the ability of these novel compounds to inhibit the formation of reactive oxygen species, especially their ability to block the formation of hydroxyl radicals, which are among the most reactive products of oxygen reactions and which produce the greatest damage to cells and tissues. The technique used to assess this antioxidant capacity of parrodienes was electron paramagnetic resonance, which allows direct assessment of inhibition of hydroxyl radical formation (.OH). The results show that these derivatives, especially octatriene, are able to exert evident antioxidant activity, thus confirming that their antioxidant properties are important for their biological activity.

Propionyl carnitine can prevent endothelin and carrageenin-induced thrombosis in the rat's tail. This protective action of propionyl carnitine is probably related to its capacity to increase the synthesis of PGI2 prostaglandins and, subsequently, the amount of prostaglandins released by endothelin. Indomethacin, a well known prostanoid synthesis blocker, is unable to inhibit the protective activity of propionyl carnitine on endothelin-induced thrombosis after prolonged propionyl carnitine administration, but only a part of this protective activity after propionyl carnitine acute administration. Subsequently, other factors in addition to prostanoids seem to be involved in protective mechanisms of propionyl carnitine on endothelin-induced thrombosis.

This investigation was conducted to ascertain whether administration of L-carnitine and coenzyme Q10 could protect from the experimentally-induced hepatic lipid infiltration and glutathione content decrease in rats exposed to hyperbaric oxygen and prolonged alcohol administration. The results indicate that administration of L-carnitine and coenzyme Q10 in association reduces damage induced by chronic alcohol poisoning and hyperbaric oxygen. This protective action is more marked when L-carnitine and coenzyme Q10 are administered together. The combined complementary biochemical activity of these two compounds is discussed.

Propionyl carnitine, a derivative of carnitine, has metabolic and cardiovascular effects similar to carnitine but with more pronounced peripheral haemodynamic activity. In these experiments we propose to prove that the administration of propionyl carnitine could prevent the experimental tail thrombosis in the rat induced by endothelin (ET-1), serotonin and K-carrageenin. In this new test of experimental thrombosis, propionyl carnitine was able to reduce the extent of tail thrombosis in a more significant manner than that of carnitine. A possible explanation of this antithrombotic effect of propionyl carnitine is its capacity to counteract the vasoconstrictor activity of endothelin modulating the release of prostanoids induced by endothelin itself.

The chemopreventive activity of resveratrol, a stilbene found in grapes and wine, was evaluated in a human monocytic leukemia cell line at the same concentration (100 nM to 1 microM) as that found in the blood-stream after moderate wine intake. As early as at 4 h after intake, resveratrol exhibited antiproliferative and cytotoxic activity. At the same time, some apoptotic-like phenomena were detected such as cell membrane perturbation (phosphatidylserine-annexin V binding), apolipoprotein (APO)-1/FAS (CD95) expression and mitochondrial (delta psi) depolarization. The anticancer drug camptothecin, used as a positive control, did not significantly increase APO-1/FAS (CD95) levels, while only a modest increase in APO-1/FAS-CD95 ligand (CD95-L) was detected. At 12 h, however, resveratrol at concentrations of 100 nM and 1 microM did not exhibit the same antiproliferative activity and increased cell proliferation was correlated to a significant increase in FAS-L expression. We conclude that treatment with low doses of resveratrol, such as those found after moderate wine intake, is not sufficient to stop human leukemia cell line proliferation and that cell resistance, marked by high FAS-L (CD95-L) expression, could be mediated by low (delta psi) mitochondria-released antiapoptotic factors such as BCL-2. It is also suggested that the synergistic action of other wine components with resveratrol might, at least partially, explain its chemopreventive activity.

Endothelin-1 (ET-1) is an amino peptide produced by endothelial cells with a potent vasoconstrictor activity; this effect is regulated by a release of other endogenous vasal factors. Recent studies have demonstrated that endothelin is capable of releasing from different tissues, and particularly from perfused organs such as spleen and kidney, many vasal factors and prostanoids. The present study investigates whether perfusion with a solution of endothelin-1 in rat isolated kidney can induce the release of histamine, another vasal factor (until now not investigated in relation with endothelin-1) and whether treatment with propionyl carnitine, a compound with vasoprotecting activity, inhibits this release. This research demonstrates that histamine released by rat kidney perfused with endothelin is lowered if previously treated with propionyl carnitine. This effect of propionyl carnitine can be considered to be another important factor in a complex mechanism involved in its vasoprotective and cardiovascular action.

