Effects of bisphosphonates on cells of the mononuclear phagocyte system.
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Biomedical subjects
Publications and source records attributed to A Bertelli.
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Coenzyme Q10 (CoQ10) distribution into rat liver, heart, kidney and plasma was investigated after intravenous and oral administrations in different vehicles. Moreover, CoQ10 skin levels following topical treatment were evaluated. The liver represented the target organ for this compound in all the cases examined. In the heart, high and persistent CoQ10 concentrations were achieved particularly after solution injection while, following oral treatment, high doses of the drug were needed to reach the same CoQ10 levels. High concentrations of CoQ10 may be achieved also in the skin by topical treatment.
The mechanisms by which carnitine and coenzyme Q10 intervene in the energetic metabolism are described. In particular, the metabolic stages in which the action of carnitine is complementary to the action of coenzyme Q10 are illustrated. The synergism of the pharmacological and therapeutic actions that is found when these compounds are administered together is explained on the basis of their biochemical and metabolic complementarity.
The effect of coenzyme Q, of L-carnitine, and of their combination, on the adenine nucleotide pool and the energy charge has been investigated in rat heart slices subjected to energy depletion and recovery. The addition of coenzyme Q or of L-carnitine alone results in a higher value of the energy charge and of the adenine nucleotide pool after hypoxia, reperfusion and rotenone inhibition of the respiratory chain, as compared to controls without additions. The protective effect is much stronger when the two compounds are given together.
The comparative biochemical activities of coenzyme Q10 and carnitine can explain the protective synergistic effect of combination of these two substances in preventing the hyperbaric oxygen toxicity in mice. Both convulsions and mortality percentages are more significantly reduced in treated animals with these two substances in combination rather than separately.
Exogenous L-carnitine and coenzyme Q are used to protect the heart against anthracycline damage and to enhance energy metabolism in the heart and in the muscle. Though their metabolic function is well known and their effects on anthracycline damage have been largely studied, their combined action has not been investigated. Therefore we have used partially CoQ-depleted bovine mitochondria to evaluate the synergic action of CoQ and carnitine on palmitoylCoA oxidation, as an experimental model in which either CoQ or L-carnitine may be the limiting factor in the oxidation of activated fatty acids. The protective effect exerted by the combined use of L-carnitine and CoQ against damage by the anthracycline derivative doxorubicin has been compared to the protection exerted by each compound alone. The effect was evaluated by assessing oxygen consumption and 14C-leucine incorporation in rat heart slices. The results obtained suggest that the administration of an association of L-carnitine and CoQ exerts a stronger protection against anthracycline damage and induces a greater utilization of fatty acids as compared to the effects of each compound alone.
Hepatoprotective actions of metadoxina and ubiquinone have been studied in alcoholic rats by evaluating hepatic triglyceride accumulation and serum biochemical parameters of liver function. The two drug-treated groups displayed significantly lower triglyceride concentrations as compared to the ethanol-treated group. No significant differences were found among the two drug-treated and the control groups. Electron-microscopic abnormalities were found only in ethanol-treated rats. Serum biochemical parameters of liver function did not show any significant difference among all four groups. These results suggest a possible protective role of metadoxina and ubiquinone in ethanol-induced liver triglyceride accumulation.
Although calcium antagonists are drugs which have been introduced relatively recently, their use is already so widespread, at least in the treatment of cardiovascular diseases as to represent one of the main therapies for diseases such as ischaemic cardiopathy, arterial hypertension, and, to a lesser extent, arrhythmias. Together with the development of clinical applications, deeper insight has been gained into the clinical and experimental pharmacology of these drugs. The authors of this review concentrate their attention on some of the less frequently discussed aspects of calcium antagonists. On the one hand, they describe some "nonprimary" uses of these drugs, both in the cardiovascular and in other therapeutic fields, which already receive confirmation from relatively solid experimental data. On the other hand, they review the side effects and some pharmacological interactions of calcium antagonists, both of which should be held in due consideration, seeing that these drugs are widely employed in clinical practice and their use often requires prolonged, intensive treatment. The most common side effects are described, together with others relatively less well known ones, and outline is given of potential undesirable effects on the cardiovascular as well as on other systems.
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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.
IL-2R serum concentrations were assayed by a sandwich enzyme immunoassay method in order to ascertain if the measurement of the soluble form of IL-2R can be considered a useful marker of allograft rejection in heart and kidney transplanted patients. Serum IL-2R levels increased significantly compared to pre-operated values (1129 +/- 215 U/ml vs. 592 +/- 209 U/ml, p less than 0.01) in six heart-transplanted patients during acute rejection crises documented by clinical findings and endomyocardial biopsy, and returned to baseline levels after successful treatment (544 +/- 395 U/ml vs. 1129 +/- 215 U/ml, p less than 0.01). Moreover, we observed that severe bacterial (n = 5) or viral (n = 2) infections were also accompanied by a significant increase of IL-2R serum levels in heart-transplanted patients (1076 +/- 263 U/ml vs. 486 +/- 146 U/ml, p less than 0.01 in bacterial, and 1290 +/- 368 U/ml vs. 370 +/- 85 U/ml in viral infections). In the six patients with renal transplant, the mean pre-operative IL-2R level was also elevated (1507 +/- 203 U/ml). A 1.5-4 fold increase of IL-2R levels has been observed at the beginning of both acute rejection and clinically evident infection. Our data show that the serum concentration of IL-2R is increased in heart and kidney transplanted patients during allograft rejection crisis. However, the information gained with this assay must be cautiously interpreted because an increase of IL-2R concentrations can also indicate bacterial or viral infections.(ABSTRACT TRUNCATED AT 250 WORDS)
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The platelet-activating factor (PAF) has been shown to stimulate the release of prostaglandins, leukotrienes and 5HT from a number of cell types. In this work we studied the effects of bolus injections of PAF on the isolated perfused rat kidney. Results showed histological damage at the proximal-tubule level and a significant histamine release.
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.
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Human neutrophils exposed to 10(-4) M doxorubicin and the derivatives epirubicin and thepirubicin revealed a different intracellular penetration and distribution pattern as demonstrated by fluorescence microscopy and fluorimetric determination of drug intracellular concentration. While doxorubicin was found to be a potent inducer of superoxide generation from resting cells, epirubicin exhibited less superoxide-inducing power. Thepirubicin on the contrary did not show any superoxide-inducing effect. Moreover the anthracyclines tested all inhibited the phorbol ester-stimulated chemiluminescent response to the same extent, which suggested a common target for the drug action. Anthracycline-stimulated superoxide production seems to correlate with the cardiotoxic effects. The most cardiotoxic drug, doxorubicin, is the most potent inducer of superoxide generation, while epirubicin, which is less cardiotoxic, has a relatively limited effect on superoxide production. Thepirubicin which has been shown not to induce delayed cardiomyopathy has no effect on superoxide release from the cells.
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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.