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Sample records for cancer patients pharmacokinetics

  1. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, Huixin; van Erp, Nielka; Bins, Sander; Mathijssen, Ron H J; Schellens, Jan H M; Beijnen, Jos H.; Steeghs, Neeltje; Huitema, Alwin D R

    Background and Objective: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Methods: Pharmacokinetic data were available from 96

  2. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, H.; Erp, N. van; Bins, S.; Mathijssen, R.H.; Schellens, J.H.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.

    2017-01-01

    BACKGROUND AND OBJECTIVE: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. METHODS: Pharmacokinetic data were available from 96

  3. Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer.

    Science.gov (United States)

    Dobbs, N A; Twelves, C J; Ramirez, A J; Towlson, K E; Gregory, W M; Richards, M A

    1993-01-01

    We have studied the practical implications and acceptability to patients of pharmacokinetic studies in 34 women receiving anthracyclines for advanced breast cancer. The following parameters were recorded: age, ECOG performance status, psychological state (Rotterdam Symptom Checklist), cytotoxic drug and dose, number of venepunctures for treatment and sampling, and time when the sampling cannula was removed. Immediately after finishing pharmacokinetic sampling, patients completed a questionnaire which revealed that (i) all patients understood sampling was for research, (ii) 35% of patients experienced problems with sampling, (iii) benefits from participation were perceived by 56% of patients. Of 20 patients later questioned after completion of their treatment course, 40% recalled difficulties with blood sampling. Factors identifying in advance those patients who tolerate pharmacokinetic studies poorly were not identified but the number of venepunctures should be minimised. Patients may also perceive benefits from 'non-therapeutic' research.

  4. A clinical pharmacokinetic microdosing study of docetaxel with Japanese patients with cancer.

    Science.gov (United States)

    Fujita, Ken-ichi; Yoshino, Etsuko; Kawara, Kaori; Maeda, Kazuya; Kusuhara, Hiroyuki; Sugiyama, Yuichi; Yokoyama, Taro; Kaneta, Toshikado; Ishida, Hiroo; Sasaki, Yasutsuna

    2015-10-01

    Whether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese patients with cancer. A microdose of docetaxel (100 μg/patient) was given by 5-min intravenous infusion on day 1, followed by a therapeutic dose of docetaxel (60-75 mg m(-2)), given by 1-h intravenous infusion on day 8. Plasma docetaxel was analyzed by liquid chromatography-tandem mass spectrometry. A two-compartment pharmacokinetic model was used to calculate the area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf). Nine patients received both a microdose and therapeutic dose of docetaxel. The AUC0-inf after microdosing was 3640 ± 1150 ng h L(-1), while that after therapeutic dosing adjusted to 100 mg/patient was 2230 ± 757 µg h L(-1). The ratio of docetaxel clearance in therapeutic dose to that in microdose was 1.8 (P = 0.0041). Plasma α1-acid glycoprotein concentrations negatively correlated with docetaxel clearance at therapeutic dose, whereas the trend was weak at microdose. Docetaxel clearance showed marginal nonlinearity between microdose and therapeutic dose, presumably because of saturation of plasma protein binding; however, the magnitude was within twofold, allowing practically acceptable extrapolation.

  5. Rectal methadone in cancer patients with pain. A preliminary clinical and pharmacokinetic study.

    Science.gov (United States)

    Ripamonti, C; Zecca, E; Brunelli, C; Rizzio, E; Saita, L; Lodi, F; De Conno, F

    1995-10-01

    Cancer pain can be treated in most cases with oral analgesics. However, during their clinical history, 53% to 70% of patients will need alternative routes of opioid administration. The rectal administration of opioids is a simple alternative route for many patients. There are no data in the literature regarding the pharmacodynamics and pharmacokinetics of rectal methadone. We evaluated the analgesia, tolerability and absorption profile of methadone hydrochloride in six opioid-naive cancer patients with pain. A blood sample was collected before administration of a single dose of drug (10 mg) and then again after fixed times. At these fixed times the patients were asked about pain, nausea and drowsiness by means of a visual analogue scale of 0-100 mm (VAS). Pain relief was statistically significant as early as 30 minutes and up to eight hours after methadone administration. None of the patients reported significant side effects. The pharmacokinetics of rectal methadone showed rapid and extensive distribution phases followed by a slow elimination phase. Rectal methadone can be considered an effective analgesic therapy for patients with cancer pain for whom oral and/or parenteral opioids are not indicated or available.

  6. Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

    Science.gov (United States)

    Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

    2016-04-01

    Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

  7. Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

    Science.gov (United States)

    Burz, C; Berindan-Neagoe, I; Balacescu, O; Todor, N; Pelau, D; Floares, C; Kacso, G; Tanaselia, C; Ursu, M; Vlase, L; Leucuta, S E; Cristea, V; Irimie, A

    2010-01-01

    The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

  8. A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

    NARCIS (Netherlands)

    Kuip, E.J.M.; Zandvliet, M.L.; Koolen, S.L.; Mathijssen, R.H.; Rijt, C.C. van der

    2017-01-01

    Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied

  9. Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients

    NARCIS (Netherlands)

    Oosten, A.W.; Abrantes, J.A.; Jonsson, S.; Bruijn, P. de; Kuip, E.J.M.; Falcao, A.; Rijt, C.C. van der; Mathijssen, R.H.

    2016-01-01

    PURPOSE: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the

  10. Treatment with subcutaneous and transdermal fentanyl: Results from a population pharmacokinetic study in cancer patients

    NARCIS (Netherlands)

    A.W. Oosten (Astrid); J.A. Abrantes (João A.); S. Jönsson (Siv); P. de Bruijn (Peter); E.J.M. Kuip (Evelien); A. Falcão (Amílcar); C.C.D. van der Rijt (Carin); A.H.J. Mathijssen (Ron)

    2016-01-01

    textabstractPurpose: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we

  11. Population pharmacokinetics of ifosfamide and its 2-and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients

    NARCIS (Netherlands)

    Kerbusch, T; vanPutten, JWG; Groen, HJM; Huitema, ADR; Mathot, RAA; Beijnen, JH

    The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer

  12. Optimizing anticancer drug treatment in pregnant cancer patients : pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel

    NARCIS (Netherlands)

    van Hasselt, J G C; van Calsteren, K; Heyns, L; Han, S; Mhallem Gziri, M; Schellens, J H M; Beijnen, J H; Huitema, A D R; Amant, F

    2014-01-01

    BACKGROUND: Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives

  13. TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

    Science.gov (United States)

    Xin, D S; Zhou, L; Li, C Z; Zhang, S Q; Huang, H Q; Qiu, G D; Lin, L F; She, Y Q; Zheng, J T; Chen, C; Fang, L; Chen, Zhe-Sheng; Zhang, S Y

    2018-03-05

    Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC>0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC>0.05 (the time during which PTX plasma concentration exceed 0.05 μmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC> 0.05 ranged from 14 to 38 h with a median time of 27 h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC>0.05 between CR+PR and SD+PD; (4) with the increasing value of TC>0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC>0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC>0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC>0.05 at 26 to 30 h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC>0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Vitamin D: Pharmacokinetics and Safety When Used in Conjunction with the Pharmaceutical Drugs Used in Cancer Patients: A Systematic Review

    International Nuclear Information System (INIS)

    Kennedy, Deborah A.; Cooley, Kieran; Skidmore, Becky; Fritz, Heidi; Campbell, Tara; Seely, Dugald

    2013-01-01

    Vitamin D has reported anti-cancer and anti-inflammatory properties modulated through gene transcription and non-genomic signaling cascades. The purpose of this review was to summarize the available research on interactions and pharmacokinetics between vitamin D and the pharmaceutical drugs used in patients with cancer. Hypercalcemia was the most frequently reported side effect that occurred in high dose calcitriol. The half-life of 25(OH)D 3 and/or 1,25(OH) 2 D 3 was found to be impacted by cimetidine; rosuvastatin; prednisone and possibly some chemotherapy drugs. No unusual adverse effects in cancer patients; beyond what is expected from high dose 1,25(OH) 2 D 3 supplementation, were revealed through this review. While sufficient evidence is lacking, supplementation with 1,25(OH) 2 D 3 during chemotherapy appears to have a low risk of interaction. Further interactions with vitamin D 3 have not been studied

  15. Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer.

    Science.gov (United States)

    Liu, Dongyang; Zhang, Li; Wu, Yiwen; Jiang, Ji; Tan, Fenlai; Wang, Yingxiang; Liu, Yong; Hu, Pei

    2015-09-01

    To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Patients (n=40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17-462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2β was within 5.31-8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients.

    Science.gov (United States)

    Nassar, Ala F; Wisnewski, Adam V; King, Ivan

    2017-05-01

    1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V 1 ) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V 2 were 73.2 L/h and 29.9 L, and inter-patient variability in V 2 was 63.1%, respectively. 4. The estimate of V ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

  17. Phase I biodistribution and pharmacokinetic study of Lewis Y targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers

    International Nuclear Information System (INIS)

    Herbertson, R. A.; Lee, F. T.; Hopkins, W.; Smyth, F. E.; Murone, C.; Tebbutt, N. C.; Micallef, N.; MacFarlane, D. J.; Bellen, J.; Sonnichsen, D. S.; Brechbiel, M. W.; Scott, A. M.; Lee, T. L.

    2009-01-01

    Full text:Background: The Lewis Y (Ley) antigen is a blood-group related antigen expressed in >70% of solid tumours. This study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 (humanized anti-Ley antibody conjugated with calichaemicin) in patients with advanced Ley expressing epithelial cancers. Methods: There were 2 dose cohorts, (1.0mg/m2 and 2.6mg/m2). Primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. The first cycle was labelled with 111In for biodistribution assessment, and subsequent cycles were administered 3 weekly to a maximum of 6 cycles. Tumour targeting was assessed using SPECT imaging, and pharmacokinetic analysis was based on gamma counting (111In-CMD-193) and ELISA (CMD-193 protein). Results: Nine patients were enrolled, and received 1-6 treatment cycles. Biodistribution imaging demonstrated initial blood pooling, followed by markedly increased hepatic uptake by day 2 (which persisted to day 8), and fast blood clearance. This pattern was seen for all patients, with no significant tumour uptake visualised in any patient. The overall T 1 /2 of 111In-CMD-193 complex formation in blood. One patient had partial metabolic response on 18F-FDG-PET. No radiologic responses were observed. Conclusions: CMD-193 demonstrates rapid blood clearance and increased hepatic uptake compared to prior studies of the original non-conjugated antibody. This trial highlights the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics in clinical development.

  18. Pharmacokinetics of Gefitinib in a Patient with Non-Small Cell Lung Cancer Undergoing Continuous Ambulatory Peritoneal Dialysis

    Directory of Open Access Journals (Sweden)

    Teppei Yamaguchi

    2015-02-01

    Full Text Available A 72-year-old man undergoing continuous ambulatory peritoneal dialysis (CAPD for chronic renal failure and who had undergone right upper lobectomy for lung adenocarcinoma (pT2aN0M0 2 years ago was admitted for recurrence of lung cancer presenting as multiple brain metastases. An epidermal growth factor receptor mutation analysis of his lung cancer revealed a deletion of 15 nucleotides (E746-A750 in exon 19. After whole-brain radiotherapy, we started daily administration of 250 mg gefitinib under the continuation of CAPD and performed a pharmacokinetic analysis. We speculated that the plasma concentration of gefitinib reached the steady state at least by day 16 after the start of gefitinib (626.6 ng/ml at trough level. On day 46, the plasma concentration was 538.4 ng/ml at trough level and the concentration in the peritoneal dialysis fluid was 34.6 ng/ml, suggesting that CAPD appeared to have little effect on the pharmacokinetics of gefitinib. During gefitinib therapy, there were no significant adverse events except for grade 2 diarrhea. Gefitinib could be safely administered to a patient undergoing CAPD.

  19. Safety, Pharmacokinetics, Immunogenicity, and Biodistribution of (186)Re-Labeled Humanized Monoclonal Antibody BIWA 4 (Bivatuzumab( in Patients with Early-Stage Breast Cancer.

    NARCIS (Netherlands)

    Koppe, M.; Schaijk, F. van; Roos, J.C.; Leeuwen, P.; Heider, K.H.; Kuthan, H.; Bleichrodt, R.P.

    2004-01-01

    The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within

  20. Vitamin D: Pharmacokinetics and Safety When Used in Conjunction with the Pharmaceutical Drugs Used in Cancer Patients: A Systematic Review

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, Deborah A.; Cooley, Kieran; Skidmore, Becky; Fritz, Heidi; Campbell, Tara [Canadian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto, Ontario, M2K 1E2 (Canada); Seely, Dugald, E-mail: dseely@ccnm.edu [Canadian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto, Ontario, M2K 1E2 (Canada); Ottawa Integrative Cancer Centre, 29 Bayswater Avenue, Ottawa, Ontario, K1Y 2E5 (Canada)

    2013-03-11

    Vitamin D has reported anti-cancer and anti-inflammatory properties modulated through gene transcription and non-genomic signaling cascades. The purpose of this review was to summarize the available research on interactions and pharmacokinetics between vitamin D and the pharmaceutical drugs used in patients with cancer. Hypercalcemia was the most frequently reported side effect that occurred in high dose calcitriol. The half-life of 25(OH)D{sub 3} and/or 1,25(OH){sub 2}D{sub 3} was found to be impacted by cimetidine; rosuvastatin; prednisone and possibly some chemotherapy drugs. No unusual adverse effects in cancer patients; beyond what is expected from high dose 1,25(OH){sub 2}D{sub 3} supplementation, were revealed through this review. While sufficient evidence is lacking, supplementation with 1,25(OH){sub 2}D{sub 3} during chemotherapy appears to have a low risk of interaction. Further interactions with vitamin D{sub 3} have not been studied.

  1. Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy.

    Directory of Open Access Journals (Sweden)

    Belen Sadaba

    Full Text Available Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV or oral routes, but subcutaneous (SC administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron.Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA.From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p=0.160. Bioavalability of SC palonosetron was 118% (95% IC: 69-168. Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration.Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy.ClinicalTrials.gov NCT01046240.

  2. Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.

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    Serdjebi, Cindy; Gattacceca, Florence; Seitz, Jean-François; Fein, Francine; Gagnière, Johan; François, Eric; Abakar-Mahamat, Abakar; Deplanque, Gael; Rachid, Madani; Lacarelle, Bruno; Ciccolini, Joseph; Dahan, Laetitia

    2017-06-01

    Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.

  3. Correlation of FCGRT genomic structure with serum immunoglobulin, albumin and farletuzumab pharmacokinetics in patients with first relapsed ovarian cancer.

    Science.gov (United States)

    O'Shannessy, Daniel J; Bendas, Katie; Schweizer, Charles; Wang, Wenquan; Albone, Earl; Somers, Elizabeth B; Weil, Susan; Meredith, Rhonda K; Wustner, Jason; Grasso, Luigi; Landers, Mark; Nicolaides, Nicholas C

    2017-07-01

    Farletuzumab (FAR) is a humanized monoclonal antibody (mAb) that binds to folate receptor alpha. A Ph3 trial in ovarian cancer patients treated with carboplatin/taxane plus FAR or placebo did not meet the primary statistical endpoint. Subgroup analysis demonstrated that subjects with high FAR exposure levels (Cmin>57.6μg/mL) showed statistically significant improvements in PFS and OS. The neonatal Fc receptor (fcgrt) plays a central role in albumin/IgG stasis and mAb pharmacokinetics (PK). Here we evaluated fcgrt sequence and association of its promoter variable number tandem repeats (VNTR) and coding single nucleotide variants (SNV) with albumin/IgG levels and FAR PK in the Ph3 patients. A statistical correlation existed between high FAR Cmin and AUC in patients with the highest quartile of albumin and lowest quartile of IgG1. Analysis of fcgrt identified 5 different VNTRs in the promoter region and 9 SNVs within the coding region, 4 which are novel. Copyright © 2017. Published by Elsevier Inc.

  4. Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Caroline eBodet-Milin

    2015-11-01

    Full Text Available Objectives. A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096 was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA to optimize bispecific antibody and labelled peptide doses, as well as the delay between their injections.Methods. Three cohorts of 3 patients received the anti-CEA x anti-histamine-succinyl-glycine (HSG humanized trivalent bispecific antibody (TF2 and the IMP288 bivalent HSG-peptide. Patients underwent a pre-therapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labelled IMP288, and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, 177Lu-labeled IMP288. The pretargeting delay was 24 or 48 hours. The dose schedule was defined based on pre-clinical TF2 pharmacokinetic studies, on our previous clinical data using the previous anti-CEA pretargeting system and on clinical results observed in the first patients injected using the same system in the Netherlands.Results. TF2 pharmacokinetics (PK was represented by a two-compartment model in which the central compartment volume was linearly dependent on the patient's surface area. PK were remarkably similar, with a clearance of 0.33 +/- 0.03 L/h per m2. 111In- and 177Lu-IMP288 PK were also well represented by a two-compartment model. IMP288 PK were faster (clearance 1.4 to 3.3 l/h. The central compartment volume was proportional to body surface area and IMP288clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modelling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumour activity PK were variable. Organ absorbed doses were not significantly different in the 3 cohorts, but the tumour dose was significantly higher with the higher molar doses of TF2 (p < 0.002. S1 imaging predicted absorbed doses calculated in S2. Conclusion. The best

  5. Can Saliva and Plasma Methadone Concentrations Be Used for Enantioselective Pharmacokinetic and Pharmacodynamic Studies in Patients With Advanced Cancer?

    Science.gov (United States)

    George, Rani; Haywood, Alison; Good, Phillip; Hennig, Stefanie; Khan, Sohil; Norris, Ross; Hardy, Janet

    2017-09-01

    Methadone is a potent analgesic used to treat refractory cancer pain. It is administered as a racemic mixture, with the l-enantiomer being primarily a μ-receptor agonist, whereas the d-enantiomer is an N-methyl-d-aspartate antagonist and inhibits serotonin and norepinephrine reuptake. Dose requirements vary greatly among patients to achieve optimal pain control and to avoid the risk of adverse effects. The relationship between plasma and saliva methadone enantiomer concentrations was investigated to determine if saliva could be a substitute for plasma in pharmacodynamic and pharmacokinetic studies for clinical monitoring and dose optimization of methadone in patients with advanced cancer. Patients with advanced cancer who were prescribed varying doses of oral methadone for pain management were recruited to obtain paired plasma and saliva samples. Pain scores were recorded at the time of sampling. The total and unbound plasma and saliva concentrations of the l- and d-enantiomers of methadone were quantified by using an HPLC-MS/MS method. The relationship between plasma (total and unbound) and saliva concentrations were compared. The saliva-to-plasma concentration ratio was compared versus the dose administered and the time after dosing for both enantiomers. The association of methadone concentrations with reported pain scores was compared by using a Mann-Whitney U test for significance. Fifty patients receiving a mean dose of 11mg/d of methadone provided 151 paired plasma and saliva samples. The median age of the population was 61 years with an interquartile range of 53-71 years with total body weight ranging from 59-88 kg. Median (interquartile) total plasma concentrations for l- and d-methadone were 50.78 ng/mL (30.6-113.0 ng/mL) and 62.0 ng/mL (28.7-116.0 ng/mL), respectively. Median (interquartile range) saliva concentrations for l- and d-methadone were 81.5 ng/mL (28.0-203.2 ng/mL) and 44.2 (16.2-149.7 ng/mL). No relationship could be established between

  6. Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Yoshino, Takayuki; Hyodo, Ichinosuke; Nishina, Tomohiro; Narahara, Hiroyuki; Sugimoto, Naotoshi; Yoshisue, Kunihiro; Boku, Narikazu

    2017-01-01

    S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC. S-1 (35 mg/m 2 ) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course. Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies. The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.

  7. Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers.

    Science.gov (United States)

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A; Gettinger, Scott N

    2015-11-01

    Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed. Regorafenib had acceptable

  8. A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

    2016-11-01

    This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher

  9. Preliminary safety, pharmacokinetics, and efficacy of regorafenib, cisplatin, and pemetrexed in patients with advanced non-squamous non-small cell lung cancers

    Science.gov (United States)

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A.; Gettinger, Scott N.

    2016-01-01

    Structured Abstract Purpose The addition of bevacizumab, an anti-angiogenesis agent, to cytotoxic chemotherapy improves survival in patients with advanced non-squamous non-small cell lung cancers (nsNSCLCs). Regorafenib is an oral multi-targeted kinase inhibitor with potent anti-angiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. This phase I trial evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Methods Chemotherapy-naïve patients with advanced nsNSCLCs were treated with regorafenib 60mg/day continuously and cisplatin 75mg/m2 plus pemetrexed 500mg/m2 once every three weeks for up to six cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Results Nine patients enrolled prior to premature termination of the study due to slow recruitment and a change in the development strategy of regorafenib by the study sponsor, partially due to slow enrollment. Five patients experienced at least one treatment-related Grade 3 adverse event. No grade 4–5 toxicity occurred. 5 of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range 1.5–15.1). Minor pharmacokinetic (PK) interactions between regorafenib and chemotherapy were observed. Conclusions Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naïve patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results. PMID:26003007

  10. Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study

    DEFF Research Database (Denmark)

    Barratt, Daniel T; Bandak, Benedikte; Klepstad, Pål

    2014-01-01

    This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl....

  11. Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Chi, K N; Tolcher, A; Lee, P; Rosen, P J; Kollmannsberger, C K; Papadopoulos, K P; Patnaik, A; Molina, A; Jiao, J; Pankras, C; Kaiser, B; Bernard, A; Tran, N; Acharya, M

    2013-01-01

    To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

  12. Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kuchcinski, Gregory; Duhal, Romain; Lalisse, Maxime; Dumont, Julien; Lopes, Renaud; Pruvo, Jean-Pierre; Leclerc, Xavier; Delmaire, Christine [University of Lille, CHU Lille, Department of Neuroradiology, Lille (France); Le Rhun, Emilie [University of Lille, CHU Lille, Department of Neurosurgery, Lille (France); Oscar Lambret Center, Department of Medical Oncology, Lille (France); Inserm U1192-PRISM-Laboratoire de Proteomique, Reponse Inflammatoire, Spectrometrie de Masse, Lille (France); Cortot, Alexis B. [University of Lille, CHU Lille, Department of Thoracic Oncology, Lille (France); Drumez, Elodie [University of Lille, CHU Lille, Department of Biostatistics, Lille (France)

    2017-09-15

    To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1 month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K{sup trans}, k{sub ep}, v{sub e}, v{sub p}) and their early variation (∇K{sup trans}, ∇k{sub ep}, ∇v{sub e}, ∇v{sub p}). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. Baseline DCE MRI parameters were not associated with the objective response. Early ∇K{sup trans}, ∇v{sub e} and ∇v{sub p} were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∇v{sub e} with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. DCE MRI and early ∇v{sub e} may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. (orig.)

  13. Population pharmacokinetics of oxaliplatin (85 mg/m(2)) in combination with 5-fluorouracil in patients with advanced colorectal cancer

    NARCIS (Netherlands)

    Kho, Y.H.; Jansman, F.G.A.; Prins, N.H.; Neef, C.; Brouwers, J.R.B.J.

    Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85mg/m(2) are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe

  14. Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer.

    Science.gov (United States)

    Koppe, Manuel; Schaijk, Frank van; Roos, Jan; Leeuwen, Paul van; Heider, Karl-Heinz; Kuthan, Hartmut; Bleichrodt, Robert

    2004-12-01

    The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within 1, 24, and 72 hours after administration. BIWA 4 concentration in plasma (ELISA and radioactivity measurements( and the development of human antihuman antibody (HAHA( responses was determined. The biodistribution of (186)Re-BIWA 4 was determined by radioactivity measurements in tumor and normal tissue biopsies obtained during surgery 1 week after administration. Administration of (186)Re-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. The mean t(1/2) in plasma of BIWA 4 (ELISA( was 81 hours (range, 67-97(, whereas the mean radioactivity t(1/2) tended to be longer, at 105 hours (range, 90-114(. RIS unmistakably showed the tumor in 3 patients. Less clear identifications were established in 3 additional patients. In 2 patients, the tumor was wrongly identified in the contralateral breast. Median tumor CD44v6 expression, as determined by immunohistochemistry, was 70% (range, 10-90%). Mean tumor uptake was 2.96% ID/kg (range, 0.92-6.27(, with no apparent correlation with either tumor CD44v6 expression, tumor-cell cellularity, or tumor diameter. Tumor-to-nontumor ratios were unfavorable for blood, bone marrow, mammary gland tissue, and skin. The (186)Re-labeled humanized MAb BIWA 4 can safely be administered to patients with early-stage breast cancer. Tumorto- nontumor ratios were unfavorable, with no apparent correlation with CD44v6 expression, tumor-cell cellularity, or tumor diameter. BIWA 4, therefore, appears to have limitations as a vehicle for radioimmunotherapy in patients with breast cancer.

  15. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

    Science.gov (United States)

    Pegram, Mark D; Borges, Virginia F; Ibrahim, Nuhad; Fuloria, Jyotsna; Shapiro, Charles; Perez, Susan; Wang, Karen; Schaedli Stark, Franziska; Courtenay Luck, Nigel

    2009-01-01

    MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours

  16. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

    2014-04-01

    The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

  17. Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose.

    Science.gov (United States)

    Venkatakrishnan, Karthik; Kim, Tae Min; Lin, Chia-Chi; Thye, Lim Soon; Chng, Wee Joo; Ma, Brigette; Chen, Ming Huang; Zhou, Xiaofei; Liu, Hua; Kelly, Virginia; Kim, Won Seog

    2015-08-01

    This phase 1 study assessed the pharmacokinetics (PK), maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the investigational Aurora A kinase inhibitor, alisertib, in East Asian patients with advanced solid tumors or lymphomas. Patients received alisertib twice-daily (BID) for 7 days in 21-day cycles. Doses were escalated (3 + 3) from 30 mg BID based on cycle 1 dose-limiting toxicities (DLTs) until the MTD, followed by expansion for PK/safety characterization. Thirty-six patients (61 % Chinese, 36 % Korean, 3 % Malay) received alisertib (30 mg BID, n = 30; 40 mg BID, n = 6; median, 2.5 cycles). Alisertib exposures increased approximately dose proportionally, and mean half-life was 16 h. Geometric mean apparent oral clearance (2.65 L/h) was 40 % lower than previous estimates in Western patients, resulting in approximately 70 % higher mean dose-normalized, steady-state exposures (735 nM*h/mg) in East Asian patients. Two patients experienced DLTs at 40 mg BID (grade 3 stomatitis; grade 4 neutropenia); the MTD/RP2D was 30 mg BID. Common toxicities (grade ≥3 at RP2D) were neutropenia (50 %), diarrhea (13 %), and stomatitis (10 %). One patient with extranodal T-/NK-cell lymphoma (nasal type) achieved a partial response and 18 (51 %) had stable disease. The MTD/RP2D of alisertib in East Asian patients (30 mg BID) was lower than in Western patients (50 mg BID), consistent with higher systemic exposures in the East Asian population. Alisertib was generally well tolerated and showed signs of antitumor activity in East Asian cancer patients.

  18. Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer.

    Science.gov (United States)

    Fukudo, Masahide; Ikemi, Yasuaki; Togashi, Yosuke; Masago, Katsuhiro; Kim, Young Hak; Mio, Tadashi; Terada, Tomohiro; Teramukai, Satoshi; Mishima, Michiaki; Inui, Ken-Ichi; Katsura, Toshiya

    2013-07-01

    Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p OSI-420 (p model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0

  19. Evaluation of 5-FU pharmacokinetics in cancer patients with DPD deficiency using a Bayesian limited sampling strategy

    NARCIS (Netherlands)

    Van Kuilenburg, A.; Hausler, P.; Schalhorn, A.; Tanck, M.; Proost, J.H.; Terborg, C.; Behnke, D.; Schwabe, W.; Jabschinsky, K.; Maring, J.G.

    Aims: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. The main purpose of this study was to develop a limited sampling strategy to evaluate the pharmacokinetics of 5FU and to detect

  20. A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

    NARCIS (Netherlands)

    Erp, N.P. van; Herpen, C.M. van; Wit, D. de; Willemsen, A.; Burger, D.M.; Huitema, A.D.; Kapiteijn, E.; Heine, R. ter

    2016-01-01

    INTRODUCTION AND OBJECTIVE: Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and

  1. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.

    Science.gov (United States)

    Hurwitz, Herbert I; Smith, David C; Pitot, Henry C; Brill, Jeffrey M; Chugh, Rashmi; Rouits, Elisabeth; Rubin, Joseph; Strickler, John; Vuagniaux, Gregoire; Sorensen, J Mel; Zanna, Claudio

    2015-04-01

    To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

  2. Particularities in the biodistribution and pharmacokinetic of labeled peptide with 99mTc in regional administration of patient with cervix cancer

    International Nuclear Information System (INIS)

    Palau San Pedro, A.; Lopez Diaz, A.; Martin Escuela, J. M.; Galvez Perez, E.

    2013-01-01

    This study had as objective characterize the biodistribution pharmacokinetic and dosimetry of labeled peptide with 9 9mTc in two dose levels, prepared in 2ml, starting from its intratumoral injection in patient with cervix cancer. The protocol selection to use, the correction and calculate methods were analysis object keeping in mind that antecedents of studies of this type didn't exist and that the administration intratumoral can originate new problems not foreseen in conventional intravenous studies. This study carried out mensurations of sensibility that should be corrected in a particular way. A careful protocol of acquisition was designed able to detect the behavior of the radio-peptide in the time, with a serial gathering of samples of blood and urine until the 24 hours, as well as images of the whole body up to 48h. For the quantification of the images they were necessary also the classic corrections of background and of overlapping of structures. The labeled peptide with 9 9mTc administered for intralesional way, like it was of waiting it presented a very high reception tumoral, being this maxim in the first images, however the product was absorbed quickly in blood, reaching its maximum levels in most of the patients as much in serum as in total blood, in the first 5-15 minutes of having administered. (Author)

  3. Pharmacokinetics of drugs in cachectic patients: a systematic review.

    Directory of Open Access Journals (Sweden)

    Katja Trobec

    Full Text Available Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

  4. Pharmacokinetics of linezolid in critically ill patients.

    Science.gov (United States)

    Sazdanovic, Predrag; Jankovic, Slobodan M; Kostic, Marina; Dimitrijevic, Aleksandra; Stefanovic, Srdjan

    2016-06-01

    Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion. This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population. While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.

  5. Plasma and pleural fluid pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small-cell lung cancer with pleural effusion.

    Science.gov (United States)

    Masago, Katsuhiro; Togashi, Yosuke; Fukudo, Masahide; Terada, Tomohiro; Irisa, Kaoru; Sakamori, Yuichi; Kim, Young Hak; Mio, Tadashi; Inui, Ken-Ichi; Mishima, Michiaki

    2011-09-01

    Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects. Copyright © 2011. Published by Elsevier Inc.

  6. Pharmacokinetics of first-line tuberculosis drugs in tanzanian patients

    NARCIS (Netherlands)

    Tostmann, A.; Mtabho, C.M.; Semvua, H.H.; Boogaard, J. van den; Kibiki, G.S.; Boeree, M.J.; Aarnoutse, R.E.

    2013-01-01

    East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling.

  7. [Pharmacokinetics of salazosulfapyridine in a hemodialysis patient].

    Science.gov (United States)

    Akiyama, Yuji; Fujimaki, Toshihisa; Sakurai, Yusei

    2003-06-01

    The patient was a 62-year-old female. Total gastrectomy was performed due to gastric ulcer in 1969. She was diagnosed as rheumatoid arthritis (RA) in 1985 and was developed to amyloidosis in 1991. She was started on hemodialysis (HD) for chronic renal failure in 1996. In 1998, her arthralgia was aggravated, and 100 mg/day of bucillamine was administered on the day of HD. Her arthralgia persisted, and switching to salazosulfapyridine (SASP) was considered. As there were no standards and no reports for the use of SASP in HD patients, we examined the pharmacokinetics of SASP and its metabolites, and compared our patient with the results of phase one study in normal subjects in Japan. In this case, the blood concentration of SASP was similar to that in healthy controls after single administration of 500 mg of SASP on the day of non-HD, while the concentration of sulfapyridine (SP) was higher than that in healthy donors. However, the blood concentrations of SASP, SP, and N4-acetyl-SP (AcSP) at 24 hours after administration were similar to those obtained in healthy men. SASP was not dialyzed, while about half of SP and AcSP, were dialyzed. In a five-day consecutive administration study also, the blood concentrations of these compounds on Day 5 were similar to those of phase one study, suggesting no accumulation. No adverse drug reaction was observed. As this case had the past history of total gastrectomy and amyloidosis, it is possible that this result is influenced by the factors. Therefore it is necessary to examine pharmacokinetics of SASP and its metabolites beforehand when administering this agent to other HD/RA patients.

  8. Pharmacokinetics of adriamycin vaginal suppository on uterine cervical cancer

    International Nuclear Information System (INIS)

    Noda, Tsuneo; Kiyozuka, Yasuhiko; Katakami, Yoshiaki

    1986-01-01

    Vaginal suppositories of Adriamycin (ADM, 5 mg), for reducing the capacity for repair from sublethal damage of X-ray-irradiated cells, were prepared using Wipepsol S-55 as the vehicle, and were intravaginally administered to patients with advanced uterine cervical cancer, and their pharmacokinetics and clinical effects were studied. The ADM concentration in the uterine cervical cancer tissues indicated high levels (17 to 566 μg/g), and migration into the cardinal ligament and regional lymph nodes was noted. However, little ADM was detected in serum (0 to 0.14 μg/g), probably because of its molecular weight and excellent tissue absorbance, and no side effects, such as cardiotoxicity and myelosuppression due to consecutive administration were detected. Histologically, the effect obtained when administered alone was limited, administration in combination with radiotherapy being more effective. Accordingly, radiotherapy of advanced uterine cervical cancer with concomitant administration of ADM vaginal suppositories seems to bring about a more powerful antitumoral effect with fewer systemic side effects. (author)

  9. Pharmacokinetics of adriamycin vaginal suppository on uterine cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Tsuneo; Kiyozuka, Yasuhiko; Katakami, Yoshiaki

    1986-03-01

    Vaginal suppositories of Adriamycin (ADM, 5 mg), for reducing the capacity for repair from sublethal damage of X-ray-irradiated cells, were prepared using Wipepsol S-55 as the vehicle, and were intravaginally administered to patients with advanced uterine cervical cancer, and their pharmacokinetics and clinical effects were studied. The ADM concentration in the uterine cervical cancer tissues indicated high levels (17 to 566 ..mu..g/g), and migration into the cardinal ligament and regional lymph nodes was noted. However, little ADM was detected in serum (0 to 0.14 ..mu..g/g), probably because of its molecular weight and excellent tissue absorbance, and no side effects, such as cardiotoxicity and myelosuppression due to consecutive administration were detected. Histologically, the effect obtained when administered alone was limited, administration in combination with radiotherapy being more effective. Accordingly, radiotherapy of advanced uterine cervical cancer with concomitant administration of ADM vaginal suppositories seems to bring about a more powerful antitumoral effect with fewer systemic side effects.

  10. Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Borghaei, Hossein; Alpaugh, Katherine; Hedlund, Gunnar

    2009-01-01

    recognizing the tumor-associated antigen 5T4. PATIENTS AND METHODS: Patients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose...

  11. Dynamic contrast-enhanced magnetic resonance imaging and pharmacokinetic models in prostate cancer

    International Nuclear Information System (INIS)

    Franiel, Tobias; Hamm, Bernd; Hricak, Hedvig

    2011-01-01

    Dynamic contrast-enhanced MRI enables noninvasive analysis of prostate vascularization as well as tumour angiogenesis and capillary permeability characteristics in prostate cancers. Pharmacokinetic models summarizing the complex information provided by signal intensity-time curves for a few quantitative pharmacokinetic parameters are increasingly being used in the routine clinical setting. This review consists of two parts. The first part discusses the advantages and disadvantages of the MR pulse sequences that can be used for performing DCE-MRI and also of the most widely used pharmacokinetic parameters and models and the parameters they describe. The second part outlines the range of current and potential future clinical applications of DCE-MRI and pharmacokinetic parametric maps in patients with prostate cancer, with reference to the current scientific literature on the topic. The potential clinical applications of DCE-MRI for prostate cancer include detection, localization, and staging, differentiation of recurrent cancer and estimation of the patient's prognosis, as well as monitoring of treatment response. (orig.)

  12. Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome

    International Nuclear Information System (INIS)

    Andersen, Erlend K.F.; Hole, Knut Håkon; Lund, Kjersti V.; Sundfør, Kolbein; Kristensen, Gunnar B.; Lyng, Heidi; Malinen, Eirik

    2013-01-01

    Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: A Brix , k ep , k el , Tofts: K trans , ν e ). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: A Brix , k el , and K trans were significantly (P e was significantly positively correlated with PFS only. k ep showed no association with any endpoint. A Brix was positively correlated with K trans and ν e , and showed the strongest association with endpoint in the log-rank testing. k el and K trans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure

  13. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    International Nuclear Information System (INIS)

    Green, S.; James, N.D.; Cruickshank, G.S.

    2006-01-01

    This presentation will describe a human pharmacokinetic study which is scheduled to begin recruitment in Summer 2006. The study has been ongoing for approximately 4 years to develop the necessary protocols, validate boron assays and to develop a new formulation of BPA. The study population will be patients with glioblastoma multiforme and the study focuses on the route of infusion (intra venous or intra carotid artery) and in each will assess the effect of administration of mannitol (as a blood-brain barrier disrupter). Mannitol will be administered as a bolus at the beginning of a two hour infusion of BPA. The BPA formulation (BPA - mannitol) is also new and avoids some of the problems of low solubility associated with BPA-fructose as well as the potential risk of fructose intolerance. The approach will include stereotactic biopsy which is necessary to confirm diagnosis. Tissue samples collected will include needle biopsy samples of tumour and brain around tumour for estimation of BPA transporter expression, together with microdialysis catheter collection of extra-cellular fluid and routine collection of blood and urine for BPA levels. Where possible, according to surgical plan and the route of entry, samples of cerebro-spinal will also be collected. These data will be used to develop a pharmacokinetic model following the general approach already established by others in the field. This paper presents initial pre-clinical studies on the BPA-mannitol formulation and some assay validation work together with suggestions for approaches to normalisation of the macroscopic boron assays using simultaneous measurement of Mg levels in tissue. (author)

  14. Effectiveness, pharmacokinetics, and safety of a new sustained-release leuprolide acetate 3.75-mg depot formulation for testosterone suppression in patients with prostate cancer: a Phase III, open-label, international multicenter study.

    Science.gov (United States)

    Marberger, Michael; Kaisary, Amir V; Shore, Neal D; Karlin, Gary S; Savulsky, Claudio; Mis, Ricard; Leuratti, Chiara; Germa, Josep R

    2010-04-01

    A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed. This study investigated the effectiveness, pharmacokinetics, and safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer. This was a Phase III, open-label, international multicenter clinical trial. Patients with prostate cancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie, n = 12), showed sustained release of leuprolide from the formulation. Values for AUC(0-t) calculated from day 0 to day 28, days 28 to 56, and days 56 to 84 were 25,976.5 (7892.0), 30,685.5 (9348.4), and 31,030.9 (10,745.0) pg/mL per day, respectively. The most common treatment-related adverse event was hot flashes (45.0% [72/160]). Fatigue, hyperhidrosis, night sweats, and headache each occurred in patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% (13/160) of the patients. Leuprolide acetate 3.75-mg depot was effective in achieving and maintaining testosterone suppression and was well tolerated throughout the study in this cohort of patients with prostate cancer. ClinicalTrials.gov identifier: NCT00128531.

  15. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    Energy Technology Data Exchange (ETDEWEB)

    Cruickshank, G.S. [University of Birmingham and University Hospital Birmingham, Birmingham (United Kingdom)], E-mail: garth.cruickshank@uhb.nhs.uk; Ngoga, D.; Detta, A.; Green, S.; James, N.D.; Wojnecki, C.; Doran, J.; Hardie, J.; Chester, M.; Graham, N.; Ghani, Z. [University of Birmingham and University Hospital Birmingham, Birmingham (United Kingdom); Halbert, G.; Elliot, M.; Ford, S. [CR-UK Formulation Unit, University of Strathclyde, Glasgow (United Kingdom); Braithwaite, R.; Sheehan, T.M.T. [Regional Laboratory for Toxicology, Sandwell and West Birmingham Hospitals Trust, Birmingham (United Kingdom); Vickerman, J.; Lockyer, N. [Surface Analysis Research Centre, University of Manchester, Manchester (United Kingdom); Steinfeldt, H.; Croswell, G. [CR-UK Drug Development Office, London (United Kingdom)] (and others)

    2009-07-15

    This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of {sup 10}B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak {sup 10}B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

  16. A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT

    International Nuclear Information System (INIS)

    Cruickshank, G.S.; Ngoga, D.; Detta, A.; Green, S.; James, N.D.; Wojnecki, C.; Doran, J.; Hardie, J.; Chester, M.; Graham, N.; Ghani, Z.; Halbert, G.; Elliot, M.; Ford, S.; Braithwaite, R.; Sheehan, T.M.T.; Vickerman, J.; Lockyer, N.; Steinfeldt, H.; Croswell, G.

    2009-01-01

    This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of 10 B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak 10 B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

  17. Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer.

    Science.gov (United States)

    Lucas, Catherine J; Galettis, Peter; Song, Shuzhen; Solowij, Nadia; Reuter, Stephanie E; Schneider, Jennifer; Martin, Jennifer H

    2018-01-06

    Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12 g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60 ng/mL. Evidence suggests that blood THC concentrations >5 ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5 ng/mL was 49 days after administration. The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  18. A phase I/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy (HAART) in HIV-positive patients with cancer: AIDS Malignancy Consortium Trial AMC 061

    Science.gov (United States)

    Rudek, Michelle A; Moore, Page C.; Mitsuyasu, Ronald T.; Dezube, Bruce J.; Aboulafia, David; Gerecitano, John; Sullivan, Ryan; Cianfrocca, Mary E.; Henry, David H.; Ratner, Lee; Haigentz, Missak; Dowlati, Afshin; Little, Richard F.; Ivy, S. Percy; Deeken, John F.

    2014-01-01

    Background Treatment of non-AIDS defining cancers (NADCs) may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium assessing targeted therapies and HAART in HIV+ cancer patients (ClinicalTrials.gov NCT00890747). Methods Patients were stratified into two arms based on whether they were taking ritonavir, a potent CYP3A4 inhibitor, in a modified phase I study of sunitinib. Patients in arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50mg/day). Arm 2 (ritonavir-based HAART) used a phase I, 3+3 dose escalation design (from 25 to 50mg/day). Cycles were with four weeks on treatment followed by a two week break (6 weeks total). Pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Results Nineteen patients were enrolled and evaluable. Patients on Arm 1 tolerated treatment with one observed dose limiting toxicity (DLT). In Arm 2, a DLT was experienced at 37.5mg, and an additional 3 of 5 patients experienced grade 3 neutropenia, an uncommon toxicity of sunitinib. No patient had a response, but 10 had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Conclusions Patients on non-ritonavir based HAART regimens tolerated standard dosing of sunitinib. Patients on ritonavir-based therapy treated with 37.5mg/day experienced higher toxicities. Dose reduction of sunitinib to 37.5mg may be warranted in patients on ritonavir. PMID:24474568

  19. Pemetrexed safety and pharmacokinetics in patients with third-space fluid

    DEFF Research Database (Denmark)

    Dickgreber, Nicolas J; Sorensen, Jens Benn; Paz-Ares, Luis G

    2010-01-01

    Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to ...... to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated....