Alcohol is noxious to the brain and peripheral nervous system. However, wine contains substances that may have positive biological and pharmacological effects. Resveratrol is the most studied and probably the most active of these substances. This naturally occurring compound, which is present in wine and grapes, reduces oxidative stress in neuronal-like cell cultures. We have shown that resveratrol induces phosphorylation of the mitogen-activated protein (MAP) kinase family members, extracellular regulated kinase 1 (ERK1) and ERK2, in the human neuroblastoma SH-SY5Y cells in vitro at much lower concentrations than those found in the plasma of rats after oral wine administration. MAP kinases are involved in numerous different aspects of signal transduction in the cells. In particular, phosphorylation of ERK2 has been related to the synaptic changes at the basis of memory and learning processes. These findings, together with our own, on resveratrol-induced activation of MAP kinases in human neuronal-like cells, and previously published epidemiological studies which have demonstrated an inverse relationship between moderate wine intake and dementia, suggest that wine (not alcohol) may have a positive effect on nervous cells.

We investigated the effect of acute and chronic stress on growth hormone (GH) plasma levels in rats. Acute stress was provoked by intravenous administrations of IL-1 beta and TNF-alpha. Determinations were made at 10, 30, 60, 120 and 180 min following i.v. injection of these cytokines into the caudal vein. We also investigated the chronic stress induced by hind paw injections of Freund's adjuvant. Arthritis was developed by 21 days following such injection. GH levels were studied at 7, 14 and 21 days after induction of arthritis on several blood samples which were withdrawn from tail veins, and long-term hormonal profiles (3 hours' sampling) were determined at 12.00 am, 1.30 pm and 3.00 pm. Local administration of dexamethasone and the monoclonal antibody anti-ICAM-1 were also used in arthritic rats. Following acute stress, a significant reduction of plasma GH levels has been evidenced, possibly related to the stimulation of corticotropin-releasing hormone. Following chronic stress, we demonstrated a significant increase of GH levels, which were significantly reduced by dexamethasone treatment and to a lesser extent by anti-ICAM-1 administration.

Nephrotoxicity has represented the major limitation in the use of cyclosporine A (CyA). The structural abnormalities at the level of the proximal tubular cells are necrosis, vacuolisation and lipid droplets, as well as CyA-induced glomerular afferent arteriole constriction and granular juxtaglomerular cell hyperplasia. The mode of action of vasoconstriction is not well known, but there appears to be substantial impairment of endothelial cell function leading to enhanced release of vasoconstrictors such as endothelin and thromboxane. L-propionylcarnitine (PC), one of the most potent analogues of carnitine, is able to correct and to prevent alterations in endothelial membrane permeability and it has been identified in the kidney of various animal species. To investigate a possible reduction of CyA-induced nephrotoxocity, we examined the effects of a pretreatment with PC before administering several doses of CyA in an isolated and perfused rat kidney. The histological findings showed that the perfusion with PC reduces the vasoconstrictive effect of CyA on the glomerular capillaries and preserves the tubular epithelium. The ratio of the diameter between the glomerular capillary tuft and Bowman's capsule was higher, while at the tubular level the ratio internal-diameter/diameter evaluated at the level of the basal membrane was lower in PC + CyA perfused kidneys than in only CyA perfused ones. The final value of perfusion pressure was lower in PC + CyA perfused kidneys than in only CyA perfused ones, confirming the histological findings. The release induced by CyA of alanine aminopeptidase (AAP) and N-acetyl-glucosaminidase (NAG), markers of tubular damage, was significantly reduced by pretreatment with PC. These data suggest that the pretreatment with PC reduces the CyA-induced nephrotoxicity in an isolated and perfused rat kidney.

