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Biomedical subjects

G Bianchetti

Publications and source records attributed to G Bianchetti.

At least 37 records · Page 2Linked to original sources
PubMed1990

High-performance liquid and gas chromatographic methods for the determination of cicloprolol.

Two methods, one based on high-performance liquid chromatography (HPLC) and the other on gas chromatography (GC), were developed for the quantification of the partial adrenergic receptor antagonist cicloprolol. In the GC method, samples are cleaned up by back-extraction, then derivatized with heptafluorobutyric anhydride and separated on a capillary cross-linked methylsilicone column. This GC method is time-consuming but, with electron-capture detection, cicloprolol can be quantified at levels down to 1 ng/ml. The HPLC method, using a reversed ODS stationary phase and fluorimetric detection, is less sensitive (5 ng/ml) but, with a single-step extraction, is faster and simpler. The determination of cicloprolol in human blood samples by the two methods gave comparable results. Routine monitoring of cicloprolol can be done easily with the HPLC method, whereas the time-consuming GC method may be reserved for pharmacokinetic studies where late-sampled tubes, with low concentrations, must be analysed.

Adrenergic beta-Antagonists↗
PubMed1990

Betaxolol: a pilot study of its pharmacological and therapeutic properties in pregnancy.

Twenty two pregnant women with mild to moderate hypertension were treated with betaxolol (10-40 mg/day), a cardioselective beta adrenoceptor blocking agent. The analysis of the changes from the baseline confirmed the antihypertensive effect of the drug with a mean decrease in SBP of 11.8 mm Hg and in DBP of 8.3 mm Hg. A diastolic BP less than 90 mm Hg was obtained in 20 patients after the first day of therapy. Fetal safety, assessed by ultrasonography and cardiotocographic recording was excellent. The 22 mothers gave birth to 23 live born babies (one twin pregnancy). Mean Apgar scores were 8.3 and 9.1 at 1 and 5 min. Only 1 newborn had an Apgar score less than 7. Three newborns suffered from fetal distress and 1 from threat for causes not related to therapy. At 9 months follow-up, all 23 babies were in good health. These data suggest that betaxolol is effective in reducing maternal blood pressure without any deleterious effect on the foetus and the newborn.

Adolescent↗
PubMed1990

Placental transfer and perinatal pharmacokinetics of betaxolol.

Betaxolol levels in blood were monitored in the perinatal period in 28 pregnant hypertensive women and in their babies. In the mothers betaxolol concentrations at delivery ranged from less than 1 to 115 ng.ml-1 after doses of 10 to 40 mg.day-1. The apparent blood half-life was 15.6 to 22.1 h mean (19 h). Umbilical cord levels indicated a rapid equilibrium between fetal and maternal units (ratio 0.93) within few hours after dosing. Milk betaxolol concentrations, measured in few cases, exceeded those in blood by a factor of 3. Amniotic fluid concentrations were similar to those observed in maternal venous blood and umbilical cord blood. In neonates, the blood betaxolol half-life ranged from 14.8 to 38.5 h, with a definite trend towards a negative correlation with gestational age. A 11-61% rise in the betaxolol concentration was observed in 64% of the neonates during the first 12 h of extrauterine life. The data indicate that betaxolol kinetics is not altered in pregnant women and they stress the need for careful and prolonged (72-96 h) intensive monitoring of neonates born to hypertensive mothers treated with beta-blocking agents.

Adult↗
PubMed1990

Pharmacodynamic without pharmacokinetic interaction between cicloprolol, a partial beta 1-adrenoceptor agonist, and digoxin in healthy subjects.

1. Cicloprolol is a partial beta 1-adrenoceptor agonist considered for the treatment of patients with coronary artery disease and impaired left ventricular function. In such patients, digoxin remains in widespread use. 2. We assessed the pharmacokinetic and pharmacodynamic interaction between oral cicloprolol 50 mg day-1 and oral digoxin 0.25 mg day-1 in 10 healthy male volunteers, using a double-blind, randomised protocol, during three 8 day periods. Digoxin was given alone during the first period to reach steady state; then digoxin was given with cicloprolol or placebo during the second and third periods, according to a cross-over design. 3. No significant adverse effects were observed. 4. The pharmacokinetics of digoxin were not different significantly at the end of the placebo-digoxin and cicloprolol-digoxin periods. 5. A significant increase in minimum heart rate and mean nocturnal heart rate, assessed by 24 h Holter recordings, was observed at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 57.1 +/- 3.2 beats min-1 vs 52.2 +/- 3.1 beats min-1, P less than 0.01; and 65.6 +/- 3.8 beats min-1 vs 59.9 +/- 3.9 beats min-1, P less than 0.01, respectively). 6. A significant increase in left ventricular ejection fraction and shortening fraction, assessed by echocardiography, was noted at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 66.4 +/- 1.4% vs 61.3 +/- 1.2%, P less than 0.05; and 37.0 +/- 1.1% vs 33.3 +/- 0.9%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Effect of cimetidine on the pharmacodynamics, pharmacokinetics and biotransformation of a single oral dose of alpidem.

