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1.
Hosp Pharm ; 56(5): 576-583, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34720163

RESUMO

Purpose: To assess chemical degradation of various liquid chemotherapy and opioid drugs in the novel RxDestruct™ instrument. Methods: Intravenous (IV) drug solutions for chemotherapy and pain management were prepared using 0.9% normal saline in Excel® bags to a final volume of 500 mL. We investigated duplicate IV solutions of methotrexate (0.1 mg/mL), etoposide (0.4 mg/mL), doxorubicin (0.25 mg/mL), cladribine (12.4 µg/mL), fentanyl (1.0 µg/mL), and hydromorphone (12.0 µg/mL) in this study. Solutions were poured into an automated instrument to undergo pulsatile chemical treatment (Fenton reactions) for 20 minutes, and then discharged from the instrument through a waste outlet. Extent of intact drug degradation was determined by measuring concentrations of drugs before entry into the instrument and after chemical treatment in the filtrate using high-performance liquid-chromatography with ultraviolet detection (HPLC-UV). Results: Following chemical reactions (Fenton processes) in the automated instrument, infusion solutions containing methotrexate, etoposide, doxorubicin, and cladribine had levels below the HPLC-UV limit of quantification (LOQ), indicating <50 ppb of each. This equated to >99.5%, 99.99%, 99.9%, and 99.8% intact drug loss, respectively. Likewise, processed samples of fentanyl and hydromorphone contained levels below the LOQ (78 and 98 ng/mL, respectively), indicating extensive degradation (>92.2% and 99.2% intact drug loss, respectively). Conclusion: The novel instrument was capable of degrading intact chemotherapy and opioid drugs prepared in infusion solutions to undetectable quantities by HPLC-UV. RxDestruct™ is a possible alternative for disposal of aqueous medication waste.

2.
Paediatr Drugs ; 23(5): 457-463, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34351604

RESUMO

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

3.
Transplant Cell Ther ; 27(11): 913.e1-913.e12, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34329753

RESUMO

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m2 busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m2 and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% µmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

5.
J Clin Pharm Ther ; 44(5): 800-804, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31111511

RESUMO

WHAT IS KNOWN AND OBJECTIVE: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. CASE SUMMARY: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. WHAT IS NEW AND CONCLUSION: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Metotrexato/uso terapêutico , Primaquina/uso terapêutico , Idoso , Humanos , Masculino
6.
Lancet Haematol ; 6(5): e266-e275, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30910541

RESUMO

BACKGROUND: Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial. METHODS: The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days -2 and -1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178. FINDINGS: Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group. INTERPRETATION: These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma. FUNDING: This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante , Adulto , Idoso , Bussulfano/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Gradação de Tumores , Condicionamento Pré-Transplante/métodos , Transplante Autólogo , Resultado do Tratamento
7.
Clin J Oncol Nurs ; 23(2): 191-196, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880803

RESUMO

BACKGROUND: Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion of drugs. Many chemotherapeutic agents have a sensitive PK index, in which a small margin in blood concentrations is the difference between nontherapeutic, therapeutic, and adverse outcomes. OBJECTIVES: This article will provide an overview of evidence-based approaches to the collection of PK samples, monitoring of PK levels, and the resulting management of patients undergoing PK testing. METHODS: A case study involving busulfan, an alkylating agent used in the pre-stem cell transplantation setting, will highlight the cross-contamination of samples while a drug is being infused through a central venous catheter with PK sample collection from a proximal peripherally inserted central catheter. The influence of false elevations in drug concentrations on PK-guided dose adjustments will also be emphasized. FINDINGS: Imprecise blood collections or cross-contamination of samples may lead to inaccurate drug concentration results and, subsequently, undesired low or high drug dosage calculations.


Assuntos
Antineoplásicos Alquilantes/sangue , Bussulfano/sangue , Monitoramento de Medicamentos/métodos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Idoso , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/uso terapêutico , Bussulfano/farmacocinética , Bussulfano/uso terapêutico , Humanos , Masculino , Neoplasias/enfermagem , Dispositivos de Acesso Vascular
8.
Lancet Haematol ; 5(11): e532-e542, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30389035

RESUMO

BACKGROUND: Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities. METHODS: This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 µmol/min (16K group) or 20 000 µmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662. FINDINGS: Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group. INTERPRETATION: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse. FUNDING: Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).