The effects of peroxidation on the erythrocytes of rats orally treated with L-propionyl carnitine for 15 days (50 mg/kg/day) were investigated. Peroxidation was produced by incubating the cells in the presence of the cytotoxic system: lactoperoxidase-hydrogen peroxide and iodide ions. Lysis of erythrocytes was evaluated by measuring the turbidity following the decrease in absorbance at 600 nm. The 50% of erythrocyte lysis of untreated animals was observed after 16 min and in about 30 min all the cells were lysed. With L-propionyl carnitine-treated rat erythrocytes the time at which 50% of lysis was observed increased to 23 min. L-propionyl carnitine also exerted its protective effect in vitro when incubated with untreated rat erythrocytes or human erythrocytes in the presence of the cytolytic system. The presence of L-propionyl carnitine in the incubation mixture markedly decreased the malonaldehyde formation. The protection was concentration-dependent. To establish if L-propionyl carnitine protects from oxygen reactive species or is able to stabilize the damaged membranes, a latent damage was produced by incubating the erythrocytes with the cytolytic system for a few minutes. The cells were then removed and suspended in buffered saline in the absence or in the presence of different L-propionyl carnitine concentrations. L-propionyl carnitine decreased the velocity of lysis of damaged erythrocytes. These data suggest that L-propionyl carnitine protects erythrocytes from oxygen reactive species and also stabilizes the damaged membrane probably by specific binding with protein and/or phospholipid domains. Low density lipoproteins (LDLs) from human blood were peroxidized by exposure to Cu2+ ions in the presence of various L-propionyl carnitine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been reported that chronic ethanol exposure during intrauterine life may cause severe adverse effects in early infancy that have been termed fetal alcohol syndrome. These alterations may perturb the normal brain development as though alcohol exposure might have altered the basic cellular interrelationship underlying neuronal plasticity. The neonatal lesion of the serotoninergic pathways in the central nervous system with the selective neurotoxin 5,7-DHT supplies an ideal model for studying the effects of substances of abuse on degenerative and regenerative events. The authors' data indicate that perinatal exposure to ethanol (3% in drinking water) causes a more rapid degeneration of the serotoninergic pathways affected by 5,7-DHT; conversely, regeneration and reinnervation of the lumbar spinal cord are markedly improved by ethanol exposure. These results suggest that perinatal ethanol exposure promotes cellular changes that at later stages are capable of improving neural repair in the brain.

Surveillance and control of hospital infections are two particularly important aspects of the surgical ward, and great activity is necessary in the identification and the elimination of the risk factors whenever possible. Today the rational use of antibiotics, in both the prevention and treatment of infections, should be used to avoid or limit nosocomial infections, and it is as important as the use of disinfectants. Cefotetan has been studied in different surgical specialties in prophylaxis and treatment of postoperative infections for its particularly broad spectrum of activity, covering both aerobic and anaerobic organisms, and for the very low incidence of side-effects. In general surgery, Cefotetan has proved able to reduce not only the occurrence of surgical wound infections, but also that of postoperative infections of the genitourinary system.

The protective effect of propionyl-L-carnitine against hyperbaric oxygen toxicity was studied by in vivo experiments on mice. The treatment reduced both the percentage of animals with convulsions and the death rate. Tissue signs of toxicity and pulmonary weight increase were less marked in treated animals than in controls. Results may indicate that propionyl-L-carnitine needs to build up to critical levels in cells and mitochondria before its metabolic effects can be fully felt.

Rat kidney was perfused using Krebs solution containing 3 or 6 mEq/l lithium or 3 or 6 mEq/l rubidium; the histological lesions thus induced were compared. Rubidium-induced lesions, irrespective of concentrations, consisted of tubular dilations, degeneration and necrosis very similar to those induced by lower concentrations of lithium; moreover, Bowman space alterations were observed. In contrast, lithium-induced damage was dose-dependent: 6 mEq/l solution induced severe tubular damage with necrosis, endoluminal cellular debris and hyaline substance.

The nephrotoxicity of aminoglycosides has been the object of numerous works of research showing that different molecules belonging to the same family of antibiotics can exert their toxic action in different ways. The aim of the present research was to evaluate the nephrotoxicity of dactimicin (DTC), a recently synthesized aminoglycoside antibiotic, as compared to gentamicin (GTM), amikacin (AMK) and fortimicin (FTM). The experimental model used was the isolated perfused rat kidney, and the parameters evaluated were histamine release and histological findings. The results showed that GTM was able to induce a significantly higher release of histamine than AMK, FTM, or DTC. AMK provoked a higher level of histamine release than FTM or DTC, although the differences between the three were not significant. Histological preparations obtained with GTM revealed large-scale lesions, which however were less detectable with AMK, and much less with DTC.

