Biomedical subjects

F Fraschini

Publications and source records attributed to F Fraschini.

At least 19 recordsLinked to original sources

PubMed1992

2-Bromomelatonin: synthesis and characterization of a potent melatonin agonist.

A practical synthesis of N-[2-(2-bromo-5-methoxy-1H-indol-3-yl)ethyl]- acetamide (2-bromomelatonin) was achieved by direct bromination of melatonin with N-bromosuccinimide (NBS) in anhydrous acetic acid at room temperature under nitrogen, followed by flash-chromatography. 1H-NMR and mass spectra showed the bromine to be incorporated at the C-2 position of the indole moiety. Tests performed in vitro with isolated melatonin receptors from rabbit parietal cortex demonstrated that the relative binding affinity of 2-bromomelatonin was about ten times higher than that of melatonin and close to that of 2-iodomelatonin. 2-Bromomelatonin behaved as a potent agonist in the physiological studies. It showed enhanced activity in inhibiting the spontaneous firing activity of cortical neurons and similarly to melatonin and 2-iodomelatonin potentiated significantly the inhibitory effect of GABA. 2-Bromomelatonin was also an extremely effective agonist in the tests performed in vivo in the Syrian hamster gonadal regression model.

Animals↗

PubMed1992

Regulation of the androgen receptors in the harderian gland of the male Syrian hamster: influence of photoperiod, castration, and chronic melatonin treatment.

Male Syrian hamsters that were exposed for 8 weeks to short photoperiod (LD 10:14) or treated with melatonin in the late afternoon under long photoperiod conditions (LD 14:10) had a significantly higher content of androgen receptors in the Lipidex-purified soluble fractions isolated from the Harderian glands as compared to the long photoperiod (LD 14:10) exposed controls. Simultaneous computer-assisted analyses of all series of saturation and competition experiments revealed that the numerical value of the apparent Kd, as determined by using the synthetic androgen R-1881 (methyltrienolone), was not different between the experimental groups, and ranged from 0.050 to 0.067 nM. Of the principal natural androgens, testosterone (T) was most potent in inhibiting methyltrienolone binding to the receptor (Ki values from 0.33 to 0.55 nM), and 5 alpha-dihydrotestosterone (DHT) and delta 4-androstenedione (AD) were less effective (Ki values between 1 and 1.9 nM). In the hypothalami and pituitaries of the same animals, used in parallel control assays, DHT was twice as potent as T. Short-term castration (24 hr post-orchidectomy) did not result in significant changes in the receptor binding characteristics. Following 8 weeks exposure to a long photoperiod (LD 14:10) the Bmax values demonstrated a four-fold increase in castrated animals (179 fmoles/mg protein vs. 47 fmoles/mg protein) over intact controls. The relative binding affinity of the major androgens under these conditions remained unchanged, with the exception of AD, where a five-fold increase in the numerical Ki values (decrease in the binding affinity) was recorded (Ki = 9.6 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Melatonin signal transduction and mechanism of action in the central nervous system: using the rabbit cortex as a model.

The cortex of the rabbit (Oryctolagus cuniculus) is rich in melatonin binding sites, and particularly abundant is the parietal cortex. Consequently, we characterized the putative melatonin receptor in the parietal cortex by a series of in vitro ligand-receptor binding experiments and biochemical and electrophysiological studies. The in vitro saturation and competition experiments demonstrated that the binding in the crude cortical membrane preparations was of high affinity and specificity. Guanine nucleotides (GDP, GTP, and GTP gamma S) inhibited the specific 2-[125I]iodomelatonin binding in a dose-dependent manner. Coincubation with a nonhydrolyzable GTP analog provoked a shift in the binding affinity; the numerical values of the Kd increased from 20-30 to 200-600 pM. Melatonin, in nanomolar concentrations, was able to inhibit the forskolin-stimulated accumulation of cAMP in parietal cortex explants, and preincubation with pertussis toxin counteracted this effect of melatonin. Apparently, the melatonin binding site in the rabbit parietal cortex is linked to its second messenger via a pertussis toxin-sensitive G-protein, probably of the inhibitory Gi class, similar to what has been described for different parts of the brain of other vertebrates. The experiments on the spontaneous firing activity of single neurons in the third to fourth layer of the parietal cortex in anesthetized animals showed that melatonin and its potent agonist 2-iodomelatonin exhibited gamma-aminobutyric acid (GABA)-like effects and were able alone, in nanomolar concentrations, to significantly slow the neuronal firing activity. Moreover, both melatonin and 2-iodomelatonin potentiated the effect of GABA on the neuronal activity, leading to powerful inhibition of the tested neurons. Undoubtedly, the binding site in the rabbit parietal cortex possesses all of the characteristics of a functional receptor. We suggest that melatonin is involved in the control of fundamental cortical functions and that it acts in concert with GABA, one of the two major inhibitory neurotransmitters in the central nervous system.

