Biomedical subjects

B Reigner

Publications and source records attributed to B Reigner.

At least 19 recordsLinked to original sources

PubMed2002

Population pharmacokinetic analysis of the major metabolites of capecitabine.

Capecitabine has been developed as an orally administered tumor selective fluoropyrimidine for use in the treatment of breast and colorectal cancer. The metabolic pathway for capecitabine includes 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to the pharmacologically active agent 5-fluorouracil (5-FU). A previous analysis showed that systemic exposure to 5'-DFUR and alpha-fluoro-beta-alanine (FBAL), a catabolite of 5-FU, was predictive of dose limiting toxicities. Therefore, a multi-response population pharmacokinetic (PK) model for the description of plasma concentrations of 5'-DFUR, 5-FU and FBAL following oral administration of capecitabine was developed using NONMEM. PK data from a bioequivalence study in 24 patients with various solid tumors were used to develop the PK structural part of the population PK model. The 5'-DFUR, 5-FU and FBAL plasma concentrations were described by a linear disposition PK model with first order absorption and lag time. Sparse plasma concentration data from 54 phase II breast cancer patients were added to the bioequivalence data and the influence of covariates on the apparent oral clearances of 5'-DFUR, 5-FU and FBAL and on the apparent volume of distribution of FBAL was investigated. This was conducted by including all significant (p < 0.05) single covariate-PK parameter pairs in the full PK model, followed by one by one deletion (p < 0.001) from the population model. Statistically significant effects were found for the influence of gender, body surface area and total bilirubin on 5'-DFUR clearance and the influence of creatinine clearance on FBAL clearance. However, none of these effects were considered to have clinical relevance.

Adult↗

PubMed2001

Clinical pharmacokinetics of capecitabine.

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps. After oral administration of 1250 mg/m2, capecitabine is rapidly and extensively absorbed from the gastrointestinal tract [with a time to reach peak concentration (tmax) of 2 hours and peak plasma drug concentration (Cmax) of 3 to 4 mg/L] and has a relatively short elimination half-life (t(1/2)) [0.55 to 0.89 h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [with a Cmax of 0.22 to 0.31 mg/L and area under the concentration-time curve (AUC) of 0.461 to 0.698 mg x h/L]. The apparent t(1/2) of fluorouracil after capecitabine administration is similar to that of the parent compound. Comparison of fluorouracil concentrations in primary colorectal tumour and adjacent healthy tissues after capecitabine administration demonstrates that capecitabine is preferentially activated to fluorouracil in colorectal tumour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration differential does not hold for liver metastasis, although concentrations of fluorouracil in liver metastases are sufficient for antitumour activity to occur. The tumour-preferential activation of capecitabine to fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmacokinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine and fluorouracil, is high (27 to 89%) and is likely to be primarily due to variability in the activity of the enzymes involved in capecitabine metabolism. Capecitabine and the fluorouracil precursors 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in plasma after repeated administration. Plasma concentrations of fluorouracil increase by 10 to 60% during long term administration, but this time-dependency is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observed. There is no evidence of pharmacokinetic interactions between capecitabine and leucovorin, docetaxel or paclitaxel.

Antacids↗

PubMed2000

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients.

PURPOSE: [corrected] Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. METHODS: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. RESULTS: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. CONCLUSIONS: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

Aged↗

PubMed2000

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours.

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).

Adult↗

PubMed1999

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients.

PURPOSE: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. METHODS: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m2 of capecitabine (treatment A), a single oral dose of 1250 mg/m2 of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m2 of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. RESULTS: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (Cmax) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the Cmax and AUC0-infinity values obtained for capecitabine and 5'-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5'-deoxy-5'-fluorouridine (5'-DFUR), 5-fluorouracil, and alpha-fluoro-beta-alanine. The Cmax and AUC0-infinity values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC0-infinity obtained for 5'-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. CONCLUSION: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox.

Administration, Oral↗

PubMed1999

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients.

