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Biomedical subjects

M Bonati

Publications and source records attributed to M Bonati.

At least 19 recordsLinked to original sources
PubMed1992

In situ perfusion in the rabbit: effects of different umbilical flow rates on placental transfer of compounds.

The effects of different umbilical flow rates on the placental transfer of compounds were studied in order to optimize an in situ placental perfusion model in the rabbit for establishing the most suitable perfusion flow rate range and assessing alterations in the placental architecture related to the umbilical flow. Placental transfer of a tool compound theophylline (TH) at different umbilical flow rates was compared with that of antipyrine (AP), the commonly used indicator of placental exchange, in maternal arterial drug steady-state conditions after a two-step infusion program. Placentas of six rabbits were perfused for 250 min with Earle's enriched bicarbonate buffer at 0.5, 1, 1.5, 2, 3, and 4 mL/min flow rates. Plasma and placental perfusate effluent biochemical parameters, gas exchange, body temperature, and electrocardiogram were recorded. Umbilical arterial perfusion pressure was controlled throughout the experiments. A detailed pharmacokinetic analysis of unbound maternal plasma, perfusate TH, and AP concentrations was made. Placental clearance of TH and AP rose up to the 3 mL/min flow rate and then remained constant. Placental clearance was linear up to 2.0 mL/min for TH and 1.5 mL/min for AP. The umbilical flow rate limit was 1.76 +/- 0.29 mL/min for TH and 1.72 +/- 0.49 mL/min for AP. The clearance index was 0.71 +/- 0.04. The correlation between umbilical flow and perfusion pressure was linear, with mean values from 4 to 25 mmHg. Placental resistances did not change significantly at all flow rates with mean values between 6 and 9 mmHg/mL/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Placental perfusion. An overview of the literature.

Placental perfusion techniques are currently used to study not only the organ functions but also the transfer profile and metabolic pathway of different compounds. In view of the interest in the mechanism of transfer and potential adverse effects of compounds there are numerous publications on the topic, but no systematic picture is yet available. Thus an overview has been made of all studies published from 1966 to 1990 that use this experimental approach. Out of 359 computer-retrieved articles, 266 (74%) actually dealt with the target topic; 68 articles were added after a systematic hand search, so a total of 334 articles were analyzed. The distribution of papers per year was constant until 1980, and rose significantly thereafter. Animal studies using placental perfusion were performed either in situ or in vitro, whereas human investigations were mostly examined by in vitro perfusion techniques. Animal experiments were done on seven species, the guinea pig being the most widely used. The aims of all studies could be divided into five main categories: 132 studies researched the kinetics of compounds in the placenta; 100 studies investigated placental metabolism; methodology of perfusion was reported in 22 articles; and 49 studies examined physiological changes of placental variables. A clear increase in pharmacological studies was noted starting from 1986 (there were 31 such studies). Compounds studied were either endogenous or exogenous. Almost all endogenous compounds were investigated, some of them quite extensively (mainly hormones, angiotensin, glucose, and lactate). There seemed to be no preferential field for exogenous compounds (62 compounds could be assigned to 20 classes).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Monitoring of blood gas parameters and acid-base balance of pregnant and non-pregnant rabbits (Oryctolagus cuniculus) in routine experimental conditions.

Blood gas parameters and acid-base balance values were determined in adult pregnant New Zealand rabbits (Oryctolagus cuniculus) in standard laboratory housing conditions and during anaesthesia with an association of ketamine-chlorpromazine, administered before surgical procedures. All the variables were also studied in adult non-pregnant female, used as controls. No differences in pH, sO2c, O2Hb, COHb, sO2m and a-vDO2 were found between pregnant and non-pregnant rabbits in physiological conditions and during anaesthesia. Ketamine-chlorpromazine and pregnancy seemed to change the other parameters used to assess the acid-base balance and the oxygenation conditions. Anaesthesia affected only Hb, O2Ct, O2Cap, CcO2 and P50. The additive effect of pregnancy and anaesthesia modified pCO2, pO2, HCO3-, TCO2, BEb, SBC, BEecf, A-aDO2, RI, MetHb, RHb, CaO2 and CvO2. The patterns described are close to those of other species, suggesting the New Zealand rabbit might be a reliable animal model for monitoring selected variables.

