Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients

This phase I-II trial was designed to assess the effect of irinotecan on oxaliplatin pharmacokinetics and to determine the MDT of both drugs when administered in combination. Treatment was repeated every 2 weeks. Pharmacokinetic studies were performed on cycle 1 and 2 to assess the best sequence and detect any interaction between the two drugs. Thirty-four patients with advanced colorectal cancer were enrolled; 28 of them (82%) had liver involvement. The main toxicities were neutropenia and delayed diarrhea; 5 patients (14%) experienced febrile neutropenia. Dose-limiting toxicity was experienced at levels 1/2/3/4/5 by 4/10, 1/6, 3/6, 3/8, and 3/4 patients, respectively. Fifteen patients responded (2 CR; 13 PR) for an ORR of 44%. No pharmacokinetic interactions between irinotecan and oxaliplatin were detected. The recommended dose for future phase II trials is oxaliplatin 85 mg/m and irinotecan 180 mg/m2 on day 1 combined with 5FU/leucovorin according to the de Gramont regimen at days 2 and 3. Twenty-nine percent of patients underwent secondary hepatectomy with curative intent, and two of them are long-term disease-free survivors. It would appear that the dose and schedule defined by this trial could be proposed as front-line therapy for advanced colorectal carcinoma to establish rapid disease control and to permit patients to proceed to surgery.     

Population pharmacokinetics of short intravenous vinorelbine infusions in patients with metastatic breast cancer

Purpose To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients.Methods Vinorelbine was administered as infusions of 5–10 min at 15, 20 or 25 mg/m² to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method.Results Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V₁) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V₁ were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data.Conclusion This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.Abbreviations ALT Alanine amino transferase - AST Aspartate amino transferase - AUC Area under the concentration curve - BSA Body surface area - BW Body weight - CL Clearance - ISV Intersubject variability - LBW Lean body weight - OFV Objective function value - SAP Serum alkaline phosphatases - SCr Serum creatinine - V₁ Distribution volume     

Potential excursion and relative tension of muscles in the shoulder girdle: relevance to tendon transfers.

Muscles used for transfer ought to have adequate structural properties. The purpose of this study was to provide a database of potential excursion (muscle excursion without reference to connective tissue restraints) and relative tension (muscle physiologic cross-sectional area in percentage among a group) in shoulder girdle muscles. Thirteen muscles in 13 human cadavers aged 17 to 89 years at death were studied. Potential excursion ranged from 6.7 cm (supraspinatus) to 33. 9 cm (latissimus dorsi). Relative tension ranged from 1.7% (levator scapulae) to 20.9% (deltoid). Significant discrepancies were found between the properties of some of the muscles used as transfers around the shoulder and the properties of the muscles for which they are commonly used as substitutes. Despite the limitations of cadaveric studies and the fact that many other factors are involved in muscle transfers, this database of structural properties of shoulder girdle muscles may help when planning tendon transfers around the shoulder.     

Comparative binding of etretinate and acitretin to plasma proteins and erythrocytes.

The interactions of etretinate and its main metabolite acitretin with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows a quantitative estimation of the plasma and erythrocyte binding. Etretinate was extensively lipoprotein-bound (75% of plasma etretinate), with a binding constant for its main low density lipoprotein carrier of 40 x 10(6) M-1, accounting for 48% of the total plasma-bound drug. Acitretin was mainly albumin-bound (91% of plasma acitretin), with a binding constant of 0.7 x 10(6) M-1. The total plasma binding of both drugs was > 99% and, in blood, the fractions associated with erythrocytes were 14.5 and 8.1% of the total amount for etretinate and acitretin, respectively.     

Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance

Objective To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters.Methods Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM.Results A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL_max (plateau), TCL₅₀ (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL_max, TCL₅₀, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL_max was negatively related to plasma albumin, and TCL₅₀ was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD.Conclusion Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.     

Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy

Purpose: A population pharmacokinetic model was developed to describe dose-exposure relationships of methotrexate (MTX) in adults with lymphoid malignancy; this is in order to explore the interindividual variability in relationship with the different physiopathological variables. The final model was applied to the Bayesian estimation of MTX concentrations using two blood samples. Methods: Fifty-one patients receiving 136 courses of MTX (1–6 per patient) were included in this study. The data was analysed using NONMEM software. A linear two-compartment model with linear elimination best described the data. Setting mean parameters values and variabilities to population values, we obtained Bayesian prediction of MTX pharmacokinetic parameters and concentrations. The predictive performance was evaluated by comparing the Bayesian estimated and observed concentrations and the Bayesian estimated parameters with the individual final model estimated parameters. Results: The population pharmacokinetic parameters and the inter-subject variablities expressed as coefficient of variation were: the total body clearance CL, 7.1 l h⁻¹ (22%), the volume of the central and peripheral compartments V1, 25.1 l (22.5%), V2, 2.7 l (64%), respectively, and the transfer constant Q, 2.7 (51%) l h⁻¹. Inter-course variability was only significant on CL. Age and serum creatinine had significant effects on CL and was included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r2=0.85).     

Expanded indications for preperitoneal hernia repair: the high risk patient.

The medically compromised patient with an inguinal hernia (primary or recurrent) is often denied surgical intervention because of potential risk. We have treated hernias in 36 “extremely high risk” patients using the preperitoneal approach. Twenty-one patients (58 per cent) had a recurrent inguinal hernia after one or more previous repairs. Eighty per cent of the patients were over the age of 70 years; six of them also had significant chronic obstructive pulmonary disease.Preperitoneal inguinal herniorrhaphy was performed using spinal or epidural anesthesia in all cases. In eight of the patients with lung disease, the operation was performed with the patient's upper torso elevated 30 degrees. Prosthetic material was used in only two repairs (5 per cent). There were no deaths, no significant pulmonary complications, and no wound infections. All patients were discharged within 4 days, which seems acceptable when compared with the length of hospitalization for primary hernia repair under local anesthesia (2 days) and for major reconstruction of recurrent inguinal hernia (6 days).The preperitoneal approach seems safe and reliable in this group of patients, with its low morbidity and absent recurrence rate, especially in patients with recurrent hernias. Good regional anesthesia is essential and alternative patient positioning useful. This approach is recommended as safe in high risk patients who require hernia repair to prevent incarceration or obstruction.     

Gastric secretory effects of chloralose and ketamine anesthesia

Heidenhain pouches were constructed in five mongrel dogs weighing between 15 and 25 kg. Surgical anesthesia was accomplished by giving ketamine im and alphachloralose iv against a background of submaximal, maximal, and supermaximal histamine doses. Ketamine caused significant acid inhibition at all dose levels of histamine when compared to histamine alone. Chloralose caused no significant inhibition at the first dose of histamine in all animals tested and no significant inhibition in one dog at all four dose levels of histamine. At almost all doses of histamine, chloralose caused significantly less acid inhibition when compared to ketamine. Thus, chloralose anesthesia is suggested as a more suitable anesthetic in acutely studying gastric acid secretory changes, but still is not comparable to studying the awake unanesthetized animal.