Alpidem is a new imidazopyridine derivative acting as an anxiolytic which may be prescribed with H2 receptor antagonists in patients with peptic ulcer. An open trial design (cimetidine, 1 g daily for 22 days) was carried out in eight healthy subjects. Alpidem, 50 mg was administered orally at 09:00 prior to any treatment and on days 2 and 18 of the cimetidine treatment period. Antipyrine clearance was also determined before and on day 21. Under these experimental conditions, the inhibitory effect of cimetidine on the cyt. P-450 monooxygenase system has been demonstrated (reduced clearance of antipyrine and its three main urinary metabolites) but the plasma pharmacokinetics of alpidem and its three main plasma metabolites did not appear to be modified. Alpidem induced no sedative effect but there was an insignificant trend to impair slightly the psychometric tests 1 h post-drug by the combination with cimetidine. Pharmacokinetic and pharmacodynamic evaluations did not show significant interactions with cimetidine following alpidem 50 mg administration.

Administration, Oral↗
PubMed1989

Plasma protein binding of alpidem in healthy volunteers, in neonates and in liver or renal insufficiency.

The binding of alpidem, a new anxiolytic drug, has been studied in plasma from 6 healthy subjects, 12 patients with renal failure, 12 patients with liver cirrhosis and 12 chronic uraemics maintained on haemodialysis, as well as in 12 serum samples from the placental cord, to represent the situation in the newborn. The unbound fraction was 0.61% (healthy volunteers), 1.31% (newborns), 0.86% (cirrhotic patients), 0.72 (patients with renal failure), 0.70% (before haemodialysis) and 0.79% (after haemodialysis). Binding in the volunteers was significantly different from that in neonates and cirrhotics only. Alpidem became bound to isolated albumin (45 g.l-1) and alpha 1-acid glycoprotein (0.75 g.l-1) to 97.2% and 97.1%, respectively. The bound fraction of the drug in a mixture of two proteins was 99.1%. For alpidem, it appears that alpha 1-acid glycoprotein may balance the effect of any decrease in the albumin concentration.

Adult↗
PubMed1989

Zolpidem excretion in breast milk.

Five, lactating, healthy white women were treated with a single 20 mg tablet of zolpidem 3-4 days after the delivery of a full term baby. The drug was administered at 20.00 h, 30 min after dinner, and milk samples were collected before and 3, 13 and 16 h. Venous blood 5 ml was taken before and 1.5, 3, 13, 16 h after zolpidem administration. The apparent elimination half life, estimated from plasma zolpidem concentrations was 2.6 h. The amount of zolpidem excreted in the milk at 3 h ranged between 0.76 and 3.88 micrograms, which represented 0.004 to 0.019% of the administered dose; no detectable (below 0.5 ng/ml) zolpidem was found in the milk at subsequent sampling times. The ratio of the zolpidem concentrations in breast milk and plasma at 3 h was 0.13. The apparent breast milk clearance of zolpidem, calculated from the ratio of the total amount of zolpidem excreted in milk to its AUC in plasma was 1.48 ml/h. The results show that the excretion of zolpidem in human milk is very low (below 0.02%) and that most of it takes place during the first 3 h following drug intake.

Adult↗
PubMed1989

Pharmacokinetics of antihypertensive drugs in the neonatal period.

A consistent body of evidence indicates that in the preterm and full-term newborn drug disposition is reduced when compared to that of infants, grown-up children, and adults. Newborns are rarely treated directly with antihypertensive agents; however they can be exposed to the action of various antihypertensive drugs in utero and during their first week of extrauterine life in the case of hypertensive mothers treated through pregnancy. In such cases, the persistence of the antihypertensive agent during the first days of life may have important consequences on neonatal haemodynamics and on the function and the maturation of vital organs such as lungs and kidneys. The available information on the placental transfer and neonatal pharmacokinetics of alpha-methyldopa, clonidine, acebutolol, atenolol, betaxolol, metoprolol, propanolol, oxprenolol, and latetalol, are reviewed. Each product has its own pharmacokinetic characteristics which should influence, depending on the clinical situation, the therapeutic choice. In the presence of comparable efficacy, preference should be given to compounds with high bioavailability, eliminated mainly via metabolic degradation, with no active metabolites. In all cases, treatment should be discontinued 8-12 h before delivery.

Antihypertensive Agents↗
PubMed1989

[Open trial of betaxolol in the treatment of arterial hypertension in pregnancy, pilot study].

