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Biomedical subjects

R Urso

Publications and source records attributed to R Urso.

At least 55 records · Page 3Linked to original sources
PubMed1986

MODDIS: a microcomputer program for model discrimination.

A computer program for a microcomputer (HP 86) is presented to discriminate between different models and to design new experiments for model discrimination. By a non-linear fitting algorithm a set of experimental data is fitted with different models suggested by the user. The parameters characterizing each model are estimated by minimizing the sum of squared residuals; different criteria are used to test the choice between two or more models at different levels of probability and the smallest number of additional experiments required for discrimination is computed. If discrimination is not achieved a direct search method is used to find the local maxima of the divergence (or information for discrimination) over a user-chosen domain of independent variables (x R'''). The x value corresponding to the absolute maximum of the divergence is the best choice to run a new experiment for discrimination.

Biometry↗
PubMed1986

Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function.

Etoposide (VP16) pharmacokinetics was investigated in three groups of cancer patients: a control group of 18 patients with renal and hepatic function tests in the normal range; a group of 8 patients with renal insufficiency; and a group of 15 patients with abnormal hepatic function. In the control group plasma clearance (Clp), volume of distribution (Vd), and elimination half-life (t1/2 beta) of VP16 were, respectively, 22.8 +/- 1.0 (SE) ml/min/m2, 11.4 +/- 0.8 liters/m2, and 5.6 +/- 0.4 h. In patients with renal insufficiency Clp was 12.8 +/- 1.1 ml/min/m2, Vd was 20.8 +/- 4.9 liters/m2, and t1/2 beta was 19.2 +/- 4.7 h. A statistically significant correlation (P = 0.0000001) was found between VP16 Clp and creatinine clearance. In 12 of 15 patients with abnormal liver tests Clp, Vd, and t1/2 beta were, respectively, 27.9 +/- 2.7 ml/min/m2, 12.4 +/- 1.5 liters/m2, and 5.4 +/- 0.6 h and are thus similar to those of the control group. In the other three cases with abnormal liver function VP16 plasma levels were very low. In these cases VP16 t1/2 beta values were similar (5.1, 4.4, and 5.1 h) whereas Clp values (320, 87, and 96 ml/min/m2) and Vd values (142, 33, and 42 liters/m2) were much larger than in controls. These results suggest that VP16 doses should be reduced in patients with renal function impairment but not necessarily in patients with liver impairment. The high VP16 Vd and Clp values found in a subset of patients with liver impairment require further elucidation.

Adult↗
PubMed1986

Comparative bioavailability of aspirin from buffered, enteric-coated and plain preparations.

The bioavailability and pharmacokinetics of acetylsalicylic acid were studied in 6 volunteers, under a cross-over design, using plain compressed aspirin, two buffered preparations and an enteric-coated tablet. Absorption, calculated from urinary excretion, was complete for all the formulations. The buffered forms gave higher peak concentrations and AUC for acetylsalicylic acid than the other forms. Absorption from the enteric-coated tablet was the slowest. Acetylsalicylic acid was not measurable in plasma (less than 0.1 micrograms/ml) at any time in 3 subjects after plain and in 2 after enteric-coated aspirin. Acetylsalicylic acid was no longer measurable in plasma after 4 hours, irrespective of the preparation given.

Administration, Oral↗
PubMed1985

Ionization constants and partition coefficients of 1-arylpiperazine derivatives.

The ionization constant (pKa) and liposolubilities (log P) of fourteen 1-arylpiperazines were determined by n-octanol/buffer partition. pKa varied little across the entire series. Log P values ranged from less than 1 to about 2 for the highly lipophilic derivatives of the preset series. The results are discussed in relation to the extent to which these derivatives, known to be centrally active, may enter the brain.

Buffers↗
PubMed1985

Kinetic and pharmacological studies on estazolam in mice and man.

After i.v. and oral doses of estazolam (5 mg/kg) to mice, the drug was rapidly cleared with a beta half-life (t1/2 beta) of 0.7 h. The active metabolite, 1-oxo-estazolam, was present in traces in mouse plasma and brain. Its elimination t1/2 (beta), determined after i.v. injection of 1-oxo-estazolam (5 mg/kg) to mice, was similar to that of the parent drug in both plasma and brain. After a single oral dose of estazolam (4 mg) to four human volunteers the drug was rapidly absorbed and reached maximum plasma concentrations in one to three hours. Elimination t1/2 of estazolam in humans was 19 h. The metabolite was undetectable in human plasma after either single or multiple doses of estazolam. These results, together with the finding that 1-oxo-estazolam was less effective than estazolam, in terms of ED50 and brain concentrations necessary to antagonize leptazol convulsions and disrupt rota-rod performance in mice, indicate that the metabolite does not contribute significantly to the pharmacological effects of its parent drug.