  20. Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis

    NARCIS (Netherlands)

    Touw, D J; Jacobs, F A; Brimicombe, R W; Heijerman, H G; Bakker, W; Briemer, D D

    This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum

  1. Pharmacodynamics and pharmacokinetics of rocuronium in intensive care patients

    NARCIS (Netherlands)

    Sparr, H.J; Wierda, J.MKH; Proost, Johannes H.; Keller, C; Khuenl-Brady, K.S

    We have studied dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients. After an initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n=27) or by

  2. A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer

    International Nuclear Information System (INIS)

    Semple, Scott; Harry, Vanessa N. MRCOG.; Parkin, David E.; Gilbert, Fiona J.

    2009-01-01

    Purpose: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results: Pretherapy radiologic parameters and pharmacokinetic K trans correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.

  3. Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

    Science.gov (United States)

    Joerger, M; von Pawel, J; Kraff, S; Fischer, J R; Eberhardt, W; Gauler, T C; Mueller, L; Reinmuth, N; Reck, M; Kimmich, M; Mayer, F; Kopp, H-G; Behringer, D M; Ko, Y-D; Hilger, R A; Roessler, M; Kloft, C; Henrich, A; Moritz, B; Miller, M C; Salamone, S J; Jaehde, U

    2016-10-01

    Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767). © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor(®)) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study.

    Science.gov (United States)

    Donders, Gilbert; Neven, Patrick; Moegele, Maximilian; Lintermans, Anneleen; Bellen, Gert; Prasauskas, Valdas; Grob, Philipp; Ortmann, Olaf; Buchholz, Stefan

    2014-06-01

    Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.

  5. Pharmacokinetic Tumor Heterogeneity as a Prognostic Biomarker for Classifying Breast Cancer Recurrence Risk.

    Science.gov (United States)

    Mahrooghy, Majid; Ashraf, Ahmed B; Daye, Dania; McDonald, Elizabeth S; Rosen, Mark; Mies, Carolyn; Feldman, Michael; Kontos, Despina

    2015-06-01

    Heterogeneity in cancer can affect response to therapy and patient prognosis. Histologic measures have classically been used to measure heterogeneity, although a reliable noninvasive measurement is needed both to establish baseline risk of recurrence and monitor response to treatment. Here, we propose using spatiotemporal wavelet kinetic features from dynamic contrast-enhanced magnetic resonance imaging to quantify intratumor heterogeneity in breast cancer. Tumor pixels are first partitioned into homogeneous subregions using pharmacokinetic measures. Heterogeneity wavelet kinetic (HetWave) features are then extracted from these partitions to obtain spatiotemporal patterns of the wavelet coefficients and the contrast agent uptake. The HetWave features are evaluated in terms of their prognostic value using a logistic regression classifier with genetic algorithm wrapper-based feature selection to classify breast cancer recurrence risk as determined by a validated gene expression assay. Receiver operating characteristic analysis and area under the curve (AUC) are computed to assess classifier performance using leave-one-out cross validation. The HetWave features outperform other commonly used features (AUC = 0.88 HetWave versus 0.70 standard features). The combination of HetWave and standard features further increases classifier performance (AUCs 0.94). The rate of the spatial frequency pattern over the pharmacokinetic partitions can provide valuable prognostic information. HetWave could be a powerful feature extraction approach for characterizing tumor heterogeneity, providing valuable prognostic information.

  6. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients.

    Science.gov (United States)

    Sime, Fekade B; Stuart, Janine; Butler, Jenie; Starr, Therese; Wallis, Steven C; Pandey, Saurabh; Lipman, Jeffrey; Roberts, Jason A

    2018-06-01

    To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC 0-∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0-∞ was 39% of the values reported for heathy volunteers. The AUC 0-∞ was only 52% of the steady-state AUC 0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in

  7. [Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas].

    Science.gov (United States)

    Wakui, A

    1982-08-01

    This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.

  8. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

    Science.gov (United States)

    Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

    2016-08-01

    Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

  9. Pharmacokinetics of paroxetine in patients with cirrhosis

    DEFF Research Database (Denmark)

    Dalhoff, K; Almdal, T P; Bjerrum, K

    1991-01-01

    with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should...

  10. Population pharmacokinetics of vancomycin in Jordanian patients

    African Journals Online (AJOL)

    predictors of vancomycin clearance include: weight, serum creatinine, chronic renal ... (http://www.budapestopenaccessinitiative.org/read), which permit ... reproduction in any medium, provided the original work is properly credited. ... fluid balance; and albumin levels]); (3) .... vancomycin half-life is prolonged in patients with.

  11. Phenytoin pharmacokinetics in critically ill trauma patients.

    Science.gov (United States)

    Boucher, B A; Rodman, J H; Jaresko, G S; Rasmussen, S N; Watridge, C B; Fabian, T C

    1988-12-01

    Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

  12. Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer

    NARCIS (Netherlands)

    Arends, T.J.H.; Lammers, R.J.M.; Falke, J.; Heijden, A.G. van der; Rustighini, I.; Pozzi, R.; Ravic, M.; Eisenhardt, A.; Vergunst, H.; Witjes, J.A.

    2015-01-01

    INTRODUCTION/BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity

  13. Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Jappe Annette

    2011-01-01

    Full Text Available Abstract Background This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors. Methods A total of 24 patients with advanced breast cancer (n = 6, gastric cancer (n = 6, non-small cell lung cancer (n = 6, or renal cell carcinoma (n = 6 who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued. Results Everolimus was absorbed rapidly; median Tmax was 3 h (range, 1-4 and 2 h (range, 0.9-6 in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7% and fatigue (16.7% and 33.3% in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83% and 6 (50% patients in the 5 and 10 mg/day groups, respectively. Conclusions Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies. Trial registration Chinese Health Authorities 2008L09346

  14. Metronidazole pharmacokinetics in patients with acute renal failure.

    Science.gov (United States)

    Somogyi, A A; Kong, C B; Gurr, F W; Sabto, J; Spicer, W J; McLean, A J

    1984-02-01

    The pharmacokinetics and metabolism of intravenous metronidazole were studied in six patients with acute renal failure. In two of the patients a single dose (500 mg) of metronidazole was administered, whereas in four patients the steady-state pharmacokinetics were studied after four days therapy of 500 mg twice daily. Plasma concentrations of metronidazole and its hydroxy and acetic acid metabolites were measured by a specific and sensitive HPLC method. The volume of distribution was 0.65 +/- 0.13 l/kg (mean +/- S.D.), elimination half-life was 9.9 +/- 2.5 h and total plasma clearance was 55.5 +/- 17.7 ml/min. Renal clearance was almost non-existent (1.4 +/- 1.4 ml/min), whereas non-renal clearance was 54.0 +/- 18.2 ml/min. Steady-state plasma concentrations of metronidazole were 15.3 +/- 3.8 mg/l, the hydroxy metabolite were 17.4 +/- 2.0 mg/l and the acetic acid metabolite were 1.2 +/- 0.8 mg/l. In the patients studied, a dosing regimen of 500 mg twice daily resulted in therapeutically adequate blood levels of metronidazole.

  15. Pharmacokinetic study of mycophenolic acid in Iranian kidney transplant patients

    Directory of Open Access Journals (Sweden)

    Saeed Rezaee

    2013-02-01

    Full Text Available Background: The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA in Iranian kidney transplant patients. Methods: Plasma MPA concentration of mycophenolate mofetile (MMF 1 gram two times a day was measured in 21 Iranian kidney transplant recipients receiving treatment. Patients who entered the study had been transplanted for more than 3 months and their drug level was supposed to be at steady state. MMF concentration was measured with high-performance liquid chromatography (HPLC. Results: The plasma MPA concentration-time curve was characterized by an early sharp peak at about 1 hour postdose. The mean Area Under Curve (AUC, Cmax and Tmax were 47.0±18.3 µg.h/ml, 18.6±8.5 µg/ml and 1.0±0.5 hours respectively. Conclusion: The plasma MPA concentration-time curve pattern of Iranian patients was similar and consistent with previously reported profiles in other populations taking the same dose. Keywords: Mycophenolate mofetil, Mycophenolic acid, Pharmacokinetics, Area Under Curve, Kidney transplantation

  16. Doripenem pharmacokinetics in critically ill patients receiving continuous hemodiafiltration (CHDF).

    Science.gov (United States)

    Hidaka, Seigo; Goto, Koji; Hagiwara, Satoshi; Iwasaka, Hideo; Noguchi, Takayuki

    2010-01-01

    Objectives of the prospective, open-label study were to investigate pharmacokinetics of doripenem and determine appropriate doripenem regimens during continuous hemodiafiltration (CHDF) in critically ill patients with renal failure (creatinine clearance times during one dosing interval were measured in order to calculate pharmacokinetic parameters and clearance via hemodiafiltration. Mean half-life (+/-standard deviation) of doripenem was 7.9+/-3.7 hours. Total body clearance of doripenem was 58.0+/-12.7 ml/min, including clearance of 13.5+/-1.6 ml/min via CHDF. An IV dose of 250 mg of doripenem every 12 hours during CHDF provided adequate plasma concentrations for critically ill patients with renal failure, without resulting in accumulation upon steady-state. Thus, under the conditions tested, CHDF appeared to have little effect on doripenem clearance. Therefore, the blood level of doripenem can be satisfactorily controlled by adjustment of doripenem dose and dosing interval, in accordance with residual renal function in patients receiving CHDF.

  17. Ceftizoxime use in trauma celiotomy: pharmacokinetics and patient outcomes.

    Science.gov (United States)

    Rosemurgy, A S; Dillon, K R; Kurto, H A; Albrink, M H

    1995-11-01

    Seriously injured patients undergo vigorous resuscitation upon arrival at the emergency department and through the immediate perioperative period. Although resuscitation leads to volume loading and fluid shifts, drug dosing and dosing intervals are often not altered to account for changes in total body volume or circulatory volume. To address this, a prospective study of pharmacokinetics of ceftizoxime in 53 injured adults who underwent emergency celiotomy was conducted. Further, the relationship between serum ceftizoxime concentrations and infectious outcomes was evaluated. Per protocol, injured adults undergoing emergency celiotomy received prophylactic ceftizoxime treatment according to standard dosing regimens. Of the patients, 6 (11.5%) experienced postoperative infections and had lower peak serum ceftizoxime levels in the recovery room than patients not experiencing infection. For severely injured adults with extensive blood loss or undergoing lengthy operations requiring rigorous volume resuscitation, doses of ceftizoxime, and indeed all antibiotics, may need to be increased beyond conventional standards to minimize infectious complications.

  18. Pharmacokinetic analysis and k-means clustering of DCEMR images for radiotherapy outcome prediction of advanced cervical cancers.

    Science.gov (United States)

    Andersen, Erlend K F; Kristensen, Gunnar B; Lyng, Heidi; Malinen, Eirik

    2011-08-01

    Pharmacokinetic analysis of dynamic contrast enhanced magnetic resonance images (DCEMRI) allows for quantitative characterization of vascular properties of tumors. The aim of this study is twofold, first to determine if tumor regions with similar vascularization could be labeled by clustering methods, second to determine if the identified regions can be associated with local cancer relapse. Eighty-one patients with locally advanced cervical cancer treated with chemoradiotherapy underwent DCEMRI with Gd-DTPA prior to external beam radiotherapy. The median follow-up time after treatment was four years, in which nine patients had primary tumor relapse. By fitting a pharmacokinetic two-compartment model function to the temporal contrast enhancement in the tumor, two pharmacokinetic parameters, K(trans) and ύ(e), were estimated voxel by voxel from the DCEMR-images. Intratumoral regions with similar vascularization were identified by k-means clustering of the two pharmacokinetic parameter estimates over all patients. The volume fraction of each cluster was used to evaluate the prognostic value of the clusters. Three clusters provided a sufficient reduction of the cluster variance to label different vascular properties within the tumors. The corresponding median volume fraction of each cluster was 38%, 46% and 10%. The second cluster was significantly associated with primary tumor control in a log-rank survival test (p-value: 0.042), showing a decreased risk of treatment failure for patients with high volume fraction of voxels. Intratumoral regions showing similar vascular properties could successfully be labeled in three distinct clusters and the volume fraction of one cluster region was associated with primary tumor control.

  19. Pharmacokinetic analysis and k-means clustering of DCEMR images for radiotherapy outcome prediction of advanced cervical cancers

    International Nuclear Information System (INIS)

    Andersen, Erlend K. F.; Kristensen, Gunnar B.; Lyng, Heidi; Malinen, Eirik

    2011-01-01

    Introduction. Pharmacokinetic analysis of dynamic contrast enhanced magnetic resonance images (DCEMRI) allows for quantitative characterization of vascular properties of tumors. The aim of this study is twofold, first to determine if tumor regions with similar vascularization could be labeled by clustering methods, second to determine if the identified regions can be associated with local cancer relapse. Materials and methods. Eighty-one patients with locally advanced cervical cancer treated with chemoradiotherapy underwent DCEMRI with Gd-DTPA prior to external beam radiotherapy. The median follow-up time after treatment was four years, in which nine patients had primary tumor relapse. By fitting a pharmacokinetic two-compartment model function to the temporal contrast enhancement in the tumor, two pharmacokinetic parameters, K trans and u e , were estimated voxel by voxel from the DCEMR-images. Intratumoral regions with similar vascularization were identified by k-means clustering of the two pharmacokinetic parameter estimates over all patients. The volume fraction of each cluster was used to evaluate the prognostic value of the clusters. Results. Three clusters provided a sufficient reduction of the cluster variance to label different vascular properties within the tumors. The corresponding median volume fraction of each cluster was 38%, 46% and 10%. The second cluster was significantly associated with primary tumor control in a log-rank survival test (p-value: 0.042), showing a decreased risk of treatment failure for patients with high volume fraction of voxels. Conclusions. Intratumoral regions showing similar vascular properties could successfully be labeled in three distinct clusters and the volume fraction of one cluster region was associated with primary tumor control

  20. Pharmacokinetic analysis and k-means clustering of DCEMR images for radiotherapy outcome prediction of advanced cervical cancers

    Energy Technology Data Exchange (ETDEWEB)

    Andersen, Erlend K. F. (Dept. of Medical Physics, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway)), e-mail: eirik.malinen@fys.uio.no; Kristensen, Gunnar B. (Section for Gynaecological Oncology, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway)); Lyng, Heidi (Dept. of Radiation Biology, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway)); Malinen, Eirik (Dept. of Medical Physics, The Norwegian Radium Hospital, Oslo Univ. Hospital, Oslo (Norway); Dept. of Physics, Univ. of Oslo, Oslo (Norway))

    2011-08-15

    Introduction. Pharmacokinetic analysis of dynamic contrast enhanced magnetic resonance images (DCEMRI) allows for quantitative characterization of vascular properties of tumors. The aim of this study is twofold, first to determine if tumor regions with similar vascularization could be labeled by clustering methods, second to determine if the identified regions can be associated with local cancer relapse. Materials and methods. Eighty-one patients with locally advanced cervical cancer treated with chemoradiotherapy underwent DCEMRI with Gd-DTPA prior to external beam radiotherapy. The median follow-up time after treatment was four years, in which nine patients had primary tumor relapse. By fitting a pharmacokinetic two-compartment model function to the temporal contrast enhancement in the tumor, two pharmacokinetic parameters, Ktrans and u{sub e}, were estimated voxel by voxel from the DCEMR-images. Intratumoral regions with similar vascularization were identified by k-means clustering of the two pharmacokinetic parameter estimates over all patients. The volume fraction of each cluster was used to evaluate the prognostic value of the clusters. Results. Three clusters provided a sufficient reduction of the cluster variance to label different vascular properties within the tumors. The corresponding median volume fraction of each cluster was 38%, 46% and 10%. The second cluster was significantly associated with primary tumor control in a log-rank survival test (p-value: 0.042), showing a decreased risk of treatment failure for patients with high volume fraction of voxels. Conclusions. Intratumoral regions showing similar vascular properties could successfully be labeled in three distinct clusters and the volume fraction of one cluster region was associated with primary tumor control

  1. Comparison of normal tissue pharmacokinetics with 111In/9Y monoclonal antibody m170 for breast and prostate cancer

    International Nuclear Information System (INIS)

    Lehmann, Joerg; DeNardo, Gerald L.; Yuan, Aina; Shen Sui; O'Donnell, Robert T.; Richman, Carol M.; De Nardo, Sally J.

    2006-01-01

    Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: 111 In-DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide (GGGF)-m170 and 111 In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for 9 Y was calculated using 111 In MAb pharmacokinetics from the initial imaging study for each patient, using reference man- and patient-specific masses. Results: The reference man-specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies

  2. Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai.

    Science.gov (United States)

    Cai, Xun; Cao, Weiguo; Ding, Honghua; Liu, Tianshu; Zhou, Xinli; Wang, Mei; Zhong, Ming; Zhao, Ziyi; Xu, Qing; Wang, Liwei

    2013-09-01

    The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley

  3. Plasma pharmacokinetics after combined therapy of gemcitabine and oral S-1 for unresectable pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Okita Yoshihiro

    2010-02-01

    Full Text Available Abstract Background The combination of gemcitabine (GEM and S-1, an oral 5-fluorouracil (5-FU derivative, has been shown to be a promising regimen for patients with unresectable pancreatic cancer. Methods Six patients with advanced pancreatic cancer were enrolled in this pharmacokinetics (PK study. These patients were treated by oral administration of S-1 30 mg/m2 twice daily for 28 consecutive days, followed by a 14-day rest period and intravenous administration of GEM 800 mg/m2 on days 1, 15 and 29 of each course. The PK parameters of GEM and/or 5-FU after GEM single-administration, S-1 single-administration, and co-administration of GEM with pre-administration of S-1 at 2-h intervals were analyzed. Results The maximum concentration (Cmax, the area under the curve from the drug administration to the infinite time (AUCinf, and the elimination half-life (T1/2 of GEM were not significantly different between GEM administration with and without S-1. The Cmax, AUCinf, T1/2, and the time required to reach Cmax (Tmax were not significantly different between S-1 administration with and without GEM. Conclusion There were no interactions between GEM and S-1 regarding plasma PK of GEM and 5-FU.

  4. Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Tomas Pascual

    Full Text Available Metastatic breast cancer (MBC progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs on outcomes from this treatment through a pharmacogenetic analysis.Blood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities, dose reductions or treatment suspensions due to toxicity, progression free survival (PFS and overall survival.We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019. ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031, while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively. Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006.CYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

  5. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

    Science.gov (United States)

    Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

    2012-04-01

    Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

  6. Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer.

    Science.gov (United States)

    Jena, Amarnath; Taneja, Sangeeta; Singh, Aru; Negi, Pradeep; Mehta, Shashi Bhushan; Ahuja, Aashim; Singhal, Manish; Sarin, Ramesh

    2017-07-01

    To study relationships among pharmacokinetic and 18 F-fluorodeoxyglucose ( 18 F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. Significant correlations were observed between SUVmean, max, peak, TLG with K trans (ρ=0.446, 0.417, 0.491, 0.430; p≤0.01); with Kep(ρ=0.303, ρ=0.315, ρ=0.319; p≤0.05); and with iAUC(ρ=0.401, ρ=0.410, ρ=0.379; p≤0.05, p≤0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ=0.420, 0.446, 0.443, 0.426; p≤0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and K trans . Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes.

    Science.gov (United States)

    Li, Jianguo; Tang, Weifeng; Storey, Robert F; Husted, Steen; Teng, Renli

    2016-09-01

    Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX. 32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed. A one-compartment model with population mean PK parameters of firstorder absorption rate constant (0.67/h), apparent systemic clearance (14 L/h), and apparent volume of distribution (221 L) was shown to best describe the PK profile of ticagrelor. Patients co-administered moderate CYP3A inducers or inhibitors increased (by 110%, 95% confidence interval (CI), 52 - 192%) or decreased (by 64%, 95% CI, 39 - 73%) apparent ticagrelor clearance, respectively, while habitual smoking decreased apparent ticagrelor clearance by 22% (95% CI, 19 - 25%). Ticagrelor bioavailability was 21% (95% CI, 19 - 22%) lower at treatment initiation (visit 1) versus subsequent visits. Compared with Caucasian patients, ticagrelor bioavailability was 39% (95% CI, 33 - 46%) higher in Asian patients and 18% (95% CI, 6 - 28%) lower in Black patients. In the current analyses, the population PK models developed for ticagrelor and AR-C124910XX described the data obtained in the DISPERSE-2 and PLATO studies well, and were consistent with previous phase I PK studies.

  8. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

    Science.gov (United States)

    Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

    2017-09-01

    Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

  9. The pharmacokinetics of meperidine in acute trauma patients.

    Science.gov (United States)

    Kirkwood, C F; Edwards, D J; Lalka, D; Lasezkay, G; Hassett, J M; Slaughter, R L

    1986-12-01

    Traumatic injury has the potential to alter the hepatic clearance and hence the efficacy and toxicity of drugs by a variety of mechanisms. These include changes in hepatic microsomal enzyme activity, hepatic blood flow rate, and plasma protein binding. Unfortunately, there have been few pharmacokinetic studies in trauma patients. Thus, few data are available to provide guidance in drug regimen design for these individuals. Meperidine clearance was therefore evaluated in patients with traumatic injury and an effort was made to identify physiologic and/or clinical predictors of clearance which could facilitate initial dosage selection. Meperidine total body clearance (TBC) was determined on 12 occasions at steady state following IM administration of meperidine to nine severely injured nonseptic trauma patients with normal renal and hepatic function. TBC of this drug averaged 684 +/- 206 ml/min (mean +/- SD) and was highly correlated with ideal body weight (IBW) (r2 = 0.735; F = 27.75; n = 12; p less than 0.01). The serum concentration of the acute phase reactant protein, alpha 1 acid glycoprotein (AGP), which binds meperidine and many other basic drugs increased strikingly in an apparent linear manner at a rate of 27 mg/dl/day up to 9 days after the traumatic event (r2 = 0.828; F = 42.30; n = 12; p less than 0.01). However, this increase in binding protein concentration was not associated with an alteration in meperidine TBC as has been reported for other drugs. It is concluded that IBW may be a useful guide initial dosage selection of meperidine in acute trauma patients.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.

    Science.gov (United States)

    Savic, Radojka M; Novakovic, Ana M; Ekblom, Marianne; Munafo, Alain; Karlsson, Mats O

    2017-10-01

    The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CL R ) was correlated with creatinine clearance (CL CR ), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CL CR  = 65 ml/min), moderate (CL CR  = 40 ml/min) and severe (CL CR  = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CL R (CL NR ) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CL CR . Trial registration number for study 25643: NCT00213135.

  11. Pharmacokinetic MRI of the prostate. Parameters for differentiating low-grade and high-grade prostate cancer

    International Nuclear Information System (INIS)

    Franiel, T.; Taupitz, M.; Asbach, P.; Beyersdorff, D.; Luedemann, L.; Rost, J.

    2009-01-01

    Purpose: to investigate whether pharmacokinetic MRI parameters ''perfusion, blood volume, mean transit time (MTT), interstitial volume, permeability, extraction coefficient, delay, and dispersion'' allow the differentiation of low-grade (Gleason score ≤ 6) and high-grade (Gleason score ≥ 7) prostate cancer. Materials and method: forty-two patients with prostate cancer verified by biopsy (PSA 2.7 to 31.4ng/ml) and scheduled for prostatectomy underwent MRI at 1.5 Tesla using the dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence (temporal resolution, 1.65 s) and a combined endorectal body phased array coil. Parametric maps were computed using a sequential 3-compartment model and the corresponding post-processing algorithms. A total of 41 areas of prostate cancer (15 low-grade, 26 high-grade cancers) in 32 patients were able to be correlated with the prostatectomy specimens and were included in the analysis. Results: low-grade prostate cancers had a higher mean blood volume (1.76% vs. 1.64%, p = 0.039), longer MTT (6.39 s vs. 3.25 s, p -1 vs. 3.86 min -1 , p = 0.011) than high-grade cancers. No statistically significant difference was found for perfusion (p = 0.069), interstitial volume (p = 0.849), extraction coefficient (p = 0.615), delay (p = 0.489), and dispersion (p = 0.306). (orig.)

  12. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer)

    DEFF Research Database (Denmark)

    Pivot, Xavier; Gligorov, Joseph; Müller, Volkmar

    2013-01-01

    Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab...

  13. Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305 in patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Wu H

    2015-02-01

    Full Text Available Huali Wu,1 Jeffrey R Infante,2 Vicki L Keedy,3 Suzanne F Jones,2 Emily Chan,3 Johanna C Bendell,2 Wooin Lee,4 Whitney P Kirschbrown,1 Beth A Zamboni,5 Satoshi Ikeda,6 Hiroshi Kodaira,6 Mace L Rothenberg,3 Howard A Burris III,2 William C Zamboni1,7–9 1UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 2Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3Vanderbilt University, Nashville, TN, 4Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 5Department of Mathematics, Carlow University, Pittsburgh, PA, USA; 6Yakult Honsha Co., Ltd., Medical Development Department, Tokyo, Japan; 7UNC Lineberger Comprehensive Cancer Center, 8UNC Institute for Pharmacogenomics and Individualized Therapy, 9Carolina Center for Cancer Nanotechology Excellence, University of North Carolina, Chapel Hill, NC, USA Abstract: IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11. The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW] were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time

  14. Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

    OpenAIRE

    Jullien, Vincent; Tréluyer, Jean-Marc; Rey, Elisabeth; Jaffray, Patrick; Krivine, Anne; Moachon, Laurence; Lillo-Le Louet, Agnès; Lescoat, Anne; Dupin, Nicolas; Salmon, Dominique; Pons, Gérard; Urien, Saïk

    2005-01-01

    The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc/F), peripheral distribution volu...

  15. Pemetrexed safety and pharmacokinetics in patients with third-space fluid

    DEFF Research Database (Denmark)

    Dickgreber, Nicolas J; Sørensen, Jens Benn; Paz-Ares, Luis G

    2010-01-01

    Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar...

  16. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

    Science.gov (United States)

    Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

    2018-03-01

    Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

  17. Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder

    Science.gov (United States)

    Tsuda, Yasuhiro; Tatami, Shinji; Yamamura, Norio; Tadayasu, Yusuke; Sarashina, Akiko; Liesenfeld, Karl-Heinz; Staab, Alexander; Schäfer, Hans-Günter; Ieiri, Ichiro; Higuchi, Shun

    2010-01-01

    AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODS Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2–16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTS Beside the priori-implemented body weight, only α1-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2–16 years) and adults when the effect of body weight was taken into consideration. PMID:20642551

  18. Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

    LENUS (Irish Health Repository)

    Gallagher, David J

    2012-02-01

    BACKGROUND: Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. OBJECTIVE: To identify predictors of response to sunitinib. DESIGN, SETTING, AND PARTICIPANTS: Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. MEASUREMENTS: BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS AND LIMITATIONS: Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3\\/4 hypertension compared with grade 0. Response was associated with low HIF-1alpha expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 x 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1alpha (p = 0.008). Results are limited by small numbers. CONCLUSIONS: Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.

  19. Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

    Directory of Open Access Journals (Sweden)

    Bouazza Naïm

    2011-12-01

    Full Text Available Abstract Background Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis. Methods Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recommended. The current dosing recommendations are 1.3 g/m2/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m2/day. Results Cysteamine concentrations were satisfactorily described by a one-compartment model. Parameter estimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were adequately described by an indirect response model where the first-order removal rate constant is stimulated by the cysteamine concentrations. Conclusions According to simulations, in order to increase the percentage of patient with cystine levels below 1 nmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID from 10 to 17 kg, 70 mg/kg/day (QID from 17 to 25 kg, 60 mg/kg/day (QID from 25 to 40 kg and 50 mg/kg/day (QID from 40 to 70 kg (these dosages remain under the maximum recommended dose. However an 8-hourly daily treatment (TID

  20. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function

    Directory of Open Access Journals (Sweden)

    Li Y

    2017-11-01

    Full Text Available Yan Li,1 Xiaomin Wang,2 Edward O’Mara,1 Meletios A Dimopoulos,3 Pieter Sonneveld,4 Katja C Weisel,5 Jeffrey Matous,6 David S Siegel,7 Jatin J Shah,8 Elisabeth Kueenburg,9 Lars Sternas,9 Chloe Cavanaugh,9 Mohamed Zaki,9 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development and Drug Metabolism and Pharmacokinetics, Celgene Corporation, Summit, NJ, USA; 3Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 5Department of Hematology, University Hospital Tübingen, Tübingen, Germany; 6Department of Hematology/Oncology, Colorado Blood Cancer Institute, Denver, CO, USA; 7Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 8Department of Lymphoma/Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA; 9Global Clinical R&D, Celgene Corporation, Summit, NJ, USA Abstract: Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide

  1. Pharmacokinetic profile of defibrotide in patients with renal impairment.

    Science.gov (United States)

    Tocchetti, Paola; Tudone, Elena; Marier, Jean-Francois; Marbury, Thomas C; Zomorodi, Katie; Eller, Mark

    2016-01-01

    Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (Cmax); 108.39 (CI: 97.85, 120.07) for area under the concentration-time curve to the time of the last quantifiable plasma concentration (AUC0-t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0-∞). These ranges were within 80%-125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC0-t, 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; Cmax, 53.8 µg/mL) were within 5%-8% of parameters after the first dose (AUC0-t, 117 µg·h/mL; AUC0-∞, 118 µg·h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%-37% and 50%-60% higher, respectively, versus controls, following single and multiple

  2. Quantification of metoprolol beta 2-adrenoceptor antagonism in asthmatic patients by pharmacokinetic-pharmacodynamic modelling

    NARCIS (Netherlands)

    Braat, M. C.; Jonkers, R. E.; van Boxtel, C. J.

    1992-01-01

    An integrated pharmacokinetic-pharmacodynamic model was used to quantify the beta 2-blocking activity of metoprolol in seven asthmatic patients. The patients received a subcutaneous dose of terbutaline on two consecutive days. On day 1 they were pretreated with placebo and on day 2 with metoprolol

  3. Pharmacokinetic profile of nifedipine GITS in hypertensive patients with chronic renal impairment.

    Science.gov (United States)

    Schneider, R; Stolero, D; Griffel, L; Kobelt, R; Brendel, E; Iaina, A

    1994-01-01

    25 hypertensive patients with normal or impaired renal function underwent pharmacokinetic and safety studies after single and multiple dose administration of nifedipine GITS (Gastro-Intestinal Therapeutic System) 60mg tablets. Complete pharmacokinetic data were obtained from 23 of these patients. Blood pressure and heart rate changes were compatible with the known properties of the drug. Impaired renal function did not affect the maximum plasma concentrations or bioavailability of nifedipine after single or multiple dose administration of nifedipine GITS, nor was there any evidence of excessive drug accumulation in the presence of renal impairment.

  4. ADAM, a hands-on patient simulator for teaching principles of drug disposition and compartmental pharmacokinetics.

    Science.gov (United States)

    Zuna, Ines; Holt, Andrew

    2017-11-01

    To design, construct and validate a pharmacokinetics simulator that offers students hands-on opportunities to participate in the design, administration and analysis of oral and intravenous dosing regimens. The Alberta Drug Administration Modeller (ADAM) is a mechanical patient in which peristaltic circulation of water through a network of silicone tubing and glass bottles creates a representation of the outcomes of drug absorption, distribution, metabolism and elimination. Changing peristaltic pump rates and volumes in bottles allows values for pharmacokinetic constants to be varied, thereby simulating differences in drug properties and in patient physiologies and pathologies. Following administration of methylene blue dye by oral or intravenous routes, plasma and/or urine samples are collected and drug concentrations are determined spectrophotometrically. The effectiveness of the simulator in enhancing student competence and confidence was assessed in two undergraduate laboratory classes. The simulator effectively models one- and two-compartment drug behaviour in a mathematically-robust and realistic manner. Data allow calculation of numerous pharmacokinetic constants, by traditional graphing methods or with curve-fitting software. Students' competence in solving pharmacokinetic problems involving calculations and graphing improved significantly, while an increase in confidence and understanding was reported. The ADAM is relatively inexpensive and straightforward to construct, and offers a realistic, hands-on pharmacokinetics learning opportunity for students that effectively complements didactic lectures. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  5. Pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients.

    OpenAIRE

    Chin, T W; Vandenbroucke, A; Fong, I W

    1995-01-01

    Current dosage regimens of trimethoprim-sulfamethoxazole used to treat Pneumocystis carinii pneumonia in AIDS patients have been based on data from healthy subjects or patients without AIDS. The clearance and absorption characteristics of the drugs may potentially be different between patients with and without AIDS. This study was conducted to assess the pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients treated for P. carinii pneumonia. P...

  6. Moxifloxacin pharmacokinetics and pleural fluid penetration in patients with pleural effusion.

    Science.gov (United States)

    Chatzika, Kalliopi; Manika, Katerina; Kontou, Paschalina; Pitsiou, Georgia; Papakosta, Despina; Zarogoulidis, Konstantinos; Kioumis, Ioannis

    2014-01-01

    The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC24) in PF (AUC24PF) to the AUC24 in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (CmaxPF) in patients with empyema/PPE was 2.23±1.31 mg/liter, and it was detected 7.50±2.39 h after the initiation of the infusion. In patients with malignant effusion, CmaxPF was 2.96±1.45 mg/liter, but it was observed significantly earlier, at 3.58±1.38 h (Ppleural effusion.

  7. Pharmacokinetic profile of defibrotide in patients with renal impairment

    Directory of Open Access Journals (Sweden)

    Tocchetti P

    2016-08-01

    Full Text Available Paola Tocchetti,1 Elena Tudone,2 Jean-Francois Marier,3 Thomas C Marbury,4 Katie Zomorodi,5 Mark Eller6 1Gentium, 2Clinical Operations, Gentium, Villa Guardia, Como, Italy; 3Reporting and Analysis Services, Pharsight, a Certara Company, Montreal, Quebec, Canada; 4Orlando Clinical Research Center, Orlando, FL, 5Early Development and Clinical Pharmacology, Jazz Pharmaceuticals, 6Early Drug Development, Jazz Pharmaceuticals, Palo Alto, CA, USA Abstract: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS, is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction, may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD on defibrotide pharmacokinetics (PK. Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78 for maximum observed plasma concentration (Cmax; 108.39 (CI: 97.85, 120.07 for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC0–t; and 109.98 (CI: 99.39, 121.70 for AUC extrapolated to infinity (AUC0–∞. These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide

  8. Depression in Cancer Patients

    Directory of Open Access Journals (Sweden)

    Beyhan Bag

    2014-06-01

    Full Text Available It is not enough to consider treatment and care depression in the oncology that is the most common psychiatric illness in cancer patient affects of cancer treatment and the patient`s quality of life negatively, which is determined through researches in the field. With development of psycho-oncology it has been demonstrated to establish an important link between the cancer patient`s treatment as well as psycho-social support for the patient and psychiatric treatment and care for the if it is needed. With this connection between them it has been proposed to use of bio-psycho-social-model in cancer patient to improve their care. To achieve this goal, it is expected from medical personnel to realize patients psychosocial need und if he/she has a psychiatric disorders or syndromes. For the medical personnel that work in oncology services, it is inevitable to organize in order to raise the awareness of depression in the cancer patients. In the present study, it is focused on raising the awareness of depression in cancer patient for the medical personnel. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(2.000: 186-198

  9. Efficacy and pharmacokinetics of intravenous paracetamol in the critically ill patient

    NARCIS (Netherlands)

    Samson, A.D.; Hunfeld, N.G.; Touw, D.J.; Melief, P.H.

    2009-01-01

    Introduction: Paracetamol (PCM) is a drug with analgesic and antipyretic properties. Despite its frequent use, little is known about its efficacy and pharmacokinetics (PK) when intravenously administered in the critically ill patient. A previous study suggests that therapeutic concentrations are not

  10. Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

    NARCIS (Netherlands)

    Lankheet, N.; Kloth, J.S.; Gadellaa-van Hooijdonk, C.G.M.; Cirkel, G.A.; Mathijssen, R.H.; Lolkema, M.P.; Schellens, J.H.; Voest, E.E.; Sleijfer, S.; Jonge, M.J. de; Haanen, J.B.; Beijnen, J.H.; Huitema, A.D.; Steeghs, N.

    2014-01-01

    Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of

  11. PHARMACOKINETICS OF ROCURONIUM BROMIDE IN PATIENTS WITH AND WITHOUT RENAL-FAILURE

    NARCIS (Netherlands)

    COOPER, RA; MIRAKHUR, RK; WIERDA, JMKH; MADDINENI, VR

    We studied the onset and duration of action and pharmacokinetics of rocuronium bromide during anaesthesia with nitrous oxide, fentanyl and isoflurane after a single bolus dose of rocuronium (0.6 mg kg(-1)) in nine patients with chronic renal failure requiring regular haemodialysis, and in nine

  12. Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

    NARCIS (Netherlands)

    Buter, H; Navis, GY; Woittiez, AJJ; de Zeeuw, D; de Jong, PE

    Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype I (AT1) receptor antagonist that is administered

  13. Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis.

    Science.gov (United States)

    Roberts, Darren M; Ranganathan, Dwarakanathan; Wallis, Steven C; Varghese, Julie M; Kark, Adrian; Lipman, Jeffrey; Roberts, Jason A

    2016-01-01

    ♦ The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ♦ As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. ♦ Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p Peritoneal Dialysis.

  14. Population pharmacokinetics of amikacin in neonatal intensive care unit patients

    Directory of Open Access Journals (Sweden)

    Paulo Caceres Guido

    2017-02-01

    Full Text Available Background Amikacin treatment requires close monitoring of blood concentrations to increase the probability that levels achieved are both effective and safe. Aims We described population pharmacokinetics parameters of amikacin in newborns from a Neonatal Intensive Care Unit with suspected or documented sepsis. Methods A nonlinear mixed-effect model approach was used to analyse the data. Results Twenty seven neonates were enrolled. Final parameter estimates were: Ke(h-1=0.232x(CR Exp-0.85; V(mL/kg=497. Conclusion Weight and serum creatinine are associated with neonatal amikacin volume of distribution and elimination constant rate, respectively. The presence of sepsis may decrease amikacin elimination, although this observation should be further explored. These results could help to individualize amikacin dosage for neonates.

  15. Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients.

    Science.gov (United States)

    Chung, Eun Kyoung; Cheatham, S Christian; Fleming, Megan R; Healy, Daniel P; Kays, Michael B

    2017-03-01

    The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary. © 2016, The American College of Clinical Pharmacology.

  16. Individual pharmacokinetic variation leads to underdosing of ciprofloxacin in some cystic fibrosis patients

    DEFF Research Database (Denmark)

    Schultz, Anders Nikolai Ørsted; Høiby, N; Nielsen, X C

    2017-01-01

    BACKGROUND: Ciprofloxacin (CIP) is frequently used when treating cystic fibrose (CF) patients with intermittent Pseudomonas aeruginosa (P. aeruginosa) lung colonization. However, approximately 20% of the patients progress to chronic infection despite early intervention. The aim of this study......, was to investigate the pharmacokinetics of CIP, to evaluate if CYP3A4-related metabolism is involved and to find the optimal dose needed to eradicate intermittently colonizing bacteria in the lungs of CF patients. Methods An open-label, prospective pharmacokinetic study was performed. Twenty-two adult CF......-patients were each given 500 mg CIP orally. One blood sample was taken at t = 0, and the following 12 hr, nine blood samples were collected. The optimal dose and interval was then calculated by Monte Carlo simulation. CYP3A4-activity was mesured using the Erythromycin Breath Test (ERMBT). Results A 14-fold...

  17. Population Pharmacokinetics of an Indian F(ab')2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii) Bites

    OpenAIRE

    Isbister, Geoffrey K.; Maduwage, Kalana; Saiao, Ana; Buckley, Nicholas A.; Jayamanne, Shaluka F.; Seyed, Shahmy; Mohamed, Fahim; Chathuranga, Umesh; Alexandre, Mendes; Abeysinghe, Chandana; Karunathilake, Harinda; Gawarammana, Indika; Lalloo, David; Janaka de Silva, H.

    2015-01-01

    Background\\ud \\ud There is limited information on antivenom pharmacokinetics. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell’s viper bites.\\ud \\ud Methods/Principal Findings\\ud \\ud Patient data and serial blood samples were collected from patients with Russell’s viper (Daboia russelii) envenoming in Sri Lanka. All patients received Indian F(ab’)2 snake antivenom manufactured by VINS Bioproducts Ltd. Antivenom concentrations were measur...

  18. Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

    Directory of Open Access Journals (Sweden)

    Quezada Wilmer

    2009-04-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam®, Mephaquin®, and Mefloquina-AC® Farma given in combination with artesunate. Methods Thirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1 Lariam, (2 Mephaquin, or (3 Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours, 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol. Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data. Results By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (Cmax and interquartile range was 2,820 ng

  19. Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Kunka, Megan E; Cady, Elizabeth A; Woo, Heejung C; Thompson Bastin, Melissa L

    2015-01-01

    Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

  20. ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study.

    Science.gov (United States)

    Murakami, H; Tamura, T; Yamada, Y; Yamamoto, N; Ueda, Y; Shimoyama, T; Saijo, N

    2002-12-01

    ZD0473 is new platinum agent that was rationally designed to circumvent platinum resistance and reduce the potential for nephro-and neurotoxicity. This Phase I dose-escalating study investigated the pharmacokinetics, tolerability and efficacy of ZD0473 in Japanese patients with solid, refractory tumours. ZD0473 was administered as a 1-h intravenous infusion every 3 weeks. Nine patients received a total of 16 cycles of ZD0473 (median 1 cycle/patient), with 3 patients treated at each of 3 doses (60, 90, 120 mg/m2). The maximum plasma concentration (C(max)) and the area under the concentration-time curve to infinity (AUC(0-infinity)) increased with dose in a linear fashion for both total platinum and ZD0473 in plasma ultrafiltrate, suggesting that the pharmacokinetics of ZD0473 are linear. Haematological and non-haematological toxicities such as nausea and vomiting were mild (grade 1 or 2) and transient. No clinically significant nephro-, oto- or neurotoxicity was observed. Dose-limiting toxicity (DLT) was not observed and the maximum tolerated dose (MTD) was not identified. ZD0473 treatment showed evidence of disease stabilisation in 3 patients (33%). In conclusion, ZD0473 appears to have linear pharmacokinetics, and an acceptable tolerability profile at doses up to 120 mg/m2 in Japanese patients with refractory solid malignancies. Following evaluation of the data from all the Western trials, the ZD0473 development programme changed and this Japanese trial was stopped.

  1. Comparison of pharmacokinetic MRI and [{sup 18}F] fluorodeoxyglucose PET in the diagnosis of breast cancer: initial experience

    Energy Technology Data Exchange (ETDEWEB)

    Brix, G. [Research Program ' ' Radiological Diagnostics and Therapy' ' , German Cancer Research Center (DKFZ), Heidelberg (Germany); Dept. of Medical Radiation Hygiene, Federal Office for Radiation Protection, Oberschleissheim (Germany); Henze, M. [Dept. of Nuclear Medicine, Univ. of Heidelberg, Heidelberg (Germany); Knopp, M.V.; Doll, J.; Hawighorst, H. [Research Program ' ' Radiological Diagnostics and Therapy' ' , German Cancer Research Center (DKFZ), Heidelberg (Germany); Lucht, R. [Dept. of Medical Radiation Hygiene, Federal Office for Radiation Protection, Oberschleissheim (Germany); Junkermann, H. [Dept. of Gynaecological Radiology, Univ. of Heidelberg (Germany); Haberkorn, U. [Research Program ' ' Radiological Diagnostics and Therapy' ' , German Cancer Research Center (DKFZ), Heidelberg (Germany); Dept. of Nuclear Medicine, Univ. of Heidelberg, Heidelberg (Germany)

    2001-10-01

    It was the aim of this methodology-oriented clinical pilot study to compare the potential of dynamic MRI and 2-[{sup 18}F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) for the detection and characterization of breast cancer. Fourteen women with suspicious breast lesions were examined. The MRI data were acquired with a turbo fast low-angle shot sequence and analyzed using a pharmacokinetic model. Emission data were detected in the sensitive 3D modus, iteratively reconstructed, and superimposed onto corresponding transmission images. In the 14 patients, 13 breast masses with a suspicious contrast enhancement and FDG uptake were detected. For these lesions, no statistically significant correlation between evaluated MR and PET parameters was found. Of the 9 histologically confirmed carcinomas, 8 were correctly characterized with MRI and PET. Two inflammatory lesions were concordantly classified as cancer. Moreover, dynamic MRI yielded another false-positive finding. In 6 patients, PET detected occult lymph node and/or distant metastases. Although both functional imaging techniques provide independent tissue information, the results concerning the diagnosis of primary breast lesions were almost identical. An advantage of PET, however, is its ability to localize lymph node involvement and distant metastases as an integral part of the examination. (orig.)

