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Biomedical subjects

P Canal

Publications and source records attributed to P Canal.

At least 19 recordsLinked to original sources
PubMed1995

Mechanism of interaction between cisplatin and human recombinant interferon gamma in human ovarian-cancer cell lines.

Human ovarian carcinoma cells (2008 and its cisplatin-resistant sub-line 2008/C13*) were sensitized to cisplatin by treatment with human recombinant gamma interferon (IFN gamma). IFN gamma produced no significant change in the uptake of CDDP. Exposure of 2008 and 2008/C13* cells to IFN gamma resulted in a time-dependent decrease of cellular glutathione and total glutathione-S-transferase activity, principally the pi isoform. By contrast, the treatment of 2008 and 2008/C13* cell lines with IFN gamma induced rather than suppressed metallothionein IIA mRNA levels. IFN gamma changed neither the formation of total platinum-DNA adducts, nor DNA repair. A significant decrease in c-erbB-2 expression was observed both in sensitive and in resistant cell lines after treatment with IFN gamma, and this decrease was dose-dependent. Our results indicate that the mechanism of IFN gamma-induced sensitization in human ovarian-cancer cell lines is multifactorial.

Cisplatin↗
PubMed1995

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Adult↗
PubMed1995

Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine.

Two patients were treated with CPT-11 for colorectal cancer and had a percutaneous biliary catheter for extrahepatic biliary obstruction. The first patient was treated with CPT-11 according to the 100-mg/m2 weekly therapeutic schedule, and the second patient was treated every 3 weeks, with a dose of 350 mg/m2 being given at the first course, after which it was decreased to 300 mg/m2 for the following courses. In plasma, the active identified metabolite of CPT-11, SN-38, occurred mainly in the form of a glucuronide conjugate. CPT-11 was mainly excreted in bile and urine as CPT-11. The cumulative biliary and urinary excretion of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide conjugate) over a period of up to 48 h ranged from 25% (100 mg/m2 weekly) to 50% (300 mg/m2 every 3 weeks). This means that CPT-11 can be excreted under other, not yet identified metabolite forms.

Antineoplastic Agents, Phytogenic↗
PubMed1995

A pharmacologically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer.

Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml-1 min.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

[Relations between hematological toxicity and total and free plasma levels of etoposide in daily oral administration].

This study was undertaken in order to evaluate the inter- and intra-individual pharmacokinetic variabilities and their impact on the toxicity of oral Vépéside Sandoz administered daily for 21 days. The pharmacokinetic results confirmed the low bioavailability of this formulation (14% +/- 10%) and its large interindividual variability. Moreover, a great intraindividual variability was shown between day 1 and day 21. This fact can explain that the relationship between the relative decrease in neutrophil count and the pharmacokinetic parameters was observed only with either the mean area under the curve of concentrations versus time (AUC) or the mean residual concentrations (Cr). The determination of the fraction of plasma etoposide unbound, which ranged from 4.6 to 24.8%, improved the pharmacokinetic-pharmacodynamy relationship for AUC but not for Cr. This study showed the potential interest of etoposide drug monitoring. However, no dosage adjustment could be performed with this oral etoposide formulation because of its large intraindividual bioavailability. Since this study was performed, the Sandoz company withdrew this formulation, and replaced it by one identical with that available in other countries.

Administration, Oral↗
PubMed1994

[Concomitant association of radiotherapy and chemotherapy (CDDP 4-6 mg/m2/daily in continuous i.v. administration) in locally advanced ORL tumors].

