Dihydropteridine reductase and tyrosine hydroxylase activities in rat brain during development and senescence: a comparative study.
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Aging↗
Biomedical subjects
M Bonati
Publications and source records attributed to M Bonati.
Proceedings: Dihydropteridine reductase: enzyme characteristics, regional distribution and ontogenetic development.
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Animals↗
Mother's knowledge of, attitudes toward, and management of fever in preschool children in Italy.
BACKGROUND: We examined mothers' knowledge of, attitudes toward, and management of fever in their children. METHODS: Interviews of mothers of preschool children were performed using a structured questionnaire administered by interviewers with no specific medical competence. RESULTS: Of a total of 1,237 mothers who were interviewed, data were analyzed for the 707 mothers who had coped with a febrile episode in their children during the previous month. Of these, 59% were concerned about fever in their children and 17% were very worried. At the onset of fever, 48% of the mothers gave their child an antipyretic and 18% called the physician immediately. In logistic regression analysis, five variables were significantly associated with mothers' concern: the absence of previous information on the management of fever, temperature > 39 degrees C, an only child, mother's low educational level, and mother's residency in the south of Italy. For the request for a physician's visit, of the variables entered, the only explanatory ones were the mother's concern and the absence of previous information on the management of fever. CONCLUSIONS: These findings suggest that informing mothers on the definition, consequences, and treatment of fever can significantly improve their confidence in managing fever, as reflected by fewer requests for physicians' visits.
Child, Preschool↗
Pharmacokinetics of theophylline and its metabolites in rabbits.
The pharmacokinetics of theophylline (1,3-DMX) and its metabolites were investigated in detail in four male rabbits after bolus intravenous injection (12 mg/kg) of the compound. Theophylline was measured in blood and urine, and its metabolites were determined only in urine. Apparent first-order rate constants for the metabolic processes involved in the formation of 1,3-DMX metabolites and their excretion in urine were calculated. An appropriate 13-compartment model was formulated to describe the disposition of 1,3-DMX and its metabolites.
Animals↗
Pharmacokinetic and pharmacodynamic modelling of atenolol in rabbits maintained on continuous peritoneal dialysis.
The pharmacokinetic and pharmacodynamic profiles of atenolol were studied in adult male rabbits on continuous peritoneal dialysis given 3 mg/kg i.v. before and during renal failure. The average terminal elimination half-life for the drug was 2.5 h calculated from blood, dialysate or urinary data. This value increased about nine times in anuric conditions. Although atenolol was eliminated in the peritoneal fluid, the amount excreted was relatively low both in normal conditions and renal failure, respectively 0.6 and 7% of the administered dose. The pharmacokinetic model was extended by an "effect compartment", which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in atenolol blood concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean equilibration half-time of atenolol effect and blood concentrations was 0.7 and 1.5 h in normal and pathological states, respectively. The mean blood concentration required to produce 50% of heart rate fall was similar in both conditions, 0.23 mg/l. The nine-fold decrease of atenolol elimination in anuria was in good agreement with the increase in duration of the drug's effect, and was suitably described by the "effect model".
Animals↗
Bioavailability of oral isbufylline in rabbits.
The bioavailability of isbufylline was assessed in male rabbits given 12 mg/kg i.v. (intravenous) or per os (oral) according to a randomized design. The concentrations of unbound (fu = 54.0) isbufylline were considered in plasma as a function of time, after i.v. and oral administration. After oral administration in saline solution, a mean absolute oral bioavailability of 59.6% was calculated. The drug is rapidly absorbed and the comparison of the kinetic profiles after i.v. and per os administration, revealed a rapid elimination: t1/2 27.3 and 28.8 min respectively, and a total body clearance of 67.06 ml/min/kg. Urinary recovery 0-48 h accounted for less than 1% of the dose.
1-Methyl-3-isobutylxanthine↗
Placental transfer of theophylline in an in vitro closed perfusion system of human placenta isolated lobule.
Theophylline (TH) is a methylated xanthine widely used in the treatment of asthmatic pregnant women. Because of the scant available information on the transplacental profile, the time course of TH transfer was studied by an in vitro human placental perfusion. 6 placentas were perfused with Earle's enriched bicarbonate buffer for 180 min using recirculating maternal and fetal circuits. The physiological and biochemical properties of the tissue were well maintained. TH data were compared to those of antipyrine (AP), an usual marker in placental perfusions. The disappearance of TH from the maternal circuit was studied after administration of 15 mg/l in maternal perfusate. TH appeared in the fetal circuit within 5 min. Equilibrium was achieved in both circuits. TH fetomaternal mass ratio became constant (FMM = 0.45 +/- 0.01) after 80 min of perfusion and maternal to fetal clearance was 2.59 +/- 0.24 ml/min. About 16% of TH maternal dose was recovered in the tissue, while 18% appeared in fetal circulation. TH recovery was 89 +/- 9%. On the basis of our results, similar concentrations could be predicted in mother and fetus after maternal TH intake. The TH transfer profile is consistent with in vivo values reported in humans and animals at delivery.