  2. Comparison of pharmacokinetic MRI and [18F] fluorodeoxyglucose PET in the diagnosis of breast cancer: initial experience

    International Nuclear Information System (INIS)

    Brix, G.; Henze, M.; Knopp, M.V.; Doll, J.; Hawighorst, H.; Lucht, R.; Junkermann, H.; Haberkorn, U.

    2001-01-01

    It was the aim of this methodology-oriented clinical pilot study to compare the potential of dynamic MRI and 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) for the detection and characterization of breast cancer. Fourteen women with suspicious breast lesions were examined. The MRI data were acquired with a turbo fast low-angle shot sequence and analyzed using a pharmacokinetic model. Emission data were detected in the sensitive 3D modus, iteratively reconstructed, and superimposed onto corresponding transmission images. In the 14 patients, 13 breast masses with a suspicious contrast enhancement and FDG uptake were detected. For these lesions, no statistically significant correlation between evaluated MR and PET parameters was found. Of the 9 histologically confirmed carcinomas, 8 were correctly characterized with MRI and PET. Two inflammatory lesions were concordantly classified as cancer. Moreover, dynamic MRI yielded another false-positive finding. In 6 patients, PET detected occult lymph node and/or distant metastases. Although both functional imaging techniques provide independent tissue information, the results concerning the diagnosis of primary breast lesions were almost identical. An advantage of PET, however, is its ability to localize lymph node involvement and distant metastases as an integral part of the examination. (orig.)

  3. Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

    Directory of Open Access Journals (Sweden)

    M.J.C. Carmona

    2005-05-01

    Full Text Available The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB, resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m², receiving propranolol before surgery (80-240 mg a day and postoperatively (10 mg a day. Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9 to 10.6 h (95% CI = 8.2-14.7; P < 0.01 and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3 to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05, while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6 vs 10.7 ml min-1 kg-1 (95% CI = 7.7-26.6; NS after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

  4. Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

    Science.gov (United States)

    Tsuji, Yasuhiro; Holford, Nicholas H G; Kasai, Hidefumi; Ogami, Chika; Heo, Young-A; Higashi, Yoshitsugu; Mizoguchi, Akiko; To, Hideto; Yamamoto, Yoshihiro

    2017-08-01

    Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF. © 2017 The British Pharmacological Society.

  5. Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy

    Directory of Open Access Journals (Sweden)

    Megan E. Kunka

    2015-01-01

    Full Text Available Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours, which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient’s actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

  6. The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care.

    Science.gov (United States)

    Koegelenberg, C F N; Nortje, A; Lalla, U; Enslin, A; Irusen, E M; Rosenkranz, B; Seifart, H I; Bolliger, C T

    2013-04-05

    There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. The therapeutic maximum plasma concentration (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

  7. Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study.

    NARCIS (Netherlands)

    Staals, L.M.; Snoeck, M.M.J.; Driessen, J.J.; Hamersvelt, H.W. van; Flockton, E.A.; Heuvel, M.W. van den; Hunter, J.M.

    2010-01-01

    BACKGROUND: Sugammadex is a selective relaxant binding agent designed to encapsulate the neuromuscular blocking agent, rocuronium. The sugammadex-rocuronium complex is eliminated by the kidneys. This trial investigated the pharmacokinetics (PKs) of sugammadex and rocuronium in patients with renal

  8. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Carey K Anders

    Full Text Available Breast cancer brain metastases (BCBM are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK and efficacy of PEGylated liposomal doxorubicin (PLD with non-liposomal doxorubicin (NonL-doxo in an intracranial model of BC.Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV × 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg or in combination (4.5 mg/kg with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence.Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31-38, which was significantly longer than controls (26d [CI 25-28]; p = 0.0012 or NonL-doxo treatment (23.5d [CI 18-28], p = 0.0002. Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31-38] versus 29.5d [CI 25-34]; p = 0.006.PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.

  9. Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

    OpenAIRE

    Giudicelli, J F; Chaignon, M; Richer, C; Giroux, B; Guedon, J

    1984-01-01

    The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 m...

  10. [Physiotherapy of cancer patients].

    Science.gov (United States)

    Gomez, Izabella; Szekanecz, Éva; Szekanecz, Zoltán; Bender, Tamás

    2016-07-01

    Physiotherapy of cancer patients is one of the most controversial issues in our country. Malignant diseases are firstly mentioned as a contraindication of physiotherapy. Until now, physiotherapy was not suggested (or only in limited accessibility) for those patients who had malignant disease in medical history. International medical practice was less restrictive in managing this topic. The development of imaging techniques put this question in a new light. On the basis of evidence, the majority of articles have reported beneficial effects of physiotherapy in cancer patients, and only few articles mentioned it as harmful. Of course, each patient requires an individual assessment, however, if we exclude the possibility of tumor recurrence and metastasis, most of physiotherapy procedures can be used safely. One of the aims of this review is to support the physicians' decisions when to prescribe treatments, in such a way, that more patients could receive physiotherapy. Orv. Hetil., 2016, 157(31), 1224-1231.

  11. Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients.

    Science.gov (United States)

    Belldina, Eric B; Huang, Mei Y; Schneider, Jerry A; Brundage, Richard C; Tracy, Timothy S

    2003-11-01

    Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic-pharmacodynamic model. Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min(-1) kg(-1), range = 17.3-52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7-32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22-0.92) between drug concentration and effect. The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.

  12. Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients.

    Science.gov (United States)

    Menkes, David B; Glue, Paul; Gale, Christopher; Lam, Frederic; Hung, Cheung-Tak; Hung, Noelyn

    2018-01-01

    Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. Clozapine and norclozapine steady state bioavailability was assessed over 24h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non-compartmental methods, and compared using unpaired t-tests. Mean pharmacokinetic parameters (AUC, C max and C min ) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Anti-cancer, pharmacokinetic and biodistribution studies of cremophor el free alternative paclitaxel formulation.

    Science.gov (United States)

    Jain, Subheet K; Utreja, Puneet; Tiwary, Ashok K; Mahajan, Mohit; Kumar, Nikhil; Roy, Partha

    2014-01-01

    The aim of the present investigation is to determine the in vivo potential of previously developed and optimized Cremophor EL free paclitaxel (CF-PTX) formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate. CF-PTX was found to have drug loading of 6 mg/ml similar to Cremophor EL based marketed paclitaxel formulation. In the present study, intracellular uptake, repeated dose 28 days sub-acute toxicity, anti-cancer activity, biodistribution and pharmacokinetic studies were conducted to determine in vivo performance of CF-PTX formulation in comparison to marketed paclitaxel formulation. Intracellular uptake of CF-PTX was studied using A549 cells by fluorescence activated cell sorting assay (FACS) and fluorescence microscopy. In vivo anti-cancer activity of CF-PTX was evaluated using Ehrlich ascites carcinoma (EAC) model in mice followed by biodistribution and pharmacokinetic studies. FACS investigation showed that fluorescence marker acridine orange (AO) solution showed only 19.8±1.1% intracellular uptake where as significantly higher uptake was observed in the case of AO loaded CF-PTX formulation (85.4±2.3%). The percentage reduction in tumor volume for CF-PTX (72.5±2.3%) in EAC bearing mice was found to be significantly (p<0.05) higher than marketed formulation (58.6±2.8%) on 14th day of treatment. Pharmacokinetic and biodistribution studies showed sustained plasma concentration of paclitaxel depicted by higher mean residence time (MRT; 18.2±1.8 h) and elimination half life (12.8±0.6 h) with CF-PTX formulation as compared to marketed formulation which showed 4.4±0.2 h MRT and 3.6±0.4 h half life. The results of the present study demonstrated better in vivo performance of CF-PTX and this formulation appears to be a promising carrier for sustained and targeted delivery of paclitaxel.

  14. Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

    2017-03-01

    Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

  15. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors

    Directory of Open Access Journals (Sweden)

    Yongkun Sun

    2016-10-01

    Full Text Available Abstract Background Anlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors. Methods Anlotinib (5–16 mg was orally administered in patients with solid tumor once a day on two schedules: (1 four consecutive weeks (4/0 or (2 2-week on/1-week off (2/1. Pharmacokinetic sampling was performed in all patients. Twenty-one patients were further enrolled in an expanded cohort study on the recommended dose and schedule. Preliminary tumor response was also assessed. Results On the 4/0 schedule, dose-limiting toxicity (DLT was grade 3 hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib had long elimination half-lives and significant accumulation during multiple oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum tolerated dose for the expanding study. Twenty of the 21 patients (with colon adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary thyroid carcinoma, and soft tissue sarcoma were assessable for antitumor activity of anlotinib: 3 patients had partial response, 14 patients had stable disease including 12 tumor burden shrinkage, and 3 had disease progression. The main serious adverse effects were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation. Conclusions At the dose of 12 mg once daily at the 2/1 schedule, anlotinib displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential, justifying the conduct of further studies.

  16. Psychotherapy for cancer patients.

    Science.gov (United States)

    Chong Guan, Ng; Mohamed, Salina; Kian Tiah, Lai; Kar Mun, Teoh; Sulaiman, Ahmad Hatim; Zainal, Nor Zuraida

    2016-07-01

    Objective Psychotherapy is a common non-pharmacological approach to help cancer patients in their psychological distress. The benefit of psychotherapies was documented, but the types of psychotherapies proposed are varied. Given that the previous literature review was a decade ago and no quantitative analysis was done on this topic, we again critically and systematically reviewed all published trials on psychotherapy in cancer patients. Method We identified 17 clinical trials on six types of psychotherapy for cancer patients by searching PubMed and EMBASE. Result There were four trials involved adjunct psychological therapy which were included in quantitative analysis. Each trial demonstrated that psychotherapy improved the quality of life and coping in cancer patients. There was also a reduction in distress, anxiety, and depression after a psychological intervention. However, the number and quality of clinical trials for each type of psychotherapy were poor. The meta-analysis of the four trials involved adjunct psychological therapy showed no significant change in depression, with only significant short-term improvement in anxiety but not up to a year-the standardized mean differences were -0.37 (95% confidence interval (CI) = -0.57, -0.16) at 2 months, -0.21 (95% CI = -0.42, -0.01) at 4 months, and 0.03 (95 % CI = -0.19, 0.24) at 12 months. Conclusion The evidence on the efficacy of psychotherapy in cancer patients is unsatisfactory. There is a need for more rigorous and well-designed clinical trials on this topic.

  17. Pharmacokinetic Analysis of Dynamic 18F-Fluoromisonidazole PET Data in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Schwartz, Jazmin; Grkovski, Milan; Rimner, Andreas; Schöder, Heiko; Zanzonico, Pat B; Carlin, Sean D; Staton, Kevin D; Humm, John L; Nehmeh, Sadek A

    2017-06-01

    Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. 18 F-fluoromisonidazole ( 18 F-FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic analysis (PKA) of 18 F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18 F-FDG and a dynamic 18 F-FMISO scan lasting 168 ± 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estimated for the volumes of interest determined using coregistered 18 F-FDG images for both the volume of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived average values of 18 F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate ( k 3 ) and delivery rate ( K 1 ), influx rate ( K i ) constants, and tissue-to-blood activity concentration ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on average, than those of normal lung and 4.4 times larger than those in muscle. Additionally, for almost all cases, k 3 and K i had a significant strong correlation for all tissue types. The TBR- k 3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K 1 - k 3 voxelwise correlations for tumors were varied, but negative for 76% of lesions, globally exhibiting a weak inverse relationship (average R = -0.23 ± 0.39). However, both

  18. The pharmacokinetics of morphine and lidocaine in nine severe trauma patients.

    Science.gov (United States)

    Berkenstadt, H; Mayan, H; Segal, E; Rotenberg, M; Almog, S; Perel, A; Ezra, D

    1999-12-01

    To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients. Clinical case study. Department of Anesthesiology and Intensive Care of a university hospital. Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study. After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration. Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively). Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

  19. Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours

    International Nuclear Information System (INIS)

    Vink, Stefan R.; Schellens, Jan H.M.; Beijnen, Jos H.; Sindermann, Herbert; Engel, Juergen; Dubbelman, Ria; Moppi, Gemi; Hillebrand, Michel J.X.; Bartelink, Harry; Verheij, Marcel

    2006-01-01

    Purpose: Perifosine is an orally applicable, membrane-targeted alkylphosphocholine analogue with antitumour activity and radiosensitising properties in preclinical models. The purpose of this phase I study was to determine the feasibility and tolerability of concurrent daily perifosine and radiation in patients with advanced cancer. Patients and methods: Starting dose of perifosine was 50 mg/day; dose escalation was in steps of 50 mg. Daily administration commenced 2 days before radiotherapy and was continued throughout the radiation treatment. At least three patients were entered at each dose level; at the 150 mg/day level 10 patients were included. Pharmacokinetic sampling was performed weekly pre-dosing. Twenty-one patients were entered. Tumour types included NSCLC (n = 17), prostate, oesophageal, colon and bladder cancer. Most patients (16/21) had received prior chemotherapy; none radiotherapy. Median number of daily perifosine administrations was 31 (range 24-53). Mean radiation dose (BED 1 ) was 59.8 Gy (range 50.7-87.5 Gy in 13-28 fractions). Results: Major drug-related toxicities according to CTC criteria were nausea in 57%, fatigue in 48%, vomiting in 38%, diarrhoea in 38% and anorexia in 19%. No bone marrow toxicity was observed. DLT (nausea/vomiting) was encountered in two of five patients at the 200 mg/day dose level. Dose-dependent steady-state plasma levels were reached after 1 week. Major radiotherapy-related acute toxicity consisted of dysphagia in 38% and pneumonitis in 29%. Conclusion: Perifosine can be safely combined with fractionated radiotherapy. A dosage of 150 mg/day, to be started at least 1 week prior to radiotherapy, is recommended for phase II evaluation

  20. The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria

    NARCIS (Netherlands)

    Koopmans, R.; Duc, D. D.; Kager, P. A.; Khanh, N. X.; Dien, T. K.; de Vries, P. J.; van Boxtel, C. J.

    1998-01-01

    Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted

  1. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys.

    Science.gov (United States)

    Kapetanovic, Izet M; Muzzio, Miguel; Hu, Shu-Chieh; Crowell, James A; Rajewski, Roger A; Haslam, John L; Jong, Ling; McCormick, David L

    2010-05-01

    SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (Solutol, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph-tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability. The Solutol formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m(2). Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys. The lipid-based surfactant/emulsifiers, especially Solutol, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.

  2. The pharmacokinetics of propofol in ICU patients undergoing long-term sedation.

    Science.gov (United States)

    Smuszkiewicz, Piotr; Wiczling, Paweł; Przybyłowski, Krzysztof; Borsuk, Agnieszka; Trojanowska, Iwona; Paterska, Marta; Matysiak, Jan; Kokot, Zenon; Grześkowiak, Edmund; Bienert, Agnieszka

    2016-11-01

    The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

    Science.gov (United States)

    Hussein, Z; Eaves, C J; Hutchinson, D B; Canfield, C J

    1996-11-01

    1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children ( 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

  4. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis.

    Science.gov (United States)

    Grassin-Delyle, S; Theusinger, O M; Albrecht, R; Mueller, S; Spahn, D R; Urien, S; Stein, P

    2018-06-01

    Tranexamic acid is used both pre-hospital and in-hospital as an antifibrinolytic drug to treat or prevent hyperfibrinolysis in trauma patients; dosing, however, remains empirical. We aimed to measure plasma levels of tranexamic acid in patients receiving pre-hospital anti-hyperfibrinolytic therapy and to build a population pharmacokinetic model to propose an optimised dosing regimen. Seventy-three trauma patients were enrolled and each received tranexamic acid 1 g intravenously pre-hospital. A blood sample was drawn after arrival in the emergency department, and we measured the plasma tranexamic acid concentration using liquid chromatography-mass spectrometry, and modelled the data using non-linear mixed effect modelling. Tranexamic acid was administered at a median (IQR [range]) time of 43 (30-55 [5-135]) min after trauma. Plasma tranexamic acid levels were determined on arrival at hospital, 57 (43-70 [20-148]) min after pre-hospital administration of the drug. The measured concentration was 28.7 (21.5-38.5 [8.7-89.0]) μg.ml -1 . Our subjects had sustained severe trauma; injury severity score 20 (16-29 [5-75]), including penetrating injury in 2.8% and isolated traumatic brain injury in 19.7%. The pharmacokinetics were ascribed a two-compartment open model with body-weight as the main covariate. As tranexamic acid concentrations may fall below therapeutic levels during initial hospital treatment, we propose additional dosing schemes to maintain a specific target blood concentration for as long as required. This is the first study to investigate plasma level and pharmacokinetics of tranexamic acid after pre-hospital administration in trauma patients. Our proposed dosing regimen could be used in subsequent clinical trials to better study efficacy and tolerance profiles with controlled blood concentrations. © 2018 The Association of Anaesthetists of Great Britain and Ireland.

  5. Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

    2008-12-01

    In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

  6. Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients.

    Science.gov (United States)

    Wang, Huifen Faye; Qiu, Feng; Wu, Xiongfe; Fang, Juanzhi; Crownover, Penelope; Korth-Bradley, Joan; Schulman, Seth

    2014-05-01

    This open-label, nonrandomized study was conducted to evaluate the steady-state pharmacokinetics of sirolimus in 24 stable Chinese renal transplant patients receiving daily oral maintenance doses of sirolimus (1-4 mg). Repeated trough and serial whole blood sirolimus concentrations over a 24-hour dosing interval were collected and assayed using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Non-compartmental analysis (NCA) was employed to calculate sirolimus pharmacokinetic parameters. Cytochrome P450 (CYP) 3A5 genotyping was performed. Cyclosporine (CsA) levels were determined for patients who took concomitant CsA. Mean (±SD) sirolimus maximum concentration (Cmax ), area under the concentration-time curve within a dosing interval of τ (AUCτ ), oral clearance (CL/F), and trough concentration (Ctrough ) at steady state were: 14.1 ± 13.4 ng/mL, 199 ± 210 ng · h/mL, 10.1 ± 4.4 L/h, and 5.9 ± 6.3 ng/mL, respectively. Median tmax (range) was 2.49 hours (1-12 hours). A strong correlation was observed between Ctrough and AUCτ . Pharmacokinetics of sirolimus in patients with and without concomitant CsA were comparable. Allele frequency of CYP3A5*3 was 70.9% and a trend of higher oral clearance was observed in CYP3A5 expressers compared with non-expressers although the number of subjects in each genotype was small. © 2014, The American College of Clinical Pharmacology.

  7. Cancer patients' evaluation of communication

    DEFF Research Database (Denmark)

    Ross, Lone; Petersen, Morten Aagaard; Johnsen, Anna Thit

    2013-01-01

    The aims of this study were to assess how communication with health care staff is perceived by Danish cancer patients and to characterise those patients who report problems in communication.......The aims of this study were to assess how communication with health care staff is perceived by Danish cancer patients and to characterise those patients who report problems in communication....

  8. Lung cancer in younger patients

    DEFF Research Database (Denmark)

    Abbasowa, Leda; Madsen, Poul Henning

    2016-01-01

    INTRODUCTION: Lung cancer remains a leading cause of cancer-related death. The incidence increases with age and the occurrence in young patients is relatively low. The clinicopathological features of lung cancer in younger patients have not been fully explored previously. METHODS: To assess the age...... differences in the clinical characteristics of lung cancer, we conducted a retrospective analysis comparing young patients ≤ 65 years of age with an elderly group > 65 years of age. Among 1,232 patients evaluated due to suspicion of lung cancer in our fast-track setting from January-December 2013, 312 newly...... diagnosed lung cancer patients were included. RESULTS: Patients ≤ 65 years had a significantly higher representation of females (p = 0.0021), more frequent familial cancer aggregation (p = 0.028) and a lower incidence of squamous cell carcinoma (p = 0.0133). When excluding pure carcinoid tumours...

  9. Pharmacokinetics of rifampin in Peruvian tuberculosis patients with and without comorbid diabetes or HIV.

    Science.gov (United States)

    Requena-Méndez, Ana; Davies, Geraint; Ardrey, Alison; Jave, Oswaldo; López-Romero, Sonia L; Ward, Stephen A; Moore, David A J

    2012-05-01

    For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (C(max)) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin C(max) was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different C(max) results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (T(max)) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.

  10. Preventing Infections in Cancer Patients

    Science.gov (United States)

    ... Protect: Know the Signs and Symptoms of Infection Neutropenia and Risk for Infection Health Care Providers Educational Materials Cancer and Flu How to Prevent Flu from Spreading Flu Symptoms Information for Families and Caregivers Flu Treatment for Cancer Patients and ...

  11. Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis.

    Science.gov (United States)

    Gallelli, L; Galasso, O; Urzino, A; Saccà, S; Falcone, D; Palleria, C; Longo, P; Corigliano, A; Terracciano, R; Savino, R; Gasparini, G; De Sarro, G; Southworth, S R

    2012-12-01

    Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

  12. A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Ying G

    2013-01-01

    Full Text Available Zhongling Zhu,1,4 Zhengzi Qian,2,4 Zhao Yan,1,4 Cuicui Zhao,2,4 Huaqing Wang,2,4 Guoguang Ying3,41Department of Clinical Pharmacology, 2Department of Lymphoma, 3Laboratory of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China; 4Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of ChinaBackground: Ursolic acid is a promising anticancer agent. The current study aims to evaluate the single- and multiple-dose pharmacokinetics (PK as well as the safety of ursolic acid nanoliposomes (UANL in healthy volunteers and in patients with advanced solid tumors.Methods: Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m2 of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m2 of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry.Results: The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (Cmax increased linearly as a function of the dose (r = 0.999. The mean area under the plasma concentration-time curve (AUC from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998. However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, Cmax, time to Cmax, and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate.Conclusions: UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m2 to 98 mg/m2. No drug accumulation was observed with repeated doses of UANL. The intravenous infusion of UANL was well

  13. Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

    Science.gov (United States)

    GIACCONE, M.; BARTOLI, A.; GATTI, G.; MARCHISELLI, R.; PISANI, F.; LATELLA, M.A.; PERUCCA, E.

    1996-01-01

    1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., Panticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients. PMID:8799524

  14. An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers.

    Directory of Open Access Journals (Sweden)

    Moran Elishmereni

    2011-09-01

    Full Text Available Interleukin (IL-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK and pharmacodynamic (PD data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected "training" data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent "validation" data in melanoma and renal cell carcinoma-challenged mice (R(2>0.90. Simulations of the verified model surfaced important therapeutic insights: (1 Fractionating the standard daily regimen (50 µg/dose into a twice daily schedule (25 µg/dose is advantageous, yielding a significantly lower tumor mass (45% decrease; (2 A low-dose (12 µg/day regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R(2>0.89, thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.

  15. Pharmacokinetics of Deferiprone in Patients with β-Thalassaemia : Impact of Splenectomy and Iron Status.

    Science.gov (United States)

    Limenta, Lie Michael George; Jirasomprasert, Totsapol; Jittangprasert, Piyada; Wilairat, Prapin; Yamanont, Praveena; Chantharaksri, Udom; Fucharoen, Suthat; Morales, Noppawan Phumala

    2011-01-01

    Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with β-thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with b-thalassaemia. However, there is wide interpatient variation in deferiprone-induced urinary iron excretion (UIE). We hypothesized that splenectomy and iron status might influence the pharmacokinetic profiles of deferiprone in patients with β-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis. Thirty-one patients with β-thalassaemia/haemoglobin E (20 splenecto-mized and 11 non-splenectomized patients) were enrolled in the study. After an overnight fast, the subjects received a single oral dose of deferiprone 25 mg/kg of body weight. Blood samples were collected pre-dosing and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after dosing. Urine output was pooled and collected at 0-2, 2-4, 4-8, 8-12 and 12-24 hour intervals. Serum and urine concentrations of deferiprone and its metabolite deferiprone glucuronide were determined using a validated high-performance liquid chromatography method. Serum deferiprone-chelated iron and UIE were determined using a validated colourimetric method. No significant difference in the pharmacokinetic parameters of non-conjugated deferiprone was observed between splenectomized and non-splenectomized patients. However, the maximum serum concentration (C max ) and the area under the serum concentration-time curve (AUC) from time zero to infinity (AUC∞) values of deferiprone glucuronide were significantly lower (both p values of serum deferiprone-chelated iron, as well as UIE, were significantly higher (p values 7.1 µmol/L, 1645 mmol · min/L and 77.1 mmol, respectively) than in non-splenectomized patients (median values 3.1 µmol/L, 545 mmol · min/L and 12.5 µmol, respectively). Urinary

  16. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

    DEFF Research Database (Denmark)

    Østergaard, Doris; Viby-Mogensen, Jørgen; Pedersen, N.A.

    2002-01-01

    age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers......age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers...

  17. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

    Science.gov (United States)

    Herbst, Roy S; Hong, David; Chap, Linnea; Kurzrock, Razelle; Jackson, Edward; Silverman, Jeffrey M; Rasmussen, Erik; Sun, Yu-Nien; Zhong, Don; Hwang, Yuying C; Evelhoch, Jeffrey L; Oliner, Jonathan D; Le, Ngocdiep; Rosen, Lee S

    2009-07-20

    PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient

  18. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus.

    Science.gov (United States)

    Morita, Shigemichi; Takahashi, Toshiya; Yoshida, Yasushi; Yokota, Naohisa

    2016-04-01

    Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic regimen and to clarify the pharmacokinetics (PK) of HCQ in Japanese patients with CLE with or without SLE (CLE/SLE), a population pharmacokinetic (PopPK) analysis was performed. In a clinical study of Japanese patients with a diagnosis of CLE irrespective of the presence of SLE, blood and plasma drug concentration-time data receiving multiple oral doses of HCQ sulfate (200-400 mg daily) were analyzed using nonlinear mixed-effects model software. The blood and plasma concentrations of HCQ were analyzed using a high-performance liquid chromatography tandem mass spectrometry method. Model evaluation and validation were performed using goodness-of-fit (GOF) plots, visual predictive check, and a bootstrap. The PopPKs of HCQ in the blood and plasma of 90 Japanese patients with CLE/SLE were well described by a 1-compartment model with first-order absorption and absorption lag time. Body weight was a significant (P < 0.001) covariate of oral clearance of HCQ. The final model was assessed using GOF plots, a bootstrap, and visual predictive check, and this model was appropriate. Simulations based on the final model suggested that the recommended daily doses of HCQ sulfate (200-400 mg) based on the ideal body weight in Japanese patients with CLE/SLE were in the similar concentration ranges. The PopPK models derived from both blood and plasma HCQ concentrations of Japanese patients with CLE/SLE were developed and validated. Based on this study, the dosage regimens of HCQ sulfate for Japanese patients with CLE/SLE should be calculated using the individual ideal body weight.

  19. Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

    Science.gov (United States)

    Grandjean, Thomas R B; Chappell, Mike J; Yates, James T W; Jones, Kevin; Wood, Gemma; Coleman, Tanya

    2011-11-01

    A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. A PHASE-II AND PHARMACOKINETIC STUDY WITH ORAL PIRITREXIM FOR METASTATIC BREAST-CANCER

    NARCIS (Netherlands)

    DEVRIES, EGE; GIETEMA, JA; WORKMAN, P; SCOTT, JE; CRAWSHAW, A; DOBBS, HJ; DENNIS, [No Value; MULDER, NH; SLEIJFER, DT; WILLEMSE, PHB

    Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase 11 study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received

  1. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors

    NARCIS (Netherlands)

    Kuenen, Bart C.; Rosen, Lee; Smit, Egbert F.; Parson, Mandy R. N.; Levi, Marcel; Ruijter, Rita; Huisman, Holger; Kedde, Marc A.; Noordhuis, Paul; van der Vijgh, Wim J. F.; Peters, Godefridus J.; Cropp, Gillian F.; Scigalla, Paul; Hoekman, Klaus; Pinedo, Herbert M.; Giaccone, Giuseppe

    2002-01-01

    Purpose: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. Patients and Methods: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously

  2. The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study

    NARCIS (Netherlands)

    van Leeuwen, R.; Lange, J. M.; Hussey, E. K.; Donn, K. H.; Hall, S. T.; Harker, A. J.; Jonker, P.; Danner, S. A.

    1992-01-01

    To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. A Phase I, open-label, single-centre study. Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts < 500 x 10(6)/l who had not received previous antiretroviral therapy completed the study. Each patient

  3. A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors.

    Science.gov (United States)

    Gray, Jhanelle E; Haura, Eric; Chiappori, Alberto; Tanvetyanon, Tawee; Williams, Charles C; Pinder-Schenck, Mary; Kish, Julie A; Kreahling, Jenny; Lush, Richard; Neuger, Anthony; Tetteh, Leticia; Akar, Angela; Zhao, Xiuhua; Schell, Michael J; Bepler, Gerold; Altiok, Soner

    2014-03-15

    Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer. Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed. Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02). We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. ©2014 AACR.

  4. Use of nanotechnology for improved pharmacokinetics and activity of immunogenic cell death inducers used in cancer chemotherapy.

    Science.gov (United States)

    Janicka, Martyna; Gubernator, Jerzy

    2017-09-01

    Immunogenic cell death inducers (ICD inducers) are a diverse group of therapeutic molecules capable of eliciting an adaptive immune response against the antigens present on the surface of dying cancer cells. Most of these molecules suffer from low bioavailability, high toxicity and poor pharmacokinetics which limit their application. It is believed that nanotechnology, in particular nano-sized nanocarriers, can address most of the issues that limit the use of ICD inducers. Area covered: The mechanism of action of ICD inducers and their limitations is discussed. In addition, we cover the novel possibilities arising from the use of nanotechnology to improve delivery of ICD inducers to the target tissue as well as the restrictions of modern nanotechnology. Expert opinion: At present, nanocarrier formulations suffer from low bioavailability, poor pharmacokinetics and stability issues. Nonetheless, there is a tremendous future for combinatorial immune-pharmacological treatments of human tumors based on nanocarrier delivery of ICD inducers.

  5. Population Pharmacokinetics of Meropenem in Plasma and Subcutis in Patients on Extracorporeal Membrane Oxygenation Treatment

    DEFF Research Database (Denmark)

    Hanberg, Pelle; Öbrink-Hansen, Kristina; Thorsted, Anders

    2018-01-01

    The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving ECMO treatment, and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We...... conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 hours. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed...... infusion would be needed for 100%fT>MIC and 100%fT>4xMIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine-clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic...

  6. Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    He, Yan-Ling; Serra, Denise; Wang, Yibin

    2007-01-01

    BACKGROUND: Vildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus. OBJECTIVES: To assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10 mg, 25 mg and 100 mg twice...... daily following oral administration in patients with type 2 diabetes. METHODS: Thirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10 mg, 25 mg and 100 mg as well as placebo...... twice daily for 28 days. RESULTS: Vildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner...

  7. Muscle dysfunction in cancer patients

    DEFF Research Database (Denmark)

    Christensen, Jesper Frank; Jones, L W; Andersen, J L

    2014-01-01

    dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL). Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented...... implications of muscle dysfunction in cancer patients. The efficacy of exercise training to prevent and/or mitigate cancer-related muscle dysfunction is also discussed. DESIGN: We identified 194 studies examining muscular outcomes in cancer patients by searching PubMed and EMBASE databases. RESULTS: Muscle...... dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle...

  8. Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients

    Science.gov (United States)

    Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Perri, Gianni Di; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J

    2006-01-01

    Background Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Methods and Findings Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared

  9. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

    Directory of Open Access Journals (Sweden)

    Julie A Simpson

    2006-11-01

    Full Text Available Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria.Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F was 2.64 (l/kg/h with 66% inter-individual variability. The apparent volume of distribution (V/F was 2.75 (l/kg with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92 (l/kg/h for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder

  10. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

    Science.gov (United States)

    Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Di Perri, Gianni; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J

    2006-11-01

    Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent

  11. Leflunomide in dialysis patients with rheumatoid arthritis--a pharmacokinetic study.

    Science.gov (United States)

    Bergner, Raoul; Peters, Lena; Schmitt, Verena; Löffler, Christian

    2013-02-01

    Pharmacokinetic data of disease modifying antirheumatic drugs during hemodialysis are limited to sulfasalazine, methotrexate, and cyclosporine. Only respective anecdotal data have been reported on leflunomide. We repeatedly measured teriflunomide (A77-1726), the active metabolite of leflunomide, during standard hemodialysis sessions and calculated teriflunomide clearances in five patients with rheumatoid arthritis (RA) and end-stage renal disease. The calculated teriflunomide clearances during a standardized dialysis session of 3-4.5 h at a blood flow rate of 160-300 ml/min were between 0 and 4.3 ml/min, the mean clearances of the total dialysis ranged between 1.1 and 3.4 ml/min. Total amount of teriflunomide removed was 5.8-8.8 μg per dialysis session. Dialytic removal of the active metabolite of leflunomide, teriflunomide (A77-1726), is negligible. Leflunomide can be used for RA patients on chronic dialysis without any dosage modification.

  12. Mefloquine pharmacokinetics in healthy subjects and in peptic ulcer patients after cimetidine administration.

    Science.gov (United States)

    Kolawole, J A; Mustapha, A; Abudu-Aguye, I; Ochekpe, N

    2000-01-01

    The pharmacokinetics of orally administered mefloquine were determined in six healthy male subjects and in six ulcer patients before and after a 3-day course of cimetidine (400 mg morning and evening). Peak plasma concentrations Cmax and AUC0-infinity were similarly and significantly (P infinity was increased by 37.5% in healthy and peptic ulcer subjects respectively. The values of t1/2ab absorption and t1/2 beta elimination, total crearance CLT/F and volume of distribution were altered to varying levels after cimetidine treatment but the changes were not statistically significant in both healthy and peptic ulcer subjects. The established long t1/2 beta and this apparent interaction between mefloquine and cimetidine which resulted in increased mefloquine plasma concentration might be of clinical significant in patients with neurological/psychiatric history.

  13. A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients

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    Alejandro Pérez-Pitarch

    2015-03-01

    Full Text Available Background: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn's disease and ulcerative colitis, is administered at predefined interdose-intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. Aims: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. Methods: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix inter-dose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. Results: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05. Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 % without reaching higher peak concentrations. Conclusions: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.

  14. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials

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    Gabrail N

    2015-03-01

    Full Text Available Nashat Gabrail,1 Ronald Yanagihara,2 Marek Spaczyński,3 William Cooper,4 Erin O'Boyle,5 Carrie Smith,1 Ralph Boccia6 1Gabrail Cancer Center, Canton, OH, USA; 2St Louise Regional Hospital, Gilroy, CA, USA; 3Department of Gynecology, Obstetrics and Gynecologic Oncology, University of Medical Sciences, Poznan, Poland; 4TFS International, Flemington, NJ, USA; 5FibroGen, Inc., San Francisco, CA, USA; 6Center for Cancer and Blood Disorders, Bethesda, MD, USA Background: Despite advances with new therapies, a significant proportion of patients (>30% suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Methods: In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively. In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated. Results: APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema

  15. An Evaluation of Ciprofloxacin Pharmacokinetics in Critically Ill Patients undergoing Continuous Veno-venous Haemodiafiltration

    LENUS (Irish Health Repository)

    Spooner, Almath M

    2011-08-04

    Abstract Background The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance. Methods This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF. Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t1\\/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L\\/hr and ultrafiltration rate of 2 L\\/hr. The blood flow rate was 200 ml\\/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter. Results Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t1\\/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L\\/hr, a median Vdss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+\\/-0.29 L\\/hr and a clearance of creatinine (Clcr) of 2.66+\\/-0.25 L\\/hr. Thus CVVHDF, at an average flow rate of ~3.5 L\\/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated Cpmax\\/MIC and AUC0-24\\/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg\\/L) and exceed the proposed criteria of >10 for Cpmax\\/MIC and > 100 for AUC0-24\\/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate. Conclusions Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic

  16. The Emergence of Linezolid Resistance among Enterococci in Intestinal Microbiota of Treated Patients Is Unrelated to Individual Pharmacokinetic Characteristics

    Science.gov (United States)

    Nguyen, T. T.; Defrance, G.; Massias, L.; Alavoine, L.; Lefort, A; Noel, V.; Senneville, E.; Doucet-Populaire, F.; Mentré, F.; Andremont, A.; Duval, X.

    2014-01-01

    Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. We assessed the impact of linezolid on the microbiota and the emergence of resistance and investigated its relationship with plasma pharmacokinetics of the antibiotic. Twenty-eight patients were treated for the first time with linezolid administered orally (n = 17) or parenterally (n = 11) at 600 mg twice a day. Linezolid plasma pharmacokinetic analysis was performed on day 7. Colonization by fecal enterococci, pharyngeal streptococci, and nasal staphylococci were assessed using selective media with or without supplemental linezolid. The resistance to linezolid was characterized. The treatment led to a decrease of enterococci, staphylococci, and streptococci in the fecal (P = 0.03), nasal, and pharyngeal (P linezolid resistance during treatment was observed only in the intestinal microbiota and unrelated to pharmacokinetic parameters. However, colonization by Gram-positive bacteria was reduced as a result of treatment in all microbiotas. PMID:24566182

  17. Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

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    Xiao W

    2012-03-01

    Full Text Available Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®. Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications

  18. Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[F-18]levodopa positron emission tomography in patients with Parkinson's disease

    NARCIS (Netherlands)

    Dietz, M; Harder, S; Graff, J; Kunig, G; Vontobel, P; Leenders, KL; Baas, H

    Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with

  19. Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia.

    Science.gov (United States)

    Kim, Dong-Wook; Tan, Eugene Y; Jin, Yu; Park, Sahee; Hayes, Michael; Demirhan, Eren; Schran, Horst; Wang, Yanfeng

    2011-02-01

    The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML). Patients (n = 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2-8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses. The area under the plasma concentration-time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone. The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  20. Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

    Science.gov (United States)

    Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

    2016-08-01

    Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

  1. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    Science.gov (United States)

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  2. Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma.

    Science.gov (United States)

    Konner, Jason; Grisham, Rachel N; Park, Jae; O'Connor, Owen A; Cropp, Gillian; Johnson, Robert; Hannah, Alison L; Hensley, Martee L; Sabbatini, Paul; Mironov, Svetlana; Miranov, Svetlana; Danishefsky, Samuel; Hyman, David; Spriggs, David R; Dupont, Jakob; Aghajanian, Carol

    2012-12-01

    To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16-120 mg/m(2)). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m(2). Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m(2). PK data were linear from 16 to 100 mg/m(2), with proportional increases in mean C(max) and AUC(tot) as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m(2) revealed the following: half-life (t (½)) = 9.1 ± 2.2 h; volume of distribution (V(z)) = 119 ± 41 L/m(2); clearance (CL) = 9.3 ± 3.2 L/h/m(2). MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m(2). Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed. KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.

  3. Cachexia among US cancer patients.

    Science.gov (United States)

    Arthur, Susan T; Van Doren, Bryce A; Roy, Debosree; Noone, Joshua M; Zacherle, Emily; Blanchette, Christopher M

    2016-09-01

    Cancer cachexia is a debilitating condition and results in poor prognosis. The purpose of this study was to assess hospitalization incidence, patient characteristics, and medical cost and burden of cancer cachexia in the US. This study used a cross-sectional analysis of the Nationwide Inpatient Sample (NIS) for 2009. Five cancers reported to have the highest cachexia incidence were assessed. The hospitalization incidence related to cachexia was estimated by cancer type, cost and length of stay were compared, and descriptive statistics were reported for each cancer type, as well as differences being compared between patients with and without cachexia. Risk of inpatient death was higher for patients with cachexia in lung cancer (OR = 1.32; CI = 1.20-1.46) and in all cancers combined (OR = 1.76; CI = 1.67-1.85). The presence of cachexia increased length of stay in lung (IRR = 1.05; CI = 1.03-1.08), Kaposi's sarcoma (IRR = 1.47; CI = 1.14-1.89) and all cancers combined (IRR = 1.09; CI = 1.08-1.10). Additionally, cachectic patients in the composite category had a longer hospitalization stay compared to non-cachectic patients (3-9 days for those with cachexia and 2-7 days for those without cachexia). The cost of inpatient stay was significantly higher in cachexic than non-cachexic lung cancer patients ($13,560 vs $13 190; p Cachexia increases hospitalization costs and length of stay in several cancer types. Identifying the medical burden associated with cancer cachexia will assist in developing an international consensus for recognition and coding by the medical community and ultimately an effective treatment plans for cancer cachexia.

  4. A Review on Clinical Pharmacokinetics of Tamsulosin in Patients with Benign Prostatic Hyperplasia

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    Tolou Ghamari

    2016-08-01

    Full Text Available Context Benign prostatic hyperplasia (BPH that disturbs aged males is described as the abundant, chronic progressive disorder usually associated with lower urinary tract symptoms. The alpha 1A-adrenergic receptor antagonist, tamsulosin (Flomax®/Omnic®, seems to be an appropriate management from the view point of urological surgeons. The current review aimed to evaluate the clinical pharmacological properties of tamsulosin in prostate disorders. Evidence Acquisition United States national library of medicine (PubMed, NLM were searched from April 1991 to March 2016. The Mesh terms were: tamsulosin, tamsulosin pharmacokinetics in urology, tamsulosin in BPH and clinical pharmacokinetics of tamsulosin in BPH. Published clinical trials and review articles applicable to pharmacotherapy of tamsulosin in BPH were reviewed. Results In patients with mild international prostate symptom score (< 8 to moderate symptoms of BPH, initial treatment with an alpha 1-adrenergic antagonist monotherapy were useful. With a half-life of 9 - 13 hours, the oral bioavailability of drug was reported 100%. The drug is metabolized by liver. Excretion through renal was reported 76%. Initial dose of drug was 0.4 mg/day and the maximum dose was reported 0.8 mg/day. The drug could cause dizziness, sever drowsiness and problems in thinking, driving and many other complications. Other serious adverse reactions could be mentioned as hives, rash, itching, and difficulty in breathing, swelling of face, lips, tongue and throat. Tamsulosin therapy should be stopped in patients who experience hypotension. Conclusions To treat BPH therapeutically, it is necessary to stabilize severities of the patient’s symptoms with potential side effects of the treatment. Tamsulosin blocks alpha 1-receptors in smooth muscles both in the bladder neck and prostate, which leads to relaxation and subsequently less resistance to urinary flow. By advancement of tamsulosin, pharmacotherapy strategies could

  5. Survival of Sami cancer patients

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    Leena Soininen

    2012-07-01

    Full Text Available Objectives. The incidence of cancer among the indigenous Sami people of Northern Finland is lower than among the Finnish general population. The survival of Sami cancer patients is not known, and therefore it is the object of this study. Study design. The cohort consisted of 2,091 Sami and 4,161 non-Sami who lived on 31 December 1978 in the two Sami municipalities of Inari and Utsjoki, which are located in Northern Finland and are 300–500 km away from the nearest central hospital. The survival experience of Sami and non-Sami cancer patients diagnosed in this cohort during 1979–2009 was compared with that of the Finnish patients outside the cohort. Methods. The Sami and non-Sami cancer patients were matched to other Finnish cancer patients for gender, age and year of diagnosis and for the site of cancer. An additional matching was done for the stage at diagnosis. Cancer-specific survival analyses were made using the Kaplan–Meier method and Cox regression modelling. Results. There were 204 Sami and 391 non-Sami cancer cases in the cohort, 20,181 matched controls without matching with stage, and 7,874 stage-matched controls. In the cancer-specific analysis without stage variable, the hazard ratio for Sami was 1.05 (95% confidence interval 0.85–1.30 and for non-Sami 1.02 (0.86–1.20, indicating no difference between the survival of those groups and other patients in Finland. Likewise, when the same was done by also matching the stage, there was no difference in cancer survival. Conclusion. Long distances to medical care or Sami ethnicity have no influence on the cancer patient survival in Northern Finland.