Administration, Oral↗
PubMed1985

Pharmacokinetics of teniposide in patients with ovarian cancer.

Pharmacokinetics of teniposide (VM26) after each of three doses were investigated by high-performance liquid chromatographic assay in eight patients with ovarian cancer with normal liver and renal functions. Treatment consisted of a first dose of 100 mg/m2 iv as a 1-hour infusion (Day 1), a second dose of 150 mg/m2 iv as a 1-hour infusion (Day 8), and a third dose of 150 mg/m2 as an approximately 1-day infusion (Day 22). Disappearance of VM26 from plasma followed a biexponential decay pattern. The mean terminal half-life (+/- SE) was 6.9 +/- 0.9 hours after the first dose, 6.1 +/- 0.7 hours after the second dose, and 9.7 +/- 1.4 hours after the third dose. VM26 levels in ascites were lower than those in plasma in the first hours after drug administration, but by 24 hours they were similar or slightly higher. Urinary elimination of VM26 as unchanged drug amounted to less than 10% of the dose.

Adult↗
PubMed1984

Pharmacokinetic study of VM26 given as a prolonged IV infusion to ovarian cancer patients.

Plasma levels of VM26 were assayed by HPLC in six ovarian cancer patients with normal renal and liver function who received the drugs as an initial 1-h IV infusion of 80 mg/m2 followed by a 24-h IV infusion of 120 mg/m2. These doses and infusion rates were chosen on the basis of mean VM26 clearance values found in a previous study, with the aim of reaching plasma steady-state levels of approximately 6 micrograms/ml in a short time. Plasma steady-state levels of 4-10 micrograms/ml, close to those predicted theoretically, were in fact attained at 4-9 h during the second, slower infusion. Mean half-lives and clearance values were 8.6 +/- 1.1 h and 0.78 +/- 0.08 l/h/m2. Six percent of the VM26 dose was recovered as unchanged drug in the urines collected up to 24 h after the end of infusion. The glucuronide of VM26 aglycone (4'-demethylepipodophyllotoxin) was identified in the urine of all patients, in amounts corresponding to about 8% of the drug dose.

Animals↗
PubMed1984

Amiodarone kinetics after single i.v. bolus and multiple dosing in healthy volunteers.

We studied three healthy volunteers after a single i.v. bolus of amiodarone, during 1 month of chronic oral dosing and after the discontinuation of the drug. Blood concentrations of amiodarone declined rapidly in a bi-exponential fashion after i.v. bolus. The terminal half-life ranged from 10 to 17 h; after discontinuation of chronic treatment the terminal half-lives were 8-21 days. The i.v. data, the trough levels during multiple dosing and the washout phase could be simultaneously fitted using a triexponential equation. The subjects were carefully monitored for cardiac and thyroid function. One subject had to stop taking amiodarone because of profound bradycardia. A reduction of serum TT3 and FT3 concentrations and an increase of serum rT3 and FT4 was found.

Adult↗
PubMed1984

Comparative kinetics of oral benz(a)anthracene, chrysene and triphenylene in rats: study with hydrocarbon mixtures.

Distribution and elimination of benz(a)anthracene (B(a)A) was compared in blood, liver, brain, parametrial adipose and mammary tissue of young female rats after oral administration of the polycyclic aromatic hydrocarbons (PAH) singly or in equimolar mixtures with chrysene (Ch) or triphenylene (Tr). The relative availability of B(a)A in tissues was not influenced by Ch or Tr in the mixture. However, the presence of B(a)A halved the relative availability of Tr and raised that of Ch. The relative availability of the three isomers decreased in the order Tr greater than B(a)A greater than Ch; this may be correlated to their solubility in water.

Adipose Tissue↗
PubMed1983

Polarographic assay of submicrogram quantities of cis-dichlorodiamineplatinum (II) in biological samples.

Differential pulse polarographic assay of the antineoplastic agent cis-dichlorodiamineplatinum II and its analogues was performed after acid oxidative hydrolysis (HClO4, HNO3, HCl) of biological samples (plasma, tissue homogenates, urine) and reaction with ethylenediamine. Platinum levels and kinetics were determined in blood and urine of patients with non-oat-cell lung carcinoma. Detection limit of the polarographic assay was 0.5 ng platinum; analytical error was +/- 3%. Levels of free cis-dichlorodiamineplatinum (II) in plasma fell in samples stored at -20 degrees C; the half-life of free drug was 38 h.

Carcinoma, Bronchogenic↗
PubMed1983

Bioavailability of drugs with long elimination half-lives.

