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Biomedical subjects

M Bonati

Publications and source records attributed to M Bonati.

At least 109 records · Page 6Linked to original sources
PubMed1987

Teicoplanin pharmacokinetics in patients with chronic renal failure.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.

Adult↗
PubMed1987

Clinical pharmacological and therapeutic considerations in general intensive care. A review.

The application of clinical pharmacological concepts and therapeutic standards in intensive care settings presents particularly difficult problems due to the lack of adequately controlled background information and the highly variable and rapidly evolving clinical conditions where drugs must be administered and their impact evaluated. In this review, an attempt has been made to discuss the available knowledge within the framework of a problem-oriented approach, which appears to provide a more clinically useful insight than a drug-centred review. Following a brief discussion of the scanty data and the most interesting models to which reference can be made from a pharmacokinetic point of view (the burn patient being taken as an example), the review concentrates on the main general intervention strategies in intensive care patients. These are based mainly on non-pharmacological measures (correction of fluid and electrolyte balance, total parenteral nutrition, enteral nutrition, oxygenation and ventilatory management) and are discussed with respect to the specific challenge they present in various clinical conditions and organ failure situations. In addition, 4 major selected clinical conditions where general management criteria and careful use of prophylactic and therapeutic drug treatments must interact to cope with the variety of presentations and problems are reviewed. These include: acute cerebral damage; anti-infective prophylaxis and therapy; cardiovascular emergencies; and problems of haemostasis. Each problem is analysed in such a way as to frame the pharmacological intervention in its broader context of the underlying (established or hypothesised) pathophysiology, with special attention being paid to those methodological issues which allow an appreciation of the degree of reliability of the data and the recommendations which appear to be practiced (often haphazardly) in intensive care units. The thorough review of the published literature provided (up to mid-1986) clearly shows that in this field the quality of randomised controlled and epidemiological studies is rather unsatisfactory. It would be highly beneficial to research and to clinical care if larger multicentric protocols and prospective epidemiological comparative investigations could be carried out to investigate more timely and adequately the variables which determine drug action, and the final outcome in the many subgroups of patients which must be considered in a proper stratification of intensive care unit populations.

Critical Care↗
PubMed1986

Pharmacokinetics of teicoplanin in patients on continuous ambulatory peritoneal dialysis.

We have studied the pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). Although teicoplanin was eliminated in the peritoneal fluid, relatively little was recovered (6.8 +/- 1.2% of the given dose). The following values were obtained: elimination half-time 102-347 h; total body clearance 4.16-7.38 ml X h-1 X kg-1, peritoneal clearance 0.31-0.37 ml X h-1 X kg-1. Because the elimination of teicoplanin is about four times less in patients undergoing CAPD compared with subjects with normal renal function, the dose of teicoplanin should be reduced appropriately in such cases.

Adult↗
PubMed1986

Experimental model for pharmacokinetic studies during continuous peritoneal dialysis in the rabbit.

An experimental model permitting continuous peritoneal dialysis in rabbits, very close to continuous ambulatory peritoneal dialysis (CAPD) as performed in humans, is described. Animals were carefully monitored before and during dialysis for plasma, urine, and dialysate biochemical parameters, and electrocardiogram, body temperature, weight, and white cell count in dialysate. Dialysis was performed successfully for 21 days without failure. Difficulties in setting up the final model are reported. The suitability of the model for pharmacokinetic and pharmacodynamic studies was borne out by administering atenolol (i.v. before CADP, i.v. after one week of CAPD, and i.p. one week later) and analyzing the findings.

Animals↗
PubMed1986

The effect of chronic oral ketoconazole on in vivo drug metabolism in the rat.

To verify the potential in vivo effects of ketoconazole, an antifungal agent with a wide spectrum of activity, on liver function, caffeine and phenytoin were chosen as probes for hepatic oxidative drug metabolism. Chronic treatment with ketoconazole (80 mg/kg oral) in the rat did not affect both pharmacokinetic profile of probes and a few biochemical parameters related to liver functions. These results indicate that further specific hepatic drug-metabolizing monoxygenase activities responsible to ketoconazole are to be identified to explain ketoconazole-drug interactions reported in vivo.

Administration, Oral↗
PubMed1985

In vitro amiodarone protein binding and its interaction with warfarin.

The binding of amiodarone to human plasma protein and to bovine serum albumin was studied by three different methods, ultracentrifugation, equilibrium dialysis and fluorescence spectroscopy. The fraction of amiodarone bound to plasma protein amounted to 96.3%. The changes in the binding properties of 1-anilino-naphthalene-8-sulfonate for bovine serum albumin using warfarin and amiodarone as independent inhibitors were analyzed in terms of binding site specificity. The findings indicated that amiodarone and warfarin have two different binding sites on bovine serum albumin, so a noncompetitive inhibition mechanism was indicated. On the basis of our data we cannot exclude other mechanisms of interaction besides direct displacement of one drug by another; nevertheless, metabolite interference between amiodarone and coagulation cofactors may better explain the enhancement of warfarin's pharmacological action in association with amiodarone.