Dactimicin (DC) is a new pseudodisaccharide aminoglycoside antibiotic containing a formimidoyl group in its molecule (1). DC exhibits a greater antibacterial activity than other aminoglycosides against the clinical isolates of Serratia marcescens and is active against many gentamicin- and amikacin-resistant bacteria. This characteristic of the drug appears to be linked with a probable protective action exerted by the formimidoyl group in its structure. The greatest limitation in the clinical use of aminoglycosides is their potential for nephrotoxicity. The present study compares the renal effects of DC versus gentamicin (GT) and amikacin (AK), respectively the most and the least nephrotoxic pseudotrisaccharide aminoglycosides in present use (2), evaluating the urinary NAG excretion and the histological changes induced in the kidney.

Dactimicin (ST 900) is a new pseudo-disaccharide aminoglycoside antibiotic which has been shown to be active against systemic infections in mice. Few data have so far been reported on dactimicin tissue accumulation or its potential nephrotoxicity. In this study, nephrotoxicity and renal tissue concentrations of gentamicin, amikacin and dactimicin were compared in Wistar rats. Liver, heart and lung accumulation of these drugs were also evaluated. Groups of 5 rats were respectively injected with 100 mg/kg body weight of the different drugs daily for 7 days. Five control rats were also injected with saline. Twenty-four hours after the last injection, all rats were sacrificed and bled to death. Blood samples were taken for BUN and serum creatinine assay. Kidney, liver, heart and lung tissues, as well as blood, were removed and processed for microbiological assay of gentamicin, amikacin and dactimicin. The results of this study showed that dactimicin, as well as amikacin, did not induce any significant increase in BUN and serum creatinine, while gentamicin administration resulted in severe uraemia in all rats. Consequently a much higher accumulation of gentamicin than amikacin and dactimicin was achieved in serum and tissues.

A set of three novel anthracyclines, active as antitumour agents, has been examined for their possible effects on rat heart mitochondrial respiration. The in vitro inhibiting effects of the compounds have been compared with that of the older doxorubicin. Aclacinomycin was generally more inhibitory than doxorubicin, 4'-epi-doxorubicin and 4'-epi-tetrahydropyranyl-adriamycin, with both succinate and NAD+-linked substrates. Attempts to prevent anthracycline from inhibiting the succinate oxidase activity by means of adding exogenous coenzyme Q10 gave encouraging results, the inhibiting effect being in fact reduced.

An investigation was undertaken of the capacity of thepirubicin (THP), a new anthracycline derivative with reduced cardiotoxicity, to be fixed in the myocardial fibre, as compared with that of adriamycin hydrochloride (ADR), using a method based on the histofluorescence of tissues treated in vivo with anthracyclines. Histological examination of heart sections from rats perfused with either THP or ADR showed similar results. The major difference was the lower quantitative localization of THP in the cytoplasm, although this quantitative difference was not so pronounced in the nuclei. This suggests that cardiac lesions may be due not to the basic action of anthracyclines on DNA but to collateral effects not yet identified.

In this study the cellular toxicity of two aminoglycosides (gentamicin and dactimicin) have been evaluated using rabbit kidney cell cultures. The correlation between toxic effect and antibiotic concentration, and between toxic effect and the period of contact have been evaluated. The toxic effect was measured in rabbit kidney cell cultures by means of the release of N-acetyl-beta-glucosaminidase. This enzyme was chosen in order to establish a correlation between in vitro and in vivo results. Gentamicin clearly shows in both tests a non-linear correlation between cellular toxicity and concentration or period of contact. Dactimicin, a new aminoglycoside probably less toxic than others, also shows in both tests a non-linear correlation between cellular toxicity and concentration or period of contact, but the release of enzyme was significantly reduced during the treatment of the cell cultures with this aminoglycoside.