  6. [Sexy cancer--sexuality for cancer patients].

    Science.gov (United States)

    Peleg-Nesher, Sharon; Yachini, Brurya; Inbar, Moshe

    2009-09-01

    Sexuality is a basic need for every human being as long as he or she is alive, irrespective of age or health status. Approximately 23,500 individuals are diagnosed with cancer each year in Israel and join the 120,000 cancer patients currently living in Israel. The results of cancer treatments are traditionally assessed and based on the outcome regarding mortality versus survival. An equally important aspect to be addressed in this assessment must relate to quality of life. One of the more painful insults to the quality of life of cancer patients relates to the deleterious effects on sexuality. This article aims to present physicians with the spectrum of sexuality-related issues which are encountered by cancer patients and their partners, starting from the moment of diagnosis, throughout the various stages of treatment and to provide basic knowledge. Many individuals contracting cancer have difficulty dealing with the issue of sexuality. They are typically embarrassed and feel uneasy when asking health care providers about such a non-life threatening issue. Partners similarly feel both shame and guilt. In many cases sexuality, intimacy and emotional attachment are important aspects and may be essential for survival. Addressing these issues during treatment can provide patients with a sense of security, avoiding embarrassment and further exacerbation of such problems. Unfortunately, little has been done to develop an optimal interventional program, although standard sexual treatments have often been applied. Prospective clinical research and outcomes are missing. The physician can use the well-known PLISSIT model (1978): to provide sexuality involvement on different levels. The very new BETTER model (2004) can help emphasize that cancer treatment and the disease have an influence on intimacy and sexuality.

  7. Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery.

    Science.gov (United States)

    Mallappa, Ashwini; Nella, Aikaterini A; Kumar, Parag; Brooks, Kristina M; Perritt, Ashley F; Ling, Alexander; Liu, Chia-Ying; Merke, Deborah P

    2017-07-01

    Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19-year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but obesity-related comorbidities persisted. After undergoing sleeve gastrectomy, the patient experienced dramatic weight loss, with improvement in insulin sensitivity and fatty liver in the postbariatric period. Cortisol clearance studies performed to evaluate changes in hydrocortisone dose requirements showed marked alternations in cortisol pharmacokinetics with decreases in volume of distribution and cortisol clearance, along with an increase in area under the curve for cortisol. Hydrocortisone dose was subsequently decreased 34% by 15 months after surgery. Effective control of androgen excess on this lower hydrocortisone dose was achieved and continues 27 months after surgery. This case highlights obesity-related complications of glucocorticoid replacement therapy in the management of CAH. Individual patient factors, such as fatty liver disease and insulin resistance, can have a clinically important effect on cortisol metabolism. Bariatric surgery was a safe and effective treatment of obesity in this patient with CAH and should be considered for patients with CAH and multiple obesity-related comorbidities.

  8. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients

    Science.gov (United States)

    Tartara, A.; Galimberti, C.A.; Manni, R.; Parietti, L.; Zucca, C.; Baasch, H.; Caresia, L.; Mück, W.; Barzaghi, N.; Gatti, G.; Perucca, E.

    1991-01-01

    1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate. 3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls. PMID:1777370

  9. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies.

    Directory of Open Access Journals (Sweden)

    Eric Laille

    Full Text Available CC-486 (oral azacitidine is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK and pharmacodynamic (PD profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS, chronic myelomonocytic leukemia (CMML or acute myeloid leukemia (AML from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05 reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle, with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle.ClinicalTrials.gov NCT00528983.

  10. Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

    Directory of Open Access Journals (Sweden)

    Silvia Regina Cavani Jorge Santos

    2015-06-01

    Full Text Available A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra, binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v, flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%, good linearity (0.25-100.0 µg/mL, r2=0.999, good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg, normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67% of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T>MIC for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients with burns.

  11. Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

    Science.gov (United States)

    Zhong, W; Zhang, Y; Zhang, M-Z; Huang, X-H; Li, Y; Li, R; Liu, Q-W

    2018-06-01

    The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V 1  = 60.6 L, V 2  = 222 L, Cl 1  = 0.825 L/min and Cl 2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further

  12. Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplant patients.

    Science.gov (United States)

    Min, Sang-Il; Ha, Jongwon; Kim, Yon Su; Ahn, Sang Hyun; Park, Taejin; Park, Dae Do; Kim, Suh Min; Min, Seung-Kee; Hong, Hyejin; Ahn, Curie; Kim, Sang Joon

    2013-12-01

    There is a growing concern about the therapeutic equivalence of the generic tacrolimus formulation (GEN Tacrolimus) to the reference tacrolimus (REF Tacrolimus) in solid organ transplantation. A prospective, randomized study of 126 de novo renal transplant patients was conducted to compare the efficacy, safety and pharmacokinetic (PK) profiles between GEN tacrolimus (n = 63) and REF tacrolimus (n = 63). The PK of tacrolimus was evaluated on Day 10 and 6 months under steady-state condition. Crossover study was carried out in 66 patients at 6 months. On Day 10, 117 patients completed PK profiles (54 GEN tacrolimus and 63 REF tacrolimus) and GEN tacrolimus showed comparable C(0) (9.8 ± 2.5 versus 9.7 ± 3.0 ng/mL, P = 0.80) but significantly higher dose-normalized C(max) (309.1 ± 191.9 versus 192.5 ± 95.2 ng/mL/mg/kg, P PK profiles evaluated at 9 months showed that generic substitution also resulted in an 'early and high C(max)'. Efficacy and safety data were comparable over the 9-month study period. Therapeutic equivalence and the PK of GEN tacrolimus should be evaluated in patients undergoing de novo renal transplantation.

  13. Gap analysis of pharmacokinetics and pharmacodynamics in burn patients: a review.

    Science.gov (United States)

    Steele, Amanda N; Grimsrud, Kristin N; Sen, Soman; Palmieri, Tina L; Greenhalgh, David G; Tran, Nam K

    2015-01-01

    Severe burn injury results in a multifaceted physiological response that significantly alters drug pharmacokinetics and pharmacodynamics (PK/PD). This response includes hypovolemia, increased vascular permeability, increased interstitial hydrostatic pressure, vasodilation, and hypermetabolism. These physiologic alterations impact drug distribution and excretion-thus varying the drug therapeutic effect on the body or microorganism. To this end, in order to optimize critical care for the burn population it is essential to understand how burn injury alters PK/PD parameters. The purpose of this article is to describe the relationship between burn injury and drug PK/PD. We conducted a literature review via PubMed and Google to identify burn-related PK/PD studies. Search parameters included "pharmacokinetics," "pharmacodynamics," and "burns." Based on our search parameters, we located 38 articles that studied PK/PD parameters specifically in burns. Twenty-seven articles investigated PK/PD of antibiotics, 10 assessed analgesics and sedatives, and one article researched an antacid. Out of the 37 articles, there were 19 different software programs used and eight different control groups. The mechanisms behind alterations in PK/PD in burns remain poorly understood. Dosing techniques must be adapted based on burn injury-related changes in PK/PD parameters in order to ensure drug efficacy. Although several PK/PD studies have been undertaken in the burn population, there is wide variation in the analytical techniques, software, and study sample sizes used. In order to refine dosing techniques in burns and consequently improve patient outcomes, there must be harmonization among PK/PD analyses.

  14. Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism.

    Science.gov (United States)

    Ng, Chee M; Tang, Fei; Seeholzer, Steven H; Zou, Yixuan; De León, Diva D

    2018-03-01

    Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI. A total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed-effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [C max ]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies. Observed concentration-time profiles of exendin-(9-39) were described by a linear two-compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half-life for adult subjects with median weight of 69 kg were 11.8 l h -1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC 0-last at the NOAEL and predicted AUC 0-inf using the PopPK model was 27 mg kg -1  day -1 intravenously. This is the first study to investigate the PopPK of exendin-(9-39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin-(9-39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response. © 2017 The British Pharmacological Society.

  15. Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.

    Science.gov (United States)

    Gomez, David S; Sanches-Giraud, Cristina; Silva, Carlindo V; Oliveira, Amanda M Ribas Rosa; da Silva, Joao Manoel; Gemperli, Rolf; Santos, Silvia R C J

    2015-03-01

    Unpredictable pharmacokinetics (PK) in burn patients may result in plasma concentrations below concentrations that are effective against common pathogens. The present study evaluated the imipenem PK profile and pharmacokinetic/pharmacodynamics (PK/PD) correlation in burn patients. Fifty-one burn patients, 38.7 years of age (mean), 68.0 kg, 36.3% total burn surface area (TBSA), of whom 84% (43/51) exhibited thermal injury, 63% inhalation injury and 16% electrical injury (8/51), all of whom were receiving imipenem treatment were investigated. Drug plasma monitoring, PK study (120 sets of plasma levels) and PK/PD correlation were performed in a series of blood samples. Only 250 μl of plasma samples were required for drug plasma measurements using the ultra filtration technique for the purification of biological matrix and quantification using liquid chromatography. Probability of target attainment (PTA) was calculated using a PD target of 40% free drug concentrations above the minimum inhibitory concentration (40%fT>MIC). Significant differences in PK parameters (medians), such as biological half-life (2.2 vs 5.5 h), plasma clearance (16.2 vs 1.4 l h(-1)) and volume of distribution (0.86 vs 0.19 l kg(-1)), were registered in burn patients via comparisons of set periods with normal renal function against periods of renal failure. Correlations between creatinine clearance and total body plasma clearance were also obtained. In addition, the PK profile did not change according to TBSA during sets when renal function was preserved. PTA was >89% for MIC values up to 4 mg l(-1). In conclusion, imipenem efficacy for the control of hospital infection on the basis of PK/PD correlation was guaranteed for burn in patients at the recommended dose regimens for normal renal function (31.1±9.7 mg kg(-1) daily), but the daily dose must be reduced to 17.2±9.7 mg kg(-1) during renal failure to avoid neurotoxicity.

  16. Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics.

    Science.gov (United States)

    Prado, Carla M M; Maia, Yara L M; Ormsbee, Michael; Sawyer, Michael B; Baracos, Vickie E

    2013-10-01

    Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

  17. Estimated cancer risk of dioxins to humans using a bioassay and physiologically based pharmacokinetic model

    International Nuclear Information System (INIS)

    Maruyama, Wakae; Aoki, Yasunobu

    2006-01-01

    The health risk of dioxins and dioxin-like compounds to humans was analyzed quantitatively using experimental data and mathematical models. To quantify the toxicity of a mixture of three dioxin congeners, we calculated the new relative potencies (REPs) for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), and 2,3,4,7,8- pentachlorodibenzofuran (PeCDF), focusing on their tumor promotion activity. We applied a liver foci formation assay to female SD rats after repeated oral administration of dioxins. The REP of dioxin for a rat was determined using dioxin concentration and the number of the foci in rat liver. A physiologically based pharmacokinetic model (PBPK model) was used for interspecies extrapolation targeting on dioxin concentration in liver. Toxic dose for human was determined by back-estimation with a human PBPK model, assuming that the same concentration in the target tissue may cause the same level of effect in rats and humans, and the REP for human was determined by the toxic dose obtained. The calculated REPs for TCDD, PeCDD, and PeCDF were 1.0, 0.34, and 0.05 for rats, respectively, and the REPs for humans were almost the same as those for rats. These values were different from the toxic equivalency factors (TEFs) presented previously (Van den Berg, M., Birnbaum, L., Bosveld, A.T.C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., Rolaf van Leeuwen, F.X., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger. L., Safe, S., Schrenk, D., Tillitt, D, Tysklind, M., Younes, M., Waern, F., Zacharewski, T., 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106, 775-792). The relative risk of excess liver cancer for Japanese people in general was 1.7-6.5 x 10 -7 by TCDD only, and 2.9-11 x 10 -7 by the three dioxins at the present level of contamination

  18. Bone health in cancer patients

    DEFF Research Database (Denmark)

    Coleman, R; Body, J J; Aapro, M

    2014-01-01

    There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major...... morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Through optimum multidisciplinary management of patients with bone metastases, including the use of bone-targeted treatments such as potent bisphosphonates or denosumab, it has been possible to transform the course of advanced...... cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling...

  19. The metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea are not influenced by ethanol

    DEFF Research Database (Denmark)

    Grønhøj Larsen, F; Jakobsen, P; Grønhøj Larsen, C

    2009-01-01

    BACKGROUND: Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids......-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined....... PATIENTS/METHODS: Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple...

  20. Misonidazole in patients receiving radical radiotherapy: pharmacokinetic effects of phenytoin tumor response and neurotoxicity

    International Nuclear Information System (INIS)

    Moore, J.L.; Biol, F.I.; Patterson, I.C.M.; Dawes, P.J.D.K.; Henk, J.M.

    1982-01-01

    In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed an initial peripheral neuropathy rate of 55%, despite a dose limitation of 12 g/m 2 of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown to shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed

  1. Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

    Science.gov (United States)

    Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

    2015-02-01

    The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

  2. Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors

    DEFF Research Database (Denmark)

    Dirix, Luc; Swaisland, Helen; Verheul, Henk M W

    2016-01-01

    ) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole...... analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib......: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically...

  3. Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease.

    Science.gov (United States)

    Vande Casteele, Niels; Mould, Diane R; Coarse, Jason; Hasan, Iram; Gils, Ann; Feagan, Brian; Sandborn, William J

    2017-12-01

    Certolizumab pegol is an effective biologic for patients with Crohn's disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy. The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates. Data collected from 2157 Crohn's disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration-time data were described by a one-compartment PK model with first-order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable. The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5-214 units/mL) increased the median CL/F by 142-174%. For a typical patient, body weight (46.8-100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32-48 g/L) decreased and C-reactive protein (0.5-54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%. By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn's disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment.

  4. Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery.

    Science.gov (United States)

    Varrique, Renan M; Lauretti, Gabriela R; Matsumoto, Julia A; Lanchote, Vera L; de Moraes, Natalia V

    2016-11-01

    To evaluate the impact of advanced age on rocuronium kinetic disposition in ASA I-III patients undergoing elective surgeries. Young adult (20-50 years, n = 15) and elderly patients (65-85 years, n = 14) submitted to surgery under general anaesthesia were investigated. All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. Rocuronium-induced neuromuscular block was monitored by train of four stimulations of the adductor muscle of the thumb on the ulnar nerve. The pharmacokinetic parameters were calculated by non-compartmental analysis. The relationship between rocuronium plasma concentration and the neuromuscular blockade was described by a sigmoidal Emax model. Elderly patients presented decreased Cl (2.1 ml/kg per min vs 2.8 ml/kg per min; P = 0.0123); increased AUC/dose (507.8 μg min/ml (mg/kg) vs 392.2 μg min/ml/(mg/kg); P = 0.0168) and reduced volume of distribution (285.4 ml/kg vs 435.6 ml/kg, P = 0.0434) compared to young adults. The concentrations required to achieve 50% of maximum neuromuscular block (EC50) were similar for young adult (338.8 ng/ml) and elderly (462.7 ng/ml) patients (P > 0.05). Elderly patients showed increased AUC/D and reduced total Cl compared to young adult patients due to the age-related reduced renal function. Differences in the PK-PD properties of rocuronium in elderly population are due to changes in drug disposition rather than to alterations in the sensitivity to the drug. © 2016 Royal Pharmaceutical Society.

  5. Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane®) on three treatment schedules in patients with solid tumors

    Science.gov (United States)

    Stinchcombe, Thomas E.; Socinski, Mark A.; Walko, Christine M.; O’Neil, Bert H.; Collichio, Frances A.; Ivanova, Anastasia; Mu, Hua; Hawkins, Michael J.; Goldberg, Richard M.; Lindley, Celeste; Dees, E Claire

    2010-01-01

    Purpose Albumin-bound paclitaxel, ABI-007 (Abraxane ®), has a different toxicity profile than solvent-based paclitaxel, including a lower rate of severe neutropenia. The combination of ABI-007 and carboplatin may have significant activity in a variety of tumor types including non-small and small cell lung cancer, ovarian cancer, and breast cancer. The purpose of this study was to determine the maximum tolerated dose (MTD) of ABI-007, on three different schedules in combination with carboplatin. Methods Forty-one patients with solid tumors were enrolled, and received ABI-007 in combination with carboplatin AUC of 6 on day 1. Group A received ABI-007 at doses ranging from 220 to 340 mg/m2 on day 1 every 21 days; group B received ABI-007 at 100 or 125 mg/m2 on days 1, 8, and 15 every 28 days; and group C received ABI-007 125 or 150 mg/m2 on days 1 and 8 every 21 days. Dose-limiting toxicities were assessed after the first cycle. Doses were escalated in cohorts of three to six patients. Fifteen patients participated in a pharmacokinetic study investigating the effects of the sequence of infusion. ABI-007 was infused first followed by carboplatin in cycle 1, and vice versa in cycle 2. Results The MTD of ABI-007 in combination with carboplatin was 300, 100, and 125 mg/m2 in groups A, B, and C, respectively. Myelosuppression was the primary dose limiting toxicity. No unexpected or new toxicities were reported. Sequence of infusion did not affect either the pharmacokinetics of ABI-007 or the degree of neutropenia. Responses were seen in melanoma, lung, bladder, esophageal, pancreatic, breast cancer, and cancer of unknown primary. Conclusions The recommended dose for phase II studies of ABI-007 in combination with carboplatin (AUC of 6) is 300, 100, 125 mg/m2 for the schedules A, B, and C, respectively. The combination of ABI-007 and carboplatin is well tolerated and active in this heavily pretreated patient population. PMID:17285317

  6. The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients

    Science.gov (United States)

    Jung, Donald; AbdelHameed, Magdy H; Hunter, John; Teitelbaum, Philip; Dorr, Albert; Griffy, Kay

    1999-01-01

    Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P = 0.0068) and increased t1/2 (18.1%, P = 0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered. PMID:10215748

  7. Cancer patients and mass media

    Directory of Open Access Journals (Sweden)

    Mirjana Rajer

    2015-06-01

    Full Text Available ABSTRACTBACKGROUNDNowadays cancer patients tend to be more involved in the medical decision process. Active participation improves health outcomes and patient satisfaction. To participate effectively patients require a huge amount of information, but time limits make it impossible to satisfy all information needs at clinics. We tried to find out which kind of media cancer patients use when searching for information and how often. Lastly, we try to find out how popular the Internet is in this regard.METODSIn this research we invited cancer patients, who had regular clinic examinations at the Oncology Institute between 21st and 25th May in 2012. We carried out a prospective research by anonymous questionnaires. We were investigating which media were used and how often. We analysed results with descriptive statistics, ANOVA, the χ²-Test and the t-test.RESULTS478 of 919 questionnaires distributed among cancer patients were returned. Mean age was 59.9 years. 61 % of responders were female, and the most common level of education was high school (33 %. Most common cancer type was breast cancer (33 %, followed by gastrointestinal and lung cancer. Patients search for information most often on television (81.4% responders, followed by specialized brochures (78%, internet (70.8% and newspapers (67.6%. Patients who do not use media for information searching are older than average (62.5 years vs. 59.9 years; p<0,000.CONCLUSIONSAccording to our results patients search for information most often on television, followed by brochures, internet and newspapers. Older patients less often search for information. This data might help doctors in everyday clinical practice.

  8. Informal Caregiving for Cancer Patients

    Science.gov (United States)

    Romito, Francesca; Goldzweig, Gil; Cormio, Claudia; Hagedoorn, Mariët; Andersen, Barbara L.

    2013-01-01

    According to the recent worldwide estimation by the GLOBOCAN project, in total, 12.7 million new cancer cases and 7.6 million cancer deaths occurred in 2008. The worldwide number of cancer survivors within 5 years of diagnosis has been estimated at be almost 28.8 million. Informal caregivers, such as family members and close friends, provide essential support to cancer patients. The authors of this report provide an overview of issues in the study of informal caregivers for cancer patients and long-term survivors in the United States and Europe, characterizing the caregivers commonly studied; the resources currently available to them; and their unmet needs, their psychosocial outcomes, and the psychosocial interventions tailored to their special circumstances. A broad overview of the state of research and knowledge, both in Europe and the United States, and observations on the directions for future research are provided. PMID:23695928

  9. Azithromycin maintenance therapy in patients with cystic fibrosis : A dose advice based on a review of pharmacokinetics, efficacy, and side effects

    NARCIS (Netherlands)

    Wilms, Erik B.; Touw, Daniel J.; Heijerman, Harry G.M.; Van Der Ent, Cornelis K.

    Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules

  10. The experiences of cancer patients.

    Science.gov (United States)

    Alifrangis, C; Koizia, L; Rozario, A; Rodney, S; Harrington, M; Somerville, C; Peplow, T; Waxman, J

    2011-12-01

    To assess the needs of cancer patients for information about their condition and to understand the psychological impact of their illness. The discussion of prognosis and treatment options in the palliative setting is an important and difficult part of oncology practice. To evaluate this, we examined the experiences of cancer patients of the physical and psychological impact of their disease on their life, and their opinions on the communication of end-of-life decisions and treatment options. A patient questionnaire was designed that encompassed communication regarding treatment and prognosis, quality-of-life attitudes subsequent to cancer diagnosis, end-of-life care and cancer drug funding. One hundred and twenty-five patients with a diagnosis of cancer were asked to participate and 96 questionnaires were completed and available for analysis. The questionnaire consisted of 63 questions and was completed in both an inpatient and outpatient setting. This survey brought to light a number of controversial issues in cancer service provision, highlighting the emotional and psychological changes brought about by a cancer diagnosis. Major concerns of our patients include fear of death and pain, changes in interpersonal relationships and financial constraints. Only 66% of the patients wanted to be given a prognosis by their clinicians and just 70% of the patients recalled being given a detailed prognosis. 11% of the patients were not prepared to undergo palliative treatment. In all, 7% were not prepared to accept treatment for 1 year and 2% for 5 years of life in exchange for the potential side effects of cytotoxic chemotherapy. 12% of the patients would not want to be in possession of the information that they were in the terminal phase of the illness with a short time to live and 16% would not want this discussed with their next of kin. This study informs medical professionals about the importance of tailoring information to the needs of the individual patient, and we

  11. The pharmacokinetics of cefazolin in patients undergoing elective & semi-elective abdominal aortic aneurysm open repair surgery

    Directory of Open Access Journals (Sweden)

    Roberts Michael S

    2011-02-01

    Full Text Available Abstract Background Surgical site infections are common, so effective antibiotic concentrations at the sites of infection are required. Surgery can lead to physiological changes influencing the pharmacokinetics of antibiotics. The aim of the study is to evaluate contemporary peri-operative prophylactic dosing of cefazolin by determining plasma and subcutaneous interstitial fluid concentrations in patients undergoing elective of semi-elective abdominal aortic aneurysm (AAA open repair surgery. Methods/Design This is an observational pharmacokinetic study of patients undergoing AAA open repair surgery at the Royal Brisbane and Women's Hospital. All patients will be administered 2-g cefazolin by intravenous injection within 30-minutes of the procedure. Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration by cefazolin. Participants will be administered indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes occurring during surgery. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters and the effect of peri-operative physiological changes on cefazolin disposition. Discussion The study will describe cefazolin levels in plasma and the interstitial fluid of tissues during AAA open repair surgery. The effect of physiological changes to the patient mediated by surgery will also be determined. The results of this study will guide clinicians and pharmacists to effectively dose cefazolin in order to maximize the concentration of antibiotics in the tissues which are the most common site of surgical site infections.

  12. Psychological aspects of cancer patients

    Directory of Open Access Journals (Sweden)

    Graça Cardoso

    2014-06-01

    Full Text Available Cancer is accompanied by important psychological distress experienced by both patient and family. From the moment of the diagnosis on, the patient has to develop a great number of mechanisms and tasks of adjustment to the illness and its circumstances. The high prevalence of anxiety and depressive disorders during the course of cancer increases in the end stage disea‐ se. Therefore, a global plan of intervention integrating somatic and psychological/ psychiatric care throughout all the phases of the illness is crucial in the treatment of these patients. Health professionals working on this field can also experience emotional reactions to their patients’ suffering. They should be aware of the emotional aspects involved and develop training to help them intervene adequately with the patient and the family. The articulation between oncologists, palliative care professionals, and mental health care teams can be of great help in providing good quality of care to cancer patients.

  13. Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response.

    Science.gov (United States)

    White, Hillary D; Brown, Lin A J; Gyurik, Robert J; Manganiello, Paul D; Robinson, Thomas D; Hallock, Linda S; Lewis, Lionel D; Yeo, Kiang-Teck J

    2015-08-01

    To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (pfibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved. Copyright © 2015. Published by Elsevier B.V.

  14. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software.

    Science.gov (United States)

    Lavielle, Marc; Mentré, France

    2007-04-01

    In nonlinear mixed-effects models, estimation methods based on a linearization of the likelihood are widely used although they have several methodological drawbacks. Kuhn and Lavielle (Comput. Statist. Data Anal. 49:1020-1038 (2005)) developed an estimation method which combines the SAEM (Stochastic Approximation EM) algorithm, with a MCMC (Markov Chain Monte Carlo) procedure for maximum likelihood estimation in nonlinear mixed-effects models without linearization. This method is implemented in the Matlab software MONOLIX which is available at http://www.math.u-psud.fr/~lavielle/monolix/logiciels. In this paper we apply MONOLIX to the analysis of the pharmacokinetics of saquinavir, a protease inhibitor, from concentrations measured after single dose administration in 100 HIV patients, some with advance disease. We also illustrate how to use MONOLIX to build the covariate model using the Bayesian Information Criterion. Saquinavir oral clearance (CL/F) was estimated to be 1.26 L/h and to increase with body mass index, the inter-patient variability for CL/F being 120%. Several methodological developments are ongoing to extend SAEM which is a very promising estimation method for population pharmacockinetic/pharmacodynamic analyses.

  15. Hope in Patients with Cancer

    Directory of Open Access Journals (Sweden)

    Selma Turan Kavradim

    2014-06-01

    Full Text Available Cancer, which is one of the major health problems leading to despair, uncertainty, pain and suffering, is perceived as a serious and chronic disease. Cancer negatively affects individuals' quality of life due to the physical, psychological, and socio-economic problems. Today, despite inspiring advances in diagnosis and treatment of cancer and increase in survival rates of patients, appearance of physical and psycho-social disorders during cancer course disrupts the adaptation mechanisms of patients and undermines expectations for the future. Most of the time in clinical practice, clinicians focus on physical assessments and treatment planning of cancer patients primarily, ignoring social, psychological, economic and cultural factors related with the disease. This approach definitely influences patients' hope levels and their effective dealing with the disease. The aim of this article is to guide medical staff and increase awareness about the concept of hope in patients with cancer. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(2.000: 154-164

  16. Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.

    Science.gov (United States)

    Bos, Jeannet C; van Hest, Reinier M; Prins, Jan M

    2017-08-01

    In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on β-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and β-lactam data are particularly lacking, whereas β-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of β-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local

  17. Effects of Body Size and Gender on the Population Pharmacokinetics of Artesunate and Its Active Metabolite Dihydroartemisinin in Pediatric Malaria Patients

    OpenAIRE

    Morris, Carrie A.; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-01-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and on...

  18. Dissociative symptomatology in cancer patients

    Science.gov (United States)

    Civilotti, Cristina; Castelli, Lorys; Binaschi, Luca; Cussino, Martina; Tesio, Valentina; Di Fini, Giulia; Veglia, Fabio; Torta, Riccardo

    2015-01-01

    Introduction: The utilization of the post-traumatic stress disorder (PTSD) diagnostic spectrum is currently being debated to categorize psychological adjustment in cancer patients. The aims of this study were to: (1) evaluate the presence of cancer-related traumatic dissociative symptomatology in a sample of cancer patients; (2) examine the correlation of cancer-related dissociation and sociodemographic and medical variables, anxiety, depression, and post-traumatic stress symptomatology; (3) investigate the predictors of cancer-related dissociation. Methods: Ninety-two mixed cancer patients (mean age: 58.94, ds = 10.13) recruited from two hospitals in northern Italy were administered a questionnaire on sociodemographic and medical characteristics, the Karnofsky Scale to measure the level of patient activity and medical care requirements, the Hospital Anxiety and Depression Scale (HADS) to evaluate the presence of anxiety and depression, the Impact of Event Scale Revised (IES-R) to assess the severity of intrusion, avoidance, and hypervigilance, and the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) to quantify the traumatic dissociative symptomatology. Results: 31.5% of participants report a PDEQ score above the cutoff. The results indicated that dissociative symptomatology was positively correlated with HADS scores (HADS-Anxiety: r = 0.476, p dissociative symptomatology. The results converged on a three predictor model revealing that IES-R-Intrusion, IES-R-Avoidance, and IES-R-Hyperarousal accounted for 53.9% of the explained variance. Conclusion: These findings allow us to hypothesize a specific psychological reaction which may be ascribed to the traumatic spectrum within the context of cancer, emphasizing the close relationship between the origin of dissociative constituents which, according to the scientific literature, compose the traumatic experience. Our results have implications for understanding dissociative symptomatology in a cancer

  19. Clinical Pharmacokinetics of Paclitaxel Monotherapy

    DEFF Research Database (Denmark)

    Stage, Tore B; Bergmann, Troels K; Kroetz, Deanna L

    2018-01-01

    Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract ...

  20. Skin cancers in elderly patients.

    Science.gov (United States)

    Malaguarnera, Giulia; Giordano, Maria; Cappellani, Alessandro; Berretta, Massimiliano; Malaguarnera, Michele; Perrotta, Rosario Emanuele

    2013-11-01

    Cancer in older people is a common problem worldwide. Among various types of cancer, skin cancers represent an important percentage. The principal risk factors are sun exposure, family history of skin cancer, fair skin color, but also the age plays an important role in the genesis of skin cancers. In older people there are a more prolonged exposure to carcinogenesis and a decreased functionality of reparation mechanisms of the cells so they acquire a selective advantage of growing and proliferating. At the same time age causes alteration in immune system by increasing NK-cells absolute number and decreasing both the endogenous and the lymphokine-induced lytic activities. The anti-tumor immune response is also mediated by the cytotoxic T- lymphocytes and in the elderly a strong reduction of T-cell function has been demonstrated. In elderly patients the diagnosis and the treatment of skin cancers can be different from younger counterpart. For example in older patients with melanoma is important to evaluate Breslow depth while higher mitotic rate has major value in younger patients. Moreover, the treatment should consider the performance status of patients and their compliance.

  1. COMPARISON OF PHARMACOKINETICS AND PHARMACODYNAMICS OF THE ORIGINAL AND GENERIC ENALAPRIL IN THE ELDERLY PATIENTS WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    O. P. Bobrova

    2015-12-01

    Full Text Available Aim. To study the pharmacokinetic, pharmacodynamic and pharmacoeconomic parameters of the original and generic enalaprils in the treatment of the elderly patients with hypertension (HT. Material and Methods. Patients (n=40 75–90 years with HT were included in the open randomized comparative study. Patients were randomized into two groups. Patients of the group 1 received generic enalapril, patients of the group 2 — the original enalapril consisting of combined therapy. Pharmacokinetic single-dose study of original and generic enalapril were carried out with high-performance liquid chromatography. Pharmacodynamic study was carried out in single-dose administration as well as after 2 and 4 weeks of treatment with original and generic enalapril. Pharmacoeconomic evaluation of antihypertensive drugs was carried out on the basis of cost minimization analysis. Results. Original enalapril dose necessary to achieve the target blood pressure (BP was 10 mg/day as a part of two-component therapy. This for generic enalapril was 20 mg/day consisting of three- or four-component therapy. Both drugs have shown an acceptable safety profile. Pharmacokinetic differences were revealed between original and generic enalapril: area under pharmacokinetic curve 204.14 (202.25–206.05 vs 136.23 (134.17–137.65 ng*h/ml, respectively; time of the drug retention in the blood plasma 5.42 (5.26–5.76 vs 4.88 (4.86–4.94 hours, respectively; p<0.001. Original enalapril demonstrated more stable 24-hour antihypertensive effect in once daily administration in comparison with this in generic enalapril: trough/peak ratio 78.67% (47.61–91.35% vs 44.96% (32.44–55.49%, respectively , p<0.01. The average daily cost of combined therapy containing generic enalapril was 15.91 rubles per patient, while this in combined therapy containing original enalapril — 13.78 rubles per patient. Conclusion. Medicines on the basis of original and generic enalapril have pharmacokinetic

  2. Socioemotional selectivity in cancer patients.

    Science.gov (United States)

    Pinquart, Martin; Silbereisen, Rainer K

    2006-06-01

    This study analyzed the contact preferences of newly diagnosed cancer patients and healthy control group participants. In line with the theory of socioemotional selectivity, patients were more likely than control participants to prefer contact with familiar social partners, but this difference was stronger in younger and middle-aged patients than in older patients. Across a 6-month interval, patients' contact preferences changed according to the perceived success of therapy. For example, if therapy was perceived to be successful, patients showed an increasing interest in contacts with unfamiliar social partners. Results indicate that contact preferences are adapted to the perception of limited versus extended future lifetime. Copyright (c) 2006 APA, all rights reserved.

  3. A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

    Science.gov (United States)

    Venugopal, B; Awada, A; Evans, T R J; Dueland, S; Hendlisz, A; Rasch, W; Hernes, K; Hagen, S; Aamdal, S

    2015-10-01

    CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

  4. The hamster cheek pouch (HCP) as an experimental model of oral cancer for BNCT: biodistribution and pharmacokinetics of BPA

    International Nuclear Information System (INIS)

    Kreimann, E.; Itoiz, M.E.; Dagrosa, A.; Garavaglia, R.; Farias, S.; Batistoni, D.; Schwint, A.E.

    2000-01-01

    We propose and validate the HCP model of oral cancer for BNCT studies. This model serves to explore new applications of the technique, study the biology of BNCT and assess Boron uptake in clinically relevant oral tissues. Tumors are induced by a process that mimics spontaneous malignant transformation instead of by the growth of implanted tumor cells. Syrian hamsters were submitted to tumor induction with a chemical carcinogenesis protocol and then used for biodistribution and pharmacokinetic studies of BPA. The data reveal selective uptake by tumor and, to a lesser degree, by precancerous tissue. Boron concentration in oral tissues and skin was higher than in blood, an issue of clinical relevance given that these tissues may be dose-limiting. Absolute and relative values of Boron concentration would be potentially therapeutic. Boron concentration exhibited a linear relationship with percentage of viable tissue in HCP tumors. The HCP model would provide a novel, contributory approach to BNCT research. (author)

  5. Targeting anti-apoptotic Bcl-2 by AT-101 to increase radiation efficacy: data from in vitro and clinical pharmacokinetic studies in head and neck cancer

    International Nuclear Information System (INIS)

    Zerp, Shuraila F.; Stoter, T. Rianne; Hoebers, Frank J. P.; Brekel, Michiel W. M. van den; Dubbelman, Ria; Kuipers, Gitta K.; Lafleur, M. Vincent M.; Slotman, Ben J.; Verheij, Marcel

    2015-01-01

    Pro-survival Bcl-2 family members can promote cancer development and contribute to treatment resistance. Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. Inhibition of anti-apoptotic Bcl-2 family members therefore represents an appealing strategy to overcome resistance to anti-cancer therapies. The aim of this study was to evaluate combined effects of radiation and the pan-Bcl-2 inhibitor AT-101 in HNSCC in vitro. In addition, we determined human plasma levels of AT-101 obtained from a phase I/II trial, and compared these with the effective in vitro concentrations to substantiate therapeutic opportunities. We examined the effect of AT-101, radiation and the combination on apoptosis induction and clonogenic survival in two HNSCC cell lines that express the target proteins. Apoptosis was assessed by bis-benzimide staining to detect morphological nuclear changes and/or by propidium iodide staining and flow-cytometry analysis to quantify sub-diploid apoptotic nuclei. The type of interaction between AT-101 and radiation was evaluated by calculating the Combination Index (CI) and by performing isobolographic analysis. For the pharmacokinetic analysis, plasma AT-101 levels were measured by HPLC in blood samples collected from patients enrolled in our clinical phase I/II study. These patients with locally advanced HNSCC were treated with standard cisplatin-based chemoradiotherapy and received dose-escalating oral AT-101 in a 2-weeks daily schedule every 3 weeks. In vitro results showed that AT-101 enhances radiation-induced apoptosis with CI’s below 1.0, indicating synergy. This effect was sequence-dependent. Clonogenic survival assays demonstrated a radiosensitizing effect with a DEF 37 of 1.3 at sub-apoptotic concentrations of AT-101. Pharmacokinetic analysis

  6. Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study

    DEFF Research Database (Denmark)

    Coiffier, Bertrand; Losic, Nedjad; Rønn, Birgitte Biilmann

    2010-01-01

    The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumu...

  7. Cancer disclosure: experiences of Iranian cancer patients.

    Science.gov (United States)

    Valizadeh, Leila; Zamanzadeh, Vahid; Rahmani, Azad; Howard, Fuchsia; Nikanfar, Ali-Reza; Ferguson, Caleb

    2012-06-01

    This study explored Iranian patients' experiences of cancer disclosure, paying particular attention to the ways of disclosure. Twenty cancer patients were invited to participate in this qualitative inquiry by research staff in the clinical setting. In-depth, semistructured interview data were analyzed through content analysis. The rigor of the study was established by principles of credibility, transferability, dependability, and confirmability. Four themes emerged: the atmosphere of non-disclosure, eventual disclosure, distress in knowing, and the desire for information. Non-disclosure was the norm for participants, and all individuals involved made efforts to maintain an atmosphere of non-disclosure. While a select few were informed of their diagnosis by a physician or another patient, the majority eventually became aware of their diagnosis indirectly by different ways. All participants experienced distress after disclosure. The participants wanted basic information about their prognosis and treatments from their treating physicians, but did not receive this information, and encountered difficulty accessing information elsewhere. These challenges highlight the need for changes in current medical practice in Iran, as well as patient and healthcare provider education. © 2012 Blackwell Publishing Asia Pty Ltd.

  8. Hypertension in Patients with Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Vinicius Barbosa de; Silva, Eduardo Nani; Ribeiro, Mario Luiz; Martins, Wolney de Andrade, E-mail: wolney@cardiol.br [Curso de Pós-Graduação em Ciências Cardiovasculares da Universidade Federal Fluminense, Niterói, RJ (Brazil)

    2015-03-15

    There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non-steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality.

  9. Hypertension in Patients with Cancer

    International Nuclear Information System (INIS)

    Souza, Vinicius Barbosa de; Silva, Eduardo Nani; Ribeiro, Mario Luiz; Martins, Wolney de Andrade

    2015-01-01

    There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non-steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality

  10. "The relationship between pharmacokinetic variables and pharmacodynamic profiles of bolus versus continuous infusion of furosemide in critically ill patients"

    Directory of Open Access Journals (Sweden)

    "Mojtaba Mojtahedzadeh

    2005-05-01

    Full Text Available In this investigation, the pharmacokinetic variables of continuous infusion and intermittent bolus injection of furosemide and the possible relationship between its pharmacokinetic characteristics and pharmacodynamic profile among intensive care unit (ICU patients were studied. In this prospective, randomized, clinical trial, twelve patients received IV bolus of 20 mg of the drug during 3 hours period and, the drug dose was doubled, when the urine output was less than 1 ml/kg/h (group 1. The other nine patients received a continuous intravenous furosemide infusion at the rate of 0.1 mg/kg/h (group 2. The amount of furosemide in serum was measured by high performance liquid chromatography (HPLC. Results showed a positive correlation between plasma clearance of furosemide and its diuretic activity (P=0.01. The pharmacokinetic parameters such as Vd (l, CL (ml/min, Ke (min-1 and t½ (min in continuous infusion patients were not significantly differed from the bolus patients (P-values 0.5, 0.9, 0.9,0.9, respectively. Nevertheless the observed plasma clearance of drug in the continuous infusion group was clinically higher than bolus injection group and as a result the cumulative urine output per hour per mg of furosemide in a continuous infusion was observed to be higher than bolus(P=0.2. Changes in serum sodium and potassium were similar for both groups, but bolus injection patients were associated with higher potassium depletion (P=0.001. Therefore, continuous infusion seems to be better means of diuretic therapy in critically ill patients.

  11. Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.

    Science.gov (United States)

    Hawi, Amale; Alcorn, Harry; Berg, Jolene; Hines, Carey; Hait, Howard; Sciascia, Thomas

    2015-04-08

    Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of μ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed μ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus. In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry. In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg. Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.

  12. Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia.

    Science.gov (United States)

    Jaruratanasirikul, Sutep; Wongpoowarak, Wibul; Jullangkoon, Monchana; Samaeng, Maseetoh

    2015-02-01

    The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 μg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  13. A pharmacokinetic analysis of diclofenac potassium soft-gelatin capsule in patients after bunionectomy.

    Science.gov (United States)

    Kowalski, Mark; Stoker, Douglas G; Bon, Charles; Moore, Keith A; Boesing, Stephen E

    2010-01-01

    The clinical utility of diclofenac potassium, a nonsteroidal anti-inflammatory drug, may be lessened by inconsistent gastrointestinal absorption. Diclofenac potassium liquid filled soft-gelatin capsule (DPSGC) is an investigational formulation that uses ProSorb dispersion technology to facilitate rapid and consistent gastrointestinal absorption. In this study, the pharmacokinetic (PK) properties of DPSGC are investigated and compared with a commercially available oral diclofenac potassium tablet in patients after primary unilateral first metatarsal bunionectomy. In an open-label, randomized study, 53 patients received ProSorb-D 12.5 mg (the liquid equivalent of DPSGC), DPSGC 25 mg, DPSGC 50 mg, or immediate-release diclofenac potassium 50-mg tablet administered every 8 hours for a 24-hour inpatient period followed by 7 days of outpatient dosing. Diclofenac steady-state PK was evaluated over an 8-hour sampling period 4 days after surgery. Delayed and/or multiple peaks in the diclofenac plasma concentration-time course profiles occurred more frequently with the commercially available oral diclofenac potassium 50-mg tablet than with the other DPSGC formulations. PK data for ProSorb-D 12.5-mg liquid, DPSGC 25 mg, DPSGC 50 mg, and diclofenac potassium 50-mg tablet revealed mean peak plasma concentrations (Cmax) of 302, 749, 1006, and 902 ng/mL, respectively, whereas area under the plasma concentration curve values were 316, 595, 1029, and 1166 ng-hour/mL, respectively. Mean times to Cmax (tmax) were 0.49, 0.63, 0.95, and 1.26 h, respectively. When compared with absorption characteristics of diclofenac potassium 50-mg tablet, DPSGC was more rapidly and consistently absorbed after bunionectomy. These characteristics should be advantageous when rapid pain relief is desired.

