Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients.

INTRODUCTION: Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. MATERIALS AND METHODS: Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. RESULTS: Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p < 0.0001) and a polymorphism in the ABCG2 transporter (421C>A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01-2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05-1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03-1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. CONCLUSIONS: This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.

Validation of an HPLC-UV method for sorafenib determination in human plasma and application to cancer patients in routine clinical practice.

Sorafenib, a new oral multikinase inhibitor with antiangiogenic properties, has demonstrated preclinical and clinical activity against several tumor types. The aims of this study were to validate a method for the measurement of sorafenib in plasma from cancer patients, then to test this method in clinical practice. Following liquid-liquid extraction, the compounds were separated with gradient elution (on a C18 ultrasphere ODS column using a mobile phase of acetonitrile/20 mM ammonium acetate), then detected at 255 nm. The calibration was linear in the range 0.5-20 mg/L. Intra- and inter-assay precision was lower than 7 and 10%, respectively, at 0.5, 3 and 20 mg/L. Plasma sorafenib concentrations were measured in 22 cancer patients (99 samples). The mean trough sorafenib concentration (C(min)) and concentration at peak were 4.3+/-2.5 mg/L (n=68, CV=57.5%) and 6.2+/-3.0 mg/L (n=31, CV=47.5%), respectively. Mean sorafenib C(min) in eight patients who experienced grade 3 drug-related adverse events was approximately 1.5-fold greater than that observed in the remaining patients (7.7+/-3.6 mg/L vs. 4.4+/-2.4 mg/L, P=0.0083). In conclusion, the method was successfully used in routine practice to monitor plasma concentrations of sorafenib in cancer patients. Finally, large interindividual variability and higher exposure in patients experiencing severe toxicity support the need for therapeutic drug monitoring to ensure an optimal exposure to sorafenib.

[Parkinson's disease, progressive lumbar kyphosis and focal paraspinal myositis]. / Maladie de Parkinson, camptocormie et myosite focale paraspinale.

INTRODUCTION: The camptocormia (bent spine) is characterized by a severe forward flexion of the thoracolumbar spine which disappears in the supine position. Clinical case. We describe a typical case observed in a parkinsonian patient. The MRI, electromyogram and biopsy of the paraspinal muscles revealed a typical myositis pattern. DISCUSSION: This case, the sixth published to our knowledge, confirms that focal myositis is associated with the camptocormia in Parkinson's disease. Typically it is observed in male subjects, appearing 4 to 6 years after the onset of Parkinson's disease, in fluctuating patients treated by an association of L-Dopa and agonist. It appears quickly and becomes the most important symptom. Antiparkinsonian drugs are useless. CONCLUSION: This exceptional picture raises original pathophysiological and therapeutic questions. Systematic studies should be performed in order to detail the pathophysiological link between these 3 entities: Parkinson's disease, focal myositis and camptocormia.

Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients.

BACKGROUND: Correction of iron deficiency is critical in chronic hemodialysis patients, and intravenous administration is superior to the oral route in this goal. Recently, concern was raised that intravenous iron administration might promote infection in dialysis patients. METHODS: We reviewed the data from a recent prospective study of 985 patients in which no link between iron therapy and bacteremia had been found. We tested the potential role of the administration route of the iron (intravenous vs. oral), the weekly amount of iron administered and the administration rate on the risk for bacteremia in these patients. RESULTS: were 4-fold: in multivariate analysis, neither intravenous iron administration in the whole population nor the weekly amount of iron in the subgroup of i.v. iron-treated patients were significant risk factors for bacteremia; iron was not given more frequently intravenously in bacteremic than in non-bacteremic patients; among patients treated with intravenous iron, the frequency and the amount of iron administered were significantly higher in those who developed bacteremia than in those who did not; and in patients receiving i.v. iron, there was an increased risk of bacteremia associated with concurrent administration of erythropoietin, which was not observed in patients receiving iron orally. CONCLUSION: This study failed to demonstrate a significant association between intravenous iron administration and the risk of bacteremia in dialysis patients. However, there might be a slightly increased risk of bacteremia in patients given high-frequency, high-dose intravenous iron.

[One-year follow-up of a population of patients with angina. Factors influencing mortality and occurrence of cardiovascular events. Results of the ELAN study]. / Le devenir à un an d'une population de patients angineux. Facteurs influençant la mortalité et la survenue des événements cardiovasculaires. Les résultats de l'étude ELAN.

