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Biomedical subjects

M Rocchetti

Publications and source records attributed to M Rocchetti.

At least 19 recordsLinked to original sources
PubMed1991

Efficiency of different criteria for selecting pharmacokinetic multiexponential equations.

Several statistical and empirical approaches have been proposed to select the multiexponential equation that best describes the time course of the plasma concentration of a drug. Recently, a new criterion (Ip) has been proposed according to which the model that best interprets a set of experimental data points is the one with the smallest area between the approximate confidence limits of estimated plasma concentration. We used large Montecarlo simulations to compare the ability of different selection criteria to select the correct model from data generated with an independent, normally distributed random error. The new criterion (Ip), Akaike's information criterion, the Schwartz test, and the F ratio test were studied. In this situation, the correct model was known and the performances of different selecting methods were assessed by examining their sensitivity to the number of exponential terms, the number of data points, and the size of the exponents in the true model. Mono-, bi-, and triexponential equations were studied. Overall mean percentages of right identification were 98.1 per cent for the new index, 82.8 per cent for Akaike's information criterion, 89.5 per cent for the Schwartz test, and 97.7 per cent for the F ratio test. The Akaike and Schwartz tests were not as efficient as the other tests with few (8-10) data points. The Ip and the F test raise the percentages of right identification of the model when the hybrid elimination rate macroconstants differ by at least a factor of four.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1990

The relationship between rate of venous sampling and visible frequency of hormone pulses.

In this paper, a stochastic model of episodic hormone secretion is used to quantify the effect of the sampling rate on the frequency of pulses that can be detected by objective computer methods in time series of plasma hormone concentrations. Occurrence times of secretion pulses are modeled as recurrent events, with interpulse intervals described by Erlang distributions. In this way, a variety of secretion patterns, ranging from Poisson events to periodic pulses, can be studied. The notion of visible and invisible pulses is introduced and the relationship between true pulses frequency and mean visible pulse frequency is analytically derived. It is shown that a given visible pulse frequency can correspond to two distinct true frequencies. In order to compensate for the 'invisibility error', an algorithm based on the analysis of the original series and its undersampled subsets is proposed and the derived computer program is tested on simulated and clinical data.

Algorithms↗
PubMed1989

Metabolism and disposition of intravenously administered acetyl-L-carnitine in healthy volunteers.

The pharmacokinetics of acetyl-L-carnitine hydrochloride were investigated in 6 healthy volunteers of both sexes after i.v. injection of 500 mg of the drug, expressed as inner salt. Plasma concentrations and urinary excretion of acetyl-L-carnitine (A), L-carnitine (B) and total acid soluble L-carnitine fraction were evaluated over a period lasting from 24 h before to 48 h after the administration. Plasma concentrations of A increased quickly after administration and then declined reaching base values within 12 h. Conversely, plasma concentrations of B rose more slowly, reaching a peak in 30-60 min, and then declined to base values within 24 h. Most of the injected dose of acetyl-L-carnitine was recovered in the urine during the first 24 h after administration as B and A. Mean renal clearance of both A and B during the first 12 h after injection was higher than the base values, suggesting the presence of a saturable tubular reabsorption process which may counterbalance major changes occurring in plasma concentrations of L-carnitine pattern.

Acetylcarnitine↗
PubMed1988

D-optimal design applied to binding saturation curves of an enkephalin analog in rat brain.

The D-optimal design, a minimal sample design that minimizes the volume of the joint confidence region for the parameters, was used to evaluate binding parameters in a saturation curve with a view to reducing the number of experimental points without loosing accuracy in binding parameter estimates. Binding saturation experiments were performed in rat brain crude membrane preparations with the opioid mu-selective ligand [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), using a sequential procedure. The first experiment consisted of a wide-range saturation curve, which confirmed that [3H]-DAGO binds only one class of specific sites and non-specific sites, and gave information on the experimental range and a first estimate of binding affinity (Ka), capacity (Bmax) and non-specific constant (k). On this basis the D-optimal design was computed and sequential experiments were performed each covering a wide-range traditional saturation curve, the D-optimal design and a splitting of the D-optimal design with the addition of 2 points (+/- 15% of the central point). No appreciable differences were obtained with these designs in parameter estimates and their accuracy. Thus sequential experiments based on D-optimal design seem a valid method for accurate determination of binding parameters, using far fewer points with no loss in parameter estimation accuracy.

Animals↗
PubMed1988

Evaluation of pulse-detection algorithms by computer simulation of hormone secretion.

