Biomedical subjects

A Iliadis

Publications and source records attributed to A Iliadis.

At least 19 recordsLinked to original sources

PubMed2004

Endoscopic snare resection of an intrapapillary pedunculated villous adenoma presenting as acute recurrent pancreatitis.

Tumors of the papillary region are an unusual and heterogeneous group of neoplasms that arise from the major papilla, the ampulla of Vater, and the peripapillary duodenum. Benign adenomas of the papilla of Vater are an increasingly recognized condition in those with familial adenomatous polyposis syndromes as well as sporadic cases. Papillary adenoma is a recognized but rare cause of acute pancreatitis. We describe a patient who presented with acute recurrent pancreatitis that was attributed to an intrapapillary pedunculated villous adenoma. Following diagnosis by endoscopic needle knife sphincterotomy and endoscopic retrograde cholangiopancreatography, endoscopic snare resection of the adenoma resulted in symptomatic improvement.

Acute Disease↗

PubMed2003

Endobiliary endoprosthesis without sphincterotomy for the treatment of biliary leakage.

Endoscopic retrograde cholangiopancreatography with biliary drainage is an effective therapeutic tool in the management of bile duct injuries associated with laparoscopic cholecystectomy. Placement of a stent or a nasobiliary drain in the common bile duct, or biliary sphincterotomy, is an effective treatment for bile leaks and obviates the need for otherwise complex biliary tract surgery. Although there are no controlled comparative trials, placement of a 7-, 8.5-, or 10-Fr biliary stent without sphincterotomy may cause the least morbidity and be the most comfortable nonoperative management option. We report a child who presented with a bile leak that occurred after laparoscopic cholecystectomy and was successfully treated with the placement of a biliary stent without sphincterotomy. To our knowledge, this is the second pediatric case of a bile leak successfully treated by endoprosthesis placement without sphincterotomy.

Amputation Stumps↗

PubMed2003

Double Dieulafoy-like lesion in the stomach.

Dieulafoy's lesion is an uncommon cause of major gastrointestinal bleeding and may be difficult to recognize. It consists of an arteriole that protrudes through a tiny mucosal defect usually within 6 cm of the gastroesophageal junction on the lesser curve of the stomach. Despite widespread awareness of this entity, it remains a diagnostic challenge for gastroenterologists because of its small size and hidden location. Emergency endoscopy is the most effective method of diagnosing the disease. We report a patient, with double Dieulafoy-like lesion, who was successfully treated endoscopically using hemostatic clip application. The characteristics of the Dieulafoy's lesion, its current diagnosis, and its treatment are discussed.

Aged↗

PubMed2003

Hemolysis caused by G-6PD deficiency after a difficult and prolonged therapeutic endoscopic retrograde cholangiopancreatography.

Endoscopic retrograde cholangiopancreatography (ERCP), together with its substantial therapeutic capabilities, carries a higher potential for complications than other endoscopic procedures. Common major complications specific to pancreaticobiliary instrumentation include pancreatitis, post-sphincterotomy hemorrhage, perforation, and cholangitis with or without systemic sepsis. Two patients underwent therapeutic ERCP for recurrent episodes of abdominal pain and elevation of hepatobiliary enzymes. Endoscopic sphincterotomy was difficult and prolonged. The calculi were successfully extracted by sweeping the choledochus with a balloon-tipped catheter or basket in both cases. The patients experienced postprocedure diffuse abdominal pain unassociated with nausea or vomiting. Laboratory data showed normal serum amylase and lipase 2, 6, and 18 h after the end of procedure, a fall in hematocrit level, and an increase of indirect bilirubin and lactic dehydrogenase. The abdominal pain subsided in 4 to 6 h. The hematocrit level remained stable during the next 3 days, and the patients were very well when discharged. Examination of glucose-6-phosphate dehydrogenase (G-6PD) enzyme levels in red cells 20 days later showed complete enzyme deficiency. This report highlights the importance of examining G-6PD deficiency in patients with post-ERCP abdominal pain, normal serum amylase and lipase, and laboratory findings of hemolysis.

Abdominal Pain↗

PubMed2001

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m(2)). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity.

Adolescent↗

PubMed2001

Optimizing drug regimens in cancer chemotherapy: a simulation study using a PK-PD model.