The ELAN (Etude longitudinale dans l'angor) study was carried out both to acquire better knowledge of the occurrence of major cardiovascular events (myocardial infarction, revascularization surgery, death) in patients followed up for angina pectoris, and to determine the factors influencing such events. A cohort of angina patients was formed in January 1997, and 3,284 patients were followed up by 488 French cardiologists during a one-year period. Of these 3,284 patients, 96 (29/1000) died; causes of death included underlying coronary heart disease in 31, sudden death in 8, other cardiac aetiologies in 35, and noncardiac causes in 22. Sixty-nine (21/1000) patients developed myocardial infarction, 240 (73/1000) underwent PTCA, and 119 (36/1000) underwent coronary bypass surgery. Factors associated with an increased risk of death were age, diabetes mellitus, heart failure and angina type, mixed and rest angina being associated with poorer prognosis compared to exertional angina. Infarction risk increased with age and a history of previous infarction. Analysis of therapeutic factors after adjustment for the above risk factors showed a beneficial effect of betablockers on both cardiovascular and all-cause mortality and of aspirin on all-cause mortality.

Selection of quality-of-life measures for a prevention trial: a psychometric analysis.

Quality-of-life (QoL) outcomes have become increasingly important in the evaluation of health interventions. The objective of the present study was to determine which of three generic QoL instruments was most suitable for use in an 8-year nutritional primary prevention trial. We compared the Duke Health Profile, the Nottingham Health Profile, and the Short Form Health Survey Questionnaire (SF36). We conducted the comparison in two stages: (1) a statistical analysis of data from a pilot study (n = 963) comparing the psychometric properties of the three instruments; and (2) an assessment of the practicality of the tools. With regard to psychometric properties, convergent validity was comparable for the three scales, and the correlation with Global Health Assessment ranged from 0.24 to 0.72. Discriminant validity was best for the SF36, with a difference between scores in healthy subjects and those with chronic disease in the range of 4.4 to 15.8 (scores could range from 0 to 100, where 100 indicates perfect health). Reproducibility was good for all three instruments, with a test-retest intraclass correlation coefficient of over 0.60 for most dimensions. DHP and SF36 performed best in terms of responsiveness. We judged the practicality of the three tools as satisfactory. We chose the SF36 for its high responsiveness. We also selected the Duke Health Profile for its practicality and favorable psychometric properties.

Effects of supplementation with a combination of antioxidant vitamins and trace elements, at nutritional doses, on biochemical indicators and markers of the antioxidant system in adult subjects.

OBJECTIVE: To test the impact of supplementation with nutritional doses of antioxidant nutrients on biochemical indicators of vitamin and trace element levels. DESIGN: A randomized double-blind trial was performed comparing two groups receiving daily either a combination of vitamins (beta-carotene, 6 mg; vitamin C, 120 mg; and vitamin E, 30 mg) and trace elements (zinc, 20 mg; and selenium, 100 micrograms); or a placebo. SUBJECTS: 401 subjects (166 males aged 45 to 60 years and 235 females aged to 35 to 60 years). MEASURE OF OUTCOME: Biological markers of vitamin and trace element status and free radical parameters were measured initially, 3 months, and 6 months after supplemention. RESULTS: Mean serum concentrations of alpha-tocopherol, vitamin C, beta-carotene, zinc and selenium increased significantly after 3 months of supplementation in the group receiving multivitamins associated with minerals. At baseline, 18.2% of the men and 5.1% of the women had low concentrations of serum vitamin C (< 20 mumol/l): 2.4% of the men and 17% of the women presented low concentrations of serum retinol (< 1.4 mumol/l): 18.7% of men and 10% of women had serum beta-carotene < 0.30 mumol/l. None of the study subjects had serum alpha-tocopherol concentrations below the limit cut-off point (< 9.3 mumol/l). Low serum zinc concentrations (< 10.7 mumol/l) were found in 15.1% of men and 23.8% of women. Low serum selenium concentrations (< 0.75 mumol/l) were found in 6% of men and 6.4% of women. A significant increase in plasma and red cell GPx activity was observed in groups receiving supplementation. No modifications were observed after 6 months of supplementation for malondyaldehyde. CONCLUSION: This study demonstrates the efficacy of an intake of antioxidant vitamins and trace elements, given at nutritional doses, on biochemical indicators of vitamin and trace elements status.

Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Minéraux AntioXydants Study.