  14. Optimal designs for population pharmacokinetic studies of oral artesunate in patients with uncomplicated falciparum malaria

    Directory of Open Access Journals (Sweden)

    Lindegardh Niklas

    2011-07-01

    Full Text Available Abstract Background Currently, population pharmacokinetic (PK studies of anti-malarial drugs are designed primarily by the logistical and ethical constraints of taking blood samples from patients, and the statistical models that are fitted to the data are not formally considered. This could lead to imprecise estimates of the target PK parameters, and/or designs insufficient to estimate all of the parameters. Optimal design methodology has been developed to determine blood sampling schedules that will yield precise parameter estimates within the practical constraints of sampling the study populations. In this work optimal design methods were used to determine sampling designs for typical future population PK studies of dihydroartemisinin, the principal biologically active metabolite of oral artesunate. Methods Optimal designs were derived using freely available software and were based on appropriate structural PK models from an analysis of data or the literature and key sampling constraints identified in a questionnaire sent to active malaria researchers (3-4 samples per patient, at least 15 minutes between samples. The derived optimal designs were then evaluated via simulation-estimation. Results The derived optimal sampling windows were 17 to 29 minutes, 30 to 57 minutes, 2.5 to 3.7 hours and 5.8 to 6.6 hours for non-pregnant adults; 16 to 29 minutes, 31 minutes to 1 hour, 2.0 to 3.4 hours and 5.5 to 6.6 hours for designs with non-pregnant adults and children and 35 to 59 minutes, 1.2 to 3.4 hours, 3.4 to 4.9 hours and 6.0 to 8.0 hours for pregnant women. The optimal designs resulted in acceptable precision of the PK parameters. Conclusions The proposed sampling designs in this paper are robust and efficient and should be considered in future PK studies of oral artesunate where only three or four blood samples can be collected.

  15. "THE EVALUATION OF THE POSSIBLE EFFECT OF POSITIVE END EXPIRATORY PRESSURE (PEEP) ON PHARMACOKINETICS OF PHENYTOIN IN PATIENTS WITH ACUTE BRAIN INJURY UNDER MECHANICAL VENTILATION."

    OpenAIRE

    "Elham Hadidi; Mojtaba Mojtahedzadeh; Mohammad Reza Rouini; Behzad Eftekhar; Mohammad Abdollahi; Atabak Najafi; Mohammad R. Khajavi; Saeed Rezaee; Reza Ghaffari; Minoo Afshar"

    2005-01-01

    Positive ventilation has shown to have an influence on pharmacokinetic and disposition of some drugs.Beacause phenytoin with a narrow therapautic range, is the most commonly used drug for prophylaxis and treatment of early seizures after acute brain injuries, in the present study the effect of short term PEEP (5-10 cm H2O for at least 8 hours) on phenytoin serum concentration and pharmacokinetic parameters such as Vmax and clearance in brain injured patients under mechanical ventilation was e...

  16. Needs and preferences of patients with cancer

    NARCIS (Netherlands)

    Wessels-Wynia, H.

    2010-01-01

    What do patients prefer in cancer care and does gender matter? Introduction: To provide patient-centred care for cancer patients it is important to have insight into the patients' specific preferences for health care. To gain such insight we have developed a questionnaire based on cancer patients’

  17. Labeled OK-432, immunomodulator of streptococcus preparation, in cancer patients

    International Nuclear Information System (INIS)

    Toki, Hironobu; Ishikawa, Morihiro; Fujii, Masashi; Yumoto, Yasuhiro; Ishimitsu, Tetsusaburo

    1982-01-01

    We investigated the pharmacokinetics of OK-432, an immunomodulator of streptococcus preparation which, is used in cancer patients for active nonspecific immunotherapy. First, OK-432 was labeled with sup(99m)Technetium in vitro. Four patients with malignancy were studied. By the method of scintigraphy using gamma camera, OK-432 administered intravenously was found to be distributed in the liver, lung and spleen, by the decreasing grade. When OK-432 was administered subcutaneously or intramuscularly in the buttocks, most of the radioactivity of sup(99m)Technetium remained locally at the injected site. These results suggested that OK-432 given intravenously was effectively phagocytized by cells of reticuloendothelial system (RES). Compared with other routes of administration, the intravenous route of OK-432 administration is thus considered more effective in order to stimulate RES, which is responsible for the first step of immune reaction. (author)

  18. Single and repeated dose pharmacokinetics of dexketoprofen trometamol in patients with impaired liver function.

    Science.gov (United States)

    Valles, J; Artigas, R; Bertolotti, M; Crea, A; Muller, F; Paredes, I; Capriati, A

    2006-06-01

    Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) used for pain relief. This study compared the pharmacokinetics of dexketoprofen in patients with impaired liver function and normal subjects following single and repeated oral dosing. Subjects with normal liver function (n = 6) and with Child-Pugh A (n = 7) or Child-Pugh B (n = 5) hepatic impairment scores completed this open-label and parallel study. They received 25 mg dexketoprofen (equivalent to 37 mg of its tromethamine salt) as a single (day 1) and a 3-day repeated dose (1 dose every 8 hours for a total of 10 doses). Dexketoprofen concentrations were determined in plasma and urine by reverse-phase high performance liquid chromatography (HPLC). Model-independent pharmacokinetic parameters were obtained. All subjects completed the study. No serious adverse events were recorded. Following the single dose, mean (+/- SEM) Cmax were 3027.7 +/- 429.3 ng/ml (healthy subjects), 2856.3 +/- 340.3 ng/ml (Child-Pugh A) and 1937.2 +/- 328.0 ng/ml (Child-Pugh B). Median tmax were 0.49 h (0.33-0.68) h, 0.50 h (0.33-0.67) h and 0.67 h (0.33-1.50) h. AUC0-x averaged 3778.0 +/- 439.0 ng.h/ml, 4890.4 +/- 539.1 ng.h/ml and 3985.0 +/- 712.0 ng.h/ml. Mean CL/F were 101.1 +/- 11.3 ml/h/kg, 73.3 +/- 9.9 ml/h/kg and 88.8 +/- 15.5 ml/h/kg and V/F averaged 0.192 +/- 0.018 l/kg, 0.162 +/- 0.006 l/kg and 0.214 +/- 0.044 l/kg. Following the repeated administration, similar results were obtained showing no drug accumulation. As related to the administered dose, median excretions of unchanged and conjugated dexketoprofen in urine were 2.1% and 67.1% in healthy subjects, 2.8% and 60.9% in Child-Pugh A subjects and 4.4% and 47.7% in Child-Pugh B volunteers. A trend towards a reduced urinary excretion of conjugated dexketoprofen in hepatic patients, more evident in the Child-Pugh B than in the Child-Pugh A groups, was observed when compared with healthy

  19. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

    Science.gov (United States)

    Yoshihara, Kazutaka; Gao, Yuying; Shiga, Hiroshi; Wada, D Russell; Hisaoka, Masafumi

    2005-01-01

    Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. Eighty-nine healthy volunteers and 383 hypertensive patients. Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant

  20. Pharmacokinetics of Snake Venom

    OpenAIRE

    Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, ...

  1. Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

    DEFF Research Database (Denmark)

    Xu, Xu Steven; Yan, Xiaoyu; Puchalski, Thomas

    2017-01-01

    New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen...... for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM. This article is protected by copyright. All...

  2. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Onkar Singh

    Full Text Available OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM pharmacokinetics in Asian patients with chronic myeloid leukemia (CML. PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each and CML patients (n = 38 were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h and clearance (CL were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T, to be significantly associated with IM clearance (p = 0.013. Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2 L/hr/mg: CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h than patients carrying 0 or 1 copy [CL (10(-2 L/hr/mg: 2.19 vs 3.29, p = 0.026; C(0h (10(-6 1/ml: 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h (p = 0.002 and 0.009, respectively. CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.

  3. Clinical pharmacokinetics of phenobarbital in neonates

    NARCIS (Netherlands)

    Touw, D J; Graafland, O; Cranendonk, A; Vermeulen, R J; van Weissenbruch, M M

    2000-01-01

    Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body

  4. Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
.

    Science.gov (United States)

    Kulmatycki, Kenneth M; Langenickel, Thomas; Ng, Wai Hong; Pal, Parasar; Zhou, Wei; Lin, Tsu-Han; Rajman, Iris; Chandra, Priyamvada; Sunkara, Gangadhar

    2017-09-01

    To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
.

  5. Population Pharmacokinetics of an Indian F(ab'2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii Bites.

    Directory of Open Access Journals (Sweden)

    Geoffrey K Isbister

    Full Text Available There is limited information on antivenom pharmacokinetics. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell's viper bites.Patient data and serial blood samples were collected from patients with Russell's viper (Daboia russelii envenoming in Sri Lanka. All patients received Indian F(ab'2 snake antivenom manufactured by VINS Bioproducts Ltd. Antivenom concentrations were measured with sandwich enzyme immunoassays. Timed antivenom concentrations were analysed using MONOLIXvs4.2. One, two and three compartment models with zero order input and first order elimination kinetics were assessed. Models were parameterized with clearance (CL, intercompartmental clearance (Q, central compartment volume (V and peripheral compartment volume (VP. Between-subject-variability (BSV on relative bioavailability (F was included to account for dose variations. Covariates effects (age, sex, weight, antivenom batch, pre-antivenom concentrations were explored by visual inspection and in model building. There were 75 patients, median age 57 years (40-70 y and 64 (85% were male. 411 antivenom concentration data points were analysed. A two compartment model with zero order input, linear elimination kinetics and a combined error model best described the data. Inclusion of BSV on F and weight as a covariate on V improved the model. Inclusion of pre-antivenom concentrations or different batches on BSV of F did not. Final model parameter estimates were CL,0.078 L h(-1, V,2.2L, Q,0.178 L h(-1 and VP,8.33L. The median half-life of distribution was 4.6 h (10-90%iles:2.6-7.1 h and half-life of elimination, 140 h (10th-90th percentilesx:95-223h.Indian F(ab'2 snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life.

  6. Pharmacokinetics of etanidazole (SR-2508) in bladder and cervical cancer: evidence of diffusion from urine

    International Nuclear Information System (INIS)

    Awwad, H.K.; el Badawy, S.; abd el Baki, H.; Zaghloul, M.; el Moneim Osman, A.; Akoush, H.; Fairchild, K.

    1989-01-01

    Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer

  7. SU-F-R-34: Quantitative Perfusion Measurement in Rectal Cancer Using Three Different Pharmacokinetic Models: Implications for Prospective Study Design

    Energy Technology Data Exchange (ETDEWEB)

    Nie, K; Yue, N; Jabbour, S; Kim, S [Rutgers-Cancer Institute of New Jersey, Rutgers-Robert Wood Johnson Medical, New Brunswick, NJ (United States); Mao, T; Shi, L; Hu, X; Qian, L; Sun, X; Niu, T [Sir Run Run Shaw Hospital, Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang (China)

    2016-06-15

    Purpose: To compare three different pharmacokinetic models for analysis of dynamic-contrast-enhanced (DCE)-CT data with respect to different acquisition times and location of region of interest. Methods: Eight rectal cancer patients with pre-treatment DCE-CTs were included. The dynamic sequence started 4–10seconds(s) after the injection of contrast agent. The scan included a 110s acquisition with intervals of 40×1s+15×3s+4×6s. An experienced oncologist outlined the tumor region. Hotspots with top-5%-enhancement were also identified. Pharmacokinetic analysis was performed using three different models: deconvolution method, Patlak model, and modified Toft’s model. Perfusion parameters as blood flow (BF), blood volume (BV), mean transit time (MTT), permeability-surface-area-product (PS), volume transfer constant (Ktrans), and flux rate constant (Kep), were compared with respect to different acquisition times of 45s, 65s, 85s and 105s. Both hotspot and whole-volume variances were also assessed. The differences were compared using the Wilcoxon matched-pairs test and Bland-Altman plots. Results: Moderate correlation was observed for various perfusion parameters (r=0.56–0.72, p<0.0001) but the Wilcoxon test revealed a significant difference among the three models (P < .001). Significant differences in PS were noted between acquisitions of 45s versus longer time of 85s or 105s (p<0.05) using Patlak but not with the deconvolution method. In addition, measurements varied substantially between whole-volume vs. hotspot analysis. Conclusion: The radiation dose of DCE-CT was on average 1.5 times of an abdomen/pelvic CT, which is not insubstantial. To take the DCE-CT forward as a biomarker in oncology, prospective studies should be carefully designed with the optimal image acquisition and analysis technique. Our study suggested that: (1) different kinetic models are not interchangeable; (2) a 45s acquisition might not be sufficient for reliable permeability measurement

  8. [Nutrition therapy of cancer patients].

    Science.gov (United States)

    Lövey, József

    2017-09-20

    The majority of cancer patients becomes malnourished during the course of their disease. Malnutrition deteriorates the efficiency of all kinds of oncologic interventions. As a consequence of it, treatment-related toxicity increases, hospital stay is lengthened, chances of cure and survival as well as the quality of life of the patients worsen. Nutritional status therefore influences all aspects of outcome of oncology care. In spite of this the use of nutritional therapy varies across health care providers but its application is far from being sufficient during active oncology interventions as well as rehabilitation and supportive care. It threatens not only the outcome and quality of life of cancer patients but also the success of oncologic treatments which often demand high input of human and financial resources. Meanwhile application of nutritional therapy is legally regulated in Hungary and a very recent update of the European guideline on cancer patient nutrition published in 2017 is available. Moreover, cost effectiveness of nutritional therapy has been proven in a number of studies. In this review we present the basics of nutritional therapy including nutritional screening and evaluation, nutritional plan, the role of nutrition support teams, oral, enteral and parenteral nutrition, the use of different drugs and special nutrients and the follow-up of the patients.

  9. Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard; Johnstone, David W.; Watson, Thomas; Smudzin, Therese; Keng, Peter C.

    2008-01-01

    Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m 2 , 20 mg/m 2 , and 25 mg/m 2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m 2 ), II (20 mg/m 2 ), and III (25 mg/m 2 ), the mean peak plasma level was 0.23 ± 0.06 μmol/l, 0.32 ± 0.05 μmol/l, and 0.52 ± 0.14 μmol/l, respectively; AUC was 0.44 ± 0.09 μmol/l, 0.61 ± 0.1 μmol/l, and 0.96 ± 0.23 μmol/l, respectively; and duration of drug concentration >0.05 μmol/l (t > 0.05 μmol/l) was 1.6 ± 0.3 h, 1.9 ± 0.2 h, and 3.0 ± 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 μmol/l for a minimum of 1.6 h was sufficient for effective radiosensitization

  10. Pharmacokinetic profile of voriconazole in a critically ill patient on therapeutic plasma exchange

    NARCIS (Netherlands)

    Spriet, I.; Bruggemann, R.J.M.; Annaert, P.; Meersseman, P.; Wijngaerden, E. van; Lagrou, K.; Willems, L.

    2013-01-01

    BACKGROUND: Extracorporeal removal of drugs during therapeutic plasma exchange (TPE) can lead to decreased efficacy, as shown in several reports discussing altered pharmacokinetics (PKs) of antibiotics during TPE. In particular, drugs with a low volume of distribution or a high protein binding are

  11. Influence of Erroneous Patient Records on Population Pharmacokinetic Modeling and Individual Bayesian Estimation

    NARCIS (Netherlands)

    van der Meer, Aize Franciscus; Touw, Daniel J.; Marcus, Marco A. E.; Neef, Cornelis; Proost, Johannes H.

    2012-01-01

    Background: Observational data sets can be used for population pharmacokinetic (PK) modeling. However, these data sets are generally less precisely recorded than experimental data sets. This article aims to investigate the influence of erroneous records on population PK modeling and individual

  12. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients

    NARCIS (Netherlands)

    Simpson, Julie A.; Agbenyega, Tsiri; Barnes, Karen I.; Di Perri, Gianni; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif; McIlleron, Helen; Miller, Raymond; Molyneux, Malcolm; Mwenechanya, James; Navaratnam, Visweswaran; Nosten, Francois; Olliaro, Piero; Pang, Lorrin; Ribeiro, Isabela; Tembo, Madalitso; van Vugt, Michele; Ward, Steve; Weerasuriya, Kris; Win, Kyaw; White, Nicholas J.

    2006-01-01

    Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with

  13. Plasma and urine, pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction

    NARCIS (Netherlands)

    Althaus, M; de Mey, C; Ezan, E; Ciecko-Michalska, [No Value; Kostka-Trabkal, E; Goszcz, A; Retzow, A

    Objective: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged alpha -dihydroergocryptine (DHEC, Almirid (R), Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and

  14. Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension.

    Science.gov (United States)

    Krause, Andreas; Zisowsky, Jochen; Dingemanse, Jasper

    2018-04-01

    Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. Sex, age, and body weight influenced the PK to a statistically significant extent. Model-based simulations showed that these variables are clinically not relevant. Concomitant use of PAH medication (PDE-5 inhibitors) did not influence macitentan trough concentration to a relevant extent. Efficacy and hemodynamics showed clear differences from placebo for macitentan concentrations on 3 and 10 mg with consistent superior effects for 10 mg. After 6 months, PAH patients showed model-predicted 6-min walk distance (6-MWD) improvements of 1.0 m on placebo compared to 29.8 and 34.1 m on 3 and 10 mg of macitentan, respectively. Higher macitentan concentrations were associated with reductions in pulmonary vascular resistance (PVR), mean right atrial and pulmonary arterial pressure, and total pulmonary resistance (TPR) and increases in cardiac index (CI) and mixed venous oxygen saturation. Statistical significance was determined for PVR, TPR, and CI but not for 6-MWD. In addition, PVR showed more pronounced differences between active treatment and placebo than 6-MWD. Modeling identified statistically significant inter-patient differences; simulations to assess the magnitude of the effects permitted clinical judgment. The same approach will allow for extrapolation to children. Hemodynamic markers might be better markers of treatment effects than 6-MWD. The SERAPHIN study and its open-label extension are registered with ClinicalTrials.gov with identifiers NCT00660179 (https://www.clinicaltrials.gov/ct2/show/NCT00660179) and NCT00667823 (https://clinicaltrials.gov/ct2/show

  15. Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients.

    Science.gov (United States)

    Uno, Takaya; Wada, Kyoichi; Matsuda, Sachi; Terada, Yuka; Oita, Akira; Kawase, Atsushi; Takada, Mitsutaka

    2018-04-24

    Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation. The tacrolimus pharmacokinetic profile was obtained from 65 patients during the first 5 weeks after heart transplantation. Differences in the patients' characteristics and tacrolimus pharmacokinetic parameters between the CYP3A5 expresser (*1/*1 or *1/*3 genotypes) and non-expresser (*3/*3 genotype) groups were assessed by the Chi-square test, Student's t test, or Mann-Whitney U test. The CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes were detected in 5, 22, and 38 patients, respectively. All patients started clotrimazole therapy approximately 1 week after starting tacrolimus. Apparent clearance and dose/weight to reach the target trough concentration (C 0 ) were significantly higher in the expresser group than in the non-expresser group (0.32 vs. 0.19 L/h/kg, p = 0.0003; 0.052 vs. 0.034 mg/kg/day, p = 0.0002); there were no significant differences in the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) and concentrations at any sampling time point between the two groups. Similar concentration-time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.

  16. Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

    Science.gov (United States)

    LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

    2013-01-01

    Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

  17. Management of locally advanced and metastatic colon cancer in elderly patients.

    Science.gov (United States)

    Kurniali, Peter C; Hrinczenko, Borys; Al-Janadi, Anas

    2014-02-28

    Colon cancer is the second leading cause of cancer mortality in the United States with a median age at diagnosis of 69 years. Sixty percent are diagnosed over the age of 65 years and 36% are 75 years or older. At diagnosis, approximately 58% of patients will have locally advanced and metastatic disease, for which systemic chemotherapy has been shown to improve survival. Treatment of cancer in elderly patients is more challenging due to multiple factors, including disabling co-morbidities as well as a decline in organ function. Cancer treatment of elderly patients is often associated with more toxicities that may lead to frequent hospitalizations. In locally advanced disease, fewer older patients receive adjuvant chemotherapy despite survival benefit and similar toxicity when compared to their younger counterparts. A survival benefit is also observed in the palliative chemotherapy setting for elderly patients with metastatic disease. When treating elderly patients with colon cancer, one has to consider drug pharmacokinetics and pharmacodynamics. Since chronological age is a poor marker of a patient's functional status, several methods of functional assessment including performance status and activities of daily living (ADL) or instrumental ADL, or even a comprehensive geriatric assessment, may be used. There is no ideal chemotherapy regimen that fits all elderly patients and so a regimen needs to be tailored for each individual. Important considerations when treating elderly patients include convenience and tolerability. This review will discuss approaches to the management of elderly patients with locally advanced and metastatic colon cancer.

  18. Acute kidney injury in the cancer patient.

    Science.gov (United States)

    Campbell, G Adam; Hu, Daniel; Okusa, Mark D

    2014-01-01

    Acute kidney injury (AKI) is a frequent and significant complication of cancer and cancer therapy. Cancer patients frequently encounter risk factors for AKI including older age, CKD, prerenal conditions, sepsis, exposure to nephrotoxins, and obstructive physiology. AKI can also be secondary to paraneoplastic conditions, including glomerulonephritis and microangiopathic processes. This complication can have significant consequences, including effects on patients' ability to continue to receive therapy for their malignancy. This review will serve to summarize potential etiologies of AKI that present in patients with cancer as well as to highlight specific patient populations, such as the critically ill cancer patient. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  19. Supporting Asian patients with metastatic breast cancer during ixabepilone therapy.

    Science.gov (United States)

    Bourdeanu, Laura; Wong, Siu-Fun

    2010-05-01

    Ixabepilone is currently FDA-approved in metastatic breast cancer, and most patients in the registrational trials were Caucasian. Studies in Asian populations receiving other cytotoxic agents have revealed differential pharmacokinetics and clinical outcomes. As such, clinicians should understand the possible contributions of Asian ethnicity and culture to the clinical profile of ixabepilone. Studies in Asian patients receiving other chemotherapeutics reported altered toxicity profiles for myelosuppression, neurotoxicity and gastrointestinal symptoms. Encouragingly, the limited clinical data in Asian patients receiving ixabepilone suggest that efficacy and toxicity in these women resemble those reported in the ixabepilone registrational trials. The reader will better understand how Asian genetics and culture may influence treatment outcomes and patient attitudes toward therapy and interaction with caregivers. Management of ixabepilone-related adverse events is also discussed with an emphasis on special considerations for Asian patients. Awareness of possible altered drug response in Asian patients will aid clinicians in monitoring for toxicity, recognizing the need for dose modification and educating patients. Sensitivity to cultural aspects that are unique to Asians may improve adherence, reporting of adverse events and trust among Asian patients receiving ixabepilone.

  20. Oral complications in cancer patients

    International Nuclear Information System (INIS)

    Carl, W.

    1983-01-01

    Ionizing radiation used in treating the head and neck area produces oral side effects such as mucositis, salivary changes, trismus and radiation caries. Sequelae of cancer chemotherapy often include oral stomatitis, myelosuppression and immunosuppression. Infections of dental origin in compromised patients are potentially lethal. Specific programs to eliminate dental pathology before radiation and chemotherapy, and to maintain oral hygiene during and after therapy, will minimize these complications

  1. Effects of smoking and body mass index on the exposure of fentanyl in patients with cancer.

    Science.gov (United States)

    Kuip, Evelien J M; Oldenmenger, Wendy H; Thijs-Visser, Martine F; de Bruijn, Peter; Oosten, Astrid W; Oomen-de Hoop, Esther; Koolen, Stijn L W; Van der Rijt, Carin C D; Mathijssen, Ron H J

    2018-01-01

    The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statistically significant difference was found, the plasma concentrations of non-smokers was 28% (95% CI [-14%; +89-%]) higher than those of smokers normalizing for a dose of 25μg/min. Patients with a low BMI ( 25 kg/m2). A wider variation in fentanyl plasma concentrations was found in this study than anticipated. Due to this variation, studies in larger patient cohorts are needed to further investigate the effect of smoking on plasma concentration of fentanyl and thereby clarify the clinical significance of our findings.

  2. Concurrent administration of anticancer chemotherapy drug and herbal medicine on the perspective of pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Yung-Yi Cheng

    2018-04-01

    Full Text Available With an increasing number of cancer patients seeking an improved quality of life, complementary and alternative therapies are becoming more common ways to achieve such improvements. The potential risks of concurrent administration are serious and must be addressed. However, comprehensive evidence for the risks and benefits of combining anticancer drugs with traditional herbs is rare. Pharmacokinetic investigations are an efficient way to understand the influence of concomitant remedies. Therefore, this study aimed to collect the results of pharmacokinetic studies relating to the concurrent use of cancer chemotherapy and complementary and alternative therapies. According to the National Health Insurance (NHI database in Taiwan and several publications, the three most commonly prescribed formulations for cancer patients are Xiang-Sha-Liu-Jun-Zi-Tang, Jia-Wei-Xiao-Yao-San and Bu-Zhong-Yi-Qi-Tang. The three most commonly prescribed single herbs for cancer patients are Hedyotis diffusa, Scutellaria barbata, and Astragalus membranaceus. Few studies have discussed herb–drug interactions involving these herbs from a pharmacokinetics perspective. Here, we reviewed Jia-Wei-Xiao-Yao-San, Long-Dan-Xie-Gan-Tang, Curcuma longa and milk thistle to provide information based on pharmacokinetic evidence for healthcare professionals to use in educating patients about the risks of the concomitant use of various remedies. Keywords: Traditional Chinese medicine, Chemotherapy drug, Pharmacokinetics, Herb–drug interaction

  3. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR), which may compensate for diminished AR activity. The

  4. Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

    Science.gov (United States)

    Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

    2013-09-01

    The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

  5. Pharmacokinetics of 111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma

    International Nuclear Information System (INIS)

    Rosenblum, M.G.; Murray, J.L.; Haynie, T.P.; Glenn, H.J.; Jahns, M.F.; Benjamin, R.S.; Frincke, J.M.; Carlo, D.J.; Hersh, E.M.

    1985-01-01

    Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111 In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111 In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111 In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111 In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111 In-labeled antibody pharmacokinetics. This suggests that the 111 In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111 In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111 In-labeled chelate complex unattached to antibody. Analysis of the 111 In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution

  6. Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function.

    Science.gov (United States)

    Kasai, Hidefumi; Tsuji, Yasuhiro; Hiraki, Yoichi; Tsuruyama, Moeko; To, Hideto; Yamamoto, Yoshihiro

    2018-04-01

    Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4) -0.68  × Total body weight/60 0.81 , omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  7. Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

    Science.gov (United States)

    Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

    2010-06-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  8. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

    2010-01-01

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  9. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

    Science.gov (United States)

    Scheen, André J

    2015-07-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results

  10. Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

    2012-06-01

    Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

  11. Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction.

    Science.gov (United States)

    Kobalava, Zhanna; Kotovskaya, Yulia; Averkov, Oleg; Pavlikova, Elena; Moiseev, Valentine; Albrecht, Diego; Chandra, Priya; Ayalasomayajula, Surya; Prescott, Margaret F; Pal, Parasar; Langenickel, Thomas H; Jordaan, Pierre; Rajman, Iris

    2016-08-01

    Concomitant renin-angiotensin-aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF. This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II-IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]). On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100- and 200-mg doses, the Cmax and AUC0-12 h for sacubitril and LBQ657 were approximately dose-proportional while that of valsartan was less than dose-proportional. Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study. © 2016 John Wiley & Sons Ltd.

  12. Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

    Science.gov (United States)

    Touw, D J; Vinks, A A; Neef, C

    1997-06-01

    The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

  13. The mechanisms of photodynamic action for treating of cancer patients

    Directory of Open Access Journals (Sweden)

    A. L. Akopov

    2015-01-01

    Full Text Available Current views on mechanisms of therapeutic effect of photodynamic therapy for treating of cancer patients are represented. The history of formation and development of the method is described. The main requirements for agents used as photosensitizers are listed. Detailed review of main photosensitizers used in clinical practice in Russia and in foreign countries with their chemical structure, main spectral characteristics was performed. Methods of its application, therapeutic dose ranges, indications, specifi c pharmacokinetic properties and side-effects are briefl y outlined. Advantages and disadvantages of the most popular modern photosensitizers, main mechanisms of entry of photosensitizers of different chemical structure into cancer cells are observed. Three main possible component of anti-tumor effect: direct damage of cancer cells, impairment of vascular stroma of tumor and elimination of tumor due to immune cells are shown and closely discussed. Necrosis and apotosis of neovascular net which are main development trends of anti-tumor action for photodynamic therapy are noticed. 

  14. Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Jasem Al Shemaili

    2016-06-01

    Full Text Available The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of ~1 µM. Frondoside B was less potent (EC50 ~2.5 µM. Frondoside C and the aglycone had no effect. At 100 µg/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cpmax was 129 nM, Cltb was 6.35 mL/min/m2, and half-life was 510 min. With i.p. administration the Cpmax was 18.3 nM, Cltb was 127 mL/min/m2 and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 µg/kg/day i.p. markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

  15. Theoretical, clinical and pharmacokinetic aspects of cancer chemotherapy administered by continuous infusion

    International Nuclear Information System (INIS)

    Sikic, B.I.

    1986-01-01

    This chapter reviews some of the theoretical and empirical aspects of the administration of anti-cancer drugs by continuous intravenous infusion in conjunction with radiation therapy. The variables contributing to schedule dependence of anti-cancer drugs are discussed. A table shows the improved therapeutic index of Bleomycin by continuous infusion in mice. The use of Cytarabine, a pyrimidine anti-metabolite which kills cells during S-phase or DNA synthesis, is examined. Fluorouracil and Doxorubicin are examined and several other drugs including vincristine, vinblastine, etoposide, and cisplatin are discussed

  16. Changes in the pharmacokinetics of teicoplanin in patients with hyperglycaemic hypoalbuminaemia: Impact of albumin glycosylation on the binding of teicoplanin to albumin.

    Science.gov (United States)

    Enokiya, Tomoyuki; Muraki, Yuichi; Iwamoto, Takuya; Okuda, Masahiro

    2015-08-01

    There is large interindividual variability in serum teicoplanin (TEIC) concentrations after administration of a loading dose, and the factors that influence the pharmacokinetics of TEIC are disputed. The aim of this study was to clarify changes in the pharmacokinetics of TEIC that occur in patients with hyperglycaemia as well as the impact of albumin glycosylation on the pharmacokinetics of TEIC. This study consisted of retrospective and prospective investigations. The pharmacokinetic parameters of TEIC were retrospectively compared between patients receiving TEIC treatment. Ninety-four patients were divided into four groups according to their serum albumin and blood glucose concentrations [(i) hyperglycaemic hypoalbuminaemia (albuminalbumin≥3.0g/dL) (n=9); and (iv) non-hyperglycaemic normoalbuminaemia (n=40)]. In addition, the concentration of glycosylated albumin was prospectively determined in 28 patients. At 12h after administration of a loading dose, patients with hyperglycaemic hypoalbuminaemia displayed significantly lower serum TEIC concentrations (Palbumin was significantly correlated with the association constant (Ka) of TEIC for albumin (r=0.53, P=0.004) and the Vd (r=0.41, P=0.031). These results suggest that hyperglycaemic hypoalbuminaemia lowers the serum TEIC concentration, which is attributable to the decreased Ka and increased Vd of TEIC by albumin glycosylation. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  17. Pharmacokinetics of Rolapitant in Patients With Mild to Moderate Hepatic Impairment.

    Science.gov (United States)

    Wang, Jing; Wang, Xiaodong; Zhang, Zhi-Yi; Arora, Sujata; Lu, Sharon; Kansra, Vikram

    2018-05-01

    Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (C max ), observed time at C max (t max ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC 0-t ), and AUC from time 0 to 120 hours (AUC 0-120 ), with hepatic group as a fixed effect. Mean rolapitant C max , AUC 0-t , and AUC 0-120 were similar in the mild hepatic impairment and healthy control groups. In subjects with moderate hepatic impairment, AUC 0-t was similar and C max was 25% lower than in healthy controls. Mean M19 C max and AUC 0-t were similar in the mild hepatic impairment group and healthy controls, but impairment versus healthy controls. Fraction of unbound rolapitant was comparable in all groups for rolapitant and M19. Rolapitant was well tolerated in all groups, without serious adverse events. Pharmacokinetic differences between healthy subjects and those with mild or moderate hepatic impairment are unlikely to pose a safety risk and do not warrant predefined dosage adjustment in the presence of hepatic impairment. © 2018, The American College of Clinical Pharmacology.

  18. Psychiatric Problems in Patients with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Munevver Tunel

    2012-06-01

    Full Text Available Cancer is a physical disorder with concurrent mental and social components. During cancer, the feelings of fear, hopelessness, guilt, helplessness, abandonment perceived as a crisis leading to destruction in the suffering person. Breast cancer is the most common type of cancer among women. Prevalence of psychiatric disorders among cancer patients is approximately 50% and most of disorders are related with the occurrence of cancer and cancer treatment. Majority of patients present with major depression, adjustment disorder, anxiety disorders, sleep disorders, suicidial ideation, and delirium. Treatment of psychiatric disorders and cancer therapy should be conducted along with special consideration of drug interactions. This article reviews the adaptation process experienced by individuals during diagnosis and treatment of breast cancer, it psychological effects, resulting psychiatric comorbidites and their treatments. [Archives Medical Review Journal 2012; 21(3.000: 189-219

  19. Nutritional status assessment in colorectal cancer patients

    OpenAIRE

    Joana Pedro Lopes; Paula Manuela de Castro Cardoso Pereira; Ana Filipa dos Reis Baltazar Vicente; Alexandra Bernardo; María Fernanda de Mesquita

    2013-01-01

    The present study intended to evaluate the nutritional status of Portuguese colorectal patients and associated it with surgery type as well as quality of life outcomes. Malnutrition can affect up to 85% of cancer patients and specifically 30-60% in colorectal cancer and can significantly influence health outcomes. A sample of 50 colorectal cancer patients was evaluated in what refers to several anthropometric measures, food intake, clinical history, complications rate before and after surgery...

  20. Predictive performance of the 'Minto' remifentanil pharmacokinetic parameter set in morbidly obese patients ensuing from a new method for calculating lean body mass.

    Science.gov (United States)

    La Colla, Luca; Albertin, Andrea; La Colla, Giorgio; Porta, Andrea; Aldegheri, Giorgio; Di Candia, Domenico; Gigli, Fausto

    2010-01-01

    In a previous article, we showed that the pharmacokinetic set of remifentanil used for target-controlled infusion (TCI) might be biased in obese patients because it incorporates flawed equations for the calculation of lean body mass (LBM), which is a covariate of several pharmacokinetic parameters in this set. The objectives of this study were to determine the predictive performance of the original pharmacokinetic set, which incorporates the James equation for LBM calculation, and to determine the predictive performance of the pharmacokinetic set when a new method to calculate LBM was used (the Janmahasatian equations). This was an observational study with intraoperative observations and no follow-up. Fifteen morbidly obese inpatients scheduled for bariatric surgery were included in the study. The intervention included manually controlled continuous infusion of remifentanil during the surgery and analysis of arterial blood samples to determine the arterial remifentanil concentration, to be compared with concentrations predicted by either the unadjusted or the adjusted pharmacokinetic set. The statistical analysis included parametric and non-parametric tests on continuous variables and determination of the median performance error (MDPE), median absolute performance error (MDAPE), divergence and wobble. The median values (interquartile ranges) of the MDPE, MDAPE, divergence and wobble for the James equations during maintenance were -53.4% (-58.7% to -49.2%), 53.4% (49.0-58.7%), 3.3% (2.9-4.7%) and 1.4% h(-1) (1.1-2.5% h(-1)), respectively. The respective values for the Janmahasatian equations were -18.9% (-24.2% to -10.4%), 20.5% (13.3-24.8%), 2.6% (-0.7% to 4.5%) and 1.9% h(-1) (1.4-3.0% h(-1)). The performance (in terms of the MDPE and MDAPE) of the corrected pharmacokinetic set was better than that of the uncorrected one. The predictive performance of the original pharmacokinetic set is not clinically acceptable. Use of a corrected LBM value in morbidly obese

  1. Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients

    NARCIS (Netherlands)

    Rook, Elisabeth J.; van Ree, Jan M.; van den Brink, Wim; Hillebrand, Michel J. X.; Huitema, Alwin D. R.; Hendriks, Vincent M.; Beijnen, Jos H.

    2006-01-01

    A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon"

  2. THE PHARMACODYNAMICS AND PHARMACOKINETICS OF ORG-9426, A NEW NONDEPOLARIZING NEUROMUSCULAR BLOCKING-AGENT, IN PATIENTS ANESTHETIZED WITH NITROUS-OXIDE, HALOTHANE AND FENTANYL

    NARCIS (Netherlands)

    WIERDA, JMKH; KLEEF, UW; LAMBALK, LM; KLOPPENBURG, WD; AGOSTON, S

    The pharmacodynamics and pharmacokinetics of a new non-depolarizing neuromuscular blocking agent, Org 9426, were investigated. Ten patients undergoing elective head and neck surgery and anaesthetized with nitrous oxide, halothane and fentanyl, received a bolus dose of Org 9426 (1 mg.kg-1, 3 x ED90).

  3. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study

    NARCIS (Netherlands)

    Semvua, H.H.; Mtabho, C.M.; Fillekes, Q.; Boogaard, J. van den; Kisonga, R.M.; Mleoh, L.; Ndaro, A.; Kisanga, E.R.; Ven, A. van der; Aarnoutse, R.E.; Kibiki, G.S.; Boeree, M.J.; Burger, D.M.

    2013-01-01

    BACKGROUND: To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. METHODS: This was a Phase II open-label multiple dose

  4. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function

    NARCIS (Netherlands)

    Buijk, S L; Gyssens, I C; Mouton, J W; Verbrugh, H A; Touw, D J; Bruining, H A

    OBJECTIVES: (1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the concentrations of fluconazole reached at the site of infection. (3) To determine if enteral

  5. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    de Jong, Jan; Sukbuntherng, Juthamas; Skee, Donna; Murphy, Joe; O'Brien, Susan; Byrd, John C; James, Danelle; Hellemans, Peter; Loury, David J; Jiao, Juhui; Chauhan, Vijay; Mannaert, Erik

    2015-05-01

    To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants. Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib.

  6. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  7. Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction

    Science.gov (United States)

    Tsuchihashi, Kenji; Shimokawa, Hozumi; Takayoshi, Kotoe; Nio, Kenta; Aikawa, Tomomi; Matsushita, Yuzo; Wada, Iori; Arita, Shuji; Ariyama, Hiroshi; Kusaba, Hitoshi; Sonoda, Koh-Hei; Akashi, Koichi; Baba, Eishi

    2017-01-01

    Abstract Rationale: Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known. Patient concerns: Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction. Diagnoses: Fundus examination revealed hemorrhage of the retinal vein. Interventions: Regorafenib treatment was discontinued and observational therapy was pursued. Outcomes: Retinal and gastrointestinal hemorrhage resolved in 1 week. Lessons: Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified. PMID:29049226

  8. Guidelines Urge Exercise for Cancer Patients, Survivors

    Science.gov (United States)

    The benefits of exercise are well documented in a number of cancers. A panel of experts in cancer, fitness, obesity, and exercise training convened by the American College of Sports Medicine is spreading what they believe to be one of the most important messages for cancer patients and survivors: Avoid inactivity.

  9. A Prospective Study of the Efficacy, Safety and Pharmacokinetics of Enteral Moxifloxacin in the Treatment of Hemodialysis Patients with Pneumonia.

    Science.gov (United States)

    Tokimatsu, Issei; Shigemura, Katsumi; Kotaki, Tomohiro; Yoshikawa, Hiroki; Yamamichi, Fukashi; Tomo, Tadashi; Arakawa, Soichi; Fujisawa, Masato; Kadota, Jun-Ichi

    2017-01-01

    Objectives To investigate the efficacy of oral moxifloxacin (MFLX) as a treatment for pneumonia in hemodialysis (HD) patients and the pharmacokinetic (PK) profile of MFLX after oral administration. Methods Thirteen adult patients who required HD due to chronic renal failure were enrolled in the present study, which was performed to investigate the treatment of community-acquired pneumonia in HD patients. A standard dose of MFLX (400 mg, once daily) was administered. The therapy was continued, discontinued, or switched to another antibiotic depending on the response of the pneumonia to MFLX. A population PK model was developed using the post-hoc method. Results In total, 13 HD patients with pneumonia (male, n=7; female, n=6) were enrolled in the present study. The evaluation on the 3rd day showed that treatment was successful in 11 patients (84.6%) and that 10 patients were cured (76.9%). In the one case in which MFLX treatment failed, the patient was cured by switching to ceftriaxone (CTRX) (2 g, intravenously) plus levofloxacin (LVFX) (250 mg, orally). The causative bacterium in this male patient was P. aeruginosa. It did not display resistance to fluoroquinolones. One patient had liver dysfunction due to MFLX. The estimated PK parameters of MFLX were as follows: AUC 0→24 , 61.04±17.74 μg h/mL; C max , 5.25±1.12 μg/mL; and C trough , 1.15±0.45 μg/mL. The PK parameters of MFLX among the patients in whom adverse events occurred or in whom a cure was not achieved did not differ from those of the other patients to a statistically significant extent. Conclusion MFLX showed good efficacy and safety in HD patients with community-acquired pneumonia and the results of the PK analysis were favorable. Further prospective studies with larger numbers of patients will be needed to draw definitive conclusions.

  10. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  11. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance = 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  12. Increased cancer risk in patients with periodontitis.

    Science.gov (United States)

    Dizdar, Omer; Hayran, Mutlu; Guven, Deniz Can; Yılmaz, Tolga Birtan; Taheri, Sahand; Akman, Abdullah C; Bilgin, Emre; Hüseyin, Beril; Berker, Ezel

    2017-12-01

    Previous studies have noted a possible association between periodontal diseases and the risk of various cancers. We assessed cancer risk in a cohort of patients with moderate to severe periodontitis. Patients diagnosed with moderate to severe periodontitis by a periodontist between 2001 and 2010 were identified from the hospital registry. Patients younger than 35 years of age or with a prior cancer diagnosis were excluded. The age- and gender-standardized incidence rates (SIR) were calculated by dividing the number of observed cases by the number of expected cases from Turkish National Cancer Registry 2013 data. A total of 280 patients were included (median age 49.6, 54% female). Median follow-up was 12 years. Twenty-five new cancer cases were observed. Patients with periodontitis had 77% increased risk of cancer (SIR 1.77, 95% CI 1.17-2.58, p = .004). Women with periodontitis had significantly higher risk of breast cancer (SIR 2.40, 95% CI 0.88-5.33) and men with periodontitis had significantly higher risk of prostate cancer (SIR 3.75, 95% CI 0.95-10.21) and hematological cancers (SIR 6.97, 95% CI 1.77-18.98). Although showing a causal association necessitates further investigation, our results support the idea that periodontitis might be associated with increased cancer risk, particularly with hematological, breast and prostate cancers.