Animals↗

PubMed1991

Localization and characterization of melatonin binding sites in the brain of the rabbit (Oryctolagus cuniculus) by autoradiography and in vitro ligand-receptor binding.

The distribution and the properties of the melatonin binding sites were characterized in the brain of the rabbit by combined use of autoradiography and in vitro ligand-receptor binding. Autoradiography revealed widespread specific binding in the brain. The pars tuberalis of the pituitary gland, suprachiasmatic nuclei, ventromedial hypothalamic nuclei, tapetum, hippocampus, indusium griseum, cingulate gyrus, cortex and the choroid plexus were intensely labelled. Diffuse specific binding was recorded in the olfactory bulb and the anterior hypothalamus. Series of in vitro ligand-receptor binding experiments, using the anterior hypothalamus, confirmed that the binding was of high affinity and specificity. Coincubation with a non-hydrolyzable GTP analogue provoked a shift in the binding affinity, the numerical values of the Kd increasing from 20-30 pM to 280-300 pM. Apparently the melatonin receptor in the rabbit brain is linked to its second messenger via a G protein, similarly to what has been described for the brain of other vertebrates.

Animals↗

PubMed1991

In vivo and in vitro studies on modulation of the pineal endocrine function by L-acetyl-carnitine in the rat.

Male Sprague-Dawley rats injected (i.p.) at 1500h with L-acetyl-carnitine in doses of 10, 30 or 90 mg/kg exhibited a notable increase in their pineal and serum melatonin content 1 hr later. Likewise, L-acetyl-carnitine administered in the same dose range induced a significant increase of pineal and serum melatonin content in rats treated at 0100h, following exposure of 30 min to bright white light to suppress endogenous melatonin. Under in vitro experimental conditions, however, 60 min of coincubation of isolated rat pineal glands with L-acetyl-carnitine (10(-5) M) did not result in an elevation in melatonin accumulated in the incubation medium. These results demonstrate that, in vivo, L-acetyl-carnitine can exert a modulatory action on synthesis and release of melatonin, possibly by modifying noradrenergic transmission and signal transduction in the pineal gland.

Acetylcarnitine↗

PubMed1991

The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans.

The diffusion of clarithromycin and roxithromycin into respiratory tract tissues was studied in 174 adult patients undergoing surgery. Patients received clarithromycin 250 mg orally (500 mg in the case of lung tissue), or roxithromycin 150 mg orally, both given every 12 h, for three days with the last dose administered at different times before surgery. Clarithromycin reached peak tissue levels 4 h after administration and achieved mean peak concentrations of 8.32 mg/kg +/- 2.57 in nasal mucosa, 6.47 mg/kg +/- 2.8 in tonsil, and 17.47 mg/kg +/- 3.29 in lung tissue. Roxithromycin reached peak tissue levels between 4 and 6 h after administration, achieving mean peak concentrations of 1.78 mg/kg +/- 0.73 in nasal mucosa, 2.2 mg/kg +/- 1.21 in tonsil, and 2.14 mg/kg +/- 0.87 in lung tissue. Clarithromycin and roxithromycin demonstrated contrasting pharmacokinetic behaviour. Roxithromycin was characterized by high concentrations in serum and low concentrations in tissues. Clarithromycin on the other hand, is characterized by therapeutic serum concentrations and high tissue concentrations.

Administration, Oral↗

PubMed1991

Characterization and mapping of melatonin receptors in the brain of three mammalian species: rabbit, horse and sheep. A comparative in vitro binding study.

