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2.
Cancer Chemother Pharmacol ; 68(2): 505-11, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21079959

ABSTRACT

PURPOSE: LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese. METHODS: Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week. RESULTS: LY2181308 was administered to 14 patients, aged 44-73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease. CONCLUSIONS: LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Oligonucleotides/administration & dosage , Oligonucleotides/adverse effects , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Disease Progression , Drug Resistance, Neoplasm , Female , Half-Life , Humans , Japan , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Male , Middle Aged , Neoplasm Staging , Neoplasms/blood , Oligonucleotides/pharmacokinetics , Oligonucleotides/therapeutic use , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/adverse effects , Oligonucleotides, Antisense/pharmacokinetics , Oligonucleotides, Antisense/therapeutic use , Survivin , Tissue Distribution
3.
Theriogenology ; 61(2-3): 399-406, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14662139

ABSTRACT

The primary objective was to determine the effect of supplemental progesterone, administered via an intravaginal device (CIDR), on conception rates to timed-artificial insemination (timed-AI) in postpartum suckled Japanese Black beef cows treated with the Ovsynch protocol. A secondary objective was to compare the effects of treatments on plasma concentrations of progesterone and estradiol. Cows in the control group (Ovsynch, n=38) received a standard Ovsynch protocol (100 microg GnRH analogue on Day 0, 500 microg PGF2alpha analogue on Day 7, and 100 microg GnRH analogue on Day 9), with AI on Day 10, approximately 20 h after the second GnRH treatment. Cows in the treatment group (Ovsynch+CIDR; n=40) received a standard Ovsynch protocol plus a CIDR for 7 days (starting on Day 0). Plasma progesterone concentrations were determined on Days 0, 1, 7, 9, 10, and 17 and plasma estradiol-17beta concentrations were determined on Days 7, 9, 10, and 17. The odds ratio for likelihood of conception was 3.29 times greater (P=0.02) in the Ovsynch+CIDR group compared to Ovsynch group. The conception rate was greater (P=0.03) in the Ovsynch+CIDR group than in the Ovsynch group (72.5% versus 47.7%). Insertion of a CIDR device significantly increased plasma progesterone concentrations only on Days 1 and 7 (P<0.001 and P=0.05, respectively), but had no significant effect on plasma estradiol-17beta concentrations. Including a CIDR with the Ovsynch protocol significantly improved conception rates in postpartum suckled Japanese Black beef cows.


Subject(s)
Cattle/physiology , Fertilization , Gonadotropin-Releasing Hormone/analogs & derivatives , Insemination, Artificial/veterinary , Progesterone/administration & dosage , Administration, Intravaginal , Animals , Dinoprost/administration & dosage , Estradiol/blood , Female , Gonadotropin-Releasing Hormone/administration & dosage , Insemination, Artificial/methods , Logistic Models , Odds Ratio , Progesterone/blood , Time Factors
4.
Biol Pharm Bull ; 21(8): 844-6, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9743254

ABSTRACT

We analyzed mexiletine in Japanese patients using population pharmacokinetics. 139 serum concentration data, which were collected for therapeutic drug monitoring from 121 patients, were used for this analysis. We also investigated influence of age and gender on pharmacokinetics, and age was found to be an influential factor on clearance. The final pharmacokinetic parameters are, CL/F=0.580-0.00369 x AGE (l/h/kg) and Vd/F=6.63 (l/kg). These results should be useful for adjusting the dosage to a patient's age for the prevention of an adverse reaction caused by overexposure.


Subject(s)
Anti-Arrhythmia Agents/pharmacokinetics , Arrhythmias, Cardiac/metabolism , Mexiletine/pharmacokinetics , Adult , Age Factors , Aged , Aged, 80 and over , Arrhythmias, Cardiac/drug therapy , Female , Humans , Male , Middle Aged
5.
Jpn J Cancer Res ; 85(9): 972-7, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7961128

ABSTRACT

In this study, we aimed to develop a population pharmacokinetic model for CPT-11 and to use the Bayesian method to estimate CPT-11 pharmacokinetic parameters in each of 43 patients who received combined therapy consisting of CPT-11 and etoposide. The group was divided into first and second data sets of 30 and 13 patients, respectively. We developed a population pharmacokinetic model of CPT-11 based on the first data set. The individual pharmacokinetic parameters [area under the concentration curve (AUC) and clearance (CL)] were subsequently estimated by using the Bayesian method on the second data set. Plasma CPT-11 concentrations were measured by high-performance liquid chromatography, and compartmental pharmacokinetic models were fitted by the Bayesian method. The population pharmacokinetic model was developed by using the nonlinear mixed effect model. We selected the volume of the central compartment (Vc), CL, and distribution rate constants (K12, K21) as population pharmacokinetic parameters. The population mean values (CV%) of Vc, CL, K12, and K21 were, respectively, 31.8 (15.7%) liter/m2, 14.1 (27.8%) liter/h/m2, 1.1 (8.4%)/h, and 0.41 (30.3%)/h. Residual intraindividual variability was 22.9%. The optimal sampling regime for estimation of the AUC and CL in using the Bayesian method was the two time points of 1 and 8 h post infusion. The mean predictive error, the mean absolute predictive error, and the root mean squared error were -3.3, 9.4, 3.2% (AUC) and 6.3, 10.0, 3.5% (CL), respectively. We concluded that the AUC and CL of CPT-11 could be estimated from plasma concentrations at two times by using the Bayesian method.


Subject(s)
Camptothecin/analogs & derivatives , Lung Neoplasms/drug therapy , Bayes Theorem , Camptothecin/pharmacokinetics , Etoposide/administration & dosage , Humans , Irinotecan , Metabolic Clearance Rate
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