Assuntos
Bussulfano/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/epidemiologia , Vidarabina/análogos & derivados , Adolescente , Adulto , Idoso , Criança , Comorbidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Vidarabina/uso terapêutico , Adulto Jovem
9.
Sarcoma ; 2018: 3143096, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29610563

RESUMO

Background: In newly diagnosed osteosarcoma (OS) patients, the time between surgery and resumption of chemotherapy is 2-7 weeks. Delays > 16 days are associated with increased risk of relapse and decreased overall survival. Identifying an effective therapy that can be used postoperatively may prevent relapse. We investigated whether aerosol gemcitabine (GCB) initiated after tumor resection inhibited the growth of OS lung metastases without affecting the wound-healing process. Methods: Mice were injected intratibially with OS cells. Amputation was performed when the tumor reached 1.5 cm. Full-thickness excisional wounds were also made on the dorsal skin and tail. Aerosol GCB or PBS was initiated 48 hours after amputation (3 times/week for 3 weeks). Wound sections were evaluated by immunohistochemistry for Ki-67 (proliferation), CD31 (vessels), VEGF, IL-10, bFGF, mast cells, macrophages, and M1/M2 macrophage ratios. The lungs were analyzed for macro- and micrometastases. Results: Aerosol GCB inhibited the growth of the lung metastases but had no effect on the 3 phases of wound healing in the dorsal skin, tail, or bone. Production of cytokines at the wound sites was the same. Conclusion: These data indicate that initiating aerosol GCB postoperatively may kill residual lung metastases thereby preventing relapse and improve survival.

10.
Expert Opin Drug Metab Toxicol ; 13(9): 901-923, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28766962

RESUMO

INTRODUCTION: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Bussulfano/administração & dosagem , Monitoramento de Medicamentos/métodos , Adulto , Animais , Antineoplásicos Alquilantes/farmacocinética , Bussulfano/farmacocinética , Criança , Interações Medicamentosas , Humanos , Farmacogenética , Transplante de Células-Tronco/métodos
11.
Drugs R D ; 17(2): 297-304, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28470465

RESUMO

BACKGROUND: Mitomycin C (MMC) is an antitumor agent that is often administered intravesically to treat bladder cancer. Pharmacologically optimized studies have suggested varying methods to optimize delivery, with drug concentration and solution volume being the main drivers. However, these MMC concentrations (e.g. 2.0 mg/mL) supersede its solubility threshold, raising major concerns of inferior drug delivery. OBJECTIVE: In this study, we seek to confirm that the pharmacologically optimized MMC concentrations are achievable in clinical practice through careful modifications of the solution preparation methods. METHODS: MMC admixtures (1.0 and 2.0 mg/mL) were prepared in normal saline using conventional and alternative compounding methods. Conventional methodology resulted in poorly soluble solutions, with many visible particulates and crystallates. However, special compounding methods, which included incubation of solutions at 50 °C for 50 min followed by storage at 37 °C, were sufficient to solubilize drug. Chemical degradation of MMC solutions was determined over 6 h using high-performance liquid chromatography (HPLC) analytics, while physical stability was tested in parallel. RESULTS: Immediately following the 50 min incubation, both MMC solutions exhibited approximately 5-7% drug degradation. Based on the measured concentrations and linear regression of degradation plots, additional storage of these solutions at 37 °C for 5 h retained chemical stability criterion (< 10% overall drug loss). No physical changes were observed in any solutions at any test time points. CONCLUSION: We recommend that the described alternative preparation methods may improve intravesicular delivery of MMC in this urological setting, and advise that clinicians employing these changes should closely monitor patients for MMC toxicities and pharmacodynamics (change in clinical outcomes) that result from the potential enhancement of MMC exposure in the bladder.