PURPOSE: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. METHODS: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. RESULTS: Based on the primary pharmacokinetic parameter, AUC(0-infinity) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-infinity) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-infinity) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. CONCLUSION: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Analysis of Variance↗

PubMed1999

A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug.

An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 microCi of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86-104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71-95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69-7.0) was collected in the feces. Over a collection period of 24-48 h, a total of 84.2% (range 80-95) was recovered in the urine as the sum of the parent drug and measured metabolites (5'-DFCR, 5'-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25-1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.

Administration, Oral↗

PubMed1999

Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies.

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined. PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, paclitaxel was increased to a target dose of 175 mg/m(2), and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently. RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted. CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.

Administration, Oral↗

PubMed1999

Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations.

This article reviews the methods available for predicting hepatic metabolic clearance in humans, and discusses their application to the processes of drug discovery and development. The application of these techniques has increased markedly during the past few years because of the improved availability of human liver samples, which has increased the opportunities to use in vitro studies to predict human clearance. The techniques available involve both empirical and physiologically based approaches. Allometric scaling using in vitro data from animals and humans combines certain aspects of both approaches. An evaluation of data retrieved from the literature indicates that, together with in vitro human data, allometric scaling based on a combination of in vitro and in vivo preclinical data can accurately predict clearance in humans. With this approach, 80% of the predictions were within a 2-fold factor of actual human clearance values, with an overall accuracy of 1.6-fold. The uncertainties and inaccuracies in predicting human clearance are related to: (i) the specific method that is used to make the prediction; (ii) the experimental design and the model used to determine the in vitro clearance; (iii) protein binding within the in vitro test system; and (iv) various in vivo factors such as the involvement of extrahepatic metabolism and active transport processes, interindividual variability and nonlinearity in pharmacokinetics. In contrast to purely empirical approaches, the physiological approach to predicting clearance gives an opportunity to integrate some of these complexities and, therefore, should provide more confidence in the prediction of clearance in humans.

Animals↗

PubMed1999

Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites.

Capecitabine (Xeloda) is a rationally designed oral, tumor-selective fluoropyrimidine carbamate aimed at preferential conversion to 5-fluorouracil (5-FU) within the tumor. Because capecitabine is extensively metabolized by the liver, it is important to establish whether liver dysfunction altered the pharmacokinetics of capecitabine and its metabolites. This was investigated in 14 cancer patients with normal liver function and in 13 with mild to moderate disturbance of liver biochemistry due to liver metastases. They received a single oral dose of capecitabine (1255 mg capecitabine/m2) with serial blood and urine samples collected up to 72 h after administration. Concentrations of capecitabine and its metabolites were determined in plasma by high-performance liquid chromatography or liquid chromatography coupled to mass spectrometry and in urine by 19F-nuclear magnetic resonance spectroscopy. Although plasma concentrations of capecitabine, 5'-deoxy-5-fluorouridine, 5-FU, dihydro-5-FU, and alpha-fluoro-beta-alanine were, in general, higher in patients with liver dysfunction, the opposite was found for 5'-deoxy-5-fluorocytidine. These effects were not clinically significant. Total urinary recovery of capecitabine and its metabolites was 71% of the administered dose in patients with normal hepatic function and 77% in patients with hepatic impairment. The absolute bioavailability of 5'-deoxy-5-fluorouridine was estimated as 42% in patients with normal hepatic function and 62% in patients with impaired hepatic function. In summary, mild to moderate hepatic dysfunction had no clinically significant influence on the pharmacokinetic parameters of capecitabine and its metabolites. Although caution should be exercised when capecitabine is administered to patients with mildly to moderately impaired hepatic function, there is no need for, a priori, adjustment of the dose.

Adult↗

PubMed1998

Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

PURPOSE: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. PATIENTS AND METHODS: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. RESULTS: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose. CONCLUSION: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.

Administration, Oral↗

PubMed1998

Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer.

PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.

Administration, Oral↗

PubMed1998

Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients.

Capecitabine (Ro 09-1978) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials.

Administration, Oral↗

PubMed1998

A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors.

Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.