A versatile method is presented for generating synthetic hormonal time series, containing peaks at known locations, to be used to objectively evaluate both the false-negative (F-) and false-positive (F+) statistical error rates of computerized pulse-detection algorithms. Synthetic data are generated by assuming hormone secretion to occur as a succession of instantaneous release pulses, distributed as Poisson events, separated by quiescent intervals. The pulses are convolved to simulate cumulation of consecutive events and clearance of the hormone. Randomly generated errors, corresponding in magnitude to typical experimental measurement error, are then added to the convolved series. The choice of different values for simulation parameters (e.g., frequency and amplitude of pulses) allows one to emulate some typical physiological patterns of hormone secretion for luteinizing hormone, growth hormone, and thyrotropin or other hormones. Various subsets can be extracted from a simulated time series to study the effect of sampling frequency on the detection of pulses. We show that in sampled series the "observable frequency" of pulses is less than the true nominal frequency. Methods for evaluating pulse-detection algorithms and expressing the results are presented. Simulations of LH secretion were analyzed with the program DETECT. We show that minimizing F+ error rates only might lead to excessively high F- rates. A proper choice of sampling frequency and program probability levels can be made to provide acceptable F+ and F- error rates for various patterns of hormone secretion.

Algorithms↗
PubMed1986

The rate of N-demethylation of N,N-dimethylanilines and N-methylanilines by rat-liver microsomes is related to their first ionization potential, their lipophilicity and to a steric bulk factor.

The N-demethylation of a series of 12 p-substituted N,N-dimethylanilines, nine m-substituted N,N-dimethylanilines, one o-substituted N,N-dimethylaniline and four p-substituted N-methylanilines by rat-liver microsomes was studied. For each compound, the apparent Vmax and Km values were determined and these parameters were correlated with their electronic, lipophilicity and steric bulk parameters reported in the literature. Multi-parameter linear regression analysis showed a good correlation between log Vmax and these parameters for the p-substituted N,N,-dimethylanilines. A lower degree of correlation was observed with the meta-substituted N,N-dimethylanilines.

Aniline Compounds↗
PubMed1983

Morphine tissue levels and reduction of gastrointestinal transit in rats. Correlation supports primary action site in the gut.

Overnight-fasted male rats given a single dose of tritium-labeled morphine either intraperitoneally or intravenously were fed a charcoal test meal by stomach tube. The drug remaining in tissues was assayed by liquid scintillation counting of thin-layer chromatograms from homogenates, and gastrointestinal transit was tested by measuring the portion of the small intestine traversed by charcoal in 5 min. Morphine, 0.15 mg/kg, given intraperitoneally either 10 min or 30 min before testing substantially reduced gastrointestinal transit (to 23% and 55% of drug-free controls, respectively), and produced maximum drug levels 5 min after administration in small intestine longitudinal muscle with attached myenteric plexus (500 +/- 42 ng/g, mean +/- SE, n = 4). Intact small intestine, plasma, and brain, respectively, contained decreasing drug concentrations that, in the latter, never exceeded 2%-3% of that in longitudinal muscle. Rats receiving 0.15 mg/kg morphine intravenously presented only minor and short-lived inhibition of gastrointestinal transit that was significantly below (approximately 35%) that of drug-free controls at 10 min, but not 30 min, after drug administration. Morphine levels in the brain and plasma of these rats were up to five times higher, and in the intact small intestine longitudinal muscle were up to 20 times lower than in intraperitoneally treated rats. Morphine concentration in the tissues assayed was plotted against the effect on gastrointestinal transit at the same interval for individual rats regardless of dose, administration route, and observation time: data analysis, in small intestine longitudinal muscle, but not in the brain or plasma, indicated a highly significant correlation and fitting of computer-generated curves described by a currently accepted equation according to the receptor occupation theory of drug response. In view of these findings, and of the complete prevention by the "peripherally selective" narcotic antagonist N-methyl naloxone of gastrointestinal transit inhibition after an intravenous analgesic dose of morphine (1 mg/kg), the investigated animal model is consistent with the primary role of a gut-located action site in opiate-induced constipation.

Animals↗
PubMed1982

Pharmacokinetics of VP16-213 given by different administration methods.

Plasma pharmacokinetics of VP16-213 were investigated after a 30-60 min infusion in 14 adult patients and six children. In adult the elimination half-life (T1/2 beta), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05 +/- 0.67 h, 26.8 +1- 2.4 ml/min/m2, and 15.7 +1- 1.8 l/m2; in children 3.37 +/- 0.5 h, 39.34 +1- 6.6 ml/min m2, and 9.97 +/- 3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20-30% of the dose. In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose. Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m2/24h) were around 2-5 micrograms/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.

