A pharmacokinetic study of Genetaxyl (G) together with cyclosporin A (CsA) administered orally in cancer patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12002-12002
Author(s):  
C. Liau ◽  
E. Lepper ◽  
H. Wang ◽  
M. Yang ◽  
T. Chiou ◽  
...  
Keyword(s):  
Equilibrium Dialysis ◽  
Volume Of Distribution ◽  
Mean Value ◽  
Phase Ii Trials ◽  
Patients With Cancer ◽  
The Mean ◽  
High Concentrations ◽  
Apparent Bioavailability ◽  
Dose Levels ◽  
Dose Dependent

12002 Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m2, 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m2. Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted. [Table: see text]

Inorganic Bromide in Higher Fungi

1984 ◽  
Vol 39 (9-10) ◽  
pp. 863-866 ◽  
Author(s):  
T. Stijve
Keyword(s):  
Trace Element ◽  
Dry Weight ◽  
Mean Value ◽  
Inorganic Salts ◽  
Chromatographic Methods ◽  
The Mean ◽  
High Concentrations

Abstract A total of 138 samples of higher fungi, representing 35 species (15 belonging to the genus Amanita), were analysed for the trace element bromine using spectrophotometric and gas chromatographic methods. High concentrations of bromine, up to 100 mg/kg on dry weight, were encountered in Amanitaceae, especially in members of the subsections Phalloideae and Eu-Amanita, whereas in other fungi the mean value for this element was only 3,3 m g/kg. Some bromine-accumulating Amanitas also contained unusually high chlorine levels. Am axi­mum concentration of 3 percent on dry weight was measured in A. phalloides. It could be demonstrated that most, if not all of bromine and chlorine was present in the fungi as ionisable inorganic salts. Two organochlorine metabolites, previously reported in some mushrooms, were absent in A. phalloides and A. muscaria.

Pharmacokinetics of Prilocaine after Intravenous Administration in Volunteers 

1999 ◽  
Vol 90 (4) ◽  
pp. 988-992 ◽  
Author(s):  
Auke Dirk van der Meer ◽  
Anton G. L. Burm ◽  
Rudolf Stienstra ◽  
Jack W. van Kleef ◽  
Arie A. Vletter ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
High Performance ◽  
Equilibrium Dialysis ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Unbound Fraction ◽  
Blood Samples ◽  
The Mean ◽  
The Difference

Background Prilocaine exists in two stereoisomeric configurations, the enantiomers S(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate. Methods Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis. Results The unbound fraction of R(-)-prilocaine (mean +/- SD, 70%+/-8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73%+/-5%). The total plasma clearance of R(-)-prilocaine (2.57+/-0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91+/-0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279+/-94 l) did not differ from that of S(+)-prilocaine (291+/-93 l). The terminal half-life of R(-)-prilocaine (87+/-27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124+/-64 min), as was the mean residence time of R(-)-prilocaine (108+/-30 min) compared with S(+)-prilocaine (155+/-59 min; P < 0.005). Conclusions The pharmacokinetics of prilocaine are enantioselective. The difference in clearance is most likely a result of a difference in intrinsic metabolic clearance. The difference in the pharmacokinetics of the enantiomers of prilocaine does not seem to be clinically relevant.

Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: simultaneous estimates of β-endorphin, adrenocorticotropin and cortisol secretion and disappearance in normal men

1993 ◽  
Vol 128 (6) ◽  
pp. 521-528 ◽  
Author(s):  
Ali Iranmanesh ◽  
German Lizarralde ◽  
Johannes D Veldhuis
Keyword(s):  
Plasma Concentrations ◽  
Metabolic Stress ◽  
Fold Increase ◽  
Volume Of Distribution ◽  
Mean Value ◽  
Cortisol Secretion ◽  
Daily Production ◽  
Deconvolution Analysis ◽  
The Mean ◽  
Normal Men