The "SUpplementation en VItamines et MinérauxAntioXydants" (SU.VI.MAX) study is a randomized double-blind, placebo-controlled, primary prevention trial designed to test the efficacy of daily supplementation with antioxidant vitamins (vitamin C, 120 mg; vitamin E, 30 mg; and beta-carotene, 6 mg) and minerals (selenium, 100 micrograms; and zinc, 20 mg), at nutritional doses (one to three times the daily recommended dietary allowances), in reducing the frequency of major health problems in industrialized countries, and especially the main causes of premature death (cancers and cardiovascular diseases). The study involves 12,735 eligible subjects (women aged 35 to 60 years; men aged 45 to 60 years) included in 1994 in France. They will be followed up for 8 years. The objectives and the specific design of this intervention study are linked to its public health aim. The targeted population is the general population (not simply high-risk subjects) and the antioxidant agents tested are being administered at a level which is not pharmacologic and which may be attained by dietary intake of natural sources of these micronutrients and/or enriched foods. The amounts we are testing in the SU.VI.MAX study are those which, in observational studies have been associated with the lowest risk of diseases. This report presents the rationale and discusses the justification of the design, doses and combination of antioxidant micronutrients chosen in the SU.VI.MAX study.

Diet, antioxidant status, and smoking habits in French men.

The aim of this study was to assess the association between smoking, food consumption, and antioxidant vitamin intake and plasma indexes of oxidative stress and antioxidant defenses in French adults. Food and nutrient intakes of 459 healthy men aged 23-57 y were estimated by the diet history method and analyzed by smoking status. Plasma alpha-tocopherol, ascorbic acid, and carotenoids were measured as antioxidants and malondialdehyde, protein Schiff bases, and autoantibodies against malondialdehyde-protein adducts as oxidative stress indexes. Smokers ate less fruit and vegetables than nonsmokers, leading to lower vitamin E, vitamin C, and carotene intakes, even after adjustment for age, education, and marital status. Unlike vitamin E, plasma ascorbic acid and beta-carotene concentrations were reduced in smokers compared with nonsmokers and were inversely related to cigarette consumption. This difference remained significant after adjustment for alcohol and dietary intakes. Among the measured oxidative stress indexes, only Schiff base concentration was positively related to the number of cigarettes smoked. In our sample of French men, smoking had an adverse effect on antioxidant status; vitamin intakes were reduced in smokers and plasma antioxidant indexes were altered independently of dietary intakes. As in other countries, in France smokers require particular attention in terms of public health intervention.

Comparison of general anesthesia with and without lumbar epidural for total hip arthroplasty: effects of epidural block on hip arthroplasty.

STUDY OBJECTIVES: To determine whether lumbar epidural anesthesia, when combined with general anesthesia, decreases perioperative blood loss, the incidence of postoperative deep vein thrombosis (DVT), cardiac dysrhythmias, and ischemia in patients undergoing total hip arthroplasty (THA). DESIGN: Randomized, controlled study. SETTING: A university hospital. PATIENTS: 37 ASA physical status I, II, and III patients, undergoing elective THA. INTERVENTION: Patients were divided into two statistically comparable groups: Group GA = general anesthesia; Group CEGA = general anesthesia plus lumbar epidural anesthesia. All patients had 48-hour perioperative Holter monitoring, applied on admission, the day prior to surgery. In both groups, general anesthesia was induced with thiopental sodium and muscle relaxant, and maintained with oxygen, nitrous oxide, isoflurane, opioid, and muscle relaxant. Group B received lumbar epidural anesthesia with 10 ml 0.5% bupivacaine with 1:200,000 epinephrine prior to anesthesia induction. Blood loss was measured by suction bottle contents, sponge weights, and collection drainage. DVT was assessed with postoperative leg scanning, plethysmography, and venogram. MEASUREMENTS AND MAIN RESULTS: Intraoperative blood loss was less after combined epidural-general anesthesia (663.8 ml +/- 299.0 ml) than after general anesthesia alone (1,259.2 ml +/- 366.0 ml). The difference was found to be statistically significant (p < 0.00005). No difference was found between the two groups in postoperative blood loss, incidence of DVT, cardiac dysrhythmias, or ischemia. CONCLUSION: Combined regional-general anesthesia decreases intraoperative blood loss in THA, and thereby offers an advantage over general anesthesia alone.

Serum bupivacaine concentrations during continuous extrapleural infusion.