  13. Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients

    Directory of Open Access Journals (Sweden)

    Abd Arwa Y

    2010-12-01

    Full Text Available Abstract Objectives To conduct a systematic review for the evidence supporting or disproving the reality of parenteral nutrition- antiepileptic drugs interaction, especially with respect to the plasma protein-binding of the drug. Methods The articles related to the topic were identified through Medline and PubMed search (1968-Feburary 2010 for English language on the interaction between parenteral nutrition and antiepileptic drugs; the search terms used were anti-epileptic drugs, parenteral nutrition, and/or interaction, and/or in vitro. The search looked for prospective randomized and nonrandomized controlled studies; prospective nonrandomized uncontrolled studies; retrospective studies; case reports; and in vitro studies. Full text of the articles were then traced from the Universiti Sains Malaysia (USM library subscribed databases, including Wiley-Blackwell Library, Cochrane Library, EBSCOHost, OVID, ScienceDirect, SAGE Premier, Scopus, SpringerLINK, and Wiley InterScience. The articles from journals not listed by USM library were traced through inter library loan. Results There were interactions between parenteral nutrition and drugs, including antiepileptics. Several guidelines were designed for the management of illnesses such as traumatic brain injuries or cancer patients, involving the use of parenteral nutrition and antiepileptics. Moreover, many studies demonstrated the in vitro and in vivo parenteral nutrition -drugs interactions, especially with antiepileptics. Conclusions There was no evidence supporting the existence of parenteral nutrition-antiepileptic drugs interaction. The issue has not been studied in formal researches, but several case reports and anecdotes demonstrate this drug-nutrition interaction. However, alteration in the drug-free fraction result from parenteral nutrition-drug (i.e. antiepileptics interactions may necessitate scrupulous reassessment of drug dosages in patients receiving these therapies. This

  14. Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients.

    Science.gov (United States)

    Salih, Muhannad R M; Bahari, Mohd Baidi; Abd, Arwa Y

    2010-12-31

    To conduct a systematic review for the evidence supporting or disproving the reality of parenteral nutrition- antiepileptic drugs interaction, especially with respect to the plasma protein-binding of the drug. The articles related to the topic were identified through Medline and PubMed search (1968-Feburary 2010) for English language on the interaction between parenteral nutrition and antiepileptic drugs; the search terms used were anti-epileptic drugs, parenteral nutrition, and/or interaction, and/or in vitro. The search looked for prospective randomized and nonrandomized controlled studies; prospective nonrandomized uncontrolled studies; retrospective studies; case reports; and in vitro studies. Full text of the articles were then traced from the Universiti Sains Malaysia (USM) library subscribed databases, including Wiley-Blackwell Library, Cochrane Library, EBSCOHost, OVID, ScienceDirect, SAGE Premier, Scopus, SpringerLINK, and Wiley InterScience. The articles from journals not listed by USM library were traced through inter library loan. There were interactions between parenteral nutrition and drugs, including antiepileptics. Several guidelines were designed for the management of illnesses such as traumatic brain injuries or cancer patients, involving the use of parenteral nutrition and antiepileptics. Moreover, many studies demonstrated the in vitro and in vivo parenteral nutrition -drugs interactions, especially with antiepileptics. There was no evidence supporting the existence of parenteral nutrition-antiepileptic drugs interaction. The issue has not been studied in formal researches, but several case reports and anecdotes demonstrate this drug-nutrition interaction. However, alteration in the drug-free fraction result from parenteral nutrition-drug (i.e. antiepileptics) interactions may necessitate scrupulous reassessment of drug dosages in patients receiving these therapies. This reassessment may be particularly imperative in certain clinical situations

  15. Psychosocial coping strategies in cancer patients

    International Nuclear Information System (INIS)

    Sprah, L.; Sostaric, M.

    2004-01-01

    Background. The aim of this review is to present common psychosocial problems in cancer patients and their possible coping strategies. Cancer patients are occupied with many psychosocial problems, which are only partially related to their health state and medical treatments. They are faced with a high social pressure, based on prejudices and stereotypes of this illness. The review presents the process of confrontation with the cancer diagnosis and of managing the psychological consequences of cancer. The effects of specific coping styles, psychosocial interventions and a social support on initiation, progression and recurrence of cancer are also described. Conclusions. Although some recent meta-analysis could not provide scientific evidence for the association between coping strategies and the cancer initiation, the progression or the recurrence (neither have studies rejected the thesis of association), the therapeutic window for the psychosocial intervention is still wide and shows an important effect on the quality of lives of many cancer patients. (author)

  16. Role of pharmacokinetic parameters derived with high temporal resolution DCE MRI using simultaneous PET/MRI system in breast cancer: A feasibility study

    Energy Technology Data Exchange (ETDEWEB)

    Jena, Amarnath, E-mail: drjena2002@gmail.com [Department of Molecular Imaging and Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India); Taneja, Sangeeta; Singh, Aru; Negi, Pradeep; Mehta, Shashi Bhushan [Department of Molecular Imaging and Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India); Sarin, Ramesh [Department of Surgical Oncology, Indraprastha Apollo Hospitals, Sarita Vihar, Delhi–Mathura Road, New Delhi 110076 (India)

    2017-01-15

    Highlights: • Simultaneous PET/MRI (with 3T MRI in the core) for quantitative pharmacokinetics. • Diagnostic accuracy of pharmacokinetic parameters like K{sup trans}, K{sub ep} and v{sub e} acquired through this system. • Incorporating high temporal resolution sequence with short acquisition time of 60 s within the routine DCE MRI in a simultaneous PET/MRI system. - Abstract: Purpose: To evaluate the reliability of pharmacokinetic parameters like K{sup trans}, Kep and v{sub e} derived through DCE MRI breast protocol using 3 T Simultaneous PET/MRI (3 Tesla Positron Emission Tomography/Magnetic Resonance Imaging) system in distinguishing benign and malignant lesions. Materials and methods: High temporal resolution DCE (Dynamic Contrast Enhancement) MRI performed as routine breast MRI for diagnosis or as a part of PET/MRI for cancer staging using a 3 T simultaneous PET/MRI system in 98 women having 109 breast lesions were analyzed for calculation of pharmacokinetic parameters (K{sup trans}, v{sub e}, and Kep) at 60 s time point using an in-house developed computation scheme. Results: Receiver operating characteristic (ROC) curve analysis revealed a cut off value for K{sup trans}, Kep, v{sub e} as 0.50, 2.59, 0.15 respectively which reliably distinguished benign and malignant breast lesions. Data analysis revealed an overall accuracy of 94.50%, 79.82% and 87.16% for K{sup trans}, Kep, v{sub e} respectively. Introduction of native T1 normalization with an externally placed phantom showed a higher accuracy (94.50%) than without native T1 normalization (93.50%) with an increase in specificity of 87% vs 84%. Conclusion: Overall the results indicate that reliable measurement of pharmacokinetic parameters with reduced acquisition time is feasible in a 3TMRI embedded PET/MRI system with reasonable accuracy and application may be extended to exploit the potential of simultaneous PET/MRI in further work on breast cancer.

  17. Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition.

    Science.gov (United States)

    Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang; Wu, Rachel T; Wang, Yuwen; Huang, Mou-Tuan; Newmark, Harold L; Huang, Qingrong; Khor, Tin Oo; Heimbach, Tycho; Kong, Ah-Ng

    2011-03-01

    The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low compared with the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50 and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4%-13.6%. The increase in AUC was not proportional to the oral doses, suggesting non-linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. An oil-in-water nanoemulsion containing DBM was formulated to potentially overcome the low F* due to poor water solubility of DBM, with enhanced oral absorption. Finally, to examine the role of Nrf2 on the pharmacokinetics of DBM, since DBM activates the Nrf2-dependent detoxification pathways, Nrf2 wild-type (+/+) mice and Nrf2 knockout (-/-) mice were utilized. There was an increased systemic plasma exposure of DBM in Nrf2 (-/-) mice, suggesting that the Nrf2 genotype could also play a role in the pharmacokinetic disposition of DBM. Taken together, the results show that DBM has low oral bioavailability which could be due in part to poor water solubility and this could be overcome by a nanotechnology-based drug delivery system and furthermore the Nrf2 genotype could also play a role in the pharmacokinetics of DBM. Copyright © 2010 John Wiley & Sons, Ltd.

  18. Pharmacokinetics of Dietary Cancer Chemopreventive Compound Dibenzoylmethane in the Rats and Impacts of Nanoemulsion and Genetic knockout of Nrf2 on its Disposition

    OpenAIRE

    Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang; Wu, Rachel T.; Wu, Yuwen; Huang, Mou-Tuan; Newmark, Harold L.; Huang, Qingrong; Khor, Tin Oo; Heimbach, Tycho; Kong, Ah-Ng

    2010-01-01

    The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low as compared to the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. A...

  19. Cancer screening in patients infected with HIV.

    Science.gov (United States)

    Sigel, Keith; Dubrow, Robert; Silverberg, Michael; Crothers, Kristina; Braithwaite, Scott; Justice, Amy

    2011-09-01

    Non-AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin's lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening.

  20. Circulating procoagulant microparticles in cancer patients

    OpenAIRE

    Thaler, Johannes; Ay, Cihan; Weinstabl, Harald; Dunkler, Daniela; Simanek, Ralph; Vormittag, Rainer; Freyssinet, Jean-Marie; Zielinski, Christoph; Pabinger, Ingrid

    2010-01-01

    Abstract Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vien...

  1. Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

    DEFF Research Database (Denmark)

    Lassen, U; Miller, W H; Hotte, S

    2013-01-01

    PURPOSE: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. METHODS: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg...... (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. RESULTS: In the ketoconazole study, 46 patients were...... dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41...

  2. Fostering hope in the patient with cancer.

    Science.gov (United States)

    Lichwala, Rebecca

    2014-06-01

    When a patient is diagnosed with cancer, feelings such as fear, anxiety, and hopelessness can negatively affect a person's frame of mind. Hope can help a patient decrease anxiety and increase quality of life. Nurses should assess hope, provide interventions, be empathetic, listen, and treat patients with dignity to help improve hope and quality of life. This article features how hope can have a positive impact and provides specific information about how nurses can promote and foster hope in patients with cancer.

  3. Taste and smell changes in cancer patients

    NARCIS (Netherlands)

    IJpma, Irene

    2017-01-01

    Patients with cancer often experience changes in taste and smell perception during chemotherapy. The aim of this dissertation was to investigate taste and smell changes and short- and long-term effects of chemotherapy in a homogeneous population of testicular cancer patients treated with

  4. Haemorheological Changes in African Breast Cancer Patients

    African Journals Online (AJOL)

    elearning

    complications, African patients with breast cancer may well be predisposed to thrombotic complications during illness. ... having breast cancer were studied. The patients were diagnosed by one of the authors from histological biopsy from the lump removed from the breast. None of ... statistics (Student's t-test for paired data.

  5. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study.

    Science.gov (United States)

    Semvua, Hadija H; Mtabho, Charles M; Fillekes, Quirine; van den Boogaard, Jossy; Kisonga, Riziki M; Mleoh, Liberate; Ndaro, Arnold; Kisanga, Elton R; van der Ven, Andre; Aarnoutse, Rob E; Kibiki, Gibson S; Boeree, Martin J; Burger, David M

    2013-01-01

    To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported. Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

  6. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill.

    Science.gov (United States)

    Mohamed, Ami F; Karaiskos, Ilias; Plachouras, Diamantis; Karvanen, Matti; Pontikis, Konstantinos; Jansson, Britt; Papadomichelakis, Evangelos; Antoniadou, Anastasia; Giamarellou, Helen; Armaganidis, Apostolos; Cars, Otto; Friberg, Lena E

    2012-08-01

    A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

  7. Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma.

    Science.gov (United States)

    Stahl, Erin; Bremond-Gignac, Dominique; Landry, Theresa; Curtis, Mike; Gedif, Kinfemichael; Al Shahwan, Sami; Dixon, El Roy

    2017-06-01

    To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad ® (TRAVATAN ® ) in pediatric patients with glaucoma or ocular hypertension. This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (C max ). Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean C max was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs. Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and C max . No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.

  8. Causes of death among cancer patients.

    Science.gov (United States)

    Zaorsky, N G; Churilla, T M; Egleston, B L; Fisher, S G; Ridge, J A; Horwitz, E M; Meyer, J E

    2017-02-01

    The purpose of our study was to characterize the causes of death among cancer patients as a function of objectives: (i) calendar year, (ii) patient age, and (iii) time after diagnosis. US death certificate data in Surveillance, Epidemiology, and End Results Stat 8.2.1 were used to categorize cancer patient death as being due to index-cancer, nonindex-cancer, and noncancer cause from 1973 to 2012. In addition, data were characterized with standardized mortality ratios (SMRs), which provide the relative risk of death compared with all persons. The greatest relative decrease in index-cancer death (generally from > 60% to deaths were stable (typically >40%) among patients with cancers of the liver, pancreas, esophagus, and lung, and brain. Noncancer causes of death were highest in patients with cancers of the colorectum, bladder, kidney, endometrium, breast, prostate, testis; >40% of deaths from heart disease. The highest SMRs were from nonbacterial infections, particularly among 1,000 for lymphomas, P death from index- and nonindex-cancers varies widely among primary sites. Risk of noncancer deaths now surpasses that of cancer deaths, particularly for young patients in the year after diagnosis. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

    Science.gov (United States)

    Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

    2017-06-01

    Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  10. Thyroid cancer outcomes in Filipino patients.

    Science.gov (United States)

    Kus, Lukas H; Shah, Manish; Eski, Spiro; Walfish, Paul G; Freeman, Jeremy L

    2010-02-01

    To compare the outcomes of patients having thyroid cancer among Filipinos vs non-Filipinos. Retrospective medical record review. High-volume tertiary referral center in Toronto, Ontario, Canada. A total of 499 patients with thyroid cancer (36 Filipino and 463 non-Filipino) treated at Mount Sinai Hospital from January 1, 1984, to August 31, 2003, with a minimum 5-year follow-up period and a minimum 1.0-cm tumor size. Patients were identified from a thyroid cancer database. Data on patient, tumor, and treatment factors were collected along with outcomes. The presence of thyroid cancer recurrence, the rate of death from disease, and the time to recurrence. The 2 groups were similar for sex, age, history of head and neck radiation exposure, family history of thyroid cancer, follow-up time, tumor size, tumor pathologic findings, presence of tumor multifocality, stage of primary disease, type of thyroid surgery, use of postoperative radioactive iodine therapy, and use of external beam radiation therapy. Filipino patients experienced a thyroid cancer recurrence rate of 25% compared with 9.5% for non-Filipino patients (odds ratio, 3.20; 95% confidence interval, 1.23-7.49; P = .004). On multivariate analysis, the increased risk of thyroid cancer recurrence persisted for Filipino patients (odds ratio, 6.99; 95% confidence interval, 2.31-21.07; P Filipino patients and non-Filipino patients regarding the rate of death from disease (5.6% vs 1.9%) and the time to recurrence (52.6 vs 53.1 months). Filipino patients have a significantly higher risk of thyroid cancer recurrence compared with non-Filipino patients. However, no significant difference was noted in the time to recurrence or the rate of death from disease. These findings justify a more aggressive initial management and follow-up regimen for Filipino patients with thyroid cancer.

  11. Cardiopulmonary resuscitation in palliative care cancer patients.

    Science.gov (United States)

    Kjørstad, Odd Jarle; Haugen, Dagny Faksvåg

    2013-02-19

    The criteria for refraining from cardiopulmonary resuscitation in palliative care cancer patients are based on patients' right to refuse treatment and the duty of the treating personnel not to exacerbate their suffering and not to administer futile treatment. When is cardiopulmonary resuscitation futile in these patients? Systematic literature searches were conducted in PubMed for the period 1989-2010 on the results of in-hospital cardiopulmonary resuscitation in advanced cancer patients and on factors that affected the results of CPR when special mention was made of cancer. The searches yielded 333 hits and 18 included articles: four meta-analyses, eight retrospective clinical studies, and six review articles. Cancer patients had a poorer post-CPR survival than non-cancer patients. Survival declined with increasing extent of the cancer disease. Widespread and therapy-resistant cancer disease coupled with a performance status lower than WHO 2 or a PAM score (Pre-Arrest Morbidity Index) of above 8 was regarded as inconsistent with survival after cardiopulmonary resuscitation. Cardiopulmonary resuscitation is futile for in-hospital cancer patients with widespread incurable disease and poor performance status.

  12. Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

    International Nuclear Information System (INIS)

    Anthoney, D Alan; Miwa, Masanori; Twelves, Christopher; Evans, TRJ; Naik, Jay; MacPherson, Iain RJ; Crawford, Donna; Hartley, John M; Hartley, Janet A; Saito, Tomohisa; Abe, Masaichi; Jones, Keith

    2012-01-01

    A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m 2 . MTD was 10 mg/m 2 ; DLTs at 12 (2/4 patients) and 10 mg/m 2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and C max from 1–10 mg/m 2 . Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage. EU-CTR2006-001345-33

  13. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

    Science.gov (United States)

    Höglund, Richard; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na-Bangchang, Kesara

    2016-02-29

    A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were

  14. Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study.

    Science.gov (United States)

    Dorlo, Thomas P C; Kip, Anke E; Younis, Brima M; Ellis, Sally J; Alves, Fabiana; Beijnen, Jos H; Njenga, Simon; Kirigi, George; Hailu, Asrat; Olobo, Joseph; Musa, Ahmed M; Balasegaram, Manica; Wasunna, Monique; Karlsson, Mats O; Khalil, Eltahir A G

    2017-11-01

    Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

  15. Misonidazole as a radiosensitizer in the radiotherapy of glioblastomas and oesophageal cancer. Pharmacokinetic and clinical studies

    International Nuclear Information System (INIS)

    Tamulevicius, P.; Streffer, C.; Bamberg, M.; Scherer, E.

    1981-01-01

    Since May 1978 the hypoxic-cell radiosensitizer, misonidazole (MIS), has been under clinical investigation in a phase III trial with multiple doses of the drug in 11 patients with brain tumours (seven glioblastomas, four recurrent brain tumours) and three patients with oesophageal carcinoma. The doses of MIS administered were usually well tolerated but the principal toxicities observed were peripheral neuropathy as well as nausea and vomiting in the glioblastoma patients. The neuropathy was completely reversible. The incidence of neuropathy was not related to the pharmacological parameters of plasma level or half-life. Pharmacological assessment by high-pressure liquid chromatography included assays of plasma, urine and cerebrospinal fluid. The demethylated product, Ro-05-9963, was detected as the major metabolite. Peak plasma levels were obtained one to four hours after administration of MIS, with a half-life of five to ten hours. Cerebrospinal fluid levels of MIS correlated well with those of the plasma. MIS was mainly excreted as the demethylated metabolite, but less than 40% of the given dose could be recovered. The results obtained suggest that the present MIS dosage for glioblastoma patients results in a low plasma level with no observable therapeutic effect. (author)

  16. Improved Insulin Pharmacokinetics Using a Novel Microneedle Device for Intradermal Delivery in Patients with Type 2 Diabetes.

    Science.gov (United States)

    Kochba, Efrat; Levin, Yotam; Raz, Itamar; Cahn, Avivit

    2016-09-01

    Currently available short-acting insulin analogs have slower absorption compared with endogenous insulin occasionally resulting in immediate postprandial hyperglycemia. Intradermal (ID) injection facilitates faster drug absorption and may result in improved insulin pharmacokinetics. Seventeen patients with type 2 diabetes were included in this single-center, pilot, open-label crossover study. Patients received 0.2 U/kg Insulin aspart ID injections using a MicronJet (MJ) needle and subcutaneous (SC) injections, using a conventional needle in a crossover design. Thirteen patients were studied under fasting conditions and four before a standard meal test. The pharmacokinetic/pharmacodynamic (PK/PD) profile, as well as the safety and tolerability of injections, was compared. Fourteen patients completed the study per-protocol. ID versus SC injection demonstrated significantly shorter Tmax (median 35 vs. 87.5 min [P < 0.001]), while the Cmax did not significantly differ (median 80 vs. 55 μU/mL [P = 0.085]). Median insulin area under the curve (AUC; 360 min) did not differ between the groups (9914 vs. 10,936 μU/mL/min [p = 0.077]), yet 0-60 min insulin AUC was higher with ID versus SC injection (mean ± SD 3821 ± 1429 vs. 2534 ± 737 μU/mL/min [p = 0.01]) and 4-6 h AUC was lower with ID versus SC injection (mean ± SD 2054 ± 858 vs. 2929 ± 1412 μU/mL/min [p = 0.02]). The relative bioavailability of the ID versus the SC insulin (AUCID/AUCSC) was similar (median 0.91 [95% confidence interval 0.73-1.27]). ID insulin injection delivered through an MJ needle demonstrated superior PK profile compared with conventional SC administration, including shorter Tmax and higher early and lower late exposure in patients with type 2 diabetes. This may help achieve better insulin coverage of meals and lower postprandial glucose excursions.

  17. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy.

    Science.gov (United States)

    Naiker, Suhashni; Connolly, Cathy; Wiesner, Lubbe; Kellerman, Tracey; Reddy, Tarylee; Harries, Anthony; McIlleron, Helen; Lienhardt, Christian; Pym, Alexander

    2014-11-19

    Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. ClinicalTrials.gov Identifier: NCT00640887.

  18. Psychosocial Intervention In Prostate Cancer Patients

    Directory of Open Access Journals (Sweden)

    Potočníková Jana

    2015-05-01

    Full Text Available Prostate cancer is the second most common cancer worldwide for males, and the fifth most common cancer overall. Using of autogenic training could reduce the influence of ADT and raise quality of prostate cancer patients. The aim of this study was to determine the effects of autogenic training in patients with prostate cancer. Patients were divided to experimental and control group. Experimental group participated in fourteen weeks long autogenic training program. Control group performed usual daily activities. Every subject of research performed input and output diagnostics which monitored psychical states of patients by psychological standardized tests - Differential questionnaire of depression (DDF and Questionnaire of anxiety (STAI X1. Our data showed autogenic training program significant improved depressions symptoms and anxiety in experimental research group (p ≤ 0.05, however there was no main change of depression symptoms and anxiety values for control group (p = n.s..

  19. Prediction of chemotherapeutic response in bladder cancer using K-means clustering of dynamic contrast-enhanced (DCE)-MRI pharmacokinetic parameters.

    Science.gov (United States)

    Nguyen, Huyen T; Jia, Guang; Shah, Zarine K; Pohar, Kamal; Mortazavi, Amir; Zynger, Debra L; Wei, Lai; Yang, Xiangyu; Clark, Daniel; Knopp, Michael V

    2015-05-01

    To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint. With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. © 2014 Wiley Periodicals, Inc.

  20. Overview on Patient Centricity in Cancer Care

    Directory of Open Access Journals (Sweden)

    Šarunas Narbutas

    2017-10-01

    Full Text Available Successful implementation of treatment in cancer care partially depends on how patients' perspectives are taken into account, as preferences of health care professionals and patients may differ. Objectives of this exploratory research were (I to identify patient preferences and values (PPVs in cancer care as indicated by patient organizations (POs, (II to determine how these PPVs are captured in cancer care guidelines and (III to review how guidelines take into account these PPVs. Based on a survey developed and completed by 19 POs, a literature review was conducted to analyse how patient perspectives are incorporated in oncology treatment guidelines. Based on survey results traditional health technology assessment value propositions of oncology care, such as extended life, treatment-free remission and pain reduction, were also highly rated by POs. However, the heterogeneity of cancer PPVs were clearly reflected in the survey results. PPVs in cancer care guidelines were mostly limited to those micro-level aspects that are strictly related to health care provision, such as side-effects and comorbidities. Patient experience, emotional support and convenience of care were relatively neglected fields in the reviewed guidelines. Patient engagement was rarely presented in the guideline development phase. POs believe that patients should be encouraged to take an active role in their own care due to the heterogeneity of cancer patients and PPVs. Even if patient-centricity is a leading paradigm in cancer policy, based on our research it is not yet standard practice to include patients or POs at all appropriate levels of decision-making processes that are related to their health and well-being. Patient engagement should be an integral part of cancer care decision-making. This complexity must be reflected throughout policy making, avoiding a population level “one-size-fits-all” solution.

  1. Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients.

    Science.gov (United States)

    Schütte, Lisette M; van Hest, Reinier M; Stoof, Sara C M; Leebeek, Frank W G; Cnossen, Marjon H; Kruip, Marieke J H A; Mathôt, Ron A A

    2018-04-01

     Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict.  Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling.  Retrospective data of 128 nonsevere HA patients (age 7-75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations.  A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin ( p  C increase of 0.47 IU/mL (median, interquartile range: 0.32-0.65 IU/mL, n  = 142). C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations.  FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further. Schattauer Stuttgart.

  2. Cancer Patient Navigator Tasks across the Cancer Care Continuum

    Science.gov (United States)

    Braun, Kathryn L.; Kagawa-Singer, Marjorie; Holden, Alan E. C.; Burhansstipanov, Linda; Tran, Jacqueline H.; Seals, Brenda F.; Corbie-Smith, Giselle; Tsark, JoAnn U.; Harjo, Lisa; Foo, Mary Anne; Ramirez, Amelie G.

    2011-01-01

    Cancer patient navigation (PN) programs have been shown to increase access to and utilization of cancer care for poor and underserved individuals. Despite mounting evidence of its value, cancer patient navigation is not universally understood or provided. We describe five PN programs and the range of tasks their navigators provide across the cancer care continuum (education and outreach, screening, diagnosis and staging, treatment, survivorship, and end-of-life). Tasks are organized by their potential to make cancer services understandable, available, accessible, affordable, appropriate, and accountable. Although navigators perform similar tasks across the five programs, their specific approaches reflect differences in community culture, context, program setting, and funding. Task lists can inform the development of programs, job descriptions, training, and evaluation. They also may be useful in the move to certify navigators and establish mechanisms for reimbursement for navigation services. PMID:22423178

  3. Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2.

    Directory of Open Access Journals (Sweden)

    Ankur Sharma

    Full Text Available SHetA2 is a small molecule drug with promising cancer prevention and therapeutic activity and a high preclinical safety profile. The study objectives were to perform interspecies scaling and pharmacokinetic (PK modeling of SHetA2 for human PK prediction. The PK data obtained from mice, rats, and dogs after intravenous and oral doses were used for simultaneous fitting to PK models. The disposition of SHetA2 was best described by a two-compartment model. The absorption kinetics was well characterized with a first-order absorption model for mice and rats, and a gastrointestinal transit model for dogs. Oral administration of SHetA2 showed a relatively fast absorption in mice, prolonged absorption (i.e., flip-flop kinetics toward high doses in rats, and an early peak followed by a secondary peak at high doses in dogs. The oral bioavailability was 17.7-19.5% at 20-60 mg/kg doses in mice, <1.6% at 100-2000 mg/kg in rats, and 11.2% at 100 mg/kg decreasing to 3.45% at 400 mg/kg and 1.11% at 1500 mg/kg in dogs. The disposition parameters were well correlated with the body weight for all species using the allometric equation, which predicted values of CL (17.3 L/h, V1 (36.2 L, V2 (68.5 L and CLD (15.2 L/h for a 70-kg human. The oral absorption rate and bioavailability of SHetA2 was highly dependent on species, doses, formulations, and possibly other factors. The limited bioavailability at high doses was taken into consideration for the suggested first-in-human dose, which was much lower than the dose estimated based on toxicology studies. In summary, the present study provided the PK model for SHetA2 that depicted the disposition and absorption kinetics in preclinical species, and computational tools for human PK prediction.

  4. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients.

    Science.gov (United States)

    Minichmayr, Iris K; Schaeftlein, André; Kuti, Joseph L; Zeitlinger, Markus; Kloft, Charlotte

    2017-06-01

    We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT >MIC  = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations. A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CL Healthy /CL Cystic fibrosis /CL Diabetic  = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (-34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients. Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

  5. Understanding male cancer patients' barriers to participating in cancer rehabilitation.

    Science.gov (United States)

    Handberg, C; Lomborg, K; Nielsen, C V; Oliffe, J L; Midtgaard, J

    2015-11-01

    The aim was to describe male cancer survivors' barriers towards participation in cancer rehabilitation as a means to guiding future targeted men's cancer rehabilitation. Symbolic Interactionism along with the interpretive descriptive methodology guided the study of 35 male cancer survivors representing seven cancer types. Data were generated through a 5-month fieldwork study comprising participant observations, semi-structured individual interviews and informal conversations. The analyses revealed two overarching findings shedding light on male cancer survivors' barriers to rehabilitation: 'Fear of losing control' and 'Striving for normality'. While 'Fear of losing control' signified what the men believed rehabilitation would invoke: 'Reduced manliness', 'Sympathy and dependency' and 'Confrontation with death', 'Striving for normality' was based on what the men believed rehabilitation would hinder: 'Autonomy and purpose', 'Solidarity and fellowship' and 'Forget and move on'. This study of male cancer survivors' and cancer rehabilitation documents how masculine ideals may constitute barriers for participation in rehabilitation and provides insights about why men are underrepresented in rehabilitation. The findings can guide practice to develop research-based rehabilitation approaches focused on preserving control and normality. Further empirical evidence is needed to: (1) explore the conduct of health professionals' towards male cancer patients and (2) address gender inequalities in cancer rehabilitation. © 2015 John Wiley & Sons Ltd.

  6. Fertility in patients treated for testicular cancer.

    Science.gov (United States)

    Matos, Erika; Skrbinc, Breda; Zakotnik, Branko

    2010-09-01

    Testicular cancer affects men mostly in their reproductive age with a cure rate over 90% and fertility is one of the main concerns of survivors. To further elucidate the question of fertility after treatment for testicular cancer, we performed a survey in patients treated in our institution. We sent a questionnaire to patients treated for testicular cancer at our institute from 1976 to 2002 (n = 490) of whom 297 (60.6%) responded. We considered the patients to have conserved fertility if they had children after treatment without assisted reproductive technologies. Before treatment 119/297 (40.1%) of patients and after treatment 150/297 (50.5%) of patients tried to have children (p = 0.019). Of 119 patients who tried to have children before treatment for testicular cancer 98 (82.4%) succeeded and 74/150 (49.3%) were successful after treatment (p years. The post-treatment fatherhood in patients treated with surgery only (orchidectomy +/- retroperitoneal lymphnode dissection-RPLND) was 59%, in those with additional radiotherapy 68%, and chemotherapy 50% (p = 0.233). Fertility rate in patients where a non nerve sparing RPLND was performed was only 37%, 62% in patients with nerve sapring RPLND, and 77% in patients where RPLND was not performed (p Fertility rate after treatment for testicular cancer is reduced. From our data, the most important treatment modality that influences fertility is non nerve sparing RPLND that should be avoided whenever possible in order improve the quality of life our patients.

  7. Sorafenib tosylate, Ribavirn and Sofosbuvir combination therapy for HCV virus infected patients with decompensated liver cancer.

    Science.gov (United States)

    Munir, Bushra; Ahmed, Bilal; Kiran, Shumaila; Jalal, Fatima; Zahoor, Muhammad Kashif; Shehzadi, Saba; Oranab, Sadaf; Kamran, Sayed Kashif; Ghaffar, Abdul

    2017-11-01

    Hepatitis C is the most common health problem worldwide and is major cause of death due to proliferation of hepatocellular carcinoma. The medicines available for HCV treatment overcome up-to 95% complications of HCV. However, liver cancer needs some additional care. Normally Sorafenib tosylate 200 mg is recommended for liver cancer. There is no such trial in which this drug could effectively be used in combination of direct acting antivirals for HCV. The study was conducted for HCV patients (n=30) with liver cancer having decompensated stage. Combination of Sorafenib tosylate, Ribavirn and Sofosbuvir were used for the pharmacokinetics of these medicines. Child pugh score less then 7 (CP A) in adults during treatment phase (received 12 weeks of Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir 400 mg once daily) have no side effect while child pugh score 7-9 (CP B) have evidence of hypertension. The main efficiency end point sustained virology response with overcoming liver cancer as well in 12 weeks after end treatment (SVR-LLC 12). Mean pharmacokinetic exposure to Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir at week 8th was 2.1, 1.5,1.2 times greater in CP B than in CP A. Adverse effects (AEs) were observed in 12 out of 30 patients but not severe as lethal for life. Treatment with Sorafenib tosylate, Ribavirn and Sofosbuvir for twelve weeks was harmless and well accepted, 100 % patients achieve (SVR LLC 12) with 10-fold cure rate more than previous ones. The combination therapy of Sorafenib tosylate, Ribavirn and Sofosbuvir was found helpful for the management of decompensated liver cancer.

  8. Researching the experience of kidney cancer patients.

    Science.gov (United States)

    Taylor, K

    2002-09-01

    The author's personal experience as a kidney cancer patient, researcher and founder of a kidney cancer support group forms the basis for consideration of the challenges involved in researching patients' experiences. The researcher needs to understand the variability of those experiences in both clinical and psychological-emotional terms, and in relation to the personal, familial and social contexts of the patient. It is also essential to define the purpose of the research and to show how an understanding of personal experiences of cancer can be used to enhance the quality of care for cancer patients. The research encounter with a patient is also in some respects a therapeutic encounter requiring a considerable degree of sensitivity on the part of the researcher. The person-centred approach of Carl Rogers is of value in supporting such an encounter.

  9. Supportive care needs of Iranian cancer patients

    Directory of Open Access Journals (Sweden)

    Azad Rahmani

    2014-01-01

    Full Text Available Background: A supportive needs assessment is an essential component of any care program. There is no research evidence regarding the supportive care needs of cancer patients in Iran or other Middle Eastern countries. Aims: The aim of this study was to determine the supportive care needs of Iranian cancer patients. Materials and Methods: This descriptive study was conducted in a referral medical center in the northwest of Iran. A total of 274 cancer patients completed the Supportive Care Needs Survey (SCNS-59. Descriptive statistics were used for data analysis. Results: In 18 items of the SCNS, more than 50% of the participants reported that their needs were unmet. Most frequently, unmet needs were related to the health system, information, physical, and daily living domains, and most met needs were related to sexuality, patient care, and support domains. Conclusions: Iranian cancer patients experience many unmet needs and there is an urgent need for establishing additional supportive care services in Iran.

  10. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function.

    Science.gov (United States)

    Li, Yan; Wang, Xiaomin; O'Mara, Edward; Dimopoulos, Meletios A; Sonneveld, Pieter; Weisel, Katja C; Matous, Jeffrey; Siegel, David S; Shah, Jatin J; Kueenburg, Elisabeth; Sternas, Lars; Cavanaugh, Chloe; Zaki, Mohamed; Palmisano, Maria; Zhou, Simon

    2017-01-01

    Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove pomalidomide from the blood circulation. Thus, pomalidomide should be administered post-dialysis on the days of dialysis.

  11. 131I therapy of thyroid cancer patients

    International Nuclear Information System (INIS)

    Reiners, C.; Farahati, J.

    1999-01-01

    Thyroid cancer is a rare malignancy with wide inter ethnic and geographic variations. In Germany thyroid carcinoma is the 13. most frequent malignancy (2.7 new cases yearly per 100,000 inhabitants). The overall temporal incidence is increasing slightly in recent years. The most common types of cancer are papillary (60-80%) and follicular cancers (10-20%). The relevant prognostic indicators are tumor stage and distant metastases. The mean survival rates in papillary thyroid cancer usually exceed 90%, whereas in follicular thyroid cancer they amount to approximately 80%. The standard treatment procedure in differentiated papillary and follicular thyroid cancer consists of total thyroidectomy followed by adjuvant ablative therapy with radioiodine. Only in papillary thyroid cancer stage pT 1 N 0 M 0 lobectomy alone is considered to be appropriate. In patients with locally invasive differentiated thyroid cancers stage pT 4 adjuvant percutaneous radiation therapy is a treatment option. Radioiodine therapy has to be performed under the stimulative influence of TSH. Usually TSH suppressive medication with Levothyroxine has to be withdrawn approximately 4 weeks prior to radioiodine therapy. In the future, exogenous stimulation by recombinant TSH may be used instead of thyroid hormone withdrawal. It has been proved by different studies that ablative radioiodine therapy reduces the frequency of recurrences and tumor spread in patients with thyroid cancer significantly. In patients with distant metastases, up to 50% of complete responses may be achieved with radioiodine treatment

  12. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.

    Science.gov (United States)

    Zhang, Tao; Li, Yanyan; Zou, Peng; Yu, Jing-yu; McEachern, Donna; Wang, Shaomeng; Sun, Duxin

    2013-09-01

    The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study.

    Science.gov (United States)

    Kobalava, Zhanna; Villevalde, Svetlana; Kotovskaya, Yulia; Hinrichsen, Holger; Petersen-Sylla, Marc; Zaehringer, Andreas; Pang, Yinuo; Rajman, Iris; Canadi, Jasna; Dahlke, Marion; Lloyd, Peter; Halabi, Atef

    2015-06-01

    Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg(-1)  day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment. © 2014 The British Pharmacological Society.

  14. Cancer Patients' Informational Needs: Qualitative Content Analysis.

    Science.gov (United States)

    Heidari, Haydeh; Mardani-Hamooleh, Marjan

    2016-12-01

    Understanding the informational needs of cancer patients is a requirement to plan any educative care program for them. The aim of this study was to identify Iranian cancer patients' perceptions of informational needs. The study took a qualitative approach. Semi-structured interviews were held with 25 cancer patients in two teaching hospitals in Iran. Transcripts of the interviews underwent conventional content analysis, and categories were extracted. The results came under two main categories: disease-related informational needs and information needs related to daily life. Disease-related informational needs had two subcategories: obtaining information about the nature of disease and obtaining information about disease prognosis. Information needs related to daily life also had two subcategories: obtaining information about healthy lifestyle and obtaining information about regular activities of daily life. The findings provide deep understanding of cancer patients' informational needs in Iran.

  15. Cognitive Behavioral Therapy in Cancer Patients

    Directory of Open Access Journals (Sweden)

    Cem Soylu

    2014-09-01

    Full Text Available Cognitive behavioral therapy is one of the structured but flexible psychosocial interventions that could be applied to patients with cancer. In many studies the positive effects of cognitive behavioral therapy in reducing psychological morbidity and improving the quality of life of cancer patients have been shown. In this article, the contents and techniques of adapted cognitive behavioral therapy for patients with cancer and its effectiveness in commonly seen psychiatric disorders have been reviewed. The aim of this article is to contribute positively to physicians and nurses in Turkey for early detection of psychological distress and referral to the therapist that would clearly increase the quality of life of cancer patients. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(3.000: 257-270

  16. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.

    Directory of Open Access Journals (Sweden)

    L John Hoffer

    Full Text Available Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail.We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement.Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type

  17. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.

    Science.gov (United States)

    Hoffer, L John; Robitaille, Line; Zakarian, Robert; Melnychuk, David; Kavan, Petr; Agulnik, Jason; Cohen, Victor; Small, David; Miller, Wilson H

    2015-01-01

    Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy

  18. Population Pharmacokinetic Modeling and Dosing Simulations of Nitrogen-Scavenging Compounds: Disposition of Glycerol Phenylbutyrate and Sodium Phenylbutyrate in Adult and Pediatric Patients with Urea Cycle Disorders

    OpenAIRE

    Monteleone, Jon P. R.; Mokhtarani, M.; Diaz, G. A.; Rhead, W.; Lichter-Konecki, U.; Berry, S. A.; LeMons, C.; Dickinson, K.; Coakley, D.; Lee, B.; Scharschmidt, B. F.

    2013-01-01

    Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data fro...

  19. Management of patients with advanced prostate cancer

    DEFF Research Database (Denmark)

    Gillessen, S; Omlin, A; Attard, G

    2015-01-01

    The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration......-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion...

  20. A phase 1 study of 131I-CLR1404 in patients with relapsed or refractory advanced solid tumors: dosimetry, biodistribution, pharmacokinetics, and safety.

    Directory of Open Access Journals (Sweden)

    Joseph J Grudzinski

    Full Text Available (131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK and safety profiles of (131I-CLR1404.Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of (131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15-35 minutes, 4-6, 18-24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on (127I-CLR1404 mass measurements. To evaluate renal clearance of (131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software.Single administrations of 370 MBq of (131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma (127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t values were 72.2 ng/mL and 15753 ng • hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow.Preliminary data suggest that (131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent.ClinicalTrials.gov NCT00925275.

  1. Posttraumatic growth in Iranian cancer patients

    OpenAIRE

    A Rahmani; R Mohammadian; C Ferguson; L Golizadeh; M Zirak; H Chavoshi

    2012-01-01

    Objectives: To investigate the level and determinants of posttraumatic growth in Iranian cancer patients. Materials and Methods: This descriptive-correlational design study was conducted within a university-affiliated oncology hospital in Iran. A convenience sample of 450 patients with a definitive diagnosis of cancer of any type completed a demographic questionnaire and a posttraumatic growth inventory. Some disease-related information was obtained from patients′ medical records. Results: Th...

  2. ESPEN guidelines on nutrition in cancer patients.

    Science.gov (United States)

    Arends, Jann; Bachmann, Patrick; Baracos, Vickie; Barthelemy, Nicole; Bertz, Hartmut; Bozzetti, Federico; Fearon, Ken; Hütterer, Elisabeth; Isenring, Elizabeth; Kaasa, Stein; Krznaric, Zeljko; Laird, Barry; Larsson, Maria; Laviano, Alessandro; Mühlebach, Stefan; Muscaritoli, Maurizio; Oldervoll, Line; Ravasco, Paula; Solheim, Tora; Strasser, Florian; de van der Schueren, Marian; Preiser, Jean-Charles

    2017-02-01

    Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each

  3. Statistical study on cancer patients of cancer research hospital

    International Nuclear Information System (INIS)

    Shim, Yoon Sang; Choi, Soo Yong; Won, Hyuk; Kim, Kee Hwa

    1991-01-01

    The total number of malignant neoplasms included on this study 7,787 cases(10.4%) among 74,928 cases for 2 years. On sex, females with 57.6% were much more than males with 42.4%. The highest proportion of cancer 50-59 age group. The most frequent primary site among males was found to be stomach with 36.2%, followed by liver(12.3%), lung(12.2%), esophagus(15.5%) and larynx(4.9%). In females, the first order was uterine cervix with 47.3%, followed most common type of morphology of malignant neoplasms was adenocarcinoma(39.0%) in males an squamous cell carcinoma(56.2%) in females. Among the cancer patients initially diagnosed in this hospital, the proportion of malignant neoplasms by the extent of disease was 4.6% for patient with carcinoma-in-situ, 76.3% for patients with localized involvement, 11.6% for patients with regional involvement and 7.5% for patients with distant involvement. Among,the cancer patients initially treatment in this hospital, the proportion of malignant neoplasms by the method of treatment was 19.0% for surgery, 27.7 for radiotherapy and 24.2% for chemotherapy. Among the cancer patients confirmed by medical records, 11.2% was traced more than 5 years. (Author)

  4. Support needs of Chinese immigrant cancer patients.

    Science.gov (United States)

    Leng, Jennifer; Lee, Trevor; Li, Yanjun; Stern, Charles; Chen, Mei Hsuan; Winkel, Gary; Gany, Francesca

    2014-01-01

    To enable better psychosocial, informational, and practical support of Chinese patients with cancer, this study was conducted to identify the specific support needs of Chinese immigrant cancer patients. The Cancer Portal Project at Memorial Sloan-Kettering Cancer Center's Center for Immigrant Health and Cancer Disparities is a patient navigation program that assists underserved and minority cancer patients in obtaining social and economic assistance at ten New York City cancer clinics. This need assessment was conducted as part of the Portal Project. Sixty-four questions were added to the existing Portal Intake Form about the needs and preferences for Chinese-language support and survivorship services. Descriptive analysis was performed, as well as an exploratory principal component's factor analysis to determine if there were any patterns in the services and programs in which patients were interested. Ninety-six patients were approached for participation; 59 agreed to participate. Eighty-eight percent of participants were born in China. Ninety-seven percent preferred to speak Mandarin, Cantonese, or Fujianese in the healthcare setting. When asked about general interest in support programs, 53 % of the participants were "very interested," 27 % were "maybe interested," and 17 % were "not interested." Programs in which more participants were "very interested" included those that would provide information about obtaining financial assistance (79 %) and social assistance (74 %), information on treatment options (67 %), help in coping with the burden of illness on the family (65 %), and information about general healthcare (63 %). The factor analysis resulted in the identification of five factors: social/financial/treatment and care issues, nutrition and exercise/networking/general health care, coping with fear and stress, herbs and dietary supplements, and acupuncture and acupressure. In this study, 80 % of the participants expressed interest in programs tailored for

  5. Hyperthyroidism in patients with thyroid cancer.

    Science.gov (United States)

    Sharma, Sunil Dutt; Kumar, Gaurav; Guner, Karen; Kaddour, Hesham

    2016-06-01

    We present a retrospective case series of patients with hyperthyroidism and thyroid cancer. Our goal was to look at their clinical characteristics and outcomes to determine which patients would require further investigation. We reviewed the case notes of all patients with a histopathologic diagnosis of thyroid cancer and biochemical evidence of hyperthyroidism who had been treated at a thyroid cancer center from January 2006 through October 2013. During that time, 66 patients had been diagnosed with thyroid cancer. Of these, 8 patients (12%)-all women, aged 29 to 87 years (mean: 55.6; median: 50.5)-had biochemical evidence of hyperthyroidism. Among these 8 patients, 4 had an autonomously functioning toxic nodule (AFTN), 3 were diagnosed with Graves disease, and 1 had a toxic multinodular goiter. Five patients had suspicious features on preoperative ultrasonography. All 8 patients were diagnosed with the papillary type of thyroid carcinoma. The mean size of the tumor in the 4 patients with AFTN was significantly larger than it was in those with Graves disease (42.3 ± 23.8 mm vs. 3.8 ± 1.6; p = 0.04). The 3 patients with Graves disease all had incidentally found papillary microcarcinoma. Between these two groups, the patients with AFTN had a poorer prognosis; 2 of them had extracapsular invasion and lymph node metastasis, and another died of her disease. We found that the incidence of hyperthyroidism in thyroid cancer patients was relatively high (12%). In contrast to what has previously been reported in the literature, patients with AFTN seem to have more aggressive disease and poorer outcomes than do patients with Graves disease. Any suspicious nodule associated with hyperthyroidism should be evaluated carefully.

