Biomedical subjects

G Coppi

Publications and source records attributed to G Coppi.

At least 37 records · Page 2Linked to original sources

PubMed1997

Effect of the thyrotropin releasing hormone analogue posatirelin (RGH 2202) on microanatomical changes induced by lesions of the nucleus basalis magnocellularis in the rat.

The effect of 4 and 8 weeks treatment with 10 mg/kg/day of the thyrotropin releasing hormone analogue posatirelin (L-6-ketopiperidine-2-carbonyl-L-leucyl-proline amide) on microanatomical changes induced by monolateral and bilateral lesions of the nucleus basalis magnocellularis (NBM) were investigated. The following parameters were assessed in the frontal cortex and hippocampus of NBM-lesioned and sham-operated rats: 1) number of nerve cell and glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte profiles; 2) density of silver-gold impregnated fibres; 3) density of choline acetyltransferase (ChAT)-immunoreactive fibres; 4) intensity of acetylcholinesterase (AChE) staining. In NBM-lesioned untreated rats, no changes in the number of nerve cell or of astrocyte profiles were found either in the frontal cortex or in the hippocampus. The only exception was a decrease in the number of granule neuron profiles in the dentate gyrus at 8 weeks after lesioning. Silver-gold impregnated fibres, which express the width of interneuronal connections, were reduced in the hippocampus but not in the frontal cortex of NBM-lesioned rats. ChAT immunoreactivity and AChE reactivity, which were localised respectively in nerve fibre-like structures and in the neuropil, were decreased in the frontal cortex but not in the hippocampus from the fourth week after NBM lesioning. Lesions did not change the number of ChAT-immunoreactive nerve fibres or intensity of AChE staining in the hippocampus. Treatment with posatirelin was without effect on the number of nerve cell profiles or of GFAP-immunoreactive astrocytes both at 4 and 8 weeks after NBM lesioning. Treatment with the compound increased the number of silver-gold impregnated fibres in the hippocampus of NBM-lesioned rats and restored in part ChAT immunoreactivity and AChE reactivity in the frontal cortex. These effects were noticeable in NBM-lesioned rats after 8 weeks of treatment. The possible significance of the neuroprotective effect elicited by posatirelin treatment after lesions of the NBM is discussed.

Acetylcholinesterase↗

PubMed1997

Effect of treatment with the neuroactive peptide posatirelin on microanatomical changes of frontal cortex and hippocampus caused by lesions of the locus coeruleus.

The influence of monolateral and bilateral lesions of the Locus coeruleus (LC) on the number of nerve cell and glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte profiles, on silver-gold impregnated fibres and on tyrosine hydroxylase (TH) immunoreactivity was assessed in the rat frontal cortex and hippocampus. The influence of treatment for 4 and 8 weeks with a 10 mg/kg/day dose of the neuroactive peptide posatirelin on the above parameters was also investigated. Lesions of the LC decreased the number of nerve cell profiles in the frontal cortex 8 weeks after lesioning and were without effect on nerve cell profiles in the frontal cortex 4 weeks after lesioning and in the hippocampus at both 4 and 8 weeks after LC lesioning. Glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes were not affected by lesions of LC. Silver-gold impregnated fibres were decreased in the frontal cortex but not in the hippocampus of LC-lesioned rats at 8 weeks after lesioning. TH immunoreactivity, which was localized in nerve fibre-like structures both in the frontal cortex and in the hippocampus was decreased in the frontal cortex and in the hippocampus from the 4th week after LC lesioning. Treatment with posatirelin was without effect on the number of nerve cell and of GFAP-immunoreactive astrocyte profiles at both 4 and 8 weeks after LC lesioning, with the exception of nerve cells of the frontal cortex in monolaterally-lesioned rats which were increased 8 weeks after lesioning. The compound increased silver-gold impregnated fibres in the frontal cortex of monolaterally lesioned rats after 8 weeks of treatment, but did not affect TH immunoreactivity both in the frontal cortex or in the hippocampus. The above results suggest that treatment with posatirelin exerts a neuroprotective effect on the frontal cortex consisting of the partial restoration of some microanatomical changes caused by lesions of LC. The possible significance of this effect is discussed.

Animals↗

PubMed1996

[Energy-dispersive X-ray analysis of pharmaceutical formulations].