Antipyrine↗
Pharmacokinetic and pharmacodynamic modelling of metoprolol in rabbits with liver failure.
The pharmacokinetic and pharmacodynamic profiles of metoprolol were studied in adult male rabbits given 3.2 mg/kg i.v. before and during liver failure. The partition of metoprolol between blood cells and plasma averaged 1.14 in both conditions. Plasma protein binding, concentration-independent, was 32% and 17% in normal and pathological status, respectively. With normal liver function the terminal elimination half-life for the drug was 0.54-0.96 h, rising to 1.0-2.1 h in liver failure. Differences of the same order were observed for total plasma drug clearance (average 3.7 vs 1.5 1/h/kg), MRT (0.77 vs 1.92 h), AUC (0.9 vs 2.2 mg h/l) and k10 (3.17 vs 1.80 h-1). Liver impairment did not affect the volume of distribution of the central compartment, the steady-state volume of distribution and the other intercompartmental rate constants. Although metoprolol was eliminated in the urine, the amount excreted was low (1.5% of the administered dose) in both conditions. The pharmacokinetic model was extended by an 'effect compartment', which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in metoprolol plasma concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean unbound plasma concentration producing 50% of this reduction was double during liver failure compared to normal condition (0.03 vs 0.07 mg/l), but the temporal aspects of drug equilibration with site of action were similar.
Animals↗
Clinical relevance of pharmacokinetics.
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Adrenergic beta-Antagonists↗
Clinical pharmacokinetics of cerebrospinal fluid.
The distribution of drugs into the cerebrospinal fluid has long been considered a challenging field of investigation in 2 major respects: (a) understanding how the physicochemical properties (molecular weight, pKa, plasma protein binding) of various molecules influence their movements across such a specific structure as the blood-brain barrier; and (b) defining the relationship between cerebrospinal fluid concentrations of various drugs and their central (side) effects. An attempt has been made to review the very dispersed information presently available to offer a clinically orientated picture of this area of pharmacokinetics. Drugs acting on the central nervous system (benzodiazepines, tricyclic antidepressants, anticonvulsants, opioids), antibacterial agents, cardiovascular drugs (beta-adrenoceptor blockers and digoxin), antineoplastic drugs (mainly methotrexate), and other miscellaneous agents (corticosteroids, cimetidine, methylxanthines) are reviewed. The available evidence seems to support the conclusion that only for methotrexate and antibacterial agents does knowledge of cerebrospinal fluid pharmacokinetics have direct therapeutic implications, while the mosaic of information available for other drugs does little more than provide a partially satisfactory picture.
Anti-Infective Agents↗
Interspecies comparison of in vivo caffeine pharmacokinetics in man, monkey, rabbit, rat, and mouse.
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Adult↗
Pharmacokinetic profile of theophylline in isolated perfused liver of rabbits at different ages. Development of drug-metabolizing activity during ontogenesis.
The ontogeny of the biotransformation of exogenous and endogenous compounds has been mostly studied using liver cells and microsomal fractions. We have used liver perfusion for the first time to characterize the development of the total P-450 cytochrome-dependent system in the rabbit, with theophylline (TH) as tool substance. Livers of 0- to 60-day-old rabbits were perfused with TH (10 micrograms/ml) for 3 hr. Metabolizing enzymes (cytochrome P-450), ATP, glutathione, and glycogen were measured in liver tissue after perfusion. Lactate dehydrogenase, glutamic-oxalacetic transaminase, glucose, and urea were assayed in the medium throughout perfusion. The pharmacokinetic profile of TH was determined. The activity of total cytochrome P-450, as well as the intrinsic unbound clearance and TH metabolites production, increased following a similar sigmoidal pattern and reached a plateau around 30-45 days of the postnatal development of rabbit liver. The perfused tissue showed no signs of age-related hepatic damage or toxic effects of TH. Thus, the results in perfused liver predict its metabolic capacity during ontogenesis.
Age Factors↗
Pharmacokinetics of theophylline in the newborn and adult rabbit. In vivo and isolated perfused liver approaches.