In the present study, we investigated the coordinate kinetic response of the corticotropic axis to the acute metabolic stress of hypoglycemia by applying deconvolution analysis to adrenocorticotropin (ACTH), β-endorphin and cortisol concentration-time series generated in seven normal men after intravenous administration of insulin. Hypoglycemic stress resulted in a 22-fold increase in the mean plasma concentration of ACTH to a maximum of 77±15 pmol/l, in conjunction with a 7.5-fold increase in the mean plasma β-endorphin concentration, the maximal value of which was 96±11 pmol/l. Plasma cortisol concentrations increased by 2.6-fold with a mean value of 734±14 nmol/l. Maximal plasma ACTH and β-endorphin concentrations were preceded by discrete secretory bursts with peak amplitudes of 10.5±2.7 and 10.6±2.0 pmol·I−1·min−1 (20-fold and ninefold increases compared to control), respectively. The mass of ACTH released was 114±20 pmol/l (3.4-fold increase), which corresponds to a total amount of 1.25 μg (50% of daily production and 0.5% of reported pituitary stores), assuming a distribution volume of 40 ml/kg. A total amount of 4.4±0.7 mg of cortisol was released after insulin-induced hypoglycemia, based on a mean cortisol secretory mass of 1088±137 nmol/l and a presumed 11.3-1 volume of distribution. Deconvolution-based estimates of the endogenous half-lives of ACTH, β-endorphin and cortisol were 17±0.6, 22±1.7 and 65±5.3 min, respectively. In summary, deconvolution analysis revealed a rapid coordinate activation of ACTH, β-endorphin and cortisol secretion after hypoglycemic stress, which correlated closely but temporally preceded increases in the respective plasma concentrations. Our inference that only a small fraction of pituitary ACTH content is released during hypoglycemic stress emphasizes the large reserve capability of the pituitary corticotropes. The percentage response of adrenal gland to the metabolic stress of hypoglycemia was of lesser magnitude, possibly owing to the rate-limiting properties of cortisol biosynthesis. We conclude that kinetic responses of the hypothalamic—pituitary—adrenal axis to hypoglycemic stress exhibit exquisite temporal synchrony and manifest a marked reserve capacity.

Artificial pulmonary surfactant inhibited by proteins

1987 ◽  
Vol 62 (2) ◽  
pp. 429-437 ◽  
Author(s):  
T. Fuchimukai ◽  
T. Fujiwara ◽  
A. Takahashi ◽  
G. Enhorning
Keyword(s):  
Surface Tension ◽  
Human Serum ◽  
Serum Protein ◽  
Pulmonary Surfactant ◽  
Protein Concentration ◽  
Mean Value ◽  
Surfactant Preparation ◽  
The Mean ◽  
Potential Inhibitors ◽  
Dose Dependent

With a pulsating bubble surfactometer we assessed the ability of various agents, fibrinogen, human serum, albumin, and a 55,000-dalton serum protein, to interfere with the surface activity of Surfactant TA. From a highest final protein concentration of 4 mg/ml the potential inhibitors were diluted down to 0.125 mg/ml in six steps, and each concentration was evaluated together with two final phospholipid concentrations, 6.25 and 1.25 mg/ml, of the surfactant preparation. The strongest inhibiting action was exerted by fibrinogen, followed by human serum and the 55,000-dalton serum protein; the weakest inhibitor was albumin. Bilirubin, when added in an amount of 1.73 mg/100 ml dissolved in human serum, significantly (P less than 0.001) augmented the inhibition over that exerted by human serum alone. Adsorption rate, as reflected in the mean value of surface tension 2 and 10 s after creation of a bubble, not pulsating, was seriously affected by each of the protein-containing inhibitors in concentrations exceeding 1 mg/ml. Surface tension was raised significantly when the pulsating bubble was at maximal and minimal size. The effect was dose dependent. At maximal size it showed no tendency to disappear during the 10-min recording, but at minimal bubble size the inhibition gradually diminished. We conclude that proteins present in the airways may seriously interfere with the activity of Surfactant TA.

BINDING OF 5α-ANDROSTANE-3α,17β-DIOL TO HUMAN PLASMA PROTEINS

1973 ◽  
Vol 57 (2) ◽  
pp. 289-298 ◽  
Author(s):  
A. F. CLARK ◽  
C. E. BIRD
Keyword(s):  
Human Plasma ◽  
Plasma Proteins ◽  
Association Constant ◽  
Equilibrium Dialysis ◽  
Paper Electrophoresis ◽  
Mean Value ◽  
Albumin Fraction ◽  
The Mean ◽  
Apparent Association ◽  
Apparent Association Constant

SUMMARY The binding of 5α-androstane-3α,17β-diol to human plasma proteins was studied by equilibrium dialysis. The mean value of 96·6% for men was significantly less than that of 97·5% for women. These values are higher than those found for 5α-dihydrotestosterone (95·0 and 97·3%, respectively) and for testosterone (92·4 and 95·3%, respectively). When the distribution of labelled steroid in the different protein fractions was studied by paper electrophoresis, male plasma showed a larger fraction of 5α-androstane-3α,17β-diol radioactivity in the albumin fraction and less in the β-globulin area than did female plasma. Similar finding were made when 5α-dihydrotestosterone was studied. No inter-α-globulin peak of radioactivity was found for 5α-androstane-3α,17β-diol and 5α-dihydrotestosterone as occurs for testosterone. Albumin binds more 5α-androstane-3α,17β-diol than 5α-dihydrotestosterone or testosterone when studied by equilibrium dialysis and this is due to a higher apparent association constant between albumin and the dihydroxysteroid.

