Bilateral Internuclear Ophthalmoplegia as a Presenting Manifestation of Primary Sjögren's Syndrome.

Bilateral internuclear ophthalmoplegia has been linked with various pathological conditions of the central nervous system (CNS), such as multiple sclerosis, stroke, tumours, and brainstem inflammatory processes. Herein the authors report a case of a 45-year-old female patient who presented with diplopia due to bilateral internuclear ophthalmoplegia, with no evidence of brainstem lesion in brain magnetic resonance imaging (MRI) and was diagnosed with primary Sjögren's syndrome.

Pheochromocytoma crisis presenting with cardiogenic shock.

Pheochromocytoma is a catecholamine-secreting tumor of the adrenal glands whose typical presentation includes the triad of headache, palpitations, and diaphoresis. Pheochromocytoma crisis is an urgent medical condition whose diagnosis and management constitute a challenge for physicians. We present the case of a 55-year-old man who developed cardiogenic shock in the setting of a pheochromocytoma crisis. After stabilizing blood pressure with combined administration of α- and ß-blockers, the tumor was surgically removed. Our diagnostic and therapeutic challenges are discussed.

Clinical pharmacokinetics of the antitumor drug navelbine (5'-noranhydrovinblastine).

Eleven patients with advanced cancer received navelbine (15 mg/m2) as a single i.v. bolus injection. At least 1 week later, the patients were given a 2-fold increased dose of navelbine (30 mg/m2) and, for seven of them, the 30-mg/m2 dose was repeated after a delay longer than a week. After each administration, plasma and urine were collected for 72 h and monitored for navelbine concentration by radioimmunoassay. The comparison of dose-normalized plasma level profiles showed significant time dependence (P less than 0.05) in four of the seven assessable patients. Some patients also exhibited significant (P less than 0.05) nonlinear (dose dependent) kinetic profiles. Only 3 of the 10 appreciable patients were characterized by both time independent and linear profiles. However, the plasma concentration decay curves presented a triphasic shape similar to that obtained with other antitumor Vinca alkaloids and the data were consistent with a three-compartment pharmacokinetic model. The dose and/or time dependence evidenced for most of the patients did not result in marked changes in pharmacokinetic parameters among courses. The pharmacokinetics of navelbine were characterized by a high plasma clearance (0.27 to 1.49 liter.h-1.kg-1), a large distribution volume (8.2 to 48.2 liter.kg-1), and a long terminal half-life (22.1 to 67.8 h). Urine excretion was low (less than 7.9%). Thus, navelbine pharmacokinetics resembles that of other antitumor Vinca alkaloids.

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.

Pharmacokinetics and pharmacodynamics of nitrosourea fotemustine: a French cancer centre multicentric study.

The nitrosourea, fotemustine, was given intravenously in 1 h constant-rate infusion to 66 patients in a multicentric study to assess both fotemustine pharmacokinetic behaviour and the pharmacokinetic-pharmacodynamic relationships. Depending on the tumour type treated, two administration and sampling protocols were used: 100 mg/m2/week as a conventional dose (six samples, 44 patients) and 300-500 mg/m2/day as a high dose (10 samples, 22 patients). The 91 time-concentration curves were best described by either a one-(55) or a two-compartment (36) model, and their mean clearance values did not differ significantly (85.3 +/- 6.5 and 101.3 +/- 9.5 l/h, respectively, P = 0.1727). Fotemustine pharmacokinetics were not influenced by repeated treatment (time-independence) nor by dose level (dose-independence). The pharmacodynamic effect observed on white blood cell count was expressed by a logit regression model involving the area under the curve mainly and the total administered dose. White blood cell toxicity could be predicted as a function of the dose for a given patient with a known fotemustine clearance value.

A limited sampling strategy for the study of pirarubicin pharmacokinetics in humans.