The efficacy and the safety of betaxolol (BTX), a cardio-selective adrenoceptor blocking agent with a long half life, was tested in 22 hypertensive pregnant women. BTX doses varied from 10 to 40 mg/day. BTX given as monotherapy (n = 19) or associated to dihydralazine (n = 3) led to a satisfactory control of arterial blood pressure (ABP). In the mother, the drug was very well tolerated. (table; see text) The fetal safety, evaluated by mean of cardiotocography and echography was also satisfactory. Fetal heart rythm was significantly slowed following first intake of BTX and remained stable until delivery; there was only one case of intra-uterine growth retardation pre-existing to the pharmacological treatment. Nine deliveries were ceasarian [fetal distress (n = 1); poor control ABPI (n = 1); obstetrical reasons (n = 7)]. Seventeen neonates were full-term and six were premature (twins included). The state of neonates at birth was very satisfactory (Apgar at 5 minutes greater than 9 in 21/23). Glycemia less than 1.66 mmoles/1 in two neonates, was normal within 24 to 48 hours. In conclusion, BTX was very efficacious in controlling increased blood pressure in pregnant women and its safety in the mother, the fetus and the newborn was very good.

Adolescent↗
PubMed1988

Plasma protein binding of zolpidem in liver and renal insufficiency.

Similar degree (65-66%) of binding of zolpidem (0.1 microgram/ml) was found with physiological concentrations of isolated human albumin (40 g/l) or alpha-1-acid glycoprotein (1 g/l). Zolpidem binding was studied in plasma from 6 healthy subjects, 12 patients with renal failure, 12 patients with liver cirrhosis and 12 chronic uremics maintained on hemodialysis as well as in 12 serum samples from the placental cord. The unbound fraction (mean +/- s.e.m.) was 8.1 +/- 0.2% (healthy volunteers), 10.8 +/- 0.4% (renal failure), 11.3 +/- 0.7% (liver cirrhosis); 14.9 +/- 1.0% (before hemodialysis); 9.8 +/- 0.4% (after hemodialysis) and 13.2 +/- 0.9% (placental cord). All values, except those after hemodialysis, were significantly different (Dunnett's test) from those of the volunteers. Hemodialysis significantly increased the binding of zolpidem in plasma. The kinetics of protein binding of zolpidem were investigated in plasma samples from 3 healthy subjects. The average number of binding sites was 1.83 x 10(-7) mol per gram protein and the average association constant was 4.49 x 10(5) M-1.

Adult↗
PubMed1988

Blood levels of progabide and its active metabolite in epileptic patients: relationships to the therapeutic outcome.

To assess the relationships between the efficacy and blood levels of progabide (PGB) and its active acidic metabolite (PGA) in epileptics, observations were carried out on 89 adult patients with epilepsy of different types and severity in two groups at Paris and Genoa. The Paris group received progabide in addition to other antiepileptic drugs for 6 to 12 months, whereas the Genoa group received a polytherapy for the first two months then a monotherapy with progabide alone for up to 22 months. Blood levels from monthly or bimonthly samples were significantly higher in both surveys when there was a satisfactory therapeutic response and levels were also higher in those receiving monotherapy suggesting a synergism among antiepileptic drugs. It is concluded that therapeutic drug monitoring of PGB and PGA blood concentrations may be a useful technique in optimizing progabide treatment in epileptic patients.

Adult↗
PubMed1987

Correlation between reversed-phase high-performance liquid chromatography and plasma protein binding.

As hydrophobic interactions are involved in both reversed-phase liquid chromatography and plasma protein binding, the relationship between retention time and binding was investigated experimentally in two series of compounds. For betaxolol and its O-alkyl analogues, the nature of the O-alkyl group strongly influences the retention time on a Spherisorb CN 5-microns column. With 0.03 M acetate buffer (pH 5.6)-acetonitrile (60:40) as the mobile phase, k' values increase from 1.8 to 8.3 with a concomitant increase in plasma protein binding from 0.5% (R = H) to 88.2% (R = cyclopentylmethyl). The relationship between the free fraction and log k' is sigmoidal. In the second example, structural changes in the propyl side-chain of alpidem (a new anxiolytic) lead to minor variations in the protein binding: 98.9 to 84.9%. This slight decrease with the more polar metabolite is correlated with a sharp decrease in the k' values from 14.7 to 0.94 on a Supelcosil LC 18 DB column. Based on retention times, it should be feasible to predict qualitatively, if not quantitatively in some instances, plasma protein binding in a series of structurally similar compounds.

Adrenergic beta-Antagonists↗
PubMed1987

[Treatment of patent ductus arteriosus in premature infants by indomethacin].