Assuntos
Antineoplásicos/química , Mitomicina/química , Soluções Farmacêuticas/química , Administração Intravesical , Estabilidade de Medicamentos , Solubilidade
12.
Am J Health Syst Pharm ; 73(24): 2083-2088, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27919876

RESUMO

PURPOSE: The chemical stability and physical compatibility of tacrolimus i.v. infusion solutions prepared in Excel bags and stored at 23 or 4 °C for up to nine days were studied. METHODS: Tacrolimus admixtures (2, 4, and 8 µg/mL) were prepared in Excel bags using 0.9% sodium chloride injection and stored at 23 °C without protection from light or at 4 °C in the dark. Test samples were withdrawn from triplicate bag solutions immediately after preparation and at predetermined time intervals (1, 3, 5, 7, and 9 days). Chemical stability was assessed by measuring tacrolimus concentrations using a validated stability-indicating high-performance liquid chromatography assay. The physical stability of the admixtures was assessed by visual examination and by measuring turbidity, particle size, and drug content. RESULTS: All test solutions stored at 23 or 4 °C had a no greater than 6% loss of the initial tacrolimus concentration throughout the nine-day study period. All test samples of tacrolimus admixtures, under both storage conditions, were without precipitation and remained clear initially and throughout the nine-day observation period. Changes in turbidities were minor; measured particulates remained few in number in all samples throughout the study. CONCLUSION: Extemporaneously prepared infusion solutions of tacrolimus 2, 4, and 8 µg/mL in 0.9% sodium chloride injection in Excel bags were chemically and physically stable for at least nine days when stored at room temperature (23 °C) without protection from light and when stored in a refrigerator (4 °C) in the dark.


Assuntos
Cloreto de Sódio/química , Cloreto de Sódio/normas , Tacrolimo/química , Tacrolimo/normas , Administração Intravenosa , Estabilidade de Medicamentos , Armazenamento de Medicamentos/métodos , Armazenamento de Medicamentos/normas , Soluções Farmacêuticas/química , Soluções Farmacêuticas/normas
13.
PLoS One ; 11(3): e0151433, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26967741

RESUMO

Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.


Assuntos
Asparaginase/farmacologia , Dexametasona/efeitos adversos , Osteonecrose/induzido quimicamente , Osteonecrose/enzimologia , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Escherichia coli/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fatores de Risco
14.
J Oncol Pharm Pract ; 22(1): 21-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25113309

RESUMO

BACKGROUND AND PURPOSE: Proflavine hemisulfate solution is a fluorescence contrast agent to visualize cell nuclei using high-resolution optical imaging devices such as the high-resolution microendoscope. These devices provide real-time imaging to distinguish between normal versus neoplastic tissue. These images could be helpful for early screening of oral cancer and its precursors and to determine accurate margins of malignant tissue for ablative surgery. Extemporaneous preparation of proflavine solution for these diagnostic procedures requires preparation in batches and long-term storage to improve compounding efficiency in the pharmacy. However, there is a paucity of long-term stability data for proflavine contrast solutions. METHODS: The physical and chemical stability of 0.01% (10 mg/100 ml) proflavine hemisulfate solutions prepared in sterile water was determined following storage at refrigeration (4-8℃) and room temperature (23℃). Concentrations of proflavine were measured at predetermined time points up to 12 months using a validated stability-indicating high-performance liquid chromatography method. RESULTS: Proflavine solutions stored under refrigeration were physically and chemically stable for at least 12 months with concentrations ranging from 95% to 105% compared to initial concentration. However, in solutions stored at room temperature increased turbidity and particulates were observed in some of the tested vials at 9 months and 12 months with peak particle count reaching 17-fold increase compared to baseline. Solutions stored at room temperature were chemically stable up to six months (94-105%). CONCLUSION: Proflavine solutions at concentration of 0.01% were chemically and physically stable for at least 12 months under refrigeration. The solution was chemically stable for six months when stored at room temperature. We recommend long-term storage of proflavine solutions under refrigeration prior to diagnostic procedure.