PURPOSE: To determine the rate of increase in serum bupivacaine concentration during continuous extrapleural infusion. METHODS: After thoracotomy for lobectomy under general anaesthesia, nine patients had an extrapleural catheter inserted, before chest closure, in a costovertebral gutter constructed surgically by lifting the parietal pleural. Bupivacaine 0.5% with epinephrine 1:200.000 was injected through the catheter as 0.3 ml.kg-1 bolus followed by 0.1 ml.kg-1.hr-1 for five days. Serum bupivacaine (free and total), albumin, alpha-1 acid glycoprotein concentrations were measured 15 min after injection and at 24 hr intervals for five days. Bupivacaine concentrations were determined by column liquid chromatography using solid phase extraction. Serum alpha-1 acid glycoprotein concentration was determined by nephelometry on QM 300 protein analyzer. Serum albumin concentration was determined by bromocresol green dye binding procedure on Hitachi 717 Autoanalyzer. RESULTS: A continuous elevation in total serum bupivacaine was observed, with an average value of 0.75 microgram.ml-1 on day 1 to 2.77 micrograms.ml-1 on day 4 (P < 0.05). There was no increase in postoperative free serum bupivacaine concentration; average value of 177 pcg.ml-1 on day 1 and 249 pcg.ml-1 on day 4 (P = 0.92). Postoperative serum alpha-1 acid glycoprotein concentration showed a steady rise with an average value of 0.94 microgram.ml-1 on day 1 and 1.47 micrograms.ml-1 on day 4 (P < 0.05). No change was observed in post-operative serum albumin with an average value of 31.4 g.l-1 on day 1 and 31.3 g.l-1 on day 4. CONCLUSION: Continuous extrapleural infusion of bupivacaine over five days after thoracotomy is associated with a steady increase in total serum bupivacaine concentration and no elevation in free serum bupivacaine concentration.

Comparative study of continuous extrapleural intercostal nerve block and lumbar epidural morphine in post-thoracotomy pain.

OBJECTIVES: To compare the efficacy of continuous extrapleural intercostal nerve block with bupivacaine 0.5% in 1:200,000 epinephrine and continuous lumbar epidural block with morphine in controlling post-thoracotomy pain and to measure serum bupivacaine concentrations during extrapleural infusion. DESIGN: A prospective, randomized, controlled trial. SETTING: St. Joseph's Hospital, Hamilton, Ont., a tertiary care teaching centre. PATIENTS: Sixty-one patients booked for elective thoracotomy were randomized by scaled envelope to two groups. INTERVENTIONS: Group A received a continuous extrapleural intercostal nerve block with bupivacaine 0.5% in 1:200,000 epinephrine as a bolus of 0.3 mL/kg followed by an infusion of 0.1 mL/kg every hour for 72 hours. Group B received a continuous lumbar epidural block with morphine as a bolus of 70 g/kg followed by an infusion of 7 g/kg every hour for 72 hours. MAIN OUTCOME MEASURES: Pain was assessed by a linear visual analogue scale (VAS) pain score. The cumulative amount of "rescue" intravenous morphine used, and serum bupivacaine concentrations were measured as secondary outcomes. RESULTS: Pain control was the same in both groups as assessed by linear VAS score (p = 0.33). The cumulative dose of intravenous morphine for supplemental analgesia was statistically significant between the groups: group A patients used more morphine than group B (p < 0.05). Accumulation of serum bupivacaine was present with no clinical toxicity. CONCLUSIONS: There is no significant difference in the degree of post-thoracotomy pain control measured by the VAS score when analgesia is provided by continuous extrapleural intercostal nerve block with bupivacaine 0.5% in 1:200,000 epinephrine or lumbar epidural block with morphine. Larger amounts of rescue analgesia were used by patients in the continuous extrapleural group with bupivacaine than those in the continuous lumbar epidural block with morphine. Serum bupivacaine concentrations rise without clinical toxicity.

Early postoperative enteral nutrition with arginine-omega-3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: an immunologic evaluation of Impact.

OBJECTIVE: To evaluate the effect of early postoperative feeding with a nutritionally complete enteral diet supplemented with the nutrients arginine, ribonucleic acid (RNA), and omega-3 fatty acids on the immune function in patients undergoing surgery for upper gastrointestinal (GI) malignancies. DESIGN: Prospective, randomized, placebo-controlled, double-blind study. SETTING: Surgical intensive care unit (ICU) in a German university hospital. PATIENTS: Forty-two consecutive patients receiving an enteral diet via needle catheter jejunostomy after GI surgery for cancer. INTERVENTIONS: Patients were randomized to receive either the arginine, RNA, and omega-3 fatty acids supplemented diet or an isocaloric and isonitrogenous placebo diet. Early enteral nutrition was started on postoperative day 1 in the surgical ICU with 20 mL/hr and progressed to the optimal goal of 80 mL/hr by postoperative day 5. MEASUREMENTS AND MAIN RESULTS: Clinical examination and adverse GI symptoms were recorded on a daily basis. Body weight was determined twice weekly. Immunoglobulin concentrations were determined by laser nephelometry. Interferon-gamma concentrations were measured with a modified enzyme-linked immunosorbent assay method. Fluorescence-activated cell scan flow cytometry was performed to analyze B cells, T lymphocytes and their subsets. Clinical patient characteristics and mean caloric intake were similar between the two groups and both formulas were well tolerated. The number of T lymphocytes and their subsets, helper T cells (CD4) and activated T cells (CD3, HLA-DR), were significantly higher in the supplemented diet group on postoperative days 10 and 16 (p < .05). Mean interferon-gamma concentration after phytohemagglutinin stimulation was higher in the supplemented diet group on postoperative day 16. In the supplemented diet group, mean immunoglobulin M concentrations were significantly higher on postoperative day 10 and mean immunoglobulin G concentrations were higher on postoperative day 16 (p < .05) compared with the results in the placebo group. B-lymphocyte indices were significantly higher in the supplemented vs. the placebo diet group on postoperative days 7 and 10 (p < .05). CONCLUSIONS: Supplementation of enteral diet with arginine, RNA, and omega-3 fatty acids in the early postoperative time period improves postoperative immunologic responses and helps to overcome more rapidly the immunologic depression after surgical trauma.