Melatonin receptors were characterized in the brains of three mammals (rabbit, horse and sheep) by an in vitro binding technique, using 2-[125I]iodomelatonin as labelled ligand. Although binding sites for melatonin have been described recently in several vertebrate species (including the sheep), the rabbit and the horse have not been the subject of investigation so far. Apart from characterization, the present report describes receptor distribution in a number of brain regions, thus allowing for direct interspecies comparison under the same methodological conditions. 2-[125I]iodomelatonin labelled high-affinity binding sites in crude membrane preparations from these species. A series of kinetic and saturation experiments revealed that the binding was rapid, stable, saturable, reversible, of high affinity (Kd in the low picomolar range) and low capacity (Bmax between 1 and 20 fmol/mg protein). The competition studies showed that the relative order of potency of a variety of indoles for inhibition of 2-[125I]iodomelatonin binding was as follows: 2-iodomelatonin greater than 6-chloromelatonin greater than melatonin much much greater than 5-methoxytryptophol greater than 5-methoxytryptamine, and that it was similar in the different brain regions. Prazosin, which has been reported as an extremely potent melatonin analog in the hamster brain, possessed no potency in all preparations from different regions in the three species under investigation. The regional distribution of the receptor showed insignificant species differences. Highest density was always recorded in the median eminence/pars tuberalis (ME/PT) area. Other regions (SCN, POA and certain cortical areas), showed lower, but significant, receptor content. Saturation and competition studies revealed that these binding sites were also of high affinity, low capacity and high specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies.

The pineal hormone melatonin (MLT) is able to exert an oncostatic action. Its possible use in the treatment of human tumors, however, has not yet been investigated. The present study was carried out to evaluate the effects of MLT in patients with metastatic solid tumors resistant to conventional therapies. The study included 54 patients, most of them were affected by lung cancer or colorectal carcinoma. MLT was given intramuscularly at a daily dose of 20 mg at 3.00 p.m. for 2 months; this induction phase was followed by a maintenance period at a dose of 10 mg orally in responder patients or in those with an improvement in performance status (PS). The clinical response was as follows: 1 partial response (cancer of pancreas), 2 minor responses (colon cancer and hepatocarcinoma) and 21 with stable disease. The remaining 30 patients rapidly progressed within the first 2 months of therapy. An evident improvement in PS was achieved in 18 of 54 (33%) cases. These results, by showing an apparent control of the neoplastic growth and an improvement in the quality of life in a reasonable number of cancer patients for whom no other standard therapy is available, would justify further clinical trials to better define the impact of MLT therapy on the survival and quality of life of untreatable advanced cancer patients.

Adult↗

PubMed1991

Kinetic profile of miocamycin in middle ear fluid and mucosa.

A group of 18 patients, before undergoing otoplastic surgery, was treated with miocamycin 600 mg in a single dose; middle ear tissue samples were collected at 2, 3, 4 and 6 h. A group of 20 patients suffering from secretory otitis media (SOM) was also treated with 600 mg of miocamycin in a single dose; collections of middle ear fluid (MEF) were performed at 1, 2, 4 and 6 h. Blood withdrawals from all patients occurred at the same time intervals. The miocamycin determination was performed by means of a microbiological method employing Sarcina lutea ATCC 9341. The highest serum levels (1.06 +/- 0.13 mg/l) were found at 2 h in the group from which middle ear mucosa had been withdrawn and at 1 h (2.2 +/- 0.5 mg/l) in the group from which the MEF had been collected; at 6 h miocamycin could be determined in both groups, with values ranging from 0.1 to 0.2 mg/l. In middle ear mucosa the miocamycin concentration was 1.52 +/- 0.27 mg/kg at 2 h and 0.2 +/- 0.09 mg/kg at 6 h. In MEF, the miocamycin concentration was 2.1 +/- 0.27 mg/l at 1 h and 0.24 +/- 0.05 mg/l at 6 h. The miocamycin concentration determined at 1 h in MEF was virtually equal to that in serum at the same time. At the following experimental times of withdrawal, the miocamycin concentration in mucosa specimens, as well as in MEF samples, proved to be markedly higher than values simultaneously found in serum.

Adult↗

PubMed1990

Hormonal circadian rhythms in eating disorders.

The circadian rhythm of several plasma hormones (prolactin, growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and melatonin) was simultaneously evaluated in 23 women with anorexia nervosa (AN), in 27 obese (OB) women, and in gender and age-matched healthy controls. A trend toward similar alterations of the circadian pattern of the different hormones was observed in the two groups of patients, with the exception of plasma growth hormone (GH), which exhibited nutrition-dependent impairments. The timing of the peaks for each hormonal rhythm revealed the existence of an internal desynchronization in both eating disorders.

Adult↗

PubMed1990

T cell subpopulations in vitiligo: a chronobiologic study.