Energy-dispersive X-ray analysis (EDS) coupled to a scanning electron microscopy (SEM) could represent a valuable tool in the study of solid dosage forms. In particular, EDS can be useful in the control of conventional pharmaceutical formulations by determining the presence and the distribution of characteristic compounds. More recently, the growth in the development of modified release dosage forms needed the determinations of parameters affecting the drug delivery. Among these, drug distribution, elements involved in crosslinking procedures and coatings of "reservoir" systems could easily and rapidly evaluated by EDS analysis. In this paper, we report the theoretical aspects and some applications of the EDS technique especially concerning controlled release dosage forms in order to show the versatility of such an analytical method which could be widely used in the future.

Chemistry, Pharmaceutical↗

PubMed1995

Pharmacokinetics of alpha-dihydroergocriptine in rats after single intravenous and single and repeated oral administrations.

The pharmacokinetics of alpha-dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged alpha-dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg-1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half-life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg-1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half-life of 0.02 h, a distribution half-life of 2.15 h and an elimination half-life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs. Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first-pass effect).

Administration, Oral↗

PubMed1995

Neuroprotective activity of alpha-dihydroergocryptine in animal models.

alpha-Dihydroergocryptine (alpha-DHEC) is a well known dopaminergic agent successfully employed in the treatment of Parkinson's disease. alpha-DHEC showed a neuroprotective activity against total cerebral ischemia induced by MgCl2 in mice and histocytic anoxia by NaCN in mice and rats. Moreover the drug promoted the recovery of locomotor activity in rats after cerebral ischemic damage and protected mice against convulsions induced by intracerebroventricular injections of NMDA and glutamate. alpha-DHEC showed a protective activity on neuronal degeneration induced by MPTP in monkeys, as evaluated through animal's behaviour and morphological-cytochemical changes in the substantia nigra, suggesting a preservative effect on neuronal morphology and brain architecture. In the MPTP-treated monkeys, the alpha-DHEC administration induced a restoration of the unstimulated MDA values to control levels. The neuroprotective activity of alpha-DHEC is related to its peculiar activity on antioxidative enzymes of GSH system and to reduction of lipid-peroxide-induced cellular degeneration.

Animals↗

PubMed1994

Interactions of P 1507, a new antioxidant agent, with phagocyte functions.

Toxic oxygen free radicals are believed to play a role in the pathogenesis of a number of respiratory diseases. In particular, pulmonary emphysema may occur because of the oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI). We report in vitro data on a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine], obtained in a series of experiments designed in view of its therapeutic potential in these clinical conditions. We found that P 1507 at the concentration of 5 x 10(-6) M was able to almost fully abolish the PMA-triggered PMN-induced oxidative impairment of alpha 1-PI. Protection may be due to the radical scavenger ability of P 1507, that markedly reduced superoxide anion production from PMNs. We also found that P 1507 did not significantly impair other defence mechanisms of PMNs (i.e. phagocytosis, chemotaxis and bactericidal activity). The release of cytokines (TNF-alpha, IL-6 and IL-8) from monocytes was not altered in the presence of P 1507. We conclude that the compound P 1507 may be considered for treatment of clinical conditions characterized by overload of oxidants, on the basis of its ability in preventing the oxidative damage of alpha 1-PI and of a lack of unwanted inhibitory effects towards defence mechanisms of phagocytes.

Antioxidants↗

PubMed1994

Experimental immunological screening tests on pidotimod.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was administered to immunodepressed (by prednisolone, cyclophosphamide or methotrexate) mice by oral and intraperitoneal route (respectively up to 400 and 200 mg/kg) during several days (up to 9 days). The stimulatory action of the drug on cell-mediated immunity is investigated by measuring the rosette formation by the murine splenic lymphocytes ex vivo, by T- and B-lymphocytes ex vivo proliferative response to mitogens, by dinitrochlorobenzene delayed hypersensitivity induced on the ear, by the graft-versus-host reaction with immunodepressed mice as donors. In all tests pidotimod reveals a potent action in restoring the depressed reactivity. The action of pidotimod on humoral immunity is showed in two tests where the antibody response is induced by a thymus dependent (sheep erythrocytes) or a thymus independent (lipopolysaccharide) antigen. Pidotimod was active in both tests. Macrophage functions, anion superoxide production and the non-stimulated ex vivo chemotaxis reveal that pidotimod significantly reduces the immunodepressant action of prednisolone; particularly in i.p. treated mice the chemotaxis is likely to be restored to the levels of the non-immunodepressed controls. The colloidal china ink blood clearance in vivo in immunodepressed mice, after pidotimod treatment, results similar to that found in the control mice.