scholarly journals Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors

2009 ◽  
Vol 27 (4) ◽  
pp. 550-556 ◽  
Author(s):  
Brigitte C. Widemann ◽  
Wendy Goodspeed ◽  
Anne Goodwin ◽  
Tito Fojo ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Phase Ii Trials ◽  
Eligibility Criteria ◽  
Dose Levels

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.Patients and MethodsPatients ≥ 2 and ≤ 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m2/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.ResultsNineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m2/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m2/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 ± 247 mL/min/m2, volume of distribution at steady-state was 12.2 ± 5.4 L/kg, and half-life was 14 hours.ConclusionThe recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m2/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors.

1985 ◽  
Vol 3 (1) ◽  
pp. 121-127 ◽  
Author(s):  
E Davila ◽  
L Klein ◽  
C L Vogel ◽  
R Johnson ◽  
F Ostroy ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Hemorrhagic Cystitis ◽  
Hypoxic Cell ◽  
Phase Ii Trials ◽  
Antitumor Effects ◽  
Normal Tissues ◽  
Mixed Response ◽  
The Mean ◽  
Dose Levels

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.

scholarly journals https://www.kau.edu.sa/Files/320/Researches/60264_31074.pdf

2011 ◽  
Vol 22 (2) ◽  
pp. 185-201
Author(s):  
Mohammed Amin M. Sharaf Mohammed Amin M. Sharaf
Keyword(s):  
Water Quality ◽  
Major And Trace Elements ◽  
Mean Value ◽  
Mineral Dissolution ◽  
Total Hardness ◽  
Mineral Contents ◽  
Domestic Use ◽  
The Mean ◽  
Sedimentary Succession ◽  
High Concentrations

This study dealt with the hydrochemistry of As Suqah area, NE of Jeddah, Saudi Arabia. The study is based on the analyses of the major and trace elements of 16 water samples. The groundwater shows relatively high concentrations in their overall mineral contents and a high EC, TDS, and total hardness as CaCO3. Two groundwater types were identified in the As Suqah area: Na-Mg-Ca-Cl-SO4 and Na-Ca-Mg-Cl water types. Sodium adsorption ratio has a mean value of 14.39. The exchangeable sodium ratio has a mean value of 0.456 and a maximum value of 1.706. The average magnesium hazard was found to be about 49.97. The groundwater in As Suqah area was slightly supersaturated with respect to calcite and supersaturated with respect to dolomite. The mean saturation indices for these species are 1.21 and 2.60 respectively. The main hydrochemical processes responsible for the above discussed variation in water quality are recharge, ion-exchange and mineral dissolution. The water quality within the sedimentary succession was found to be of relatively higher salinity. Its use is restricted for domestic use only if adequately treated.

Erythropoiesis Equivalence, Pharmacokinetics and Antibody Analysis Following Subcutaneous and Intravenous Hematide™ Administration in Cynomolgus Monkeys.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1143-1143 ◽  
Author(s):  
Kathryn W. Woodburn ◽  
Peter J. Schatz ◽  
Kei-lai Fong ◽  
Paul L. Beaumier
Keyword(s):  
Small Volume ◽  
Volume Of Distribution ◽  
Sampling Interval ◽  
Mean Value ◽  
Terminal Phase ◽  
Rest Periods ◽  
Repeat Administration ◽  
Dose Levels ◽  
Erythropoietic Response ◽  
Plasma Compartment