Methods for estimating the bioavailability of drugs with long elimination half-lives are examined. Provided both absorption and disposition are linear a simple linear regression method is developed which can be used to calculate bioavailability in situations where only an incomplete estimate of the area under the curve (AUC) is available. The regression method and the traditional method of comparing the AUC following an oral dose to the AUC following an i.v. dose were applied to simulated data. It was found that the AUC ratio method works well as long as absorption is complete within the time over which the AUC is computed. The regression method is less precise than the AUC ratio method but is more accurate for drugs with long absorption half-lives. When applied to published data on a beta blocker the two methods produced comparable results. The bioavailability of amiodarone in three human subjects was calculated to be 0.20, 0.44 and 0.98 using the regression method with similar results from the ratio method. It is not possible to estimate the clearance of amiodarone from single dose data.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Amiloride pharmacokinetics in rat.

The kinetics of amiloride was investigated in plasma, urine, faeces and tissues of rats after oral (10 mg/kg) and i.v. (10 mg/kg bolus and 35 microg/h for 4-days infusion) administration. Initially the experimental data were analyzed by a multiexponential model, then a compartmental model was developed to describe the drug kinetics in plasma, urine, faeces and tissues after the i.v. bolus and the oral administration simultaneously. Aim of the model was also to predict the drug kinetics in plasma and tissues of rats after continuous i.v. infusion. The results of the prediction and the discrepancies between prediction and observed data allowed a deeper insight into the pharmacokinetics of amiloride.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of heptastigmine in rats.

Heptastigmine is a new long acting cholinesterase inhibitor that affects behaviour in a number of cognitive tests in animals. We have studied its pharmacokinetics in rats: plasma kinetics were evaluated after single intravenous dose (2 mg/kg), intramuscular (4 mg/kg) and oral (4 and 8 mg/kg) administration. Tissue distribution (heart, liver, kidney and brain) was studied after single intramuscular (4 mg/kg) and oral (8 mg/kg) administration. Plasma and tissue kinetics were also investigated after repeated oral doses (8 mg/kg b.i.d. for 7 days). Heptastigmine levels in plasma and tissues were determined using an HPLC method with an electrochemical detector. After a single dose, heptastigmine remained for a long time in plasma (the terminal half-life was about 12 h), distributed widely in tissues (the volume of distribution was about 61) and brain concentrations were very high (4-22 times those found in plasma). After repeated oral doses, the drug levels increased in plasma and, to a lesser extent, in liver and kidney.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of amiodarone in rats.

We studied the kinetics of amiodarone in the rat. After an intravenous dose of 50 mg/kg, the time-course of the drug concentrations was assessed by high-pressure liquid chromatography in blood and tissues up to 16 h. The drug disappeared from the blood with an elimination half-life (t1/2beta) of 514 min and distributed extensively into tissues [apparent volume of distribution (Vd)= 29.51 L/kg]. Concentrations were highest in liver, kidney, and heart, and lowest at all times in the brain. The highest concentrations were found within 5-30 min of administration. Amiodarone accumulated extensively in adipose tissue and reached a fat/blood concentration ratio of about 1,000 at 16 h. Single-pass rat liver perfusion experiments gave an hepatic extraction ratio of 0.49 and an intrinsic clearance of 5.48 ml/min. Amiodarone disappearance in rat liver recirculation experiments was biexponential, with a half-life of 58 min.

Amiodarone↗
PubMedDate not supplied

A short introduction to pharmacokinetics.

Phamacokinetics is proposed to study the absorption, the distribution, the biotransformations and the elimination of drugs in man and animals. A single kinetic profile may be well summarized by Cmax, Tmax, t 1/2 and AUC and, having more than one profile, 8 parameters at least, the mean and standard deviation of these parameters, may well summarize the drug kinetics in the whole population. A more carefull description of the data can be obtained interpolating and extrapolating the drug concentrations with some mathematical functions. These functions may be used to reduce all the data in a small set of parameters, or to verify if the hypotheses incorporated in the functions are confirmed by the observations. In the first case, we can say that the task is to get a simulation of the data, in the second to get a model. The functions used to interpolate and reduce the pharmacokinetic data are the multiexponential functions and the reference models are the compartmental models whose solutions are just the multiexponential functions. Using models, new meaningfull pharmacokinetic parameters may be defined which can be used to find relationships between the drug kinetic profile and the physiological process which drive the drug absorption, distribution and elimination. For example, compartmental models allow to define easily the clearance which is dependent on the drug elimination process, or the volume of distribution which depends on the drug distribution in the tissues. Models provide also an easy way to get an estimate of drug absorption after extravasculare drug administration (bioavailability). Model building is a complex multistep process where, experiment by experiment and simulation by simulation, new hypothesis are proven and disproven through a continuous interaction between the experimenter and the computer.

Algorithms↗