Biomedical subjects

M del Tacca

Publications and source records attributed to M del Tacca.

12 recordsLinked to original sources

PubMed2000

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer.

BACKGROUND: Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naïve patients with advanced NSCLC. PATIENTS AND METHODS: Escalating doses of GEM (800-2000 mg/m2) and TAX (60-100 mg/m2) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. RESULTS: Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m2 plus GEM 1750 and, respectively, 2000 mg/m2). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hematological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of Cmax and AUC. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients. CONCLUSIONS: The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m2 of GEM and 100 mg/m2 of TAX are recommended for phase II studies.

Adult↗

PubMed1995

Inhibitory effect of the somatostatin analogue SMS 201-995 and cytokines on the proliferation of human colon adenocarcinoma cell lines.

The activity of the synthetic somatostatin analogue SMS 201-995 was investigated in vitro on the growth of SW480 and SW620 human colon adenocarcinoma cell lines. The inhibition of cell proliferation was significant in SW480 cells (-19.6 +/- 1.4% at SMS 201-995 10-9 M, P < 0.05), but not in SW620 cells (-5.5 +/- 0.8% at SMS 201-995 10-8 M) as compared to untreated cultures. Moreover, SMS 201-995 10-8 M decreased the mitogenic effect of epidermal growth factor (EGF) on the SW480 cell line (-26.6 +/- 3.4% vs. cells exposed to EGF 10 ng ml-1 alone, P < 0.05). The effect of combining SMS 201-995 plus the cytokines interleukin-2 (IL-2) or gamma-interferon (gamma-IFN) on SW480 and SW620 cancer cell growth was also evaluated. The treatment produced a synergistic antiproliferative effect against SW620 cells as compared to untreated cultures, with growth inhibition being -20.2 +/- 1.2 and -19.3 +/- 1.3%, at SMS 201-995 10-8 M plus IL-2 or gamma-IFN 100 IU ml-1, respectively, but did not increase the activity of SMS 201-995 against the SW480 cells. In conclusion, the effect of SMS 201-995 on colon cancer cell growth can be enhanced by its combination with cytokines in SW620 but not in SW480 colon adenocarcinoma cells.

Adenocarcinoma↗

PubMed1990

Alpha 2-adrenoceptor-mediated inhibitory and excitatory effects of detomidine on rat gastric acid secretion.

The effects of the selective alpha 2-adrenoceptor agonist detomidine on gastric acid secretion from pylorus-ligated and stomach-perfused rats have been investigated. In pylorus-ligated rats i.p. injection of detomidine markedly inhibited acid secretion, this effect being prevented by yohimbine or idazoxan. Under the same conditions, idazoxan significantly increased secretion in a dose-independent fashion. In non-vagotomized and vagotomized stomach-perfused rats i.p. detomidine stimulated acid secretion: this excitatory effect was antagonized by idazoxan. The present results suggest that both inhibitory and excitatory gastric secretory effects of detomidine are mediated by alpha 2-adrenoceptors on cholinergic and adrenergic nerves, respectively. The stimulant activity of idazoxan on gastric secretion from pylorus-ligated rats may be interpreted in terms of increased excitatory vagal tone following the blockade of inhibitory alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1988

Central and peripheral inhibition of exocrine pancreatic secretion by alpha-2 adrenergic agonists in the rat.

The effect of ST91, a clonidine derivative crossing poorly the blood-brain barrier, was compared to that of clonidine on exocrine pancreatic secretion in rats. The experiments were performed in anaesthetized rats after stimulation by a maximal dose of 2-deoxy-D-glucose, and in conscious rats under basal interdigestive conditions. In anaesthetized rats, the 2-deoxy-D-glucose-induced stimulation of pancreatic secretion was suppressed by clonidine but not by ST91, both injected subcutaneously. This effect of clonidine was not antagonized by prazosin, but was decreased by 70-100% (according to the variables measured) by yohimbine. The alpha-2 antagonists rauwolscine and corynanthine were less efficient than yohimbine, while idazoxan suppressed totally the effect of clonidine. In conscious rats, the basal interdigestive secretion was inhibited by ST91 and by clonidine. After sc injections, the potency of ST91 was about ten times smaller than that of clonidine, whereas after injections in the cerebral ventricles, ST91 was as potent as clonidine to inhibit pancreatic secretion. Most (70-90%) of the inhibition induced by sc ST91 and clonidine in conscious rats was suppressed by yohimbine or by prazosin. It is concluded that both ST91 and clonidine inhibit pancreatic secretion in rats, and that this effect has probably both central and peripheral components. The central effect involves alpha-2 receptors, while the peripheral effect may involve alpha-1 and alpha-2 receptors.