The isolated perfused liver technique is the in vitro system most nearly comparable to the intact liver for experimental investigations on drug metabolism. The model currently used employs liver from different species, but only adults. For the first time, we have set up an experimental investigation involving perfusion of the liver of newborn animals. Using theophylline (TH) as tool drug, an in vivo/in vitro and adult/newborn disposition study was made in the rabbit. After a 10 mg/kg dose iv to adult rabbits and ip to rabbits at birth, the pharmacokinetic profile of TH was analyzed during liver perfusion at comparable TH concentrations in the medium. A few biochemical variables were recorded. No age-related differences were observed in the release of glutamic-oxalacetic transaminase and lactate dehydrogenase over the perfusion time. O2 consumption was higher in adults than in newborns, in accordance with the lower metabolic capacity of the neonatal liver, supported by the lower values of cytochrome P-450, cytochrome c, and glutathione. In vivo and in vitro values were close in adults and newborns for half-life (average 5.2 vs. 5.4 and 27 vs. 35 hr, respectively) and intrinsic clearance of TH (13 vs. 11 and 0.032 vs. 0.021 ml/min). The qualitative and quantitative TH metabolic patterns in the medium and in vivo also were close in adult animals. Only unchanged TH was detected in newborn perfusate. The isolated perfused liver technique appears to offer a reliable model for studying the in vitro ontogeny of drug metabolism, and for making in vitro and in vivo physiological and pharmacological comparisons.
Aging↗
Placental transfer, tissue distribution, and pharmacokinetics of cyclosporine in the pregnant rabbit.
The disposition of cyclosporine during pregnancy is described for the first time using the pregnant rabbit model. After a detailed kinetic study, in which a 5 mg/kg dose of cyclosporine was used, the apparent tissue-to-blood partition coefficients were determined at steady state in six pregnant rabbits after a two-step infusion of cyclosporine for 8 hr at a mean arterial blood concentration of 1.25 mg/liter, detected by HPLC. Muscle and fat were major drug deposits, and the maternal kidney--site of considerable side effects--accumulated the highest concentration of the drug. Spleen, mammary gland, liver, lung, heart, bile, and adrenal gland showed intermediate ability to accumulate the drug. The whole fetus accumulated little cyclosporine, and the drug was not detectable in maternal and fetal brains and in the amniotic fluid. At delivery, the mean cyclosporine concentration in fetal blood was 0.07 mg/liter, amounting to 6% of the mother's concentration. It would appear that diffusional resistance governs the transfer of cyclosporine into brain and fetus. Although caution obviously must be applied in extrapolating experimental data to clinical situations, the present findings do suggest that: a) exposure of the fetus to cyclosporine is low at a high maternal steady-state concentration; and b) caution should be applied in suggesting breastfeeding by these patients, since cyclosporine was found in a considerable amount in the mammary gland.
Animals↗
[Vaccination today in Italy].
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Communicable Disease Control↗
[Drugs and pregnancy].
The need for further information on drug utilization patterns during pregnancy in different countries was assessed by reviewing literature by hand and computer searches. The resulting profile, from 13 identified studies, was that pregnant women used an average of 4.7 drugs. The most commonly ingested medications were vitamins and iron preparations (almost all women), analgesics, antiemetics and antacids. However, important variables (such as date of surveillance; country; size of involved population; habits; physiopathological and demographic characteristics), differently taken into account in each selected study, made it impossible to construct a comprehensive, detailed, up-to-date picture about drug utilization during pregnancy. The evaluation confirmed the need for and value of systematic permanent surveillance of drug utilization in pregnancy, so as to avoid the use of data obtained in widely differing contexts, times, and methods, in a field where knowledge is often based on scanty information.
Abnormalities, Drug-Induced↗
Pharmacokinetics of paraxanthine, one of the primary metabolites of caffeine, in the rat.
The pharmacokinetic of paraxanthine, one of the primary metabolites of caffeine, is described for the first time. Groups of adult male rats were given different doses of paraxanthine as iv bolus injections. Blood cell/plasma partition and the binding of the compound to rat plasma proteins (determined by equilibrium dialysis) were investigated. The fraction bound (15%) remained constant in the concentration range of 1-100 micrograms/ml. Partition was also constant over a wide range of doses. Up to the 10 mg/kg dose, the paraxanthine followed first order kinetics and blood concentrations vs. time data were described by a one-compartment, open model system. The mean half-life and elimination rate constant were 1 hr and 0.70 hr-1, respectively. The average apparent volume of distribution was 1.50 liters/kg and total clearance was 0.90 liter/hr/kg. After larger doses (15 and 30 mg/kg), kinetics were nonlinear. The area under the blood concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were shown. These findings indicate that in the rat paraxanthine is eliminated by a saturable process with an apparent Km of about 31 micrograms/ml and an apparent Vmax of about 0.40 micrograms/ml/min. Close estimates were obtained by two different methods of calculation. Our results suggest that the pharmacokinetic profile of paraxanthine could be important to understand the kinetics and the potential toxic effects of its parent compound, caffeine, in animals and man.
Animals↗