Acid-Base Equilibrium↗
PubMed1992

Sexual dimorphism of the autonomic nervous system response to weight loss in obese patients.

The sex-related response of the sympathoadrenal system to very low calorie diet (VLCD) with sodium restriction has been studied in a group of 16 obese subjects (8 men; 8 women). Once in sodium balance obese men were different from women in respect to initial body weight, mean daily 4 h urinary excretion of epinephrine (E) and norepinephrine (NE) measured for 48 h. After 20 days of VLCD the weight loss was higher in men than women (P < 0.01), E excretion increased in men more than in women (P < 0.01), and was correlated with weight decrement (r = 0.78; P < 0.01). NE excretion decreased in a similar way in both sexes. The present findings demonstrate sexual dimorphism in catecholamine excretion during VLCD and provide further evidence of the relative autonomy of adrenomedullary secretion from sympathetic nervous system activity.

Adolescent↗
PubMed1992

Feasibility of a long-term low-sodium diet in mild hypertension.

The present study set out to assess the feasibility of long-term moderate dietary sodium restriction in patients with mild hypertension in general practice. After screening and a run-in phase of 6-8 weeks, a total of 77 previously undiagnosed mildly hypertensive patients were identified. Half of them were randomized to receive a few simple dietary instructions from their general practitioners in order to reduce salt usage; the others were randomized to receive no advice. The patients were followed up for 12 months with quarterly visits. A total of 56 patients (72.7%) completed the study, 26 on a low-sodium diet (LD) and 30 on their usual diet (UD). At each visit in the diet phase, patients provided 24h urine, which was analysed for volume and sodium concentration in order to assess their sodium intake. Blood pressure, heart the rate and body weight were recorded. The mean urinary sodium excretion for all diet phase visits overlapped in the two groups (177.0 +/- 32.9 vs. 169.3 +/- 49.4 mEq/24h respectively in the LD and UD groups). Nevertheless the mean systolic and diastolic blood pressures for all diet phase visits were significantly lower in the LD than in UD group (144.2 +/- 11.1/91.6 +/- 6.4 and 148.0 +/- 13.7/95.6 +/- 4.7 mmHg respectively, P less than 0.01). Our data suggest that it is not feasible at present to reduce sodium intake in mild hypertensives with simple and inexpensive dietary instructions, the only ones suitable for widespread application in general practice.

Adult↗
PubMed1992

Theophylline transfer across human placental cotyledon during in vitro dual perfusion.

In vitro placental perfusion is widely used to investigate the placental transfer of endogenous compounds and, to a lesser extent, that of drugs. The aim of this study was to assess the suitability and reliability of such in vitro systems for application on drug placental transfer studies. We investigated the time course of theophylline (TH) transfer, a drug frequently used in the perinatal period. Eight experiments were performed with maternal and fetal circuits maintained in an open system, perfusing placentas for 160 min with Earle's enriched bicarbonate buffer containing two test substances, antipyrine (AP), (80 mg/L) and creatinine (CR), (150 mg/L), and the tool drug TH (15 mg/L). All substances equilibrated in our system with times proportional to the chemical-physical characteristics of each compound, being the time required to reach the steady state 5 to 12 min for AP, 12 to 31 min for CR and 10 to 35 min for TH. AP and CR clearances were 2.94 +/- 0.33 and 0.83 +/- 0.26 mL/min, respectively. The transfer profile of TH was similar to that of AP and its clearance was 2.39 +/- 0.37 mL/min, with a clearance index of 0.80 +/- 0.11. Transfer percentages of TH are in agreement with in vivo values for both humans and animals, and with results obtained during in situ placental perfusion in the rabbit. Physiological conditions and biochemical properties of the tissue were well maintained throughout perfusion. Glucose consumption and lactate release were, respectively, 0.65 +/- 0.16 and 0.73 +/- 0.11 mumoles/min/g. Oxygen consumption was 5.29 +/- 1.32 mL/min/kg and oxygen transfer from the maternal to fetal circuit was 0.99 +/- 0.43 mL/min/kg. The findings support the reliability of this technique to study transplacental passage of drugs, and the relevance of such a model to obtain information concerning potential therapeutic or toxicologic effects of drugs during the last trimester of pregnancy.