Adrenergic alpha-Agonists↗

PubMed1987

Exogenous doxorubicinol induces cardiotoxic effects in rats.

An investigation was performed in the rat to assess the cardiotoxic effects of exogenous doxorubicinol compared with those induced by an equimolar dose of its parent drug doxorubicin. Rats received synthetic doxorubicinol or doxorubicin 3 mg/kg i.v. weekly for 3 weeks and were observed for a further period of 4 weeks. Survival, body growth, ECG parameters, and heart histopathology were studied. Doxorubicin markedly affected rat body growth, as well as several ECG parameters such as S alpha T, R alpha T, alpha TP and T-wave. Typical cardiac histological alterations were also induced by doxorubicin. In a similar way, doxorubicinol treatment was associated with a significant inhibition of rat body weight increase, and the appearance of ECG alterations as well as both macro- and microscopic signs of cardiac tissue damage. However these effects were delayed in time and their severity was lower compared with doxorubicin. Overall results indicate that doxorubicinol induces a doxorubicin-like toxic syndrome mainly affecting the heart, although to a lower degree of severity than that caused by the parent drug. It is suggested that the lower toxic potential displayed by doxorubicinol might be due at least in part to its greater polarity and a consequently lower cardiac tissue uptake compared with doxorubicin.

Animals↗

PubMed1983

The pharmacokinetics of clofoctol in healthy neonates and adults studied by an original HPLC technique.

The pharmacokinetics of clofoctol [(tetramethyl-1,1,3,3,butyl)-4-(dichloro-2,4-benzyl)-2-hydroxy-1-benzene ] was investigated in six healthy newborns and compared with the kinetic parameters of the drug in six healthy adults. The concentration of the drug in plasma was measured by means of an original sensitive HPLC technique. In both neonates and adults treated rectally with clofoctol, the plasmatic peak occurred at the 30th min, although the maximal peak of adults was significantly lower. Kel and T1/2 exhibited a similar pattern, whereas the AUC was about 5 times higher in newborns. The present findings suggest that clofoctol is well absorbed rectally. The higher plasmatic levels of clofoctol in neonates may result from their lower degree of hepatic metabolic activity.

Adult↗

PubMed1982

Simultaneous histochemical demonstration of noradrenergic nerves and tissue components in guinea-pig renal pelvis after treatment with daunomycin.

A standard histochemical technique for detecting catecholamines has been applied to tissues from the renal pelvis of untreated and daunomycin-pretreated guinea-pigs. Under the fluorescence microscope, muscular, mucosal, and endothelial cells exhibited the drug-specific orange-red fluorescence, in contrast to the dark background of control tissues. The presence of daunomycin in the cells also greatly improved the visibility of numerous noradrenergic fibres which appeared to originate from perivascular plexuses and distribute to the smooth cells. A dense noradrenergic innervation was detected in the submucosa, but the epithelium did not contain any yellow-green fluorescent fibres. A typical arrangement was observed consisting of muscular, nervous and vascular components, enveloped by connective tissue: this formation appeared to be related to the system modulating the pacemaker activity of the renal pelvis.

Animals↗

PubMed1981

The pharmacokinetics of two erythromycin esters in plasma and in saliva following oral administration in humans.

An improved highly sensitive fluorimetric methods has been employed to measure plasma and saliva levels of erythromycin propionate and stearate in eight healthy volunteers following a single oral dose of 7.5 mg/kg. The plasma curves exhibited a mean half-life of 5.22 +/- s. e. m., 0.86 h-1 for the propionate and 2.97 +/- 0.22 h-1 for the stearate. Peak levels were reached at the 2nd h (4.07 +/- 0.29 microgram/ml for the propionate; 2.15 +/- 0.14 microgram/ml for the stearate). The area under the total plasma concentration curve was about 3-fold higher in the case of propionate. The concentration in saliva was about 20% of the corresponding concentration in plasma for the propionate and about 25% for the stearate. A significant positive correlation was observed between plasma and saliva levels for both macrolides.

Administration, Oral↗

PubMed1980

Noradrenergic innervation of the heart in untreated and daunomycin-pretreated animals.