Pirarubicin (4'-O-tetrahydropyranyldoxorubicin, THP-Adriamycin) is a new anthracycline antibiotic that has recently been developed because its reduced cardiac toxicity is associated with an antitumour efficacy similar to that of doxorubicin. Pirarubicin is characterised by strong haematological toxicity, which has been shown to be correlated with pharmacokinetic parameters, especially the area under the time-concentration curve. To obtain routine pharmacokinetic evaluations of pirarubicin for dose monitoring we developed a limited sampling strategy relying on three blood samples taken at the end of the infusion and at 12 and 24 h post-infusion. The characteristics of interindividual variability were assessed on the first courses of treatment performed in 18 patients; the model was then validated on 10 independent first courses of treatment performed in 10 other patients. The main pharmacokinetic parameters (half-lives, total volume of distribution, total plasma clearance) were estimated in the test group by maximum-likelihood estimation using all samples and by Bayesian estimation using three samples. The concordance between the two estimates was correct (the bias and precision for clearance were 2.3% and 12.1%, respectively), which shows that this limited sampling strategy can be used in routine drug monitoring.

Time dependency of adriamycin and adriamycinol kinetics.

Adriamycin was administered by IV injection to seven patients with various solid tumors at a dose of 30 mg/m2 during successive courses. Extraction was carried out by the SEP-PAK method for plasma and by solvents for urine. Plasma and urinary levels of adriamycin and adriamycinol were determined by high-performance liquid chromatography over 72-h period after injection. Pharmacokinetic parameters for adriamycin and adriamycinol were calculated for each course of treatment. The results show significant inter- and intra-individual variations in the kinetics and elimination of both compounds. The analysis of pharmacokinetic data reveals a wide variability in the fluctuations observed during the successive courses in different patients. This study confirms the time-dependency of ADR kinetics.

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.

Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation.

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.

Steady state pharmacokinetics of conventional versus controlled-release carbamazepine in patients with epilepsy.

The purpose of the present study was to compare the pharmacokinetic parameters of two carbamazepine (CBZ) tablet formulations (conventional (CBZ-CO) and controlled-release (CBZ-CR)) in patients with epilepsy receiving the drug as monotherapy or polytherapy. The absorption rate constant (Ka), steady-state volume of distribution (Vdss) and total clearance (CL) were computed with the APIS software using 31 blood level profiles from 23 patients who were divided into four groups: patients receiving CBZ-CO in polytherapy, the same patients switched to CBZ-CR in the same polytherapy conditions, patients receiving CBZ-CO in monotherapy and patients receiving CBZ-CR in monotherapy. The four groups were compared in order to assess the significance of differences in Ka, Vdss, CL and diurnal fluctuations of plasma CBZ concentration. The results show a significant decrease of the Ka in the CBZ-CR groups compared to the CBZ-CO groups, both on monotherapy and on polytherapy. The comparison between the monotherapy and polytherapy groups shows increases of Vdss and CL, both in CBZ-CO and CBZ-CR polytherapy groups. Dispersion of pharmacokinetic data was higher in patients on CBZ-CO; among patients on CBZ-CR, dispersion was lowest in the monotherapy group. Clinical improvement was found in four of eight patients switched from CBZ-CO to CBZ-CR. CBZ-CR is therefore a valuable alternative to CBZ-CO.

Effect of renal failure on the pharmacokinetics of ethyl loflazepate (Victan) in man.

The kinetics of ethyl loflazepate were studied in patients with various degrees of renal failure. A strong correlation was noted between urinary excretion of metabolite loflazepate and creatinine clearance. In contrast, elimination half-life and total plasma clearance of the sum of loflazepate + descarboxyloflazepate seemed to be independent of the degree of renal impairment. These results indicate the absence of a risk of accumulation of the 2 main and active metabolites of ethyl loflazepate in patients with renal failure.

Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers.

The pharmacokinetic behaviour of flunitrazepam and its main active metabolite, N-desmethyl flunitrazepam, was investigated in 12 patients with liver disease (cirrhosis or hepatitis) compared to 6 healthy volunteers. A gas-liquid chromatographic method allowing for simultaneous determination of flunitrazepam and N-desmethyl flunitrazepam in plasma samples was developed. The accuracy and the precision near the quantification limit of ca. 1 ng/ml were better than 5%. Plasma levels of flunitrazepam were not significantly altered by hepatic failure, whereas plasma levels of N-desmethyl flunitrazepam were lower in patients than in healthy subjects. Pharmacokinetic parameters did not differ significantly between healthy subjects and liver disease patients: the oral clearance was 3.5 +/- 0.8, 3.5 +/- 1.9 and 4.0 +/- 1.2 ml/min/kg, respectively in healthy subjects, patients with hepatitis and patients with cirrhosis. The apparent elimination half-life was 22 +/- 5 h in healthy subjects, 25 +/- 10 h in patients with hepatitis and 20 +/- 6 h in patients with cirrhosis. However, the expected increase of the drug free fraction during liver disease could decrease the therapeutic and toxic ranges of flunitrazepam in these patients.