In cancer chemotherapy, it is important to design treatment strategies for drug protocols that ensure a desired rate of tumor cell kill without overdosing the host. Mathematical modeling was used for optimization in which we minimize the end value of the tumor cells while limiting toxicity by always maintaining the white blood cell count beyond a limit. The optimal solution for this is a mixture of an initial bolus application of drug followed by no drug and then continuous infusion that keeps the normal cell population at its lower limit while decreasing the tumor cell population.

Antineoplastic Agents↗

PubMed2001

Fractal volume of drug distribution: it scales proportionally to body mass.

PURPOSE: To develop the physiologically sound concept of fractal volume of drug distribution, vf, and evaluate its utility and applicability in interspecies pharmacokinetic scaling. METHODS: Estimates for vf of various drugs in different species were obtained from the relationship: vf = (v - Vpl)(Vap - Vpl)/V + Vpl where v is the total volume of the species (equivalent to its total mass assuming a uniform density Ig/mL), Vpl is the plasma volume of the species and Vap is the conventional volume of drug distribution. This equation was also used to calculate the fractal analogs of various volume terms of drug distribution (the volume of central compartment, Vc, the steady state volume of distribution, Vss, and the volume of distribution following pseudodistribution equilibrium, Vz). The calculated fractal volumes of drug distribution were correlated with body mass of different mammalian species and allometric exponents and coefficients were determined. RESULTS: The calculated values of vf for selected drugs in humans provided meaningful and physiologically sound estimates for the distribution of drugs in the human body. For all fractal volume terms utilized, the allometric exponents were found to be either one or close to unity. The estimates of the allometric coefficients were found to be in the interval (0,1). These decimal values correspond to a fixed fraction of the fractal volume term relative to body mass in each one of the species. CONCLUSIONS: Fractal volumes of drug distribution scale proportionally to mass. This confirms the theoretically expected relationship between volume and mass in mammalian species.

Animals↗

PubMed2001

Nonlinear dynamics and chaos theory: concepts and applications relevant to pharmacodynamics.

The theory of nonlinear dynamical systems (chaos theory), which deals with deterministic systems that exhibit a complicated, apparently random-looking behavior, has formed an interdisciplinary area of research and has affected almost every field of science in the last 20 years. Life sciences are one of the most applicable areas for the ideas of chaos because of the complexity of biological systems. It is widely appreciated that chaotic behavior dominates physiological systems. This is suggested by experimental studies and has also been encouraged by very successful modeling. Pharmacodynamics are very tightly associated with complex physiological processes, and the implications of this relation demand that the new approach of nonlinear dynamics should be adopted in greater extent in pharmacodynamic studies. This is necessary not only for the sake of more detailed study, but mainly because nonlinear dynamics suggest a whole new rationale, fundamentally different from the classic approach. In this work the basic principles of dynamical systems are presented and applications of nonlinear dynamics in topics relevant to drug research and especially to pharmacodynamics are reviewed. Special attention is focused on three major fields of physiological systems with great importance in pharmacotherapy, namely cardiovascular, central nervous, and endocrine systems, where tools and concepts from nonlinear dynamics have been applied.

Biopharmaceutics↗

PubMed2001

A stochastic model describes the heterogeneous pharmacokinetics of cyclosporin.

The pharmacokinetics of cyclosporin (CsA) are unusual because of several heterogeneous features which include the presence of more than one conformer, considerable accumulation in erythrocytes and lipoproteins, extensive plasma protein binding, distribution into deep tissues, biliary secretion and hepatic clearance involving a large number of metabolites. In this study, a stochastic compartmental model was developed to describe the heterogeneous elimination kinetics of CsA. This new approach relies on a probabilistic transfer model with a gamma distributed probability intensity coefficient for drug elimination. For comparative purposes both the stochastic model and compartmental deterministic models were fitted to real post infusion data from patients receiving CsA as a 2-hr intravenous infusion. The criteria for selecting the best model showed that the stochastic model, although simpler than the compartmental deterministic models, is more flexible and gives a better fit to the kinetic data of CsA than the compartmental deterministic models. The stochastic model with a random rate intensity coefficient adequately describes the heterogeneous pharmacokinetics of CsA.