  6. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

    Science.gov (United States)

    Scheen, André J

    2014-09-01

    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  7. Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Mizuno, Kana; Dong, Min; Fukuda, Tsuyoshi; Chandra, Sharat; Mehta, Parinda A; McConnell, Scott; Anaissie, Elias J; Vinks, Alexander A

    2018-05-01

    High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m 2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2  = 0.98; p strategy promises to achieve the target area under the curve as part of precision dosing.

  8. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

    Directory of Open Access Journals (Sweden)

    Galactéros Frédéric

    2011-05-01

    Full Text Available Abstract Background Hydroxyurea (HU is the first approved pharmacological treatment of sickle cell anemia (SCA. The objectives of this study were to develop population pharmacokinetic(PK-pharmacodynamic(PD models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF% and mean corpuscular volume (MCV were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV of clearance was 11.6 L/h (30%, the central volume was 45.3 L (35%. PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%; the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and

  9. Radiation therapy in aged lung cancer patients

    International Nuclear Information System (INIS)

    Ohtake, Eiji; Tobari, Chitose; Matsui, Kengo; Iio, Masahiro.

    1982-01-01

    The results and problems of radiotherapy were analyzed in 57 lung cancer patients more than 65 years of age (average age: 74.8 years). Of these, 45 (79%) were irradiated with a total dose exceeding 40 Gy. In these patients, the median survival was 13 months for Stages I and II, 6.5 months for Stage III, and 5 months for Stage IV. The results of combined radiotherapy and chemotherapy were better than those of radiotherapy alone. Also, slightly better results were obtained in patients treated with split-course than continuous-course irradiation. In aged lung cancer patients the prognosis was highly influenced by their respiratory function. Double cancers were present in 9 (16%) of the 57 patients. (author)

  10. Skin cancer in patients with psoriasis

    DEFF Research Database (Denmark)

    Egeberg, A; Thyssen, Jacob Pontoppidan; Gislason, G. H.

    2016-01-01

    Background: Psoriasis is a chronic inflammatory skin disease that is commonly treated with ultraviolet phototherapy and systemic immunosuppressant drugs, which may confer a risk of skin cancer. Previous studies on the risk of skin cancer in patients with psoriasis have shown conflicting results....... Objectives: We investigated the risk of new-onset melanoma and non-melanoma skin cancer (NMSC), respectively, in a large cohort of patients with psoriasis and psoriatic arthritis. Methods: Data on all Danish individuals aged ≥18 years between 1 January 1997 and 31 December 2012 were linked at individual...... of skin cancer is only modestly increased in patients with psoriasis, clinicians should remain vigilant. © 2016 European Academy of Dermatology and Venereology...

  11. Pharmacokinetics and pharmacodynamics of edivoxetine (LY2216684), a norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Kielbasa, William; Quinlan, Tonya; Jin, Ling; Xu, Wen; Lachno, D Richard; Dean, Robert A; Allen, Albert J

    2012-08-01

    Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V(ss)/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing

  12. Evaluation of a Pharmacokinetic-Pharmacodynamic Model for Hypouricemic Effects of Febuxostat Using Datasets Obtained from Real-world Patients.

    Science.gov (United States)

    Hirai, Toshinori; Itoh, Toshimasa; Kimura, Toshimi; Echizen, Hirotoshi

    2018-06-06

    Febuxostat is an active xanthine oxidase (XO) inhibitor that is widely used in the hyperuricemia treatment. We aimed to evaluate the predictive performance of a pharmacokinetic-pharmacodynamic (PK-PD) model for hypouricemic effects of febuxostat. Previously, we have formulated a PK--PD model for predicting hypouricemic effects of febuxostat as a function of baseline serum urate levels, body weight, renal function, and drug dose using datasets reported in preapproval studies (Hirai T et al., Biol Pharm Bull 2016; 39: 1013-21). Using an updated model with sensitivity analysis, we examined the predictive performance of the PK-PD model using datasets obtained from the medical records of patients who received febuxostat from March 2011 to December 2015 at Tokyo Women's Medical University Hospital. Multivariate regression analysis was performed to explore clinical variables to improve the predictive performance of the model. A total of 1,199 serum urate data were retrieved from 168 patients (age: 60.5 ±17.7 years, 71.4% males) who received febuxostat as hyperuricemia treatment. There was a significant correlation (r=0.68, p<0.01) between serum urate levels observed and those predicted by the modified PK-PD model. A multivariate regression analysis revealed that the predictive performance of the model may be improved further by considering comorbidities, such as diabetes mellitus, estimated glomerular filtration rate (eGFR), and co-administration of loop diuretics (r = 0.77, p<0.01). The PK-PD model may be useful for predicting individualized maintenance doses of febuxostat in real-world patients. This article is protected by copyright. All rights reserved.

  13. Efficacy, tolerability, and pharmacokinetics of oxcarbazepine oral loading in patients with epilepsy.

    Science.gov (United States)

    Kim, Dong Wook; Gu, Nami; Jang, In-Jin; Chu, Kon; Yu, Kyung-Sang; Cho, Joo-Youn; Yoon, Seo Hyun; Kim, Hwa Suk; Oh, Jeeyoung; Lee, Sang Kun

    2012-01-01

    The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

  14. Melanosis coli in patients with colon cancer

    Directory of Open Access Journals (Sweden)

    Dorota Biernacka-Wawrzonek

    2016-12-01

    Full Text Available Intoduction: Melanosis coli is a benign lesion affecting the mucosa of the large intestine. There is a relationship between the presence of melanosis and anthraquinone laxative use. Melanosis coli is also observed in patients with colon cancer, but there is doubt whether these two conditions are related. Aim : To analyze the correlation between melanosis and colon cancer. Material and methods: We analyzed retrospectively 436 patients undergoing colon cancer surgery. There were 246 women and 190 men. Patients were divided into three age groups: under 50 years, between 51 and 65 years, and over 66 years. We analyzed sections of the cancer and intestinal mucosa from the tumor’s proximal (2–5 cm and distal (8–10 cm zone. Results : Melanosis coli was present in 52 patients, which represents 11.9% of patients with colon cancer. More often it was present in women. The most common location of melanosis and colon cancer was the terminal part of the large intestine. In patients below 50 years of age in both sexes melanosis coli did not occur. In men, melanosis was more common in the age group over 66 years. Intensity of pigmentation was higher in the tumor’s distal zone. Conclusions : The incidence of melanosis coli increases with age, similar to that of colon cancer. Melanosis was not present inside tumors, in almost half of the cases it was not present in the proximal zone, and the degree of pigmentation increased in distal zone. The cause-effect relationship between melanosis coli and colon cancer remains uncertain.

  15. Pharmacokinetics of Imipenem/Cilastatin Burn Intensive Care Unit Patients Undergoing High-Dose Continuous Venovenous Hemofiltration.

    Science.gov (United States)

    Boucher, Bradley A; Hudson, Joanna Q; Hill, David M; Swanson, Joseph M; Wood, G Christopher; Laizure, S Casey; Arnold-Ross, Angela; Hu, Zhe-Yi; Hickerson, William L

    2016-12-01

    High-dose continuous venovenous hemofiltration (CVVH) is a continuous renal replacement therapy (CRRT) used frequently in patients with burns. However, antibiotic dosing is based on inference from studies assessing substantially different methods of CRRT. To address this knowledge gap for imipenem/cilastatin (I/C), we evaluated the systemic and extracorporeal clearances (CLs) of I/C in patients with burns undergoing high-dose CVVH. Prospective clinical pharmacokinetic study. Ten adult patients with burns receiving I/C for a documented infection and requiring high-dose CVVH were studied. Blood and effluent samples for analysis of I/C concentrations were collected for up to 6 hours after the I/C infusion for calculation of I/C total CL (CL T otal ), CL by CVVH (CL HF ), half-life during CVVH, volume of distribution at steady state (Vd ss ), and the percentage of drug eliminated by CVVH. In this patient sample, the mean age was 50 ± 17 years, total body surface area burns was 23 ± 27%, and 80% were male. Nine patients were treated with high-dose CVVH for acute kidney injury and one patient for sepsis. The mean delivered CVVH dose was 52 ± 14 ml/kg/hour (range 32-74 ml/kg/hr). The imipenem CL HF was 3.27 ± 0.48 L/hour, which accounted for 23 ± 4% of the CL T otal (14.74 ± 4.75 L/hr). Cilastatin CL HF was 1.98 ± 0.56 L/hour, which accounted for 45 ± 19% of the CL T otal (5.16 + 2.44 L/hr). The imipenem and cilastatin half-lives were 1.77 ± 0.38 hours and 4.21 ± 2.31 hours, respectively. Imipenem and cilastatin Vd ss were 35.1 ± 10.3 and 32.8 ± 13.8 L, respectively. Efficient removal of I/C by high-dose CVVH, a high overall clearance, and a high volume of distribution in burn intensive care unit patients undergoing this CRRT method warrant aggressive dosing to treat serious infections effectively depending on the infection site and/or pathogen. © 2016 Pharmacotherapy Publications, Inc.

  16. Clinical Characteristics of Patients with Sporadic Colorectal Cancer and Primary Cancers of Other Organs

    Directory of Open Access Journals (Sweden)

    Jung-Yu Kan

    2006-11-01

    Full Text Available Most cancer patients often neglect the possibility of secondary cancer. Colorectal cancer (CRC is the third leading cause of cancer death in Taiwan. It is important to be aware of the clinical characteristics of double cancer in CRC patients for early diagnosis and treatment. We retrospectively analyzed 1,031 CRC patients who underwent surgical treatment at the Department of Surgery of Kaohsiung Medical University Hospital between January 1998 and December 2004. Among these patients, CRC was accompanied by cancer of other organs in 17 patients (1.65%, either synchronously or metachronously. Therefore, we describe our experience regarding the location of CRC, the clinical symptoms and signs of these patients, the TNM stage, histology, phase, association with other malignancies, interval between cancers and clinical outcomes. Of the 17 patients in whom CRC was accompanied by primary cancer of other organs, there were four synchronous and 13 metachronous multiple cancer patients. Our patient group comprised six men and 11 women with ages ranging from 47 to 88 years (median age, 66 years. The most common location of CRC was the sigmoid colon. Six gastric cancers (35.2% and six breast cancers (35.2% were associated with primary CRC. The remaining six second primary cancers were one lung cancer, one thyroid cancer, one cervical cancer, one ovarian cancer, one skin cancer, and one urinary bladder cancer. Of the 13 metachronous multiple cancer patients, eight patients developed subsequent CRC after primary cancers of other organs, whereas two patients developed a subsequent second primary cancer after CRC. The intervals between the development of metachronous multiple cancers ranged from 2 to 19 years. In this retrospective analysis, breast and gastric cancer patients were at increased risk of developing subsequent secondary CRC. Careful attention should always be paid to the possibility of secondary CRC in treating these cancer patients. Cancer

  17. Haemorheological changes in cancer patients on chemotherapy

    International Nuclear Information System (INIS)

    Omoti, C.E.; Osime, E.

    2007-01-01

    To assess the rheological changes in haematological and non-haematological cancer patients pre and post chemotherapy. It is a prospective study of 50 patients comprising 16(32%) haematological and 34(68%) non-haematological cancers of various types from March to December 2005 at University of Benin Teaching Hospital, Nigeria. Rheologic parameters estimated by the various specific diagnostic methods were determined in cancer patient's pre and post chemotherapy. The rheological tests estimated were relative plasma viscosity (RPV) measured by means of a capillary viscometer, whole blood viscosity (WBV), erythrocyte sedimentation rate (ESR) and plasma fibrinogen concentration (PFC) estimated by the Ingram's Clot weight method. The RPV in pre chemotherapy (p=0.006) and WBV in post chemotherapy (p=0.0231) patients measured revealed a significant difference when compared to controls. The fibrinogen concentration (P<0.0001) and ESR values (P<0.0001) were significantly increased in cancer patients when compared to controls. We conclude that total reduction of hyperviscosity and hyperfibrinogenaemia may contribute to effective treatment strategies in cancer patients. (author)

  18. Posttraumatic growth in Iranian cancer patients.

    Science.gov (United States)

    Rahmani, A; Mohammadian, R; Ferguson, C; Golizadeh, L; Zirak, M; Chavoshi, H

    2012-01-01

    To investigate the level and determinants of posttraumatic growth in Iranian cancer patients. This descriptive-correlational design study was conducted within a university-affiliated oncology hospital in Iran. A convenience sample of 450 patients with a definitive diagnosis of cancer of any type completed a demographic questionnaire and a posttraumatic growth inventory. Some disease-related information was obtained from patients' medical records. The mean of posttraumatic growth reported by participants was 76.1. There was a statistically significant association between experience of posttraumatic growth and age (r = - 0.21, P=0.001), education at university level (F = 8.9, P=0.001) and history of treatment by radiotherapy (t = 2.1, P=0.03). The findings of this study suggest that Iranian cancer patients experience a moderate to high level of posttraumatic growth and confirm the hypothesis that the level of posttraumatic growth in non-Western cancer patients is more than that of Western cancer patients. Although, assessing the reasons for this difference needs more investigations.

  19. Pharmacokinetics of digoxin cross-reacting substances in patients with acute yellow oleander (Thevetia peruviana) poisoning, including the effect of activated charcoal.

    Science.gov (United States)

    Roberts, Darren M; Southcott, Emma; Potter, Julia M; Roberts, Michael S; Eddleston, Michael; Buckley, Nick A

    2008-01-01

    Intentional self-poisonings with seeds from the yellow oleander tree (Thevetia peruviana) are widely reported. Activated charcoal has been suggested to benefit patients with yellow oleander poisoning by reducing absorption and/or facilitating elimination. Two recent randomised controlled trials (RCTs) assessing the efficacy of activated charcoal reported conflicting outcomes in terms of mortality. The effect of activated charcoal on the pharmacokinetics of Thevetia cardenolides has not been assessed. This information may be useful for determining whether further studies are necessary. Serial blood samples were obtained from patients enrolled in a RCT assessing the relative efficacy of single dose (SDAC) and multiple doses (MDAC) of activated charcoal compared to no activated charcoal (NoAC). The concentration of Thevetia cardenolides was estimated using a digoxin immunoassay. The effect of activated charcoal on cardenolide pharmacokinetics was compared between treatment groups using the AUC24, the 24h Mean Residence Time (MRT24), and regression lines obtained from serial concentration points adjusted for exposure. Erratic and prolonged absorption patterns were noted in each patient group. The apparent terminal half-life was highly variable, with a median time of 42.9h. There was a reduction in MRT24 and the apparent terminal half-life estimated from linear regression in patients administered activated charcoal compared to the control group (NoAC). This effect was approximately equal in patients administered MDAC or SDAC. Activated charcoal appears to favourably influence the pharmacokinetic profile of Thevetia cardenolides in patients with acute self-poisoning, which may have clinical benefits. Given the conflicting clinical outcomes noted in previous RCTs, this mechanistic data supports the need for further studies to determine whether a subgroup of patients (eg. those presenting soon after poisoning) will benefit from activated charcoal. PMID:17164695

  20. Fertility preservation in young cancer patients

    Directory of Open Access Journals (Sweden)

    Ariel Revel

    2010-01-01

    Full Text Available As a result of advances in treatment, almost 80% of children and adolescents who receive a diagnosis of cancer become long-term survivors. The increased survival rate of children and adolescents with cancer has resulted in a major interest in the long-term effects of cancer treatment on the possibility for future fertility. Currently established methods for the preservation of fertility are available only for pubertal males and females. Pubertal male cancer patients should be encouraged to freeze numerous sperm samples even when sperm count and motility are poor. In these cases, intracytoplasmic sperm injection is a powerful technique compared with intrauterine insemination since thawed sperm samples with poor parameters can produce relatively high fertilization rates resulting in normal pregnancies and deliveries. Married pubertal women should be proposed ovulation induction, follicular aspiration, and fertilization with husband sperm. Single women could benefit from vitrification of oocytes. This requires a delay of about 3 weeks in the commencement of chemotherapy to enable follicular growth. Fertility preservation for prepubertal patients is more of a problem. Young girls could be offered cryopreservation of gametes in the gonadal tissue. Cryopreservation of testicular tissue was suggested for fertility preservation for young boys, but this method is totally experimental and not currently offered. Discussing future fertility is part of the consultation of young female and male patients facing potentially gonadotoxic cancer therapy. It is the role of reproductive specialists to create various options in their laboratory to preserve fertility potential of cancer patients.

  1. Symptom attributions in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Jensen, Line Flytkjær; Hvidberg, Line; Pedersen, Anette Fischer

    2015-01-01

    Størstedelen af kolorektal cancere opdages gennem patienters symptomatiske henvendelse i almen praksis. Man ved dog ikke meget om, hvordan patienter selv oplever deres symptomer. Formålet med studiet var, at undersøge om symptom attributioner er associeret med hvilket symptom man oplevede før...

  2. Multidisciplinary approach for patients with esophageal cancer

    Institute of Scientific and Technical Information of China (English)

    Victoria M Villaflor; Marco E Allaix; Bruce Minsky; Fernando A Herbella; Marco G Patti

    2012-01-01

    Patients with esophageal cancer have a poor prognosis because they often have no symptoms until their disease is advanced.There are no screening recommendations for patients unless they have Barrett's esophagitis or a significant family history of this disease.Often,esophageal cancer is not diagnosed until patients present with dysphagia,odynophagia,anemia or weight loss.When symptoms occur,the stage is often stage Ⅲ or greater.Treatment of patients with very early stage disease is fairly straight forward using only local treatment with surgical resection or endoscopic mucosal resection.The treatment of patients who have locally advanced esophageal cancer is more complex and controversial.Despite multiple trials,treatment recommendations are still unclear due to conflicting data.Sadly,much of our data is difficult to interpret due to many of the trials done have included very heterogeneous groups of patients both histologically as well as anatomically.Additionally,studies have been underpowered or stopped early due to poor accrual.In the United States,concurrent chemoradiotherapy prior to surgical resection has been accepted by many as standard of care in the locally advanced patient.Patients who have metastatic disease are treated palliatively.The aim of this article is to describe the multidisciplinary approach used by an established team at a single high volume center for esophageal cancer,and to review the literature which guides our treatment recommendations.

  3. Depression and Resilience in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Gordana Ristevska-Dimitrоvska

    2015-11-01

    CONCLUSION: This study shows that patients who are less depressed have higher levels of resilience and that psychological resilience may independently contribute to lower levels of depression among breast cancer patients. The level of psychological resilience may be a protective factor for depression and psychological distress.

  4. Active listening to cancer patients' stories.

    Science.gov (United States)

    ten Kroode, H F

    1998-08-01

    Approximately two thirds of all Dutch cancer patients have severe emotional problems; shortly after their change from the treatment regime into the regime of medical controls. Half of them even need professional support. It is, therefore, important that a professional listens with empathy to the patient's version of the illness story. Story telling helps to overcome the existential crisis of being a cancer patient; it is an essential step in the revalidation process. Themes and open questions which structure the communication are suggested in this article.

  5. Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

    Science.gov (United States)

    Couffignal, Camille; Pajot, Olivier; Laouénan, Cédric; Burdet, Charles; Foucrier, Arnaud; Wolff, Michel; Armand-Lefevre, Laurence; Mentré, France; Massias, Laurent

    2014-11-01

    Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia and evaluate several dosage regimens. This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >40%. Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 μg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h. This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients, the best dosage regimen of imipenem is 750 mg every 6 h and not 1000 mg every 8 h. © 2014 The British Pharmacological Society.

  6. Intersectionality and the LGBT Cancer Patient.

    Science.gov (United States)

    Damaskos, Penny; Amaya, Beau; Gordon, RuthAnn; Walters, Chasity Burrows

    2018-02-01

    To present the ways in which race, ethnicity, class, gender, and sexual orientation interact in the context of cancer risk, access to care, and treatment by health care providers. Cancer risk factors, access to care, and treatment for lesbian, gay, bisexual, and transgender (LGBT) patients are discussed within the context of intersectionality and cultural humility. Peer reviewed articles, cancer organizations, and clinical practice. LGBT patients have multiple identities that intersect to create unique experiences. These experiences shape their interactions with the health care system with the potential for positive or negative consequences. More data is needed to describe the outcomes of those experiences and inform clinical practice. Oncology nurses have an obligation to acknowledge patients' multiple identities and use the practice of cultural humility to provide individualized, patient-centered care. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Understanding taste dysfunction in patients with cancer.

    Science.gov (United States)

    McLaughlin, Laura; Mahon, Suzanne M

    2012-04-01

    Taste dysfunction is a significant but underestimated issue for patients with cancer. Impaired taste results in changes in diet and appetite, early satiety, and impaired social interactions. Nurses can play a key role in educating patients and families on the pathophysiology of taste dysfunction by suggesting interventions to treat the consequences of taste dysfunction, when available, and offering psychosocial support as patients cope with this often devastating consequence of treatment. Taste recognition helps humans identify the nutritional quality of food and signals the digestive tract to begin secreting enzymes. Spoiled or tainted foods typically are recognized by their bad taste. Along with the other sensory systems, taste is crucial for helping patients treated for cancer feel normal. This article will review the anatomy and physiology of taste; define the different types of taste dysfunction, including the underlying pathophysiologic basis related to cancer treatment; and discuss potential nursing interventions to manage the consequences of taste dysfunction.

  8. A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.

    Directory of Open Access Journals (Sweden)

    Corey Saba

    Full Text Available Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV. Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within

  9. Safety, pharmacokinetics and efficacy findings in an open-label, single-arm study of weekly paclitaxel plus lapatinib as first-line therapy for Japanese women with HER2-positive metastatic breast cancer.

    Science.gov (United States)

    Inoue, Kenichi; Kuroi, Katsumasa; Shimizu, Satoru; Rai, Yoshiaki; Aogi, Kenjiro; Masuda, Norikazu; Nakayama, Takahiro; Iwata, Hiroji; Nishimura, Yuichiro; Armour, Alison; Sasaki, Yasutsuna

    2015-12-01

    Lapatinib is the human epidermal growth factor receptor 2 (HER2) targeting agent approved globally for HER2-positive metastatic breast cancer (MBC). The efficacy, safety and pharmacokinetics (PK) of lapatinib combined with paclitaxel (L+P) were investigated in this study, to establish clear evidence regarding the combination in Japanese patients. In this two-part, single-arm, open-label study, the tolerability of L+P as first-line treatment in Japanese patients with HER2-positive MBC was evaluated in six patients in the first part, and the safety, efficacy and PK were evaluated in a further six patients (making a total of twelve patients) in the second part. Eligible women were enrolled and received lapatinib 1500 mg once daily and paclitaxel 80 mg/m(2) weekly for at least 6 cycles. The only dose-limiting toxicity reported was Grade 3 diarrhea in one patient. The systemic exposure to maximum plasma concentration and area under the plasma concentration curve (AUC) for lapatinib, as well as the AUC of paclitaxel, were increased when combined. The most common adverse events (AEs) related to the study treatment were alopecia, diarrhea and decreased hemoglobin. The majority of drug-related AEs were Grade 1 or 2. The median overall survival was 35.6 months (95 % confidence interval 23.9, not reached). The response rate and clinical benefit rate were both 83 % (95 % confidence interval 51.6, 97.9). The L+P treatment was well tolerated in Japanese patients with HER2-positive MBC. Although the PK profiles of lapatinib and paclitaxel influenced each other, the magnitudes were not greatly different from those in non-Japanese patients.

  10. Statistical study on cancer patients of Korea cancer centre hospital

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Soo Yong; Kim, Kee Hwa; Mok, Kang Sung [Korea Cancer Center Hospital of Korea Atomic Energy Research Institute, Seoul (Korea, Republic of)

    1994-12-01

    The total number of malignant neoplasms included in this study 53,566 cases(14.1%) among 379,582 patients from 1984 to 1993. On sex, females with 51.3% were much more than males with 48.7%. The highest proportion of cancer patients by age was 35.0% in males and 28.4% in females, respectively for 50-59 age group. The most frequent primary site among males was found to be stomach with 33.2%, followed by liver(15.1%), lung(14.9%), esophagus(5.3%) and larynx(3.3%). In females, the first order was uterine cervix with 37.8%, followed by stomach(16.5%), breast(14.8%), thyroid gland(4.3%) and lung (3.8%). The proportion of malignant neoplasms diagnosed by histology made up 67.0%, whereas 20.2% was diagnosed by clinical investigation(X-ray, CT, MRI etc). Among the cancer patients initially diagnosed in this hospital, the proportion of malignant neoplasms by the extent of disease was 3.7% for patient with carcinoma-in-situ, 58.7% for patients with localized involvement, 18.4% for patients with regional involvement and 11.1% for patients with distant involvement. Among the cancer patients initially treatment in this hospital, the proportion of malignant neoplasms by the method of treatment was 27.5% for surgery, 22.5% for radiotherapy and 30.1% for chemotherapy. The proportion of cancer patients traced to death was only to 3.6%, 1,944 cases. Among them, 72.5% survived for less than 1 year. 17 figs, 7 tabs, 28 refs. (Author).

  11. Statistical study on cancer patients of Korea cancer centre hospital

    International Nuclear Information System (INIS)

    Choi, Soo Yong; Kim, Kee Hwa; Kang Sung Mok

    1994-12-01

    The total number of malignant neoplasms included in this study 53,566 cases(14.1%) among 379,582 patients from 1984 to 1993. On sex, females with 51.3% were much more than males with 48.7%. The highest proportion of cancer patients by age was 35.0% in males and 28.4% in females, respectively for 50-59 age group. The most frequent primary site among males was found to be stomach with 33.2%, followed by liver(15.1%), lung(14.9%), esophagus(5.3%) and larynx(3.3%). In females, the first order was uterine cervix with 37.8%, followed by stomach(16.5%), breast(14.8%), thyroid gland(4.3%) and lung (3.8%). The proportion of malignant neoplasms diagnosed by histology made up 67.0%, whereas 20.2% was diagnosed by clinical investigation(X-ray, CT, MRI etc). Among the cancer patients initially diagnosed in this hospital, the proportion of malignant neoplasms by the extent of disease was 3.7% for patient with carcinoma-in-situ, 58.7% for patients with localized involvement, 18.4% for patients with regional involvement and 11.1% for patients with distant involvement. Among the cancer patients initially treatment in this hospital, the proportion of malignant neoplasms by the method of treatment was 27.5% for surgery, 22.5% for radiotherapy and 30.1% for chemotherapy. The proportion of cancer patients traced to death was only to 3.6%, 1,944 cases. Among them, 72.5% survived for less than 1 year. 17 figs, 7 tabs, 28 refs. (Author)

  12. PET/MRI in cancer patients

    DEFF Research Database (Denmark)

    Kjær, Andreas; Loft, Annika; Law, Ian

    2013-01-01

    Combined PET/MRI systems are now commercially available and are expected to change the medical imaging field by providing combined anato-metabolic image information. We believe this will be of particular relevance in imaging of cancer patients. At the Department of Clinical Physiology, Nuclear...... described include brain tumors, pediatric oncology as well as lung, abdominal and pelvic cancer. In general the cases show that PET/MRI performs well in all these types of cancer when compared to PET/CT. However, future large-scale clinical studies are needed to establish when to use PET/MRI. We envision...... that PET/MRI in oncology will prove to become a valuable addition to PET/CT in diagnosing, tailoring and monitoring cancer therapy in selected patient populations....

  13. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials

    International Nuclear Information System (INIS)

    Gabrail, Nashat; Yanagihara, Ronald; Spaczyński, Marek; Cooper, William; O’Boyle, Erin; Smith, Carrie; Boccia, Ralph

    2015-01-01

    Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy. In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated. APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively. After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron

  14. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    International Nuclear Information System (INIS)

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile

  15. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

    Science.gov (United States)

    Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

    2013-05-28

    Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks

  16. Volume of hydration in terminal cancer patients.

    Science.gov (United States)

    Bruera, E; Belzile, M; Watanabe, S; Fainsinger, R L

    1996-03-01

    In this retrospective study we reviewed the volume and modality of hydration of consecutive series of terminal cancer patients in two different settings. In a palliative care unit 203/290 admitted patients received subcutaneous hydration for 12 +/- 8 days at a daily volume of 1015 +/- 135 ml/day. At the cancer center, 30 consecutive similar patients received intravenous hydration for 11.5 +/- 5 days (P > 0.2) but at a daily volume of 2080 +/- 720 ml/day (P palliative care unit patients required discontinuation of hydration because of complications. Hypodermoclysis was administered mainly as a continuous infusion, an overnight infusion, or in one to three 1-h boluses in 62 (31%), 98 (48%) and 43 (21%) patients, respectively. Our findings suggest that, in some settings, patients may be receiving excessive volumes of hydration by less comfortable routes such as the intravenous route. Increased education and research in this area are badly needed.

  17. Patient-initiated breast cancer screening

    International Nuclear Information System (INIS)

    Chilcote, W.

    1990-01-01

    This paper reviews the results of a breast cancer screening program sponsored by organizations at workplace or community locations. A comprehensive mobile breast cancer screening program, including education, breast physical examination, and mammography, was provided to 89 local organizations at $50.00 per examination over an 18-month period. The examination was patient initiated, following the ACS screening guidelines. Estimates of eligible women were provided by each organization. A total of 5,030 women at 89 organizations were screened for breast cancer. Approximately 25,727 women were eligible

  18. Statistical study on cancer patients of cancer research hospital

    International Nuclear Information System (INIS)

    Shim, Yun Sang; Choi, Soo Yong; Kim, Ki Wha; Kang, Sung Mok

    1993-01-01

    The total number of malignant neoplasms included in this study 15,737 cases(11.8%) among 133,251 cases for 3 years. On sex, females with 52.9% were much more than males with 47.1%. The highest proportion of cancer patients by age was 33.7% in males and 28.5% in females, respectivelty for 50-59 age group. The most frequent primary site among males was found to be stomach with 35.5%, followed by liver(14.7%), lung(13.0%), esophagus(5.4%) and colon (3.2%). In females, the first order was uterine cervix with 40.6%, followed by stomach(17.2%), breast(14.4), rectum(3.7%) and lung(3.4%). The most common type of morphology of malignant neoplasms was adenocarcinoma(47.4%) in males an squamous cell carcinoma(58.0%) in females. Among the cancer patients initially diagnosed in this hospital, the proportion of malignant neoplasms by the exent of disease was 2.5% for patient with carcinoma-in-situ, 54.1% for patients with localized involvement, 13.3% for patients with regional involvement and 8.5% for patients with distant involvement. Among the cancer patients initially treatment in this hospital, the proportion of malignant neoplasms by the method of treatment was 23.6% for surgery, 25.3% for radiotherapy and 30.3% for chemotherapy. Among the cancer patients confirmed by medical records, 7.7% was traced more than 5 years. (Author)

  19. [Psychosocial problems and needs among cancer patients].

    Science.gov (United States)

    Mehlsen, Mimi Yung; Jensen, Anders Bonde; Zachariae, Bobby

    2007-04-30

    Cancer can have a serious impact on patient well-being and quality of life. The international literature reports a higher prevalence of psychosocial problems among cancer patients; primarily problems associated with difficulties in the family, duties in the household, work and leisure, sexuality and finances. The prevalence of these problems among Danish cancer patients is still unknown. A questionnaire assessing psychosocial problems and needs was mailed out to all patients who had been at the Department of Oncology, Aarhus Hospital in week 35, 2004. A total of 71%, i.e. 515 patients (34% men and 66% women) in active treatment and control returned the questionnaire. High levels of emotional distress were reported by 39% of the patients. High levels of distress were primarily related to problems with worries about their spouses, household duties, financial problems and experiences of insufficient collaboration between health care and social services. Between 19% and 25% of the patients required further help to handle emotional problems, legal and financial problems and practical problems in the home. A considerable proportion of oncology patients experience significant levels of distress. This group of distressed patients also report unmet needs for psychosocial support.

  20. Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review

    NARCIS (Netherlands)

    Bos, Jeannet C.; van Hest, Reinier M.; Prins, Jan M.

    2017-01-01

    Background: In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the

  1. Functional dynamic MR imaging and pharmacokinetics of Gd-DTPA in patients with renal failure

    International Nuclear Information System (INIS)

    Krestin, G.P.; Neufang, K.F.R.; Friedmann, G.; Clauss, W.; Schuhmann-Giampieri, G.; Stoeckl, B.

    1989-01-01

    This paper reports excretion of Gd-DTPA analyzed in 20 patients with renal parenchymal disease and decreased creatinine clearance (20-80 mL/min) and compared with excretion in five patients with normal renal function. All 25 underwent a dynamic MR study that employed fast gradient-echo sequences with single images during breath holding. The time between appearance of the contrast agent in the renal cortex and signal intensity drop in the medulla was an indicator of glomerular filtration rate and correlated well with creatinine clearance values. Fractionate urine collection and serum analysis up to 120 hours showed a prolonged but complete (98%) elimination of Gd-DTPA. Renal functional parameters did not change after administration of Gd-DTPA, and no nephrotoxic effects were observed. Thus, MR imaging provides a good quantitative evaluation of the glomerular filtration rate; moreover, administration of Gd-DTPA in patients with renal failure does not impair excretory function and can therefore be safely applied in patients with reduced excretory function

  2. Pharmacokinetic properties of micafungin in critically ill patients diagnosed with invasive candidiasis

    NARCIS (Netherlands)

    Boonstra, J M; van der Elst, K C; Veringa, A; Jongedijk, E M; Brüggemann, R J; Koster, R A; Kampinga, G A; Kosterink, J G; van der Werf, T S; Zijlstra, J G; Touw, D J; Alffenaar, J W C

    2017-01-01

    Background: The estimated attributable mortality rate for invasive candidiasis (IC) in the Intensive Care Unit (ICU) setting varies from 30-40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin and therefore dosing adjustments might be

  3. Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients

    Directory of Open Access Journals (Sweden)

    David B. Menkes

    2018-01-01

    Discussion: Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways.

  4. Severe Rhabdomyolysis from Pharmacokinetic Interaction of Statin in Patient with Diabetic Nephropathy: A Case Report

    Directory of Open Access Journals (Sweden)

    Teerapong Monmaturapoj, M.Sc. in Pharm

    2015-09-01

    Full Text Available Rhabdomyolysis is a potentially life-threatening syndrome characterized by muscle necrosis and the release of intracellular muscle contents into systemic circulation. The authors report a rhabdomyolytic patient with chronic kidney disease who had reduction of renal function owing to undiagnosed hypothyroidism, from drug interaction of simvastatin with gemfibrozil and amlodipine.

  5. Pharmacokinetics, Safety, and Efficacy of Chemoembolization with Doxorubicin-Loaded Tightly Calibrated Small Microspheres in Patients with Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Malagari, Katerina; Kiakidis, Theodoros; Pomoni, Maria; Moschouris, Hippokratis; Emmanouil, Emmanouil; Spiridopoulos, Themis; Sotirchos, Vlasios; Tandeles, Savvas; Koundouras, Dimitrios; Kelekis, Alexios; Filippiadis, Dimitrios; Charokopakis, Angelos; Bouma, Evanthia; Chatziioannou, Achilles; Dourakis, Spyridon; Koskinas, John; Karampelas, Theodoros; Tamvakopoulos, Konstantinos; Kelekis, Nikolaos; Kelekis, Dimitrios

    2016-01-01

    PurposeThis study examines safety, efficacy, and pharmacokinetics of chemoembolization with loadable microspheres ≤100 μm for hepatocellular carcinoma.Materials and MethodsA pilot safety study was performed in 19 patients with size and dose escalation and then 52 patients were enrolled prospectively and randomly assigned to chemoembolization with TANDEM™ loaded with 150 or 100 mg of doxorubicin.ResultsThe mean diameter of the tumors was 7.28 ± 2.09 cm (range 4–12) and distribution dominant/multiple 51.9/48.1 %. Child A/B distribution was 32/20 (61.5/38.5 %) and etiology HBV/HCV/HBV/HCV-hemochromatosis was 61.6/9.6/9.6/15.4 %. Twenty-five patients were assigned in the low and 27 in the high loading group. There was 1.92 % thirty-day mortality due to lesion rupture. Biliary damage was seen in 3 patients (5.7 %) in the high loading. Mean maximum plasma concentration of doxorubicin C_m_a_x ± SD was 284.9 ± 276.2 ng/mL for the high and 108.5 ± 77.6 ng/mL for the low loading (p < 0.001). According to m-RECIST overall objective response after two sessions reached 61.22 and 63.82 % at 6 months. Notably, complete target lesion response (CR) after the second session was observed in 28.57 % and maintained in 23.40 % at 6 months. No statistical differences in the local response rates were observed between the two loading groups. Overall survival (OS) at 6 months, 1 , 2, and 3 years was 98.08, 92.3, 88.46, and 82.6 %, respectively. OS and Progression-Free Survival did not demonstrate statistical significance between the two loading groups.ConclusionInitial evidence shows that (a) TANDEM™ achieves high rates of local response and mid-term survival, (b) high loading provides no clinical benefit and is associated with biliary toxicity.

  6. Pharmacokinetics, Safety, and Efficacy of Chemoembolization with Doxorubicin-Loaded Tightly Calibrated Small Microspheres in Patients with Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Malagari, Katerina, E-mail: kmalag@otenet.gr; Kiakidis, Theodoros; Pomoni, Maria; Moschouris, Hippokratis; Emmanouil, Emmanouil; Spiridopoulos, Themis; Sotirchos, Vlasios; Tandeles, Savvas; Koundouras, Dimitrios; Kelekis, Alexios; Filippiadis, Dimitrios; Charokopakis, Angelos; Bouma, Evanthia; Chatziioannou, Achilles [National and Kapodistrian University of Athens, Medical School, Evgenidion Hospital, 2nd and 1st Department of Radiology (Greece); Dourakis, Spyridon; Koskinas, John [National and Kapodistrian University of Athens, Medical School, Hippokration General Hospital, 2nd Department of Internal Medicine, Hepatology (Greece); Karampelas, Theodoros; Tamvakopoulos, Konstantinos [Foundation Biomedical Research of Academy of Athens (FBRA) (Greece); Kelekis, Nikolaos; Kelekis, Dimitrios [National and Kapodistrian University of Athens, Medical School, Evgenidion Hospital, 2nd and 1st Department of Radiology (Greece)

    2016-10-15

    PurposeThis study examines safety, efficacy, and pharmacokinetics of chemoembolization with loadable microspheres ≤100 μm for hepatocellular carcinoma.Materials and MethodsA pilot safety study was performed in 19 patients with size and dose escalation and then 52 patients were enrolled prospectively and randomly assigned to chemoembolization with TANDEM™ loaded with 150 or 100 mg of doxorubicin.ResultsThe mean diameter of the tumors was 7.28 ± 2.09 cm (range 4–12) and distribution dominant/multiple 51.9/48.1 %. Child A/B distribution was 32/20 (61.5/38.5 %) and etiology HBV/HCV/HBV/HCV-hemochromatosis was 61.6/9.6/9.6/15.4 %. Twenty-five patients were assigned in the low and 27 in the high loading group. There was 1.92 % thirty-day mortality due to lesion rupture. Biliary damage was seen in 3 patients (5.7 %) in the high loading. Mean maximum plasma concentration of doxorubicin C{sub max} ± SD was 284.9 ± 276.2 ng/mL for the high and 108.5 ± 77.6 ng/mL for the low loading (p < 0.001). According to m-RECIST overall objective response after two sessions reached 61.22 and 63.82 % at 6 months. Notably, complete target lesion response (CR) after the second session was observed in 28.57 % and maintained in 23.40 % at 6 months. No statistical differences in the local response rates were observed between the two loading groups. Overall survival (OS) at 6 months, 1 , 2, and 3 years was 98.08, 92.3, 88.46, and 82.6 %, respectively. OS and Progression-Free Survival did not demonstrate statistical significance between the two loading groups.ConclusionInitial evidence shows that (a) TANDEM™ achieves high rates of local response and mid-term survival, (b) high loading provides no clinical benefit and is associated with biliary toxicity.

  7. Thyroid cancer in patients with hyperthyroidism

    International Nuclear Information System (INIS)

    Kabir, M.F.; Nahar, N.; Haque, F.S.; Alam, F.; Hasan, M.

    2007-01-01

    Full text: The coexistence of hyperthyroidism and thyroid cancer is a rare event. The aim of this study was to evaluate the relevance of the association of hyperthyroidism and thyroid cancer. Method: From 1st January 2006 to 31st December 2006, a total of 388 new hyperthyroid patients attended the Institute of Nuclear Medicine and Ultrasound for radioiodine therapy. Eighty-two of them were selected before radioiodine therapy, on the basis of findings on palpation and ultrasound (USG) examination, to undergo fine needle aspiration cytology (FNAC) for cytological diagnosis. USG examination was performed to localize and mark the position of nodule/nodules for FNAC and, in cases of nonpalpable nodules, USG guided FNAC was done. In the case of non-nodular patients, guided FNAC was done in sonographically suspicious areas. Results: FNAC report was positive for thyroid cancer in 4 patients. Histopathology examination revealed the presence of papillary carcinoma. Among the four positive cases, one had multi-nodular goitre, two had uni-nodular goiters and one had no nodule. Another patient had a negative FNAC report but due to a huge goiter, the patient underwent surgery and histopathology revealed the presence of papillary carcinoma. Conclusion: Although the occurrence of thyroid cancer in hyperthyroid patients is rare, the presence of a nodule should be carefully evaluated to exclude the presence of concurrent malignancy. FNAC (USG guided in case of non-palpable nodules) is found helpful before radioiodine therapy or surgery. (author)

  8. Nutritional support for malnourished patients with cancer.

    Science.gov (United States)

    Baldwin, Christine

    2011-03-01

    Cancer and its treatments frequently have a negative impact on the weight and nutritional status of patients. Weight loss is associated with reduced survival and poorer outcomes of treatment but is not well characterized and frequently confused with cachexia, which may complicate the interpretation of studies of nutritional support. The aims of this review were to examine the impact of cancer on nutritional status and to review the role of simple oral nutritional interventions and novel agents. The terms weight loss, malnutrition and cachexia refer to different entities and new definitions have recently been proposed that take account of the role of the underlying inflammatory processes. Oral nutritional interventions are widely recommended for malnourished cancer patients, but the evidence for their benefits to clinical, nutritional and patient-centred outcomes is limited. Meta-analysis has highlighted the variability in response to simple nutritional interventions of different cohorts of cancer patients and suggested that improvements in nutritional endpoints and aspects of quality of life may be achieved in some patients. Recent research has largely focused on treatments aiming to modulate the inflammatory processes associated with cachexia, but to date has not identified a single treatment with clear efficacy. Studies characterizing the potential for nutritional support in combination with anti-inflammatory agents in defined patient groups are defined to advance the evidence base in this area.