The innervation of guinea-pig and rat cardiac tissue consists of thin noradrenergic axons running parallel to the myocardial fibres and producing well-developed fluorescent networks which are denser in guinea-pig tissue. Transverse sections of arterial vessels exhibit a marked polar-like disposition of adrenergic nerves, which mainly appear to be concentrated in two opposite areas. Tissue sections from daunomycin-treated animals fluoresced a striking orange-red. This drug-specific fluorescence emanated from all parts of the ventricular tissue, with particular intensity in the nuclei. Neither the density nor the shape of the adrenergic nerves were affected by treatment with the drug. Despite penetration and storage of the antibiotic into the ventricular tissue, cardiotoxicity was not found in the present study.

Adrenergic Fibers↗

PubMed1977

Histochemical studies of noradrenergic innervation of the liver in untreated and daunomycin-pretreated guinea-pigs.

The pattern of noradrenergic innervation of guinea-pig hepatic tissue was examined by using the fluorescence method of Falk et al. (1962). The distribution of monoaminergic nerve fibers in untreated animals was clearly evident at the level of the portal vein, the hepatic artery and the bile duct. The hepatic artery was the most densely innervated. Mast cells and Kupffer cells had no connection with the adrenergic fibres. In daunomycin-pretreated animals, the hepatic cells appeared to be deep red in colour owing to the presence of the antibiotic. Some noradrenergic nervous fibres, never previously described, were unexpectedly distinguishable in the liver parenchyma against the background red colour of daunomycin-pretreated tissue. They appeared to be contiguous to the hepatocytes and were of different shapes: comma-like, V-like, or like a string of pearls. The nature and the functional role of these elements is briefly discussed.

Adrenergic Fibers↗

PubMedDate not supplied

Central alpha-2 adrenoceptors regulate central and peripheral functions.

Central alpha-2 adrenoceptors regulate a variety of functions including blood pressure, gastrointestinal activity, hormonal secretion, sleep-waking cycle, analgesia, anxiety and some aspects of the withdrawal reaction to opioids. Evidence has been provided that clonidine decreases blood pressure, inhibits salivary secretion and reduces gastrointestinal secretion and motility. Several alpha-2 adrenoceptor agonists reduce wakefulness and inhibit paradoxical sleep, whereas novel imidazoline derivatives, such as detomidine, display sedative and analgesic properties which have been related to the activation of central alpha-2 adrenoceptors. Recent data emphasize the importance of somatodendritic alpha-2 autoreceptors compared to presynaptic alpha-2 autoreceptors as physiological modulators of noradrenergic activity in the central nervous system. In addition, increasing experimental evidence has been provided on the relevant role played by central alpha-2 heteroreceptors (presynaptic and somatodendritic) in the regulation of several functions. Some effects mediated by the activation of alpha-2 adrenoceptors are very similar to those following stimulation of mu opioid receptors. This parallelism can be explained, at least in part, by the presence of these receptors on the same neurons on which they exert an inhibitory action mediated by the same cellular mechanisms. This review resumés the most prominent data about the role played by central alpha-2 adrenoceptors in the regulation of overall functions.

Animals↗

PubMedDate not supplied

Doxorubicin affects both the number and the morphology of specific atrial granules in dog heart.

A morphometric study was performed in dog atria to assess the effects of both single and repeated doses of doxorubicin on specific granules containing the natriuretic factor. Male beagle dogs were divided into 4 groups and treated i.v. as follows: groups A and B were controls and received isotonic saline; group C was given doxorubicin 2.4 mg/kg in a single injection; group D received doxorubicin 1.2 mg/kg once a week for 3 consecutive weeks. Samples of left atrium were taken 8 hours (groups A and C) or 28 days (groups B and D) after the last dose, and examined by the electron microscope. Compared with controls, the atrial tissue of group C dogs showed a significant increase in the number of specific granules; by contrast, the granularity was found to decrease significantly in the atria from group D dogs. These observations indicate a significant biphasic effect of doxorubicin on specific atrial granules of dog heart. The increase in granule density might be due to a block of the secretory process which is dependent on the metabolic energy supply. The reduction in cardiomyocyte granularity may be ascribed to the impairment of nucleic acid and protein synthesis induced by doxorubicin. Such alterations may play a significant role in doxorubicin-induced cardiovascular toxicity.

Animals↗