Amiodarone↗
PubMed1985

Elimination kinetics of thiopentone in mothers and their newborn infants.

The elimination kinetics of thiopentone was studied in 7 newborns delivered by Caesarean section and in their mothers who had received the drug for induction of anaesthesia. At delivery, 4-9 min after induction, drug concentrations in cord blood were half those in material blood. The mean half-life of thiopentone in the newborns was about double that in their mothers (15 vs 7 h) confirming a disposition similar to other barbiturates. For the first time renal clearance of thiopentone was estimated in the newborn; 0.074 ml/h/kg. Only 0.0007% (about 2 micrograms) of the maternal dose was recovered in the urine of newborns over 36 h. Pentobarbitone, an active metabolite, was not detected in any specimen. The findings demonstrate the reliability of current anaesthesiological technique (thiopentone-succinylcholine-oxygen) with minimal fetal exposure to the drug.

Cesarean Section↗
PubMed1985

Pharmacokinetics of theobromine and its metabolites in rabbits.

The pharmacokinetics of theobromine (3, 7-DMX) and its metabolites was investigated in detail in four male rabbits after bolus intravenous injection (4 mg/kg) of the compound. Apparent first-order rate constants for the metabolic processes involved in the formation of 3,7-DMX metabolites and their excretion in urine were calculated. Theobromine, 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX) were measured in blood and urine, and the other metabolites were determined only in urine. An appropriate model of 14 compartments is formulated to describe the disposition of 3,7-DMX and its metabolites.

Animals↗
PubMed1985

Caffeine distribution in acute toxic response among inbred mice.

The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.

Animals↗
PubMed1985

Quality control in antiepileptic drug monitoring in Italy.

Measurement of drug concentrations in physiological fluids is increasingly becoming part of the routine management of drug therapy, thus calling for particular care to ensure reliability and avoid misguided management. As part of a long-term national project to set up a network of hospitals where clinical chemists, pharmacists, and physicians could interact and evaluate their activities in connection with therapeutic drug monitoring, the results of a quality control scheme for antiepileptic drugs, which included 50 national hospital laboratories, are described here.

Anticonvulsants↗
PubMed1985

Caffeine disposition after oral administration to pregnant rats.

Caffeine disposition was studied over 24 h in rats on the 12th day of pregnancy given 80 mg/kg of drug as a single oral dose or in four divided doses every three hours. Peak blood levels of caffeine were reached at three hours after the single dose, and at 10 h (at half the previous value) after the first of the divided doses. At the end of the experiment both caffeine and its dimethylxanthine metabolites were higher in blood, amniotic fluid and fetuses after divided doses than after the single dose. Urinary excretion over 24 h was the same for the two groups. The overall conclusions underline that caffeine per se and not its metabolites are responsible for the teratogenic effects.

Administration, Oral↗
PubMed1985

Pharmacokinetics of theobromine in male rats in different traumatic conditions.

The pharmacokinetics of theobromine after four i.v. administrations was investigated in male rats submitted to an increasingly "stressing" experimental design. Calculated parameters agreed with those previously described. No difference was found between baseline and pathological conditions, or between dosing and sampling at different sites. The findings raise consistent objections about the general utility of widely applied small mammal trauma models.

Animals↗
PubMed1984

Kinetics and metabolism of theobromine in male rats.

On the basis of general pharmacological information (blood cells/plasma partition, plasma protein binding) and using HPLC as the principal analytical method, we investigated the kinetics and metabolism of theobromine (a caffeine metabolite) in male rats after a single dose and after a 2 week chronic application. Doses in both conditions varied between 1 and 100 mg/kg. In in vitro and in vivo the fraction of theobromine unbound to plasma proteins averaged 0.90 over a wide range of concentrations. No significant difference was found in the pharmacokinetic profile of the drug after acute or chronic treatment at different doses except for a reduction in the absorption rate constant as the dose increased. AUC values increased in proportion to the dose. The 2 treatment schedules were also similar as regards metabolism, at least 50% of the administered dose of theobromine being excreted unchanged, and 25% as 6-amino-5-[N-methyl- formylamino ]1-methyluracil. Only at the highest doses was there a tendency for theobromine to accumulate at the expense of its major metabolite (a uracil compound).

Animals↗
PubMed1984

Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits.

The kinetics and metabolism of theobromine (3,7- DMX ) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7- DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7- DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7- DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7- DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7- DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.

Animals↗