Over a 4-year period, 63 premature babies presenting with patent ductus arteriosus were treated with indomethacin at two different dosage levels (0.1 and 0.2 mg/kg). For all infants the permanent closure rate was 68% (56% with 0.1 mg/kg and 75% with 0.2 mg/kg - n.s.) and the positive response rate (i.e. permanent and transient closure) 84%. There was no difference between the two dosages in the incidence of side-effects, particularly on diuresis, and in mortality and morbidity rates; the overall mortality rate was 31%. Pharmacokinetic studies performed in 51 cases did not show any difference related to indomethacin dosage. The changes observed after 2 or 3 doses resulted from improvement in haemodynamics. This study confirms the effectiveness of indomethacin in the treatment of patent ductus arteriosus and suggests an advantage for the 0.2 mg/kg dose.

Diuresis↗
PubMed1986

Clonazepam pharmacokinetics and therapeutic efficacy in neonatal seizures.

Eighteen newborns (gestational age 28 to 42 weeks and post-natal age 0.5 to 44 days) suffering from convulsions not controlled by phenobarbital were treated with clonazepam 0.1 mg/kg (8 cases) or 0.2 mg/kg (10 cases) administered by slow intravenous infusion. The plasma half-lives in these "phenobarbital pretreated neonates' were of the same order of magnitude as those reported in adults (20-43 h). Post-natal age did affect clearance, which was 50-70% less than in adults and older children. At the end of the infusion period, plasma clonazepam ranged from 28 to 117 ng/ml in the 0.1 mg/kg group and from 99 to 380 ng/ml in the 0.2 mg/kg group. In the former an immediate therapeutic response was observed in 7 out of 8 cases, and in the latter a significant and somehow delayed effect on convulsion was present only in 6 cases. The data suggest that optimal therapeutic response might already have been achieved with the 0.1 mg/kg dose. Higher doses and toxic concentrations of clonazepam may be detrimental to complete control of seizures and may expose the newborn to an unnecessary risk of adverse events.

Adult↗
PubMed1986

Pharmacokinetics of betaxolol in middle aged patients.

The pharmacokinetics of betaxolol was studied in 8 middle-aged (40-60 years) subjects after oral (20 mg) and intravenous (10 mg) administration. The principal parameters were almost identical to those observed in young healthy volunteers. The recommended therapeutic regimen, a single daily dose of 20 mg, appears well suited for middle aged, hypertensive patients.

Administration, Oral↗
PubMed1986

To nurse when receiving acebutolol: is it dangerous for the neonate?

The concentrations of acebutolol and of its main active metabolite diacetolol in milk and plasma were studied in 7 hypertensive mothers treated with acebutolol, a cardioselective beta-adrenoceptor blocking agent. Clinical monitoring on their newborn babies was also done, as well as measurement of plasma level of the drug in them. The ratio between milk and plasma concentrations ranged from 1.9 to 9.2 for acebutolol and from 2.3 to 24.7 for diacetolol, and in any given milk sample, the diacetolol concentration was always higher than that of acebutolol. In a newborn infant, plasma concentrations of the two transplacentally acquired substances was raised when breast feeding started and remained high. Clinical signs of pharmacological beta-blockade were observed. Evaluation of the iatrogenic risk shows that pharmacologically active amounts of acebutolol might be received by a neonate if the daily maternal dosage exceeds 400 mg/day and/or renal function in the mother is impaired.

Acebutolol↗
PubMed1984

Determination of progabide and its main acid metabolite in biological fluids using high-performance liquid chromatography and electrochemical detection. Application to the measurement of blood/plasma partition ratio.

A method for the measurement in plasma, blood and urine of progabide, its main acid metabolite, and the corresponding benzophenone is described. This assay allows the determination of progabide and its acid metabolite for therapeutic drug monitoring, and with a minimum detectable concentration of 1-10 ng/ml for progabide and its acid metabolite, it is sensitive enough for pharmacokinetic studies. Progabide and its metabolites are extracted from biological samples with toluene at pH 4.5. Following reduction of the imine bond with sodium borohydride, the reduced drugs are back-extracted into an aqueous phase at acid pH and reextracted by diethyl ether at alkaline pH. Progabide, its acid metabolite and the benzophenone are separated by high-performance liquid chromatography using a 3-micron ODS column with a quaternary solvent mixture of methanol-acetonitrile-phosphate buffer (0.033 M, pH 5.5)-sodium chloride (1.5 M) (30:30:40:9, v/v), and detected electrochemically at a potential of +850 mV vs. an Ag/AgCl electrode. Antiepileptic drugs like carbamazepine, carbamazepine epoxide, phenytoin, valproic acid and ethosuximide do not interfere with the assay. Blood/plasma partition ratios of 0.69 and 0.55 for progabide and its acid metabolite, respectively, indicate that the former but not the latter is present in red blood cells.

Anticonvulsants↗