  9. Modeling Pharmacokinetics and Pharmacodynamics of Glucagon for Simulation of the Glucoregulatory System in Patients with Type 1 Diabetes

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye

    The goal of this thesis was to develop a pharmacokinetics/pharmacodynamics (PK/PD) model for glucagon. The proposed PD model included multiplication of the stimulating glucagon effect and inhibiting insulin effect on the endogenous glucose production (EGP). Moreover, the concentration-response re......The goal of this thesis was to develop a pharmacokinetics/pharmacodynamics (PK/PD) model for glucagon. The proposed PD model included multiplication of the stimulating glucagon effect and inhibiting insulin effect on the endogenous glucose production (EGP). Moreover, the concentration...

  10. COPING STRATEGIES IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    J. R. Gardanova

    2015-01-01

    Full Text Available Diagnostics of psycho-emotional disorders of patients with malignant diseases of the prostate is not doubt, because timely correction contributes to the shortening of rehabilitation period and restoration of the quality of life of patients after treatment. Detection and diagnosis of prostate cancer for many patients is stressful and causes changes in the affective sphere, and manifests itself in increased levels of anxiety and depression in men. To cope with stress is possible due to the used coping strategies.Purpose. Studying the coping mechanisms in prostate cancer patients.Materials and methods. 56 men treated in FGBU "LRTS" Russian Ministry of Health. The average age was 65.7 ± 6.1 years. The average duration of the disease prostate cancer is 3 ± 2 months. All men were subjected to the standard algorithm for the evaluation of hormonal status, the PSA, taking a history, inspection and physical examination, magnetic resonance imaging and scintigraphy of bones of a skeleton. All the patients underwent laparoscopic radical prostatectomy. Psychological testing with the use of the method of "Coping test" the scale of reactive and personal anxiety for the differentiated evaluation of anxiety. Results. The most common for prostate cancer revealed constructive coping strategies are "planning solve", "selfcontrol" and "search of social support". According to the scale Spielberg–Hanin a high level of situational anxiety was revealed.Conclusion. According to the results of the research, patients with prostate cancer are likely to use constructive coping strategies, that leads to stabilization of psycho-emotional state of men and promotes more effective adaptation in the terms of stress, that is caused by treatment of prostate cancer.

  11. Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

    Institute of Scientific and Technical Information of China (English)

    Li-Yan Zhou; Ye-Hui Shi; Yong-Sheng Jia; Zhong-Sheng Tong

    2015-01-01

    Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were‘‘pemetrexed’’ or‘‘LY231514’’ or“Alimta”,“metastatic breast cancer”, and“advanced breast cancer”. Results: There were 15 studies (n ¼ 1002) meeting our criteria for evaluation. Eight single-agent trials (n ¼ 551) and seven using combinations with other agents (n ¼ 451) were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8%to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS) and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Com-munications Co., Ltd. This is an open access article under the CC BY-NC-ND license

  12. Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery

    OpenAIRE

    Mallappa, Ashwini; Nella, Aikaterini A.; Kumar, Parag; Brooks, Kristina M.; Perritt, Ashley F.; Ling, Alexander; Liu, Chia-Ying; Merke, Deborah P.

    2017-01-01

    Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19-year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but...

  13. Variations of blood glucose in cancer patients during chemotherapy

    African Journals Online (AJOL)

    2016-05-23

    May 23, 2016 ... Purpose: The aim of this study was to analyze the blood glucose (BG) variations in cancer patients .... cancer, brain tumor, cervical cancer, and leukemia were the ... excess glucose supply for these glucose‑hungry cells and it.

  14. Depression Screening and Patient Outcomes in Cancer : A Systematic Review

    NARCIS (Netherlands)

    Meijer, Anna; Roseman, Michelle; Milette, Katherine; Coyne, James C.; Stefanek, Michael E.; Ziegelstein, Roy C.; Arthurs, Erin; Leavens, Allison; Palmer, Steven C.; Stewart, Donna E.; de Jonge, Peter; Thombs, Brett D.

    2011-01-01

    Background: Several practice guidelines recommend screening for depression in cancer care, but no systematic reviews have examined whether there is evidence that depression screening benefits cancer patients. The objective was to evaluate the potential benefits of depression screening in cancer

  15. EXPRESSING DISTRESS IN PATIENTS WITH ADVANCED CANCER

    Directory of Open Access Journals (Sweden)

    Maura Gabriela FELEA

    2014-11-01

    Full Text Available Negative emotions (distress are recognized as part of the psychological profile of patients diagnosed with advanced stage cancer. However, most patients are not accustomed to verbalize feelings towards their physician, and generally towards family and medical care personnel. The purpose of this paper is to analyze the expression of emotions by patients in advanced stages of cancer, respectively the means by which they get to express emotions. To this respect, we identified the most common types of emotions expressed, or metaphors used by patients to describe their emotions and topics that trigger emotions. Words and phrases most commonly used are in relation to: fear, anxiety, depression, guilt, negligence, concern. They are uttered in order to depict the network created between disclosed emotions and topics on health status, symptoms, adverse effects and therapeutic choice, patient privacy, and social and family issues.

  16. Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients.

    Science.gov (United States)

    Chang, W H; Lin, S K; Jann, M W; Lam, Y W; Chen, T Y; Chen, C T; Hu, W H; Yeh, E K

    1989-07-01

    Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

  17. An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

    Science.gov (United States)

    Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  18. Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

    Science.gov (United States)

    Morris, Carrie A; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

    2013-12-01

    Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

  19. "THE EVALUATION OF THE POSSIBLE EFFECT OF POSITIVE END EXPIRATORY PRESSURE (PEEP ON PHARMACOKINETICS OF PHENYTOIN IN PATIENTS WITH ACUTE BRAIN INJURY UNDER MECHANICAL VENTILATION."

    Directory of Open Access Journals (Sweden)

    "Elham Hadidi

    2005-04-01

    Full Text Available Positive ventilation has shown to have an influence on pharmacokinetic and disposition of some drugs.Beacause phenytoin with a narrow therapautic range, is the most commonly used drug for prophylaxis and treatment of early seizures after acute brain injuries, in the present study the effect of short term PEEP (5-10 cm H2O for at least 8 hours on phenytoin serum concentration and pharmacokinetic parameters such as Vmax and clearance in brain injured patients under mechanical ventilation was examined. Ten patients with moderate to severe acute brain injury who were placed on mechanical ventilation with an initial PEEP level of 0-5 cm H2O were included in the study. Patients received phenytoin loading dose of 15 mg/kg followed by a maintenance daily dose of 3-7 mg/kg initiated within 12 hours of loading dose. Sampels were taken on two different occasions before and after PEEP elevation. Total phenytoin serum concentrations were determined by HPLC method. A time invarient Michaelis-Menten pharmacokinetic model was used to calculate Vmax and clearance for each patient.Derrived variables were calculated as follows: Vmax, 3.5-6.8 and 3.7-8.2 mg/kg/day; Clearance, 0.1-0.7 and 0.1-1.2 l/kg/day (before and after PEEP elevation, respectively. Our data have shown a wide range of variability (2.6-32.5 mg/l in phenytoin serum concentrations. There were no statistically significant differences in the measured total concentrations (p=0.721 and calculated Vmax and clearance (p=0.285before and after PEEP elevation. Administration of fluid and inotropic agents, limitation in application of higher levels of PEEP and drug interactions, shall be considered as possible explanations for these findings.

  20. Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD

    Directory of Open Access Journals (Sweden)

    Ying Xie

    2017-01-01

    Full Text Available Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1 to determine the association of UGT1A1*28 polymorphism with the area under the plasma concentration-time curves (AUCs for silybin A (SA and silybin B (SB; (2 to evaluate the effect of UGT1A1*28 polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3 to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between different UGT1A1*28 genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the three UGT1A1 genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects with UGT1A1*28/*28 genotype compared to subjects carrying wild type alleles. Differences in SA and SB in vitro intrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observed in vivo indicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect of UGT1A1 polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of the UGT1A1*28 allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease.

  1. Patient representatives? views on patient information in clinical cancer trials

    OpenAIRE

    Dellson, Pia; Nilbert, Mef; Carlsson, Christina

    2016-01-01

    Background Patient enrolment into clinical trials is based on oral information and informed consent, which includes an information sheet and a consent certificate. The written information should be complete, but at the same time risks being so complex that it may be questioned if a fully informed consent is possible to provide. We explored patient representatives? views and perceptions on the written trial information used in clinical cancer trials. Methods Written patient information leaflet...

  2. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.

    Science.gov (United States)

    Karaiskos, Ilias; Friberg, Lena E; Pontikis, Konstantinos; Ioannidis, Konstantinos; Tsagkari, Vasiliki; Galani, Lamprini; Kostakou, Eirini; Baziaka, Fotini; Paskalis, Charalambos; Koutsoukou, Antonia; Giamarellou, Helen

    2015-12-01

    Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while

  3. Phase I/II clinical and pharmacokinetic study evaluating a fully human monoclonal antibody against EGFr (HuMax-EGFr) in patients with advanced squamous cell carcinoma of the head and neck

    DEFF Research Database (Denmark)

    Bastholt, Lars; Specht, Lena; Jensen, Kenneth

    2007-01-01

    PURPOSE: To assess safety, tolerability, pharmacokinetics and clinical activity of HuMax-EGFr in patients with SCCHN. PATIENTS AND METHODS: Twenty-eight patients with SCCHN were enrolled. The study comprised a single-dose escalation part for assessment of safety issues followed by a repeat dose e...

  4. Kundalini yoga as a support therapy for cancer patients

    OpenAIRE

    Kröneck, Mia

    2016-01-01

    This study was designed to describe cancer patient’s experience of kundalini yoga and its effect on their internal coping resources. The intention of this study is to put forward kundalini yoga as a support therapy for cancer patients for improving their wellbeing during active cancer treatment. This is a descriptive study. An academic literature review was conducted for cancer, cancer treatment, internal coping resources and yoga as therapy topics. Four voluntary female cancer patients (...

  5. Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients.

    Science.gov (United States)

    Dong, Haiyan; Xie, Jiao; Wang, Taotao; Chen, Lihong; Zeng, Xiaoyan; Sun, Jinyao; Wang, Xue; Dong, Yalin

    2016-09-01

    Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC24/MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC ≤ 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  6. Cachexia in patients with oesophageal cancer.

    Science.gov (United States)

    Anandavadivelan, Poorna; Lagergren, Pernilla

    2016-03-01

    Oesophageal cancer is a debilitating disease with a poor prognosis, and weight loss owing to malnutrition prevails in the majority of patients. Cachexia, a multifactorial syndrome characterized by the loss of fat and skeletal muscle mass and systemic inflammation arising from complex host-tumour interactions is a major contributor to malnutrition, which is a determinant of tolerance to treatment and survival. In patients with oesophageal cancer, cachexia is further compounded by eating difficulties owing to the stage and location of the tumour, and the effects of neoadjuvant therapy. Treatment with curative intent involves exceptionally extensive and invasive surgery, and the subsequent anatomical changes often lead to eating difficulties and severe postoperative malnutrition. Thus, screening for cachexia by means of percentage weight loss and BMI during the cancer trajectory and survivorship periods is imperative. Additionally, markers of inflammation (such as C-reactive protein), dysphagia and appetite loss should be assessed at diagnosis. Routine assessments of body composition are also necessary in patients with oesophageal cancer to enable assessment of skeletal muscle loss, which might be masked by sarcopenic obesity in these patients. A need exists for clinical trials examining the effectiveness of therapeutic and physical-activity-based interventions in mitigating muscle loss and counteracting cachexia in these patients.

  7. Renal cancer in kidney transplanted patients.

    Science.gov (United States)

    Frascà, Giovanni M; Sandrini, Silvio; Cosmai, Laura; Porta, Camillo; Asch, William; Santoni, Matteo; Salviani, Chiara; D'Errico, Antonia; Malvi, Deborah; Balestra, Emilio; Gallieni, Maurizio

    2015-12-01

    Renal cancer occurs more frequently in renal transplanted patients than in the general population, affecting native kidneys in 90% of cases and the graft in 10 %. In addition to general risk factors, malignancy susceptibility may be influenced by immunosuppressive therapy, the use of calcineurin inhibitors (CNI) as compared with mammalian target of rapamycin inhibitors, and the length of dialysis treatment. Acquired cystic kidney disease may increase the risk for renal cancer after transplantation, while autosomal dominant polycystic kidney disease does not seem to predispose to cancer development. Annual ultrasound evaluation seems appropriate in patients with congenital or acquired cystic disease or even a single cyst in native kidneys, and every 2 years in patients older than 60 years if they were on dialysis for more than 5 years before transplantation. Immunosuppression should be lowered in patients who develop renal cancer, by reduction or withdrawal of CNI. Although more evidence is still needed, it seems reasonable to shift patients from CNI to everolimus or sirolimus if not already treated with one of these drugs, with due caution in subjects with chronic allograft nephropathy.

  8. Patient Delay in Colorectal Cancer Patients

    DEFF Research Database (Denmark)

    Pedersen, Anette Fischer; Hansen, Rikke P; Vedsted, Peter

    2013-01-01

    Blødning fra endetarmen ses normalt som et alarmsymptom på kolorektalkræft. Alligevel vælger mange patienter at lade være med at opsøge lægen. Denne artikel ser nærmere på sammenhængen mellem et alarmsymptom (rektal blødning), forsinkelser i patientforløbet og tanker om kræft. Resultaterne viser,...

  9. Anemia, tumor hypoxemia, and the cancer patient

    International Nuclear Information System (INIS)

    Varlotto, John; Stevenson, Mary Ann

    2005-01-01

    Purpose: To review the impact of anemia/tumor hypoxemia on the quality of life and survival in cancer patients, and to assess the problems associated with the correction of this difficulty. Methods: MEDLINE searches were performed to find relevant literature regarding anemia and/or tumor hypoxia in cancer patients. Articles were evaluated in order to assess the epidemiology, adverse patient effects, anemia correction guidelines, and mechanisms of hypoxia-induced cancer cell growth and/or therapeutic resistance. Past and current clinical studies of radiosensitization via tumor oxygenation/hypoxic cell sensitization were reviewed. All clinical studies using multi-variate analysis were analyzed to show whether or not anemia and/or tumor hypoxemia affected tumor control and patient survival. Articles dealing with the correction of anemia via transfusion and/or erythropoietin were reviewed in order to show the impact of the rectification on the quality of life and survival of cancer patients. Results: Approximately 40-64% of patients presenting for cancer therapy are anemic. The rate of anemia rises with the use of chemotherapy, radiotherapy, and hormonal therapy for prostate cancer. Anemia is associated with reductions both in quality of life and survival. Tumor hypoxemia has been hypothesized to lead to tumor growth and resistance to therapy because it leads to angiogenesis, genetic mutations, resistance to apoptosis, and a resistance to free radicals from chemotherapy and radiotherapy. Nineteen clinical studies of anemia and eight clinical studies of tumor hypoxemia were found that used multi-variate analysis to determine the effect of these conditions on the local control and/or survival of cancer patients. Despite differing definitions of anemia and hypoxemia, all studies have shown a correlation between low hemoglobin levels and/or higher amounts of tumor hypoxia with poorer prognosis. Radiosensitization through improvements in tumor oxygenation/hypoxic cell

  10. Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

    Science.gov (United States)

    Rosenblum, M G; Keating, M J; Yap, B S; Loo, T L

    1981-05-01

    Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

  11. Fertility preservation in young patients with cancer

    Directory of Open Access Journals (Sweden)

    Virender Suhag

    2015-01-01

    Full Text Available Infertility can arise as a consequence of treatment of oncological conditions. The parallel and continued improvement in both the management of oncology and fertility cases in recent times has brought to the forefront the potential for fertility preservation in patients being treated for cancer. Many survivors will maintain their reproductive potential after the successful completion of treatment for cancer. However total body irradiation, radiation to the gonads, and certain high dose chemotherapy regimens can place women at risk for acute ovarian failure or premature menopause and men at risk for temporary or permanent azoospermia. Providing information about risk of infertility and possible interventions to maintain reproductive potential are critical for the adolescent and young adult population at the time of diagnosis. There are established means of preserving fertility before cancer treatment; specifically, sperm cryopreservation for men and in vitro fertilization and embryo cryopreservation for women. Several innovative techniques are being actively investigated, including oocyte and ovarian follicle cryopreservation, ovarian tissue transplantation, and in vitro follicle maturation, which may expand the number of fertility preservation choices for young cancer patients. Fertility preservation may also require some modification of cancer therapy; thus, patients' wishes regarding future fertility and available fertility preservation alternatives should be discussed before initiation of therapy.

  12. Interest in screening examinations among cancer patients

    Directory of Open Access Journals (Sweden)

    Humeniuk Ewa

    2017-09-01

    Full Text Available Aim. To determine the influence of socio-demographic variables on attendance rate at screening examinations in cancer patients. Material and methods. The research group comprised of 100 cancer patients. The method applied in the research was a diagnostic survey. The research instrument was the authors‘ own questionnaire specially compiled to measure cancer patients‘ interest in screening examinations. The research material was analysed with the statistical packet STATISTICA 12 and Microsoft Office Excel software. Significance level was assumed at p<0.05 to determine statistically significant differences and dependencies. A Chi2 test was used in the research. Results. The surveyed patients mostly did not participate in screening examinations aimed at diagnosing cancer (66%. Their Age (p=0.05, gender (p=0.003 and place of residence (p=0.04 determined their participation rate in screening tests. The patients‘ marital status (p=0.47, education (p=0.85 and economic status (p=0.13 did not affect their willingness to attend screening examinations. Conclusions. The process of cancer incidence and death rate limitation requires greater participation of the population in prevention programmes.

  13. Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

    NARCIS (Netherlands)

    Reddy, Venkatesh Pilla; Kozielska, Magdalena; Johnson, Martin; Mafirakureva, Nyashadzaishe; Vermeulen, An; Liu, Jing; de Greef, Rik; Rujescu, Dan; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2013-01-01

    The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective

  14. Pharmacokinetics and 48-week safety and efficacy of generic lopinavir/ritonavir in Thai HIV-infected patients

    NARCIS (Netherlands)

    Ramautarsing, Reshmie A.; van der Lugt, Jasper; Gorowara, Meena; Sophonphan, Jiratchaya; Ananworanich, Jintanat; Lange, Joep M. A.; Burger, David M.; Phanuphak, Praphan; Ruxthungtham, Kiat; Avihingsanon, Anchalee

    2013-01-01

    Background: Generic products reduce the costs of HIV treatment. Few generic second-line antiretroviral products are available. We assessed pharmacokinetics, safety and efficacy of generic lopinavir/ritonavir (LPV/r) produced by the Government Pharmaceutical Organization (GPO) of Thailand in Thai

  15. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

  16. [Nutritional risk screening and nutrition assessment for gastrointestinal cancer patients].

    Science.gov (United States)

    Du, Yan-ping; Li, Ling-ling; He, Qing; Li, Yun; Song, Hu; Lin, Yi-jia; Peng, Jun-sheng

    2012-05-01

    To investigate the nutritional status, and provide evidence for nutritional treatment option. A total of 452 patients with gastrointestinal cancer were selected, including 156 gastric cancer,117 colon cancer, and 180 rectal cancer. The nutritional risk screening 2002(NRS2002) was applied to grade the nutritional risk. A multi-frequency bioelectrical impedance analysis was used to measure the patients' body composition. Albumin (Alb), prealbumin(PA), transferring(Tf), retinol binding protein(RBP), red blood cell(RBC), hemoglobin (Hb), haematocrit(Hct) were measured after fasting. The rate of patients with NRS2002 score more than 3 was 70.5%(110/156) for gastric cancer, 53.8%(63/117) for colon cancer, and 46.7%(86/180) for rectal cancer. The score for impaired nutritional status more than 1 for gastric cancer was higher than that for colorectal cancer(Pgastric cancer(Pgastric cancer patients as compared to colorectal cancer patients(Pgastric cancer patients(Pgastric cancer and colon cancer(Pgastric cancer are prone to fat loss and therefore have a higher nutritional risk and malnutrition than those with colorectal cancer. Combination of body composition analysis and laboratory examination may achieve comprehensive evaluation of the nutritional status of patients, and provide the evidence of nutritional therapy by being combined with NRS2002 score.

  17. Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients.

    Science.gov (United States)

    Welte, R; Eller, P; Lorenz, I; Joannidis, M; Bellmann, R

    2018-04-01

    Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 μg/ml) and in pleural effusion (0.32 to 2.02 μg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 μg/ml, respectively) and below the MIC values for several pathogenic Candida strains. Copyright © 2018 American Society for Microbiology.

  18. Patient representatives' views on patient information in clinical cancer trials

    DEFF Research Database (Denmark)

    Dellson, Pia; Nilbert, Mef; Carlsson, Christina

    2016-01-01

    of future simplified and more attractive informed consent forms. CONCLUSIONS: The emotional and cognitive responses to written patient information reported by patient representatives provides a basis for revised formats in future trials and add to the body of information that support use of plain language......BACKGROUND: Patient enrolment into clinical trials is based on oral information and informed consent, which includes an information sheet and a consent certificate. The written information should be complete, but at the same time risks being so complex that it may be questioned if a fully informed...... consent is possible to provide. We explored patient representatives' views and perceptions on the written trial information used in clinical cancer trials. METHODS: Written patient information leaflets used in four clinical trials for colorectal cancer were used for the study. The trials included phase I...

  19. Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

    Science.gov (United States)

    Hai, Xin; Guo, Meihua; Gao, Chunlu; Zhou, Jin

    2017-04-15

    Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU- 13 C 1 , 15 N 2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200μg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

    Science.gov (United States)

    Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

    2015-03-01

    Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

  1. Exercise effects on HRV in cancer patients.

    Science.gov (United States)

    Niederer, D; Vogt, L; Thiel, C; Schmidt, K; Bernhörster, M; Lungwitz, A; Jäger, E; Banzer, W

    2013-01-01

    The present study evaluated the effects of physical exercise on heart rate variability (HRV) in cancer patients. 3 matched groups of each 15 tumour patients (60.4±8.9 years, 27 male, 18 female) were recruited: Physical exercise group 1 (acute treatment), Physical exercise group 2 (post treatment) and non-intervention group (acute treatment, no exercise). Exercise group patients received counselling for exercise and participated in a Nordic-Walking program. Short-term HRV-recordings, assessments of fatigue and quality of life (QoL) were performed prior to and 16 weeks after the exercise program initiation. MANCOVA revealed group × time differences in total power frequency domain of HRV and QoL (pHRV-parameters and prolonged survival in cancer patients, improvement in autonomic control may be an important goal of exercise. © Georg Thieme Verlag KG Stuttgart · New York.

  2. Isoflavone pharmacokinetics and metabolism after consumption of a standardized soy and soy-almond bread in men with asymptomatic prostate cancer.

    Science.gov (United States)

    Ahn-Jarvis, Jennifer H; Clinton, Steven K; Grainger, Elizabeth M; Riedl, Kenneth M; Schwartz, Steven J; Lee, Mei-Ling T; Cruz-Cano, Raul; Young, Gregory S; Lesinski, Gregory B; Vodovotz, Yael

    2015-11-01

    Epidemiologic associations suggest that populations consuming substantial amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week randomized, phase II, crossover trial was conducted in 32 men with asymptomatic prostate cancer. The crossover involved 8 weeks each of soy bread (SB) and soy-almond bread (SAB). The primary objective was to investigate isoflavone bioavailability and metabolite profile. Secondary objectives include safety, compliance, and assessment of biomarkers linked to prostate carcinogenesis. Two distinct SBs were formulated to deliver approximately 60 mg aglycone equivalents of isoflavones per day. The isoflavones were present as aglycones (∼78% as aglycones) in the SAB whereas in the standard SB predominantly as glucosides (18% total isoflavones as aglycones). Compliance to SB (97% ± 4%) and SAB (92% ± 18%) was excellent; toxicity was rare and limited to grade 1 gastrointestinal complaints. Pharmacokinetic studies between SB and SAB showed modest differences. Peak serum concentration time (Tmax) was significantly faster with SAB meal compared with SB in some isoflavonoids, and AUC0 to 24 h of dihydrodaidzein and O-desmethylangolensin was significantly greater after an SB meal. An exploratory cluster analysis was used to identify four isoflavone-metabolizing phenotypes. Insulin-like growth factor-binding protein increased significantly by 41% (P = 0.024) with soy intervention. Findings from this study provide the necessary framework to study isoflavone-metabolizing phenotypes as a strategy for identification of individuals that might benefit or show resistance to cancer preventive strategies using dietary soy. A standardized SB used for future large-scale randomized clinical trials to affect human prostate carcinogenesis is feasible. ©2015 American Association for Cancer Research.

  3. Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review

    Directory of Open Access Journals (Sweden)

    Juan Lao

    2013-01-01

    Full Text Available Drug delivery systems can provide enhanced efficacy and/or reduced toxicity for anticancer agents. Liposome drug delivery systems are able to modify the pharmacokinetics and biodistribution of cytostatic agents, increasing the concentration of the drug released to neoplastic tissue and reducing the exposure of normal tissue. Anthracyclines are a key drug in the treatment of both metastatic and early breast cancer, but one of their major limitations is cardiotoxicity. One of the strategies designed to minimize this side effect is liposome encapsulation. Liposomal anthracyclines have achieved highly efficient drug encapsulation and they have proven to be effective and with reduced cardiotoxicity, as a single agent or in combination with other drugs for the treatment of either anthracyclines-treated or naïve metastatic breast cancer patients. Of particular interest is the use of the combination of liposomal anthracyclines and trastuzumab in patients with HER2-overexpressing breast cancer. In this paper, we discuss the different studies on liposomal doxorubicin in metastatic and early breast cancer therapy.

  4. Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction: A case report.

    Science.gov (United States)

    Tsuchihashi, Kenji; Shimokawa, Hozumi; Takayoshi, Kotoe; Nio, Kenta; Aikawa, Tomomi; Matsushita, Yuzo; Wada, Iori; Arita, Shuji; Ariyama, Hiroshi; Kusaba, Hitoshi; Sonoda, Koh-Hei; Akashi, Koichi; Baba, Eishi

    2017-10-01

    Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known. Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction. Fundus examination revealed hemorrhage of the retinal vein. Regorafenib treatment was discontinued and observational therapy was pursued. Retinal and gastrointestinal hemorrhage resolved in 1 week. Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified.

  5. Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections

    Directory of Open Access Journals (Sweden)

    Matsumoto K

    2016-03-01

    Full Text Available Kazuaki Matsumoto,1 Erika Watanabe,1 Naoko Kanazawa,1 Tomohide Fukamizu,1 Akari Shigemi,1 Yuta Yokoyama,1,2 Kazuro Ikawa,2 Norifumi Morikawa,2 Yasuo Takeda1 1Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 2Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan Background: Teicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration–time curve (AUC/minimum inhibitory concentration (MIC was identified as a pharmacokinetic–pharmacodynamic (PK–PD parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK–PD are needed, a PK–PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA infections has not yet been performed. Thus, this study examined patients with MRSA infections, who were administered with teicoplanin in order to determine the target AUC/MIC ratio. Methods: This study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring (TDM of teicoplanin therapy in 46 patients with MRSA infections at Kagoshima University Hospital. Serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a Bayesian PK estimation to estimate AUC for 24 hours (AUC24. The MIC value for teicoplanin was determined using a standardized agar dilution method. The effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment. Results: The estimated AUC24/MIC ratios with and without bacteriological responses were 926.6±425.2 µg·h/mL (n=34 and 642.2±193.9 µg·h/mL, respectively (n=12; P<0.05. On the basis of a logistic regression analysis, AUC24/MIC ratios of 500 µg·h/mL, 700 µg·h/mL, and

  6. Parenteral nutrition in the elderly cancer patient.

    Science.gov (United States)

    Orrevall, Ylva

    2015-04-01

    Parenteral nutrition may be considered when oral intake and/or enteral nutrition are not sufficient to maintain nutritional status and the patient is likely to die sooner from starvation than from the cancer. A detailed assessment should be made prior to the decision about whether parenteral nutrition should be started. A follow up plan should be documented with objective and patient centred treatment goals as well as specific time points for evaluation. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Systemic therapy for patients with colorectal cancer

    DEFF Research Database (Denmark)

    Pfeiffer, Per; Qvortrup, Camilla; Tabernero, Josep

    2015-01-01

    Recent modalities and strategies have increased the complexity of treatment choice in patients with colorectal cancer (CRC), and therefore all cases should be assessed at a multidisciplinary conference. Adjuvant chemotherapy for 6 months increases the chance of cure by absolutely 5 % in stage II...

  8. PET/MRI in cancer patients

    DEFF Research Database (Denmark)

    Kjær, Andreas; Loft, Annika; Law, Ian

    2013-01-01

    Combined PET/MRI systems are now commercially available and are expected to change the medical imaging field by providing combined anato-metabolic image information. We believe this will be of particular relevance in imaging of cancer patients. At the Department of Clinical Physiology, Nuclear Me...

  9. Haemorheological Changes in African Breast Cancer Patients ...

    African Journals Online (AJOL)

    Several Studies have indicated the existence of thrombo-embolic complications in cancer patients and that this could be associated with changes in heamorheological parameters. Packed cell volume (PCV), heamoglobin (Hb), relative plasma viscosity (RPV) and plasma Fibrinogen concentration (PFC) were measured in ...

  10. [Treatment of elderly patients with breast cancer

    DEFF Research Database (Denmark)

    Paaschburg, B.; Pedersen, A.; Tuxen, M.K.

    2008-01-01

    The latest investigations have been searched in order to present new guidelines for the treatment of elderly patients with primary breast cancer. It is concluded that breast-conserving surgery should be offered as well as the sentinel node technique. Axillary lymph node dissection is not necessary...

  11. MANAGEMENT OF CANCER IN PATIENTS WITH HIV

    African Journals Online (AJOL)

    populations of patients with HIV infection that a causal relationship is difficult to exclude. These cancers are associated with declining immune function and are considered to be ... the chemotherapy or radiotherapy is strongly associated with response rates. ... organ dysfunction such as hepatitis, renal failure and respiratory ...

  12. History of Depression in Lung Cancer Patients

    DEFF Research Database (Denmark)

    Iachina, M; Brønserud, M M; Jakobsen, E

    2017-01-01

    . To estimate the effect of depression on the diagnostic process and the choice of treatment in lung cancer we fitted a logistic regression model and a Cox regression model adjusting for age, gender, resection and stage. RESULTS: Depression in a patient's anamnesis had no significant effect on the delay...

  13. Prevention of chemotherapy-induced neutropenia with pegfilgrastim: pharmacokinetics and patient outcomes.

    Science.gov (United States)

    Yang, Bing-Bing; Savin, Michael A; Green, Michael

    2012-01-01

    Patients receiving cytotoxic chemotherapy are at risk for developing chemotherapy-induced neutropenia (CIN). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF) that stimulates the proliferation, differentiation and function of neutrophils, is approved for the prevention of CIN. To eliminate the burden of daily filgrastim injection, pegfilgrastim, a long-acting form of filgrastim, was developed by covalently attaching a 20-kDa polyethylene glycol molecule to filgrastim to increase molecular size and thus reduce renal elimination. Consequently, neutrophil-mediated clearance is the primary mechanism for pegfilgrastim elimination. Therefore, after a single pegfilgrastim injection following chemotherapy treatment, pegfilgrastim concentration is sustained during neutropenia and decreases with neutrophil recovery. Pegfilgrastim has received marketing authorization approval from many regions to reduce the incidence of CIN based on the similar efficacy and safety of a single injection of 6 mg of pegfilgrastim administered once per chemotherapy cycle and 10 to 11 daily injections of filgrastim at 5 µg/kg. The efficient self-regulating clearance of pegfilgrastim allows administration once per chemotherapy cycle, thereby providing a more convenient treatment regimen than filgrastim. Copyright © 2012 S. Karger AG, Basel.

  14. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions

    NARCIS (Netherlands)

    Breedveld, Pauline; Zelcer, Noam; Pluim, Dick; Sönmezer, Ozgür; Tibben, Matthijs M.; Beijnen, Jos H.; Schinkel, Alfred H.; van Tellingen, Olaf; Borst, Piet; Schellens, Jan H. M.

    2004-01-01

    The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an

  15. Multidimensional fatigue and its correlates in hospitalised advanced cancer patients.

    NARCIS (Netherlands)

    Echteld, M.A.; Passchier, J.; Teunissen, S.; Claessen, S.; Wit, R. de; Rijt, C.C.D. van der

    2007-01-01

    Although fatigue is a multidimensional concept, multidimensional fatigue is rarely investigated in hospitalised cancer patients. We determined the levels and correlates of multidimensional fatigue in 100 advanced cancer patients admitted for symptom control. Fatigue dimensions were general fatigue

  16. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

    Science.gov (United States)

    Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

    2016-05-01

    VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

  17. Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care

    Directory of Open Access Journals (Sweden)

    David P. Kodack

    2017-12-01

    Full Text Available Personalized cancer therapy is based on a patient’s tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient’s living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.

  18. Hope in newly diagnosed cancer patients.

    Science.gov (United States)

    Duggleby, Wendy; Ghosh, Sunita; Cooper, Dan; Dwernychuk, Lynne

    2013-11-01

    Hope is important to cancer patients as it helps them deal with their diagnosis. Little is known about hope in newly diagnosed cancer patients. Based on the Transcending Possibilities conceptual model of hope, the purpose of this study was to examine the relationship of hope with pain, energy, and psychological and demographic characteristics in newly diagnosed adult oncology outpatients. Data from 310 New Patient Assessment Forms from cancer outpatients' health records were collected. Health records from the first six months of 2009 were reviewed and data were collected on hope, energy, pain, depression, anxiety, feeling overwhelmed, and demographic variables. A generalized linear modeling approach was used to study the relationship of hope scores with these variables. Hypothesized variables and variables that were significant at the P = 0.01 level from the univariate analysis were entered into the multivariate model, with hope scores as the dependent variable. Hope scores were significantly negatively related to age (P = 0.02). More specifically, oncology patients who were 65 years of age or older had significantly less hope than those under the age of 65 years (P = 0.01). Gender (P = 0.009) also was a significant factor, with men having higher hope scores than women. No other variables were significant. Older adults comprise the majority of persons in Canada with cancer. The lower hope scores found in this age group compared with their younger counterparts underscore the importance of further research. This study provides a foundation for future research in this important area for oncology patients. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

  19. Inadequate Nutritional Status of Hospitalized Cancer Patients

    Directory of Open Access Journals (Sweden)

    Ali Alkan

    2017-03-01

    Full Text Available Objective: In oncology practice, nutrition and also metabolic activity are essential to support the nutritional status and prevent malignant cachexia. It is important to evaluate the patients and plan the maneuvers at the start of the therapy. The primary objective of the study is to define the nutritional status of hospitalized patients and the factors affecting it in order to define the most susceptible patients and maneuvers for better nutritional support. Methods: Patients hospitalized in oncology clinic for therapy were evaluated for food intake and nutritional status through structured interviews. The clinical properties, medical therapies, elements of nutritional support were noted and predictors of inadequate nutritional status (INS were analyzed. Results: Four hundred twenty three patients, between 16-82 years old (median: 52 were evaluated. Nearly half of the patients (185, 43% reported a better appetite at home than in hospital and declared that hospitalization is an important cause of loss of appetite (140/185, 75.6%. Presence of nausea/vomiting (N/V, depression, age less than 65 and use of non-steroidal anti-inflammatory drugs (NSAIDs were associated with increased risk of INS in hospitalized cancer patients. On the contrary, steroid medication showed a positive impact on nutritional status of cancer patients. Conclusion: N/V, younger age, presence of depression and NSAIDs medication were associated with INS in hospitalized cancer patients. Clinicians should pay more attention to this group of patients. In addition, unnecessary hospitalizations and medications that may disturb oral intake must be avoided. Corticosteroids are important tools for managing anorexia and INS.

  20. Ofloxacin pharmacokinetics in renal failure.

    OpenAIRE

    Fillastre, J P; Leroy, A; Humbert, G

    1987-01-01

    The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution...

  1. Classification of neuropathic pain in cancer patients

    DEFF Research Database (Denmark)

    Brunelli, Cinzia; Bennett, Michael I; Kaasa, Stein

    2014-01-01

    and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP...... in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, and standardized PRO assessment for NP screening. Median consensus scores (MED) and interquartile ranges (IQR) were calculated to measure expert consensus after both rounds. Twenty-nine experts answered, and good agreement...... was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients....

  2. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort.

    Science.gov (United States)

    Abdul-Aziz, Mohd H; Lipman, Jeffrey; Akova, Murat; Bassetti, Matteo; De Waele, Jan J; Dimopoulos, George; Dulhunty, Joel; Kaukonen, Kirsi-Maija; Koulenti, Despoina; Martin, Claude; Montravers, Philippe; Rello, Jordi; Rhodes, Andrew; Starr, Therese; Wallis, Steven C; Roberts, Jason A

    2016-01-01

    We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025]. Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e

  3. Outcome of severe infections in afebrile neutropenic cancer patients

    Directory of Open Access Journals (Sweden)

    Strojnik Ksenija

    2016-12-01

    Full Text Available In some neutropenic cancer patients fever may be absent despite microbiologically and/or clinically confirmed infection. We hypothesized that afebrile neutropenic cancer patients with severe infections have worse outcome as compared to cancer patients with febrile neutropenia.

  4. Radiation therapy for cancer patients

    International Nuclear Information System (INIS)

    Mileikowsky, C.

    1987-01-01

    This patent describes an apparatus for irradiating a patient comprising: a source of a radiation beam directed along a radiation axis; means mounting the source for pivotal movement about a first horizontal axis which intersects the source, is stationary with respect to the apparatus, and extends in a direction substantially normal to the radiation axis, whereby the beam is capable of an angular scan in a vertical plane; table means adapted to support a patient to be irradiated; and suspension means mounted the table means for arcuate movement to any positions angularly spaced about the first horizontal axis and for pivoting movement about a second horizontal axis displacement from and substantially parallel to the first horizontal axis. The suspension means maintain the second horizontal axis in substantially intersecting relation to the radiation axis in each of the positions while maintaining a fixed angular position of the table means with respect to the environment

  5. Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

    Science.gov (United States)

    Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

    2016-07-01

    BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

  6. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment.

    Science.gov (United States)

    Panhuizen, I F; Gold, S J A; Buerkle, C; Snoeck, M M J; Harper, N J N; Kaspers, M J G H; van den Heuvel, M W; Hollmann, M W

    2015-05-01

    This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. NCT00702715. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Understanding male cancer patients' barriers to participating in cancer rehabilitation

    DEFF Research Database (Denmark)

    Handberg, Charlotte; Lomborg, Kirsten; Nielsen, Claus Vinther

    2015-01-01

    The aim was to describe male cancer survivors' barriers towards participation in cancer rehabilitation as a means to guiding future targeted men's cancer rehabilitation. Symbolic Interactionism along with the interpretive descriptive methodology guided the study of 35 male cancer survivors...

  8. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Wacheck V

    2011-05-01

    Full Text Available Volker Wacheck1, Michael Lahn2, Gemma Dickinson3, Wolfgang Füreder4, Renata Meyer4, Susanne Herndlhofer4, Thorsten Füreder1, Georg Dorfner5, Sada Pillay2, Valérie André6, Timothy P Burkholder7, Jacqueline K Akunda8, Leann Flye-Blakemore9, Dirk Van Bockstaele9, Richard F Schlenk10, Wolfgang R Sperr4, Peter Valent4,111Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 2Early Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA; 3Department of Pharmacokinetics, Eli Lilly and Company, Erl Wood Research Centre, Windlesham, Surrey, UK; 4Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 5Eli Lilly GesmbH, Medical Department, Vienna, Austria; 6Department of Statistics, Eli Lilly and Company, Erl Wood Research Centre, Surrey, UK; 7Discovery Chemistry Research and Technology, Eli Lilly and Company, Indianapolis, IN, USA; 8Nonclinical Toxicology, Eli Lilly and Company, Indianapolis, IN, USA; 9Flow Cytometry and Cell Analysis, Esoterix Clinical Trials Services, Mechelen, Belgium; 10Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm, Germany; 11Ludwig Boltzmann Cluster Oncology, Vienna, AustriaBackground: Acute myeloid leukemia (AML is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML.Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI were assessed.Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg

  9. Nutritional status assessment in colorectal cancer patients.

    Science.gov (United States)

    Lopes, Joana Pedro; de Castro Cardoso Pereira, Paula Manuela; dos Reis Baltazar Vicente, Ana Filipa; Bernardo, Alexandra; de Mesquita, María Fernanda

    2013-01-01

    The present study intended to evaluate the nutritional status of Portuguese colorectal patients and associated it with surgery type as well as quality of life outcomes. Malnutrition can affect up to 85% of cancer patients and specifically 30-60% in colorectal cancer and can significantly influence health outcomes. A sample of 50 colorectal cancer patients was evaluated in what refers to several anthropometric measures, food intake, clinical history, complications rate before and after surgery procedure. The sample was divided between convention and fast-track procedures. Most of the individuals were overweight or obese but had lost weight on the past six months. Despite mild, there were signs of malnutrition in this sample with high losses of fat free mass, weight and also fat mass during the hospitalization period. These results reinforce the importance of malnutrition assessment in colorectal patients as well as consider weight loss on the past months and body composition in order to complement nutritional status evaluation. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

  10. Palliative Care Use Among Patients With Solid Cancer Tumors: A National Cancer Data Base Study.

    Science.gov (United States)

    Osagiede, Osayande; Colibaseanu, Dorin T; Spaulding, Aaron C; Frank, Ryan D; Merchea, Amit; Kelley, Scott R; Uitti, Ryan J; Ailawadhi, Sikander

    2018-01-01

    Palliative care has been increasingly recognized as an important part of cancer care but remains underutilized in patients with solid cancers. There is a current gap in knowledge regarding why palliative care is underutilized nationwide. To identify the factors associated with palliative care use among deceased patients with solid cancer tumors. Using the 2016 National Cancer Data Base, we identified deceased patients (2004-2013) with breast, colon, lung, melanoma, and prostate cancer. Data were described as percentages. Associations between palliative care use and patient, facility, and geographic characteristics were evaluated through multivariate logistic regression. A total of 1 840 111 patients were analyzed; 9.6% received palliative care. Palliative care use was higher in the following patient groups: survival >24 months (17% vs 2%), male (54% vs 46%), higher Charlson-Deyo comorbidity score (16% vs 8%), treatment at designated cancer programs (74% vs 71%), lung cancer (76% vs 28%), higher grade cancer (53% vs 24%), and stage IV cancer (59% vs 13%). Patients who lived in communities with a greater percentage of high school degrees had higher odds of receiving palliative care; Central and Pacific regions of the United States had lower odds of palliative care use than the East Coast. Patients with colon, melanoma, or prostate cancer had lower odds of palliative care than patients with breast cancer, whereas those with lung cancer had higher odds. Palliative care use in solid cancer tumors is variable, with a preference for patients with lung cancer, younger age, known insurance status, and higher educational level.