Cyclosporine↗

PubMed2001

Information tools for exploratory data analysis in population pharmacokinetics.

For a group of individuals, population pharmacokinetic studies describe the interindividual variability through a statistical distribution. These studies conducted during the drug development serve as a useful marker of the safety of the drug, provide information that might be decisive for future experiments and, in a clinical context, help establish guidelines for optimal use in each patient. As complementary tools to the existing statistical and graphical techniques for population pharmacokinetic data analysis, indexes derived from information theory were used to select the most appropriate modelfor the statistical distribution, to detect atypical individuals, and to screen influential covariates. The rationale for using these indexes is shown using simulated and real data.

Humans↗

PubMed2001

New approach for accurate simulation of human pharmacokinetics in an in vitro pharmacodynamic model: application to ciprofloxacin.

An in vitro pharmacodynamic model using a disposable dialyser unit and computer-controlled devices was developed. Feedback control of peristaltic pump flow rates is used to maintain constant flow rates, thus avoiding the problem of the modification of the physical properties of the tubing that generally occurs. Fast equilibrium is obtained with capillaries, which allows simulation of the same kinetic profile in the central and the peripheral compartments. Thus, more accurate simulation of plasma, extracapillary fluid or whole tissue kinetics can be performed. Our model was validated by simulation of a 30 min infusion of a 200 mg dose, and of an oral administration of a 500 mg dose of ciprofloxacin.

Administration, Oral↗

PubMed2001

Diazepam poisoning with one-month monitoring of diazepam and nordiazepam blood levels.

A 54-y-old man ingested 2 g of bulk laboratory diazepam and was treated with activated charcoal, enhanced diuresis and flumazenil infusion. The treatment resulted in awakening, but the patient had drowsiness, dysarthria, diplopia, and dizziness for 9 d. Blood levels of diazepam and its main metabolite, nordiazepam, were obtained for 1 mo. The half-lives in this benzodiazepine overdose were longer than those seen with therapeutic doses. Benzodiazepines should not be readministrated when patients awake after suicide attempts.

Anti-Anxiety Agents↗

PubMed2001

Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo.

We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield was achieved by either transfecting cells with human TP gene (A. Evrard et al., Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d-Ino), a modulator providing the tumors with TP cofactor deoxyribose 1-phosphate (J. Ciccolini et al., Clin. Cancer Res., 6: 1529-1535, 2000). The purpose of the present work was to study the effects of a combined modulation (TP gene transfer + use of d-Ino) on the sensitivity to FUra of the LS174T human colorectal cell line. Results showed a near 4000 times increase of cell sensitivity in vitro after double (genetic + biochemical) modulation. This potentiation of tumor response was accompanied by a total change in the FUra anabolic pathway with a 5000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and longer inhibition of thymidylate synthase, and 300% augmentation of DNA damage. Besides, whereas thymidine failed to inhibit FUra cytotoxicity in LS174T wild-type cells, the potentiation of the antitumor activity observed in the modulating regimen was partly reversed by thymidine, indicative of thymidylate synthase as the main drug target. The impact of this double modulation was next investigated in xenograft-bearing nude mice. Results showed that whereas FUra alone was completely ineffective on wild-type tumor growth, the size of TP-transfected tumors in animals treated with the FUra/d-Ino combination was reduced by 80% (P < 0.05). Our results suggest that FUra exhibits stronger antiproliferative activity when activated via TP through the DNA pathway and that high tumoral TP activity therefore leads to enhanced sensitivity to fluoropyrimidines.

Animals↗

PubMed2000

Non-linear regression analysis with errors in both variables: estimation of co-operative binding parameters.

Four different parameter estimation criteria, the geometric mean functional relationship (GMFR), the maximum likelihood (ML), the perpendicular least-squares (PLS) and the non-linear weighted least squares (WLS), were used to fit a model to the observed data when both regression variables were subject to error. Performances of these criteria were evaluated by fitting the co-operative drug-protein binding Hill model on simulated data containing errors in both variables. Six types of data were simulated with known variances. Comparison of the criteria was done by evaluating the bias, the relative standard deviation (S.D.) and the root-mean-squared error (RMSE), between estimated and true parameter values. Results show that (1) for data with correlated errors, all criteria perform poorly; in particular, the GMFR and ML criteria. For data with uncorrelated errors, all criteria perform equally well with regard to the RMSE. (2) Use of GMFR and ML lead to lower values for S.D. but higher biases compared with WLS and PLS. (3) WLS performs less well when equal dispersion is applied to the two observed variables.