Rat cardiac microsomes treated with NADPH generated a chemiluminescence, detected by the chemilumigenic probe lucigenin. The chemiluminescent signal, which is an index of lipid peroxidation, was found to be inhibited by acetylcarnitine in a dose-dependent way. Superoxide dismutase (SOD) and inhibitors of arachidonate metabolism were also effective in preventing light emission. The combined action of acetylcarnitine plus SOD and acetylcarnitine plus indomethacin suggested a possible common target for the compounds. When tested on superoxide production from isolated human neutrophils detected both by luminol-amplified chemiluminescence and cytochrome C reduction, acetylcarnitine did not show any inhibitory effect. The results of these experiments demonstrate the antioxidant properties of acetylcarnitine, even if they cannot clarify the specific target of the drug action.

Two methodologies have been developed to monitor cyclosporine (CsA) therapy: high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Recently, a fluorescence polarization immunoassay (FPIA) has also become commercially available for the assay of CsA and its metabolites. The authors compared the results obtained with a modified FPIA with those found with two RIAs which use a polyclonal antibody, in order to verify if the FPIA assay is suitable for routine measurements in blood samples. Moreover, the accuracy of the RIAs and of the modified FPIA was checked against the results obtained by an HPLC technique assumed as a reference assay. The FPIA assay for CsA in blood samples seems preferable to the RIAs; in fact, as far as specificity is concerned, the TDx assay is comparable to polyclonal RIAs, while the precision (both within- and between-laboratories) is significantly better. Moreover, the TDx method is easier and faster to perform (20 samples can be assayed in about 30 min, while 2-4 h are necessary with RIA), with fewer handling steps; the instrumentation is automated and the reagents are more stable and less hazardous than those used in RIA.

In an attempt to confirm the presence of endogenous substances with cardiac glycoside-like activity, the biological and immunological cardiac glycoside-like activity was measured by a sensitive solid-phase radioimmunological assay (RIA), two radioreceptor assays (RRA), and a 86Rb uptake method in normal subjects and in some pathophysiological conditions characterized by sodium retention and volume expansion. Significant concentrations of digoxin-like immunoreactive substances (DLIS) were measured in plasma (or serum) of normal subjects while significantly higher levels were found in pregnant women, newborns and in patients with renal impairment, and in some with essential hypertension. Concentrations in urine of normal adults or newborns were several times higher than in plasma. The results obtained by RIA correlated with those obtained by RRA and 86Rb uptake methods. In 88 normal subjects, DLIS excretion rates (overnight urine collection) in men were significantly higher than in women (68.6 +/- 23.6 pg/min vs 50.9 +/- 21.0 pg/min, p less than 0.01). The DLIS excretion rates correlated with creatinine, Na and K urinary excretion rates, and also with the subjects' body weight, height, body mass index, and systolic blood pressure. These findings confirm the presence of endogenous substances with immunological and biological activity similar to cardiac glycosides in human body fluids and also confirm the hypothesis that these endogenous factors may be involved in fluid and electrolyte regulation in man. In addition, the present data indicate that urinary excretion of DLIS is dependent on body mass and renal glomerular filtration.

Aclacinomycin, 4'-epi-doxorubicin and 4'-epi-tetrahydropyranyl-adriamycin, three novel anthraquinone derivatives under investigation for their antitumour activity, showed an inhibitory effect on the in vitro respiration of mitochondria from rat hearts. The inhibition proved to be concentration-dependent in the range 0.05 to 1.40 mM and both the NADH-oxidase and the succinate oxidase systems were affected to different extents. Among the compounds tested, 4'-epi-tetrahydropyranyl-adriamycin appeared to be the least powerful effector, requiring a significantly higher concentration for 50% inhibition of oxidation than doxorubicin and the other analogues examined.

Dactimicin is a new aminoglycoside antibiotic with an interesting low nephrotoxicity in animal experimental models. In order to establish if a correlation exists between the nephrotoxic effect and renal pharmacokinetic behaviour of aminoglycosides, tobramycin, sisomicin and dactimicin were studied in a model of isolated and perfused rat kidney. Concentrations in venous and urinary effluent during a continuous perfusion of a constant concentration of drugs were evaluated. The influence of active transport was studied comparing excretion data obtained with perfusion buffer with or without glucose. In the present experimental model the renal excretions of the aminoglycosides tested are quite similar and cannot account for the different nephrotoxicity observed in animals.