Female↗
PubMed1991

Simultaneous determination of isbufylline and its major metabolites in rabbit blood and urine by reversed-phase high-performance liquid chromatography.

A sensitive high-performance liquid chromatographic assay for isbufylline and its major metabolites in rabbit blood and urine is described. After extraction, samples were eluted by a linear reversed-phase gradient. Specimens obtained after intravenous administration of isbufylline to rabbits were analysed to identify and subsequently quantify the potential metabolites. Using the ultraviolet absorption trace on the recorder as a reference, elution fractions were collected and analysed by mass spectrometry with the direct inlet system and gas chromatography-mass spectrometry after derivatization. Seven metabolites were identified and another five quantified. The method is specific, accurate, reproducible and recommended for pharmacokinetic studies.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Placental transfer of theophylline during in situ perfusion in the rabbit.

Many physiological changes take place during pregnancy, and the disposition profile of endogenous and exogenous compounds may change, too. Thus knowledge of the disposition pattern of a compound may be useful in relation to its therapeutic effect(s) and its potential toxicity on the fetus and the newborn. Because the amount of a compound received by the fetus is a product of placental transfer rate, and available maternal amount, and because it is difficult to control and evaluate the factors that may affect such a transfer in women, we set up an in situ perfused placental model in the rabbit. The reliability of the model was borne out by comparing the placental transfer of theophylline with antipyrine, a commonly used marker of placental exchange, at steady state after a two-step infusion at mean arterial plasma concentrations of 8 and 5 mg/L, respectively for theophylline and antipyrine. The rabbit placenta was perfused in situ with a modified Earle's buffer at a 1-mL/min flow rate. During perfusion, maternal plasma, placental perfusate, biochemical parameters, gas exchange, body temperature, and electrocardiogram were carefully monitored. The maternal plasma and perfusate drug concentrations over time were fitted by appropriate models and kinetic parameters were calculated. Umbilical vein/maternal artery concentration ratios reached equilibrium soon after the loading infusion was stopped for both drugs. Placental clearance averaged 0.62 and 0.77 mL/min for theophylline and antipyrine, respectively, and the clearance index of theophylline was 0.81 +/- 0.07. Although human and rabbit placentas are structurally dissimilar, the rabbit placenta perfused in situ appears to be a useful preparation for measuring the transfer processes and the related and governing factors, of different compounds.

Animals↗
PubMed1991

A computer filing system for drug use in a pregnancy consultation service.

A computerized database for documenting drug use in pregnancy was set up on a personal computer. Summaries of the information available from the literature on more than 700 drugs taken during pregnancy have already been entered and are currently in use. This reliable, cheap, handy, and personal system (the first available on the topic) may be a potentially useful instrument not only for drug consultation services, but for individual physicians, too.

Databases, Factual↗
PubMed1991

Changes in smoking and drinking behaviour before and during pregnancy in Italian mothers: implications for public health intervention. ICGDUP (Italian Collaborative Group on Drug Use in Pregnancy).