Binding Sites↗

PubMed2000

Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity mathematical model.

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that can minimize the tumor burden while limiting toxicity at the level of the white blood cells. The main result is that the optimal drug administration is an initial high-dose chemotherapy up to saturation of constraints associated with normal cell toxicity and a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were used in a feasibility study. Simulations with the optimized protocol showed better performances than usual clinical protocols. Model-based optimal drug doses provide for greater cytoreduction, while limiting the risk of unacceptable toxicity.

Antineoplastic Agents↗

PubMed1999

A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients.

Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhibitor. A number of studies have highlighted a correlation between hematologic toxicity and pharmacokinetic or physiological parameters. Other studies have also suggested that the anti-tumor response could be related to the plasma etoposide concentration. Therefore, it would seem of interest to individualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the patient. A total of 34 patients (54 kinetics) received VP16 at various dose regimens, with doses ranging between 30 and 200 mg and infusion times varying between 0.5 and 2 h. The statistical characteristics of the pharmacokinetic parameters were assessed from the first courses of treatment performed in 23/34 patients; then the following three-sample protocol was designed: the end of the infusion and 5 and 24 h after the start of the infusion. For validation of the model the main pharmacokinetic parameters (clearance, half-lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and by Bayesian estimation (BE) using the three sampling times designed. Statistical comparison showed a good concordance between ML and BE estimates (the bias for clearance was -1.72%). The limited-sampling strategy presented herein can thus be used for accurate estimation of VP16 pharmacokinetic parameters.

Adult↗

PubMed1999

An alternative method for the estimation of the terminal slope when a few data points are available.

Phase plane plots are graphical expressions for differential equations plotting the state derivative dc/dt versus the state c. Using these plots, we developed a novel method for the estimation of the terminal slope from time-concentration data. The values of the derivatives used for the construction of the phase plane plots were calculated by two different methods of numerical differentiation. The first method (D1) is based on the classical calculation of slope of the line connecting two successive data points. The alternative method (D2) relies on an initial second-order polynomial interpolation utilizing three successive data points followed by the calculation of the derivative at each one of the concentration values. A forced-through-zero linear regression of the phase plane plot data is used to derive an estimate for the slope. For comparative purposes, the standard approach based on the semilogarithmic plot was also applied. For a hypothetical drug absorbed by first-order process into a one-compartment model, simulated time-concentration data disturbed by a Gaussian zero mean random error with various coefficients of variation were generated. Various sampling schedules, with two, three, four, or five data points, were utilized for the estimation of the terminal slope. Performances of the proposed methods on simulated data were expressed by means of root-mean-squared error, bias, and standard deviation. In all cases, D2 was superior to D1. The D2 method outperforms the standard method in that it furnishes estimates closer to the real values in all cases when two data points and in most cases when three data points were used. All methods behave similarly when four or five data points were used.

Pharmacokinetics↗

PubMed1997

[Bayesian estimation of pharmacokinetic parameters of etoposide].

Studies of the relationships between the pharmacokinetics of a drug and its pharmacodynamics could significantly improve chemotherapy efficacy. However, despite their proven value, pharmacokinetic studies sometimes appear as cumbersome and difficult procedures. The bayesian approach associated with an optimal sampling time strategy (OST) allows the determination of the pharmacokinetic parameters of a drug with a smaller number of blood samples compared with that required by the classic maximum likelihood estimation (MLE). Therefore, the bayesian approach may lead to a less discomfort to the patients and less work for the medical staff. Such a method was developed to determine the individual pharmacokinetic parameters of etoposide (VP16). First, the statistical characteristics of the pharmacokinetic parameters were evaluated in 14 courses from 14 patients. Then, based on these results, a three-sample strategy was developed. Validation of this methodology was performed in 7 new patients and evaluated by computing bias and precision. The performance of the developed methodology shows that it could successfully be applied for the determination of VP16 pharmacokinetic parameters.

Adult↗