Adjuvants, Immunologic↗

PubMed1994

Protective effects of pidotimod against experimental bacterial infections in mice.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) protected mice against experimental bacterial infections in different experimental models. In all tests the drug's effect was measured as protection from death. The activity of pidotimod was evident and statistically significant after 5 administrations before the bacterial challenges. Pidotimod was active against many bacterial species infections, its active dosages ranging from 0.01 to 100 mg/kg i.p. x 5 times. Pidotimod showed against some bacterial infections a protection similar or better than those of bestatin, N-acetylmuramyl-L-Ala-D-isoGlu-OH and tuftsin. It showed high protection against bacterial infections in cyclophosphamide-immunodepressed mice. Finally, pidotimod showed an additive or synergic activity in combination with beta-lactam antibiotics (cefotaxime, ampicillin) against bacterial infections in mice.

Adjuvants, Immunologic↗

PubMed1994

General pharmacology of pidotimod and testing for drug interactions.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a new biological response modifier. General pharmacology and interactions with some drugs were tested. The drug, at doses of 200 mg/kg i.p. and 400 mg/kg p.o., did not affect the normal behaviour, did not modify the responses to stimulation of autonomic nervous system or central nervous system. Pidotimod did not display any cardiovascular or respiratory effect up to 125 mg/kg i.v. in 3 animal species. The drug did not show antimicrobial or antifungal activities nor interact with some of the most common therapeutics (antibiotics, tolbutamide, pentobarbital, antihypertensives, chlorothiazide, warfarin, non-steroidal antiinflammatory agents). On the basis of these results pidotimod shows a safe profile; moreover it does not interact with many therapeutic agents.

Animals↗

PubMed1994

Toxicological evaluation of pidotimod.

This paper reports the toxicological evaluation of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6). Its acute toxicity in mice, rats and dogs was very low after oral, i.v., i.m. and i.p. administration. The repeated administration studies in rats were performed for 4 months via the i.p. route and for 12 months via the oral route. Pidotimod did not show toxic effects at dosages up to 200 mg/kg i.p. and 800 mg/kg p.o. These dosages correspond to 32.5 times the maximum dosage intended for clinical use. The repeated administration studies in dogs were performed for 26 weeks via the i.m. route and for 52 weeks via the oral route. Pidotimod did not show toxic effects at dosages up to 300 mg/kg i.m. and 600 mg/kg p.o.. It did not affect male or female rat fertility at dosages up to 600 mg/kg by oral and 500 mg/kg by i.v. route. The compound was not teratogenic in rats (600 mg/kg p.o. and 1000 mg/kg i.v.), with no effects on subsequent embryofoetal development at dosages up to 1000 mg/kg/day, and in rabbits (300 mg/kg p.o. and 500 mg/kg. i.v.). There were no peri- and postnatal toxic effects in rats (600 mg/kg p.o. and 500 mg/kg i.v.). Local tolerability of pidotimod after i.m. administration was very good. In conclusion pidotimod is characterized by a high safety margin in all animal species.

Animals↗

PubMed1994

Genotoxicity testing of pidotimod in vitro and in vivo.

The mutagenic potential of pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was assessed in a series of five assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Animals↗

PubMed1994

Pharmacokinetics of pidotimod in rats and dogs.

The pharmacokinetic studies on pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) a new biological response modifier, following intravenous, intramuscular or oral administrations in rats and dogs are reported in this paper. Plasma, urine and organ concentrations were determined by HPLC. Analytical methods were validated for specificity, sensitivity, recovery, accuracy and reproducibility; recovery was very close to 100%, the coefficients of variation of accuracy and reproducibility showed low values. In the rat the pharmacokinetic parameters obtained after oral administration demonstrate that pidotimod is a very fast absorbed, distributed and eliminated drug (t1/2el = 1 h) and that it shows high total clearance and distribution volume. Bioavailability was 100% in the intramuscular route and 27% in the oral route. Pidotimod distributes quickly in the main organs, in particular in kidneys and liver; the time course of the levels in organs follows that of plasma levels after intramuscular administration. After repeated intramuscular administrations no phenomena of accumulation or autoinduction were evident. The urinary excretion of the unmodified drug is 75.6% after intravenous and 31.1% after oral administration. The behaviour of pidotimod in dog after oral administration is quite similar to that observed in rat, with a t1/2el of 1.47 h, absolute bioavailability of 37%, high total clearance and distribution volume. Also in the dog the repeated intravenous and oral administrations do not cause any accumulation or autoinduction phenomena.