Administration, Oral↗
PubMed1982

The simulated randomization test.

Non-parametric statistical methods have been the subject of renewed interest. They are particularly useful in the behavioral sciences as they can be applied to a large class of distributions, and because the investigator is not forced into making any erroneous assumptions about a Gaussian distribution for the parent population or about equal variances in the contrasted groups. The randomization test is the most powerful non-parametric test [1] but it is rarely used because it calls for a prohibitive amount of computation. However, two tools now available make it more feasible: simulation and high-speed computer calculations. This test's importance lies in the extremely simple logic by which it is set up. The program described here is written in BASIC language for a microcomputer and carries out an approximate randomization test using a simulated distribution instead of the entire distribution. This version is slightly less powerful, a small price to pay for reducing the enormous calculation capacity otherwise required.

Computers↗
PubMed1982

SPBS: statistical programs for biological sciences. Minicomputer software for applying routine biostatistical methods.

The main routine statistical analyses can be carried out from start to finish on a minicomputer with basic language capability and greater than or equal to 32000 bytes of random access memory. However, no statistical software packs for minicomputers are ever complete enough for exhaustive analysis of most problems. Taking account of the requirements of statistical models, this paper gives an outline of how to set up a program. Examples are given from the package of statistical programs developed at this institute. The advantages and disadvantages of making these analyses on minicomputers are discussed, in comparison with the use of statistical programs requiring large computers.

Biometry↗
PubMed1982

Walker carcinoma 256: a model for studies on tumor-induced anorexia and cachexia.

Data on anorexia and cachexia induced by Walker carcinoma 256 in Sprague-Dawley rats were analyzed in order to standardize an experimental model using a statistical (nondeterministical) procedure for assessing the efficacy of potential orexigenic agents. This model was characterized by a mean survival time of 14 +/- 1 days and by food intake and body weight loss starting from day 6 after tumor implantation. The complex course of cachexia was characterized by reduction in the weight of gastrocnemius muscle and epididymal adipose tissue, taken as representative sites of loss of proteins and lipids.

Adipose Tissue↗
PubMed1982

Species differences in the kinetics and metabolism of fenfluramine isomers.

After single oral doses of racemic fenfluramine to man and animals (male CD-COBS Sprague-Dawley rat, male CD1-COBS mice and male beagle dogs) plasma and/or brain concentrations of the d- and l-isomers and their deethylated metabolite were measured by gas-liquid chromatography. In rat and mouse d-fenfluramine had a longer half-life (T 1/2) and gave a larger area under the curve (AUC) than the l-isomer. These differences were consistent with stereoselective N-deethylation of l-fenfluramine. Thus, in both species the plasma and brain AUC of the l-metabolite were double that of the d-form. In man and dog slight or no differences were seen between te kinetic and metabolic profiles of the isomers. Comparison of the plasma concentrations time curve of fenfluramine showed slower elimination in man than in the other species. The T 1/2 of the d-isomer was 2.6 hr in rat, 2.5 +/- 0.2 hr in the dog. 4.3 hr in the mouse and 17.8 +/- 0.9 hr in man. The deethylated metabolite norfenfluramine was present in plasma or brain, or both, of all the species examined as a major metabolite of the drug. At the oral doses of racemic fenfluramine tested the ration of the AUC for d-norfenfluramine to d-fenfluramine was 4.4, 2.0, 0.8, 0.3, and the dog, rat man and mouse respectively. The T 1/2 of the metabolite was longer than that of the parent drug in all these species. Similar studies with d-fenfluramine indicated that its kinetic profile was identical to that of d-fenfluramine administered in the racemic form. The l-isomer therefore does not change the absorption, distribution and metabolism of the d-isomer which should be considered as the active form.

Adult↗
PubMedDate not supplied

NL-FIT: a microcomputer program for non-linear fitting.

A program for a microcomputer (HP 85) has been written using BASIC language. Given the analytical form of a model y: R leads to R the program computes the optimal parameters for non-linear least-squares fitting and gives information for its statistical evaluation. The program uses the Gauss-Newton algorithm with Marquardt's modification and other tricks. During the run a message is displayed if there is a high correlation between one or more couples of parameters to establish an interactive dialogue with the user on critical problems. The authors' aim was to make the program sufficiently quick and easy to use, efficient for a wide class of models and robust enough to deal with bad starting parameters.

Computers↗