The circadian rhythms of helper (CD4) and suppressor (CD8) T cells from the peripheral blood of 12 vitiligo patients (seven with active disease, five with static) and 12 healthy control subjects were studied. Patients with active vitiligo had a lower percentage of CD4+ cells than did control subjects at 0000 hours and at 0600 and 1200 hours; there were no differences between these values in patients with static vitiligo and those in control subjects. The percentage of CD8+ cells were lower at 1200 and 1800 hours in both active and static vitiligo patients than in control subjects. Cosinor analysis of the CD4+ cells showed a circadian rhythm in static vitiligo, whereas the rhythmicity was lost in active vitiligo. CD8+ cells did not show any circadian rhythm in either active or static vitiligo. Our data show more striking aberrations for T cell subtypes in active vitiligo than in static vitiligo. They suggest that cell-mediated immunity may play a role in the pathogenesis of the disease.

Adolescent↗

PubMed1990

Pharmacokinetics and tissue distribution of amoxicillin plus clavulanic acid after oral administration in man.

Augmentin (875 amoxicillin and 125 mg potassium clavulanate) was administered orally to patients with chronic bronchitis. Concentrations of amoxicillin and clavulanic acid were measured in serum, sputum and urine. Peak serum levels for amoxicillin of 11.23 +/- 2.61 micrograms/ml were observed at 2 hours and for clavulanic acid of 2.55 +/- 0.54 micrograms/ml at 1 hour. After 9 hours, 50% of the amoxicillin and 39% of the clavulanic acid had been renally excreted. The peak sputum concentration of amoxicillin was 1.31 +/- 0.42 micrograms/ml at 4 hours and of clavulanate was 0.79 +/- 0.23 micrograms/ml at 2 hours. Patients awaiting surgery received an oral dose of augmentin as above. Samples of lung, tonsil, middle ear mucosa and prostate were obtained and tissue concentrations of both compounds measured. Peak levels of amoxicillin ranged from 0.87 micrograms/g (tonsil) to 2.56 micrograms/g (lung) and of clavulanic acid from 0.20 micrograms/g (prostate) to 0.56 micrograms/g (lung) between 3 and 4 hours after dosing.

Administration, Oral↗

PubMed1990

Pathogen-host interaction.

Host defense, as it generally applies to humans, refers to the individual's ability to withstand infections. Human host defense mechanisms are numerous, diversified, complex, and often interdependent. The administration of drugs may influence some phases of immunocompetence mechanisms. The effect of several antimicrobial agents on organic defenses has been studied. The parameters considered were chemotaxis, phagocytosis, intracellular killing, superoxide-anion production, antibody production, lymphocyte subset behavior, and natural killer cell activity. Some antibacterial agents inhibit these parameters, whereas others can enhance some of these immune parameters to differing extents. Some antibacterial agents have a neutral effect on these parameters.

Anti-Bacterial Agents↗

PubMed1990

In-vitro postantibiotic effects of miocamycin and erythromycin on gram-positive cocci.

The capability of miocamycin to induce a postantibiotic effect (PAE) on a Group A Streptococcus beta-haemolyticus clinical isolate and on Staphylococcus aureus ATCC 29213 has been studied. Erythromycin was chosen as a reference molecule. The exposure time to antibiotics was 90 min. The removal technique of the antibiotic agents consisted of a 1:200 dilution in cultural broth. Miocamycin displayed a PAE of 2 h 30 min in relation to the minimum inhibitory concentration (MIC) of Streptococcus and a PAE of 2 h 30 min in relation to the MIC of Staphylococcus. The PAE value lasting longer than the others was of 5 h 40 min towards Streptococcus and of 4 h 18 min towards Staphylococcus at a concentration eightfold the MIC. Erythromycin showed a PAE of 1 h 36 min in relation to the MIC of Streptococcus and a PAE of 1 h 30 min in relation to the MIC of Staphylococcus. The PAE value lasting longer than the others was of 3 h 15 min against Streptococcus and of 2 h 30 min against Staphylococcus at a concentration eightfold the MIC. In some cases a PAE was observed in relation to subinhibitory concentrations (1/2 MIC). Miocamycin therefore proved to possess a more evident capability to induce a PAE against the clinical isolate of Group A Streptococcus beta-haemolyticus and on Staphylococcus aureus ATCC 29213 than did erythromycin.

Adult↗

PubMed1990

Miocamycin distribution in tonsillar and pulmonary tissues after repeated administration.