Administration, Oral↗

PubMed1994

Pharmacokinetics and oral bioavailability of pidotimod in humans.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was investigated in 3 different pharmacokinetic experiments in healthy volunteers. A first trial was carried out with a cross-over design in 12 subjects, given the drug in single administration by intravenous route (200 mg in bolus) and by oral route at 3 dose levels: 200, 400 and 800 mg (tablets). The second experiment was performed in 36 subjects, by intramuscular route at 50, 100 and 200 mg (12 volunteers/group) twice a day for 15 days. Blood samples were drawn and urine collected at different times after the first and the last administration (29th) of the compound. The third experiment was done in 12 subjects given the product at the same single oral dose (800 mg) in different galenic formulations: sachets, vials and tablets, to assess the relative bioavailability, with a cross-over design. Pidotimod plasma and urinary levels were measured by HPLC. The plasma levels after parenteral administration followed a second-order pharmacokinetic, while after oral administration they were processed by a first order input-output model.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Pharmacokinetics of pidotimod in elderly volunteers and in renal failure patients.

The pharmacokinetics of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) in elderly volunteers and in patients with renal failures were investigated. No differences in absorption, excretion and pharmacokinetic parameters was evident between old volunteers and the youngs of a previous work. Patients with impaired renal function showed different pharmacokinetic parameters of pidotimod in relation to different grade of kidney function. There were linear relationships between elimination half-lives and plasma levels of creatinine and urea; longer half-lives correspond to higher levels of creatinine and urea. As the half-life of the compound did never exceed 8-9 h, the data do not support any change of pidotimod administration schedule (every 24-12 h).

Administration, Oral↗

PubMed1993

Local tolerance of a new ciclopirox olamine vaginal preparation in rats and rabbits.

A new ciclopirox olamine vaginal preparation was tested for toxicity after topical vaginal administration for 28 days to rats and rabbits. At the end of the experiments animals were sacrificed for autopsy, the main organs were weighed, hematological, coagulative and biochemical parameters were checked and histological examinations were performed on uterus and vagina. The results demonstrated the good topical and systemic tolerance of this new vaginal formulation in rats and rabbits.

Administration, Intravaginal↗

PubMed1993

Pharmacokinetics of ciclopirox olamine after vaginal application to rabbits and patients.

The authors reported the plasma levels and pharmacokinetic parameters of ciclopirox olamine in rabbits after i.v. and intravaginal administrations and in female patients after vaginal administration. Plasma levels of total and free ciclopirox were determined by a HPLC method. In rabbit ciclopirox showed a half-life of 2.22 h and an intravaginal bioavailability of about 2%. In female patients ciclopirox showed low intravaginal absorption; this value might explain the good local and systemic tolerability and also the penetration of drug in deep tissue.

Administration, Intravaginal↗

PubMed1993

Evaluation of the mutagenicity of a-dihydroergocryptine in vitro and in vivo.

The mutagenic potential of the ergot alkaloid a-dihydroergocryptine (a-DEC, CAS 14271-05-7) was assessed in a series of 5 assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Animals↗

PubMed1993

A new HPLC method for pidotimod plasma levels determination.

This paper describes a HPLC method for the determination of Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid; PGT/1A), a new biological response modifier, in plasma. The column was an Aminex Ion Exclusion HPX 874 with a PRP precolumn, the mobile phase was 0.05% sulfuric acid-acetonitrile (88:12, v/v), the flow rate was 0.6 ml/min, the detection wavelength was 210 nm. Plasma (1 ml) was added with internal standard (Oxiracetam, concentration 400 micrograms/ml) (50 microliters) and 35% perchloric acid (100 microliters). The supernatant (0.5 ml) was added with mobile phase (0.5 ml) and, after centrifugation, injected into the column. The retention times of Pidotimod and Oxiracetam were 16.5 and 13.8 min. respectively. The method was validated for recovery, accuracy and reproducibility. The results after oral administration of 800 mg of Pidotimod in male volunteers were also given. This method is better than that previously described because it utilizes an internal standard and reaches a lower detection limit.

Adult↗