In order to enhance radiation effects in the treatment of unresectable Head and Neck squamous cell carcinoma, we initiated a phase I-II study in February 1991 with concomitant radiation and cisplatin in the treatment of resectable Head and Neck squamous cell carcinoma. The first patient was treated in a palliative intend for a cervical recurrence (cutaneous metastatic lymphangitis) of laryngeal cancer. The seven other patients had a Stage IV M0, previously untreated, oropharyngeal carcinoma. Standard external radiation was carried out up to a total dose of 60 Gy/6 weeks (7 MeV electron beam) for the 1st patient and 72 Gy/8 weeks (Co60 beam) for the 7 other patients. Cisplatin was given during the entire radiation treatment, by continuous infusion, 5 days a week, at doses of 4 mg/m2/d for the 1st patient, 5 mg/m2/d for the two following patients and 6 mg/m2/d for the last five patients. One patient with a poor initial performance status (three in the WHO scale) stopped his treatment on the 6th week due to a grade 3 mucositis with deglutition pneumonia. He died 2 months later with progressive carcinoma. For one other patient, treatment was discontinued for 1 week after 48 Gy, due to a grade 3 mucositis. The other patients completed the planned protocol without any interruption. Mucositis (grade 3 in two cases, grade 2 in four cases), dermitis (grade 3 in two cases, grade 2 in four cases) and neutropenia (grade 2 in two cases) were the most frequent acute toxicity. Of the seven patients treated with a curative intend, six are free of disease at 6 to 28 months after completion of treatment. A pharmacokinetic study showed a total platinum accumulation. The mean value at the end of treatment reached 1157 ng/ml. Only one patient experienced an accumulation of the ultrafilterable platinum (137 ng/ml at the end of treatment).

Antineoplastic Agents↗
PubMed1992

Confluence-dependent resistance in human colon cancer cells: role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells.

In vitro sensitivity of HT29 human colon cancer cells to doxorubicin (DXR), vincristine (VCR), etoposide (VP16), cisplatin (CDDP), melphalan (L-PAM) and 5-fluorouracil (5FU) was markedly reduced when cell-culture density increased. For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.

Antineoplastic Agents↗
PubMed1992

Human pharmacokinetics of N-L-leucyl-doxorubicin, a new anthracycline derivative, and its correlation with clinical toxicities.

A pharmacokinetic study of N-L-leucyl-doxorubicin, a new derivative of doxorubicin, has been undertaken during a phase I trial in 19 patients with advanced cancer after intravenous bolus administration at doses ranging from 30 to 240 mg/m2. The pharmacokinetics of N-L-leucyl-doxorubicin was linear with a total body clearance of 41.3 +/- 25.7 L/hr/m2. N-L-leucyl-doxorubicin was extensively metabolized into doxorubicin, which appeared in plasma immediately after N-L-leucyl-doxorubicin infusion. The mean molar doxorubicin/N-L-leucyl-doxorubicin area under the curve (AUC) ratio was 0.49 +/- 0.22 and was independent of the administered dose. A relationship has been established between the doxorubicin AUC (r = 0.74; p less than 0.001) and the surviving factor in white blood cell counts. Other toxic side effects (thrombocytopenia or stomatitis) did not correlate with any pharmacokinetic parameter. These findings suggest that the degree of metabolization of N-L-leucyl-doxorubicin into doxorubicin may be responsible for the toxicity, that is, N-L-leucyl-doxorubicin may simply represent a pro-drug for doxorubicin.

Dose-Response Relationship, Drug↗
PubMed1992

Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study.