[Prevention of postoperative anaerobic bacterial infections in abdominal surgery with metronidazole suppositories]. / Prophylaxie des infections postopératoires à germes anaérobies en chirurgie abdominale par les suppositoires de métronidazole.

Metronidazole is widely used for the prevention and treatment of post-operative anaerobic infections. In this study, the prophylactic effectiveness of metronidazole suppositories was tested in patients undergoing abdominal surgery. The suppositories had previously been tested in healthy subjects for drug absorption and tolerance. Patients were divided into three treatment groups: one group received the drug intravenously, another as suppositories and the third one by both routes. Clinical effectiveness was evaluated and plasma metronidazole levels were measured. On the basis of the results obtained, we suggest that a 1 g suppository should be administered 8-hourly over the 20 hours preceding surgery, then 12-hourly if preparation of the digestive tract can be inserted between two administrations. In emergency surgery, 1 suppository must be given at least 1 hour before induction, the 12-hourly, and a 500 mg intravenous infusion at the time of induction.

Quantitative liquid chromatography of allopurinol and oxypurinol in human plasma and urine.

A high performance liquid chromatographic (HPLC) assay is described for allopurinol and oxypurinol determination in human plasma and urine, in the range expected during therapy. The procedure involves addition of trichloroacetic acid to samples, followed by centrifugation. The supernatant is then neutralized and analyzed by reversed-phase HPLC. Characteristics of the method are reported, and data are presented on its application to the pharmacokinetics studies. Separation is optimal with an octadecylsilane (ODS) stationary phase and a sodium acetate mobile phase adjusted to pH 7.2 for plasma and pH 5 for urine.

[Prevention of postoperative anaerobic infections. Economic significance of metronidazole suppositories]. / Prophylaxie des infections postopératoires à germes anaérobies. Intérêt économique des suppositoires de métronidazole.

Metronidazole is widely used in the preventive and curative treatment of post-operative anaerobic infections. As the intravenous form is very expensive, a 1 g suppository has been developed. The pharmacokinetics of metronidazole injection and suppository was studied comparatively in 10 healthy subjects. The serum bioavailability of the rectal form was 80% with a peak serum concentration of 10 mg/l four hours after dosing. From calculated pharmacokinetic values it may be suggested that: (1) in cases of elective surgery treatment could begin with the rectal form alone at the rate of one suppository 12-hourly, starting 48 hours before surgery; (2) in emergency surgery, 0,5g of metronidazole i.v. over 20 minutes and a 1 g suppository should be administered at the time of premedication, treatment being continued with one suppository 12-hourly; (3) in patients at high risk of anaerobic infection, one suppository should be given 8-hourly, starting 24 hours before surgery. The main advantage of the rectal treatment is that it is much cheaper than the intravenous treatment administered during the same period.

[Comparison of the penetration of various short venous catheters]. / Etude comparative de la pénétration des cathéters de veine courts.

Two methods used to measure the degree of the forces involved, in an experimental model--a polyethylene film stretched over a drum, during the penetration of different short venous catheters were compared. One involved strain gauge force sensors, whilst the other used simple and easy to use equipment. The forces necessary for the penetration of introducer needles are on the one hand relatively slight and secondly quite close to each other. By contrast, there are wide differences between the degree of force necessary to obtain penetration of the catheter itself. These forces are in general less for teflon catheters than for those made of polypropylene. The degree does not appear to be related to the size. It remains to attempt to establish a correlation between ease of penetration and tolerance.