Administration, Oral↗

PubMed1995

Eversion endarterectomy of the internal carotid artery: midterm results of a new technique.

A new eversion endarterectomy technique was used in 65 internal carotid artery reconstructions in 56 patients. The original features of the technique include a complete oblique transection of the internal carotid artery distal to the lesion and eversion endarterectomy through a longitudinal incision of the common carotid and external carotid arteries. The mean age of the patients was 68.2 +/- 7.8 years. Seventy-three percent of the patients had hypertension and 45.5% had coronary heart disease. Fifty-four percent experienced neurologic symptoms (transient in 36%, reversible in 6%, and permanent in 11%). Operations were performed under general anesthesia. An indwelling shunt was inserted whenever routine stump pressure was < 50 mmHg. There were no neurologic complications but one patient died of a compression hematoma of the neck, for a combined mortality and morbidity rate of 1.5%. Arteriograms were obtained from all patients on day 5 and showed complete restoration of normal anatomy in all cases and thrombosis of the external carotid artery in one. During a mean follow-up of 27 +/- 4.7 months no strokes were observed. Follow-up duplex scans showed no hemodynamically significant restenoses. Eversion endarterectomy is a reliable alternative to other reconstruction procedures of the internal carotid artery.

Aged↗

PubMed1995

[Angiographic study of collateral circulation in coronary occlusion].

To define the collateral circulation pathways between coronary arteries, 101 coronarographies of patients who had at least one occlusion of a coronary artery (left-anterior descending artery, circumflex, right coronary) were analysed. We found 12 collateral pathways for the right coronary, 8 for the anterior descending artery, and 4 for the circumflex artery. These collateral circulation pathways have been mapped and compared to those of literature.

Cardiac Care Facilities↗

PubMed1994

Surgical anatomy and dissection of the petrous and peripetrous area. Anatomic basis of the lateral approaches to the skull base.

The purpose of this study is to review the topographic anatomy of the petrous and peripetrous structures, with emphasis on the relationships important to the lateral approaches to the posterior and lateral skull base. Surgical exposure of the clivus, the posterior aspect of the petrous bone, the ventral aspect of the brain stem, and of all the intradural structures in the area, remains difficult because of the presence of the so-called "petrous and peripetrous complex". However, the lateral approach to the skull base is the most suitable approach if the lesion lies lateral to the cavernous portion of the internal carotid artery, and of course if the lesion develops laterally behind the petrous apex. Consequently, neurosurgeons should be familiar with the anatomy of the intrapetrous cavities and their contents, and with the relationships in the area. Middle cranial fossa dissections (dry and fresh specimens) allow us to study the anatomical relationships between the intrapetrous carotid artery, the facial nerve, the porus, the cochlea, the geniculate ganglion and the petrosal nerves, the trigeminal ganglion and nerve, the auditory tube and the middle ear. While briefly reviewing some approaches (anterior petrosectomy, sub-temporal preauricular infratemporal fossa approach, pre-sigmoid approach), we explore the concept of the approach and the limitations of surgical technique and exposure.

Humans↗

PubMed1994

Popliteal arterial traumas: prognosis factors: multi-center prospective study apropos of 40 cases.

Forty cases of arterial popliteal traumas occurring in the course of 1992 were collected by 20 centers. The purpose of this prospective study was to evaluate a preoperative prognosis score suggested by Crolais from a retrospective study. Five clinical criteria are taken in account to establish the score: delay, degree of ischemia, contusion, general condition of the patient and wound apperture. Each of the criteria is affected by a progressive note according to the gravity. Analysis of our series confirms the seriousness of this pathology: one death, 8 major amputations and 50% of morbidity. The statistical analysis of pre-operative score and post-operative recovery confirms the existence of three groups at progressive risk: Low risk, score < 30 points. Revascularization must be done. Post-operative recovery is simple. Average risk, score is between 31 and 50 points. Revascularization must be done. Post-operative recovery is particularly simple as the delay before revascularisation will be short and systematic fasciotomies will be done. Major risk, score > 50 points. An amputation must be carried out.

Adult↗