PURPOSE: A prospective clinical study was performed to determine the incidence of high-dose continuous intravenous infusion fluorouracil (5FU-CIV) cardiotoxicity. PATIENTS AND METHODS: Three hundred sixty-seven patients who were given first-cycle high-dose 5FU-CIV were monitored for cardiac function by clinical examination, ECG, and laboratory tests. 5FU-CIV was administered during a 96- or 120-hour period at doses that ranged from 600 to 1,000 mg/m2/d. Associated drugs included cisplatin (56%), mitomycin (12.5%), folinic acid (leucovorin) (7%), and others (14%). Thirty-nine patients (10.5%) received 5FU as a single agent. RESULTS: 5FU-induced cardiac events occurred in 28 patients (7.6%; 95% confidence interval, 4.9% to 10.3%). Nine of them had a history of cardiac disease. Primary tumors included head and neck (n = 13), gastrointestinal (n = 6), breast (n = 3), and others (n = 6). The mean onset time of cardiac symptoms was 3 days (range, 2 to 5). Inaugural symptoms included angina pectoris (n = 18), hypotension (n = 6), hypertension (n = 5), malaise (n = 4), dyspnea (n = 2), arrhythmia (n = 1), or sudden death (n = 1). At 5FU discontinuation, six patients' cardiac symptoms returned to baseline, but 21 patients experienced unstable angina (n = 8), hypotension/cardiovascular collapse (n = 11), pulmonary edema (n = 1), or sudden death (n = 4). The lethality rate was 2.2% (five sudden deaths plus three irreversible collapses). ECG showed repolarization changes (ST segment deviation; T-wave inversion) in 65% and/or diffuse microvoltage in 22% of the patients who presented with cardiac events. Echocardiography showed partial or global hypokinesia in nine of the 16 patients who were examined, and one case of prolonged akinesia. Cardiac enzymes rarely showed an increase (n = 2). In severe but reversible cases, clinical, ECG, and echographic parameters returned to baseline status within 48 hours after the drug discontinuation. A fluorine 19 nuclear magnetic resonance (19F NMR) analysis of urine was performed on 14 patients; six had cardiac symptoms and eight did not. Fluoroacetate (FAC), a known cardiotoxic compound, was detected in all cases. CONCLUSION: In our study, the incidence of high-dose 5FU-CVI cardiotoxicity was 7.6%. The hypothesis of a toxic cardiomyopathic process requires further confirmation.

Adult↗
PubMed1991

Pharmacokinetic modeling of plasma and cerebrospinal fluid methotrexate after high-dose intravenous infusion in children.

A pharmacokinetic study was performed in plasma and cerebrospinal fluid (CSF) of patients suffering from brain tumors to describe the disposition of methotrexate. An open three-compartment model was developed to fit together the data obtained in plasma and CSF. The pharmacokinetic parameters obtained by the model agreed with those obtained with classical analysis and the fitting correctly depicted the plasma and CSF concentration decays. According to the results, such a model could be applied to other anticancer drugs.

Adolescent↗
PubMed1991

Chronopharmacokinetics of doxorubicin in patients with breast cancer.

The chronopharmacokinetics of doxorubicin (DOX) has been studied in 18 patients suffering from breast cancer. They received combined chemotherapy including DOX (50 mg/m2 as an iv bolus), given at two different times (09.00 h or 21.00 h). The two randomized courses of the protocol were given to each patient at a four week interval. The total body clearance (CL) of DOX was significantly decreased when the drug was administered at 21.00 h, resulting in a longer elimination half-life and an increase in AUC. The renal clearance of DOX did not differ at the different times of administration, and it appears that the decrease in CL was related to a change in hepatic blood flow. The volume of distribution of the drug was not changed.

Adult↗
PubMed1991

Phase I/II pharmacokinetic study of mitoxantrone by continuous venous infusion in patients with solid tumours and lymphoproliferative diseases.

Phase I and pharmacokinetic studies were performed in order to evaluate the maximum tolerated dose and the efficiency of 120 h continuous venous infusion (CVI) of mitoxantrone. 25 patients suffering from either metastatic solid tumour or refractory lymphoproliferative disease were included in the study. The starting dose was 2 mg/m2 per day and was increased by a 0.2 mg/m2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m2 per day (12 mg/m2 over a 120 h period); this dose was defined as the maximal tolerated dose in these pretreated patients. One partial response and three stable diseases were observed. A plasma plateau concentration of mitoxantrone (2.13 [S.D. 0.54] micrograms/1 at 2 mg/m2 per day, 2.56 [1.32] micrograms/1 at 2.2 per day and 3.46 [1.32] micrograms/l at 2.4 mg/m2 per day) was reached within 24-48 h. It was linearly related to the administered dose. The mean plasma clearance of mitoxantrone was 27.8 [14.2] l/h/m2 and the volume of distribution of the beta phase averaged 2327 [2125] l/m2. An inverse relationship was established between the mitoxantrone clearance and the degree of hematologic toxicity. This 120 h CVI mitoxantrone schedule was safe and could be repeated every 3 weeks in an outpatient setting. The relationship between mitoxantrone clearance and the drug related haematotoxicity could be used for an individual dose adjustment.

Adolescent↗
PubMed1991

Radiosensitivity of jejunal mucosa after whole abdomen irradiation and CDDP pretreatment.