Abstract Hematide™ is a synthetic PEGylated peptidic erythropoiesis stimulating agent (ESA) that is presently being developed for the correction of anemia in patients with chronic kidney disease and cancer. The objectives of this study were to evaluate the pharmacokinetics (PK), erythropoietic response, and the potential of Hematide to induce the formation of antibodies in monkeys following subcutaneous (SC) and intravenous (IV) administration. Hematide was administered Q2Wx3 at 10 mg/kg SC (n=5) and IV (n=5) beginning on Day 1 with repeat administration (Q2Wx3) beginning on Day 71. A third dose cycle began on Day 141 with animals (n=10) receiving 10 mg/kg SC. Blood was collected following the first dose for PK analysis and then repeatedly throughout the study for anti-Hematide antibody analysis, hematology, and serum chemistry analysis. To avoid the possible consequences of chronic polycythemia 30 to 40 mL of blood was collected approximately every two weeks. As expected, Hematide induced significant erythropoiesis with characteristic increases in reticulocytes, red blood cells, hematocrit and hemoglobin (Hgb) levels. At Day 14, reticulocytes were 9.1 ± 2.1 and 9.6 ± 0.8% following IV and SC administration respectively, compared to 1.0 ± 0.2 and 1.4 ± 0.5 % at pre-dose. Hgb levels at Day 14 were also similar between the IV and SC dosing groups with Hgb levels of 16.9 ± 0.6 and 17.8 ± 1.5 g/dL corresponding to increases of 2.5 and 3.2 g/dL. Hgb levels progressively increased to a plateau by study Day 48. No differences were noted between the IV and the SC dosed groups with Hgb levels of 20.9 ± 2.5 and 20.3 ± 2.1 g/dL respectively, corresponding to increases of 6.5 and 6.7 g/dL over pre-dose levels. Following IV administration, PK analyses revealed disappearance of Hematide from plasma in a bi-exponential fashion, with a rapid initial phase followed by a dominant, prolonged terminal phase. The plasma clearance estimate was small, with a mean value of 0.17 mL/h·kg and the volume of distribution at steady state (Vss) was also small, 25.9 mL/kg indicating that Hematide is confined to the plasma compartment. The terminal half-life of Hematide following IV administration was 114 h. Hematide was slowly absorbed following SC injection, with a delayed pseudo Cmax at 48 to 168h. Essentially, a sustained and plateau plasma concentration was observed throughout the entire PK sampling interval. A terminal elimination apparently was not reached even at 169 h post SC dose. The SC bioavailability, estimated by AUC240h after IV and SC routes, was 57.1%. No detectable levels of Hematide-specific antibodies were observed in any of the ten monkeys dosed IV and/or SC with Hematide Q2W, with intermittent rest periods, for a total of 9 doses. In conclusion, Hematide is a potent erythropoiesis stimulating agent which exhibits a low clearance and small volume of distribution in monkeys. Similar erythropoietic responses were produced following IV and SC administration. The absence of antibody development in the repeatedly dosed animals indicates that Hematide is non-immunogenic at the dosing regimen tested.

scholarly journals Au and Te Minerals in Seafloor Massive Sulphides from Semyenov-2 Hydrothermal Field, Mid-Atlantic Ridge

Minerals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 294 ◽  
Author(s):  
Anna Firstova ◽  
Tamara Stepanova ◽  
Anna Sukhanova ◽  
Georgy Cherkashov ◽  
Irina Poroshina
Keyword(s):  
Low Temperature ◽  
Mean Value ◽  
Hydrothermal Field ◽  
Additional Contribution ◽  
Core Complex ◽  
Mid Atlantic Ridge ◽  
The Mean ◽  
High Concentrations ◽  
Seafloor Massive Sulphides ◽  
Massive Sulphides

The Semyenov-2 hydrothermal field located at 13°31′N of the Mid-Atlantic Ridge (MAR) is associated with an oceanic core complex (OCC) and hosted by peridotites and basalts with minor amounts of gabbro and plagiogranites. Seafloor massive sulphides (SMS) are represented by chimneys with zonality, massive sulphides without zonality and sulphide breccia cemented by opal and aragonite. The mean value of Au (20.6 ppm) and Te (40 ppm) is much higher than average for the MAR SMS deposits (3.2 ppm and 8.0 ppm, respectively). Generally, these high concentrations reflect the presence of a wide diversity of Au and Te minerals associated with major mineral paragenesis: primary native gold, melonite (NiTe2) and tellurobismuthite (Bi2Te3) are related to high-temperature chalcopyrite (~350 °C); electrum (AuAg)1, hessite (Ag2Te) and altaite (PbTe) are related to medium- and low-temperature Zn-sulphide and opal assemblages (260–230 °C). Calaverite (AuTe2) and Te-rich “fahlore” Cu12(Sb,As,Te)4S13 are texturally related to the chalcopyrite-bornite-covellite. Enrichment of Au in sulphide breccia with opal and aragonite cement is driven by the re-deposition and the process of hydrothermal reworking of sulphide. The low-temperature fluid mobilizes gold from primary sulphide, along with Au and Te minerals. As a result, the secondary gold re-precipitate in cement of sulphide breccia. An additional contribution of Au enrichment is the presence of aragonite in the Cu-Zn breccia where the maximal Au content (188 ppm) is reached.

Sign in / Sign up

Export Citation Format

Share Document