Assuntos
Meios de Contraste/química , Estabilidade de Medicamentos , Soluções Farmacêuticas/química , Proflavina/química , Armazenamento de Medicamentos/métodos , Neoplasias Bucais/tratamento farmacológico , Soluções Farmacêuticas/uso terapêutico , Proflavina/uso terapêutico , Refrigeração/métodos
15.
J Oncol Pharm Pract ; 22(1): 31-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25122633

RESUMO

BACKGROUND AND PURPOSE: Carboplatin is a platinum-containing compound with efficacy against various malignancies. The physico-chemical stability of carboplatin in dextrose 5% water (D5W) has been thoroughly studied; however, there is a paucity of stability data in clinically relevant 0.9% sodium chloride infusion solutions. The manufacturer's limited stability data in sodium chloride solutions hampers the flexibility of carboplatin usage in oncology patients. Hence, the purpose of this study is to determine the physical and chemical stability of carboplatin-sodium chloride intravenous solutions under different storage conditions. METHODS: The physico-chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL carboplatin-sodium chloride solutions prepared in polyvinyl chloride bags was determined following storage at room temperature under ambient fluorescent light and under refrigeration in the dark. Concentrations of carboplatin were measured at predetermined time points up to seven days using a stability-indicating high-performance liquid chromatography method. RESULTS: All tested solutions were found physically stable for at least seven days. The greatest chemical stability was observed under refrigerated storage conditions. At 4℃, all tested solutions were found chemically stable for at least seven days, with nominal losses of ≤6%. Following storage at room temperature exposed to normal fluorescent light, the chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions was three days, five days, and seven days, respectively. CONCLUSION: The extended physico-chemical stability of carboplatin prepared in sodium chloride reported herein permits advance preparation of these admixtures, facilitating pharmacy utility and operations. Since no antibacterial preservative is contained within these carboplatin solutions, we recommend storage, when prepared under specified aseptic conditions, no greater than 24 h at room temperature or three days under refrigeration.


Assuntos
Carboplatina/química , Estabilidade de Medicamentos , Soluções Farmacêuticas/química , Cloreto de Polivinila/química , Cloreto de Sódio/química , Embalagem de Medicamentos/métodos , Armazenamento de Medicamentos/métodos , Infusões Intravenosas/métodos , Refrigeração/métodos , Temperatura
16.
Clin Cancer Res ; 21(12): 2704-14, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25724525

RESUMO

PURPOSE: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. RESULTS: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. CONCLUSIONS: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Criança , Ciclofosfamida , Dexametasona , Doxorrubicina , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , Recidiva , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Vincristina , Adulto Jovem
17.
Clin Lymphoma Myeloma Leuk ; 14 Suppl: S14-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25486949

RESUMO

Cure rates in pediatric acute lymphoblastic leukemia have significantly improved over the past decades. Now, almost 90% of children will survive the disease. The cure rates in adolescents, young adults, and adults have not kept pace with the improvements in younger patients, even though almost an equal proportion of adult patients achieve complete remission as their pediatric counterparts. Differences in treatment regimens might be important. Intensive use of asparaginase has been a key component of successful pediatric therapy. In this review, we focus on the use of asparaginase and the potential of optimizing asparaginase use via monitoring to minimize adverse drug events and improve efficacy of the drug.


Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores Etários , Antineoplásicos/farmacologia , Asparaginase/farmacologia , Monitoramento de Medicamentos , Humanos , Resultado do Tratamento
18.
Oncologist ; 19(10): 1040-1, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25170013

RESUMO

BACKGROUND: EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC. METHODS: The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed. RESULTS: MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes. CONCLUSION: The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dasatinibe/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinases da Família src/antagonistas & inibidores , Biomarcadores Tumorais/análise , Dasatinibe/efeitos adversos , Dasatinibe/farmacocinética , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/farmacocinética , Humanos , Dose Máxima Tolerável , Resultado do Tratamento
19.
J Oncol Pharm Pract ; 20(1): 51-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23512269

RESUMO

PURPOSE: Ifosfamide plus mesna have been used recently in a high-dose regimen that allows this chemotherapy to be given to outpatients with less toxicity over 14 days using a portable pump. However, there is a need for published stability information. The aim of this study was to investigate the physicochemical stability of ifosfamide with mesna in normal saline at room temperature over a prolonged period of 14 days. METHODS: Infusion solutions of 1:1 ifosfamide and mesna at final concentrations of 10, 20 and 30 mg/mL were prepared with 0.9% sodium chloride in PVC bags. Solutions were stored at room temperature. Concentrations of ifosfamide and mesna were measured at 0 and 1, 3, 7