Pretreatment of mice with a single radiation dose of 11.5 Gy or with fractionated irradiation (2 x 6.5 or 7.5 Gy, with an interval time of 12 hr) led to a relative decrease in the radiosensitivity of jejunal crypt cells when a second single dose of radiation was delivered 2 months later. When the same irradiation pretreatment was combined with CDDP (6 mg/kg, i.p.) injected 12 hr after single radiation or between two equal doses of radiation, similar crypt cells resistance was obtained. The combination of CDDP with irradiation did not modify the radiosensitivity of jejunal crypts in comparison with irradiation alone, even when the total radiation dose was delivered in 2 split doses. This induced radioresistance was demonstrated to be a reflection of late injury on intestinal tissue, presumably due to hypoxia resulting from vascular damage. It seems that the administration of CDDP did not change the possible hypoxia suspected in crypt cells of mice pretreated with single radiation dose. However, mouse lethality increased significantly when CDDP was combined with irradiation.

Animals↗
PubMed1991

Concomitant evaluation of efficiency, acute and delayed toxicities of combined treatment of radiation and CDDP on an in vivo model.

The efficiency, acute and delayed toxicities of different radio-chemotherapeutic combinations were assessed on an in vivo model (Krebs II ascitic carcinoma grafted to female Swiss mice). Mice were given whole abdomen irradiation (WAI) 2.5 to 10 Gy as a single dose (WAI). CDDP was given intraperitoneally at 0.5 to 4 mg/kg dose level, 12 hr before or after WAI. There was a relationship between dose of CDDP and increase of life span (ILS) of mice. However, WAI did not increase the life span. When a single dose of 2 mg/kg CDDP was given prior to a 2.5 Gy WAI, the ILS reached 47%. By contrast, it was only 37% when treatment sequence was reversed. When the WAI dose level was increased to 5 Gy, the ILS was not increased. The jejunal crypt cell number, determined 3 days after the last treatment, was not modified, regardless of the treatment sequence. There was no delayed renal toxicity. The study on the Krebs II ascites model confirms the tumor cell therapeutic potentiation without exacerbation of normal tissue damage.

Animals↗
PubMed1991

Teniposide and cisplatin given by intraperitoneal administration: preclinical and phase I/pharmacokinetic studies.

Cisplatin and teniposide given by intraperitoneal (IP) route exert a synergistic therapeutic effect against ascitic P388 leukemia in mice. As single agents, they display different dose-limiting toxicities and favourable pharmacokinetic characteristics in IP phase I trials. We administered cisplatin (fixed dose: 200 mg/m2) and teniposide (escalating doses) by IP route without dwell-time to investigate the toxicity, pharmacokinetics and clinical activity of this 2-drug combination. Nine patients received a total of 14 courses. Myelosuppression, nausea and vomiting were the most frequent toxicities. Leukopenia was the dose-limiting toxicity. The maximum tolerated dose of teniposide was 100 mg/m2 when administered with a fixed dose of 200 mg/m2 cisplatin. Pharmacokinetic analysis showed that the main parameters of both cisplatin and teniposide in the peritoneum and in the plasma were not modified when the drugs were combined. It appears that a pharmacodynamic interaction exists between cisplatin and teniposide which results in increased hematologic toxicity. Although an objective response has been observed in one patient with refractory ovarian cancer, such association should not be applicable for further clinical development due to marked toxicity and the low dose of teniposide recommended.

Adult↗
PubMed1990

Hyperphosphatasemia related to three intestinal alkaline phosphatase isoforms: biochemical study.

An unexplained hyperphosphatasemia was noted in a healthy 47-year-old woman. The electrophoretic pattern on agarose gel with and without wheat germ lectin of the serum of this patient showed the presence of three isoforms which have been characterised as being of intestinal origin: their biochemical (neuraminidase, phenylalanine) and thermodenaturation properties are similar to those of intestinal tissue extract. The pI and pH optima of these isoforms agree with an intestinal origin. Our results suggest the existence of different allelozymes of intestinal alkaline phosphatase.

Alkaline Phosphatase↗