Ursodeoxycholic acid modulates cyclosporin A oral absorption in liver transplant recipients.

The aim was to study the ursodeoxycholic acid (UDC) effect on the cyclosporin A (CsA) pharmacokinetics after oral administration of the microemulsion formulation Neoral (CsA-ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA-ME-induced toxicity. At entry into the study, 12 patients who underwent orthotopic liver transplantation received CsA-ME, for at least 6 months. They then received a cotreatment CsA-ME plus UDC (13.8 mg x kg(-1) x day(-1)) for three months. Blood concentrations of CsA were measured using a monoclonal antibody specific for the parent compound. The kinetic data were analysed by a mathematical model incorporating a time dependent rate coefficient for CsA intestinal absorption, before and after UDC treatment. Changes in serum markers of hepatic and renal injury were assessed. Individual serum bile acids were determined by chromatography. Serum levels of UDC increased from 3 to about 45% of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absorption. In the nine non-cholestatic patients, UDC reduced the absorption rate and the bioavailability of CsA without modifying the elimination rate constant of CsA and the CsA pre-drug levels. In contrast, in the three cholestatic patients, the bioavailability tended to be higher and the absorption rate faster when CsA was combined with UDC. UDC significantly decreased elevated gamma-glutamyl transferase and creatinine serum levels and induced some clinical improvements such as disappearance of headaches in four patients. In conclusion, a 3-month UDC treatment modifies CsA intestinal absorption without affecting CsA elimination rate constant. On the other hand, UDC supplementation appears to improve CsA tolerability.

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.

Population pharmacokinetics of mitoxantrone performed by a NONMEM method.

To date, the pharmacokinetics of mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2- hydroxyethyl)amino]ethyl]amino]anthraquinone) has been described either by an open two- or three-compartment model, showing high interindividual variability. In order to evaluate this variability, residual intraindividual variability, and measurement error, we carried out a population study. A sensitive HPLC method allowed analysis of blood samples drawn from 21 patients with breast cancer or acute nonlymphocytic leukemia. Individual data treatment (22 kinetics) using weighted nonlinear least squares regression confirmed the huge interindividual variability whatever the administration protocol of mitoxantrone: bi- or tri-exponential models fitted the data. The NONMEM population method used herein describes all concentration-time curves by a single three-compartment model, considering biphasic kinetics as fragmentary data. Residual intraindividual variability was 21.4%. Population mean values (+/- interindividual SD) of clearance, terminal half-life, and total volume of distribution were, respectively, 23.40 (+/- 10.76) L/h, 46.87 (+/- 12.18) h, and 385.49 (+/- 196.60) L. These results are of particular interest in clinical routines to calculate dosage regimens by Bayesian estimation methods.

Application of Bayesian estimation for the prediction of an appropriate dosage regimen of amikacin.

A Bayesian approach was developed to determine an amikacin dosage regimen to achieve the desired plasma concentrations for each patient. Statistical characteristics of pharmacokinetic parameters were first evaluated in a group of patients (reference population), which when combined with three individual plasma concentrations of drug led to a Bayesian estimation of individual pharmacokinetic parameters. By using these parameters, an individual dosage regimen was then established to avoid residual and peak amikacin concentrations of up to 3 and 25 micrograms/mL, respectively. In a test group of 33 patients, adapted amikacin dosage regimens ranged from 4 to 43 mg/kg/d, with schedules requiring up to four infusions per day. Infusion time varied from 40 min to 4 h. These differences in drug administration protocol result from the wide interindividual variability of amikacin pharmacokinetic parameters. Performance of the developed methodology was evaluated by computing bias and precision of the estimated total body clearance and of the trough and peak amikacin concentrations that were reached after dosage regimen determinations.

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.

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.

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.