Cigarette and alcohol use before and during pregnancy were studied in 4966 Italian women who delivered single liveborn infants. Using a standardized questionnaire mothers were interviewed in the early postpartum period about pregnancy-related events. Data are part of the Drug Use in Pregnancy (DUP) Study, an international epidemiological co-operative survey conducted under the auspices of the World Health Organization, in 22 countries during 1989-1990. Italian pregnant smokers were women under 30 years of age with a middle-school education or less, and drinkers were 30 years of age and more with more than a middle-school education. When pregnancy was confirmed, most of them cut down smoking and drinking but more so for smoking than drinking: 12% stopped smoking and 6% stopped drinking. Less than 1% gave up both. The more the mother smoked during pregnancy the lower was the infant's birthweight and the association between reduced fetal growth and higher smoking level persisted after controlling for confounding variables. Only smoking habits were associated with delivery of small-for-gestational age babies. A large proportion of Italian women use alcohol and cigarettes before and during pregnancy. Smoking during pregnancy is an important preventable risk factor for the delivery of a small-for-gestational-age child. Thus it may be worth campaigning more vigorously to encourage women to give up smoking during pregnancy.

Adult↗
PubMed1991

Plasma protein binding of theophylline during development in the rabbit.

The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (THu), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). THu, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 microEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between THu and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.

Age Factors↗
PubMed1990

Placental transfer and tissue distribution of vitamin E in pregnant rabbits.

alpha-Tocopherol (vitamin E) is widely prescribed in neonatal intensive care units, in large doses and by different schedules, for the prevention of retrolental fibroplasia, intraventricular haemorrhage, bronchopulmonary dysplasia, and haemolytic anaemia. Since the efficacy of the drug in premature newborns seems related to early administration, the physicochemical characteristics of the drug itself and available formulations limit the major therapeutic aim of promptly raising levels of vitamin E in premature babies during the early hours of life. It has thus been suggested that vitamin E be given to the mother before delivery to produce higher drug concentrations in the newborn. To see whether this would work, the tissue distribution and transplacental transfer of vitamin E were studied in six pregnant rabbits at steady-state after an i.v. bolus + infusion to give a mean venous blood concentration of about 325 mumol l-1 of alpha-tocopherol acetate, corresponding to about 30 mumol l-1 of alpha-tocopherol. Endogenous levels were measured in six control pregnant rabbits. In treated animals alpha-tocopherol was increased in liver, spleen, placenta, lung, mammary gland, blood, and bile but not in brain, heart, fat, muscle or adrenals probably because distribution into these tissues is very slow. Vitamin E levels in the placenta of treated mothers were 15 times those of control rabbits, but the vitamin was not detectable in amniotic fluid and only very low levels were found in fetal blood. These findings do not indicate any advantage of giving mothers alpha-tocopherol acetate before delivery.

Animals↗
PubMed1990

Drug use in pregnancy: an overview of epidemiological (drug utilization) studies.

The need for further information on drug utilization patterns during pregnancy in different countries was assessed by reviewing literature obtained by hand and computer searches for the years 1960-1988. The 13 identified studies showed 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, the important variables taken into account differently in each study, such as date of surveillance, country, size of population, personal habits, and physiopathological and demographic characteristics, may it impossible to construct a comprehensive, detailed, up-to-date picture of drug utilization during pregnancy. The evaluation confirmed the need for systematic permanent surveillance of drug utilization in pregnancy, so as to avoid the use of data based on widely differing contexts, times and methods, in a field where knowledge is often derived from scanty information.

Drug Utilization↗
PubMed1990

Thiopental efficacy in phenobarbital-resistant neonatal seizures.

The successful treatment with thiopental (10 mg/kg, i.v.) of 9 severely asphyxiated newborns, under artificial ventilation, with neonatal seizures resistant to phenobarbital, is reported in this pilot study. The clinical and electroencephalogram control of seizures was prompt and resolute. No adverse effect on cardiovascular function (heart rate, blood pressure) was observed. The terminal half-life of thiopental averaged 9 h, the total plasma clearance 0.20 l/h/kg, and the steady-state volume of distribution 3.6 l/h/kg. The kinetic profile of the drug compared to phenobarbital and phenytoin in newborns suggests that its action is quicker and shorter lasting. Thus, from these findings, thiopental may offer a useful and handy approach for the safe and effective treatment of phenobarbital-resistant neonatal seizures.

Drug Evaluation↗