Twenty patients undergoing tonsillectomy were treated with a peroral administration of 600 mg of miocamycin every 12 hours for 4 days. On the 5th day, after a last administration of a dose of 600 mg the ablation of the tonsils was carried out on groups of 4 subjects, each one at the following times after oral intake of the drug: 2, 4, 6, 8, 12 h. Twenty-nine patients, admitted to hospital to undergo lung resection were treated with peroral administration of miocamycin in accordance with the above mentioned dose scheme. The operation was carried out on groups of 5 subjects, each on the fifth day at the following times after the last administration: 2, 3, 4, 6, 8 and 12 h (4 subjects). Simultaneously blood was withdrawn for the determination of miocamycin in serum. Miocamycin was measured by a microbiological procedure using Sarcina lutea ATCC 9341. The highest levels of miocamycin were observed after 2h in tonsils (3.2 +/- 0.82 mg/kg) and serum (1.3 +/- 0.33 mg/l). After 12h miocamycin proved to be still measurable in the tissue (0.12 +/- 0.05 mg/kg), whereas it was not detected in serum. In pulmonary tissue, the highest levels of miocamycin were likewise identified at the 2nd hour (2.82 +/- 0.59 mg/kg), simultaneously with the highest serum levels (2.3 +/- 0.61 mg/l). At the 12th hour miocamycin could still be dosed in 3 tissue samples, with values between 0.1 and 0.2 mg/kg and was found just at dosing limits in only one serum sample.

Adolescent↗

PubMed1990

Serum protein binding and extravascular diffusion of methoxyimino cephalosporins. Time courses of free and total concentrations of cefotaxime and ceftriaxone in serum and pleural exudate.

A new approach to the study of the distribution pharmacokinetics of variably bound beta-lactams is to plot the concentration time course of their free (dialysable) and total (free and bound) forms. In the present study, the 6-h concentration time course was plotted of the total and free concentrations of cefotaxime and ceftriaxone in serum and pleural exudate in 12 patients per group, after iv dosing with 1 g of either cefotaxime or ceftriaxone. Samples were taken at 0.5, 1, 1.5, 2, 3, 4 and 6h after dosing. The results of a study of similar design, but conducted over 24 h in ten patients per group, following iv dosing with either cefotaxime 1 g 12-hourly or ceftriaxone 1 g daily are also reported. Samples were taken at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 14, 16 and 24 h after dosing. Areas under the curve of free cefotaxime in pleural fluid were greater than those of free ceftriaxone, in both the 6 h (+54.6%) and 24 h studies (+29.8% after 12 h and +71.0% after 24 h). The free cefotaxime/free ceftriaxone Cmax ratio was 1.75 in the 6 h study. Cefotaxime was superior to ceftriaxone in terms of the diffusion of the free (antibacterially active) fraction into a typical inflammatory exudate. Assessment of the effects of protein binding must be taken into account in antibiotic pharmacokinetic profiles.

Adult↗

PubMed1990

Alpha-1 adrenoceptor involvement in the control of melatonin secretion in the golden hamster.

The nocturnal peak in pineal and serum melatonin content was reduced following administration of the selective alpha-1 adrenoceptor antagonist prazosin in a dose of 0.25 mg/kg. The effect was pronounced one hour post treatment during the late dark phase of the daily photocycle. These data confirm the reported findings that the hamster pineal sensitivity to adrenergic challenge is confined to the second part of the dark phase and indicate that postsynaptically located alpha-1 adrenoceptors are also involved in the physiological control of melatonin synthesis and/or release in that species.

Animals↗

PubMed1990

Failure of prazosin to mimic the effects of melatonin under in vivo and in vitro conditions.

The gonads of male hamsters exposed to short photoperiod (LD, 10:14) or treated with melatonin in the late afternoon under long photoperiod (LD, 14:10) had undergone complete regression by the end of the treatments (8 weeks). Animals treated for the same period of time with prazosin (a putative melatonin analogue) under the same conditions failed to show a difference in their gonadal status as compared to the long photoperiod controls. Prazosin was unable to prevent melatonin-induced gonadal atrophy when injected either in the morning or 30 min before melatonin. Moreover, prazosin was without any effect on (and unable to prevent the melatonin-stimulated) progesterone production by rat adrenals under in vitro conditions. These data demonstrate that prazosin, which reportedly inhibits 2-[125I]iodomelatonin binding in the hamster brain in an affinity-related manner, does not possess properties of a biological melatonin analogue under conditions of two different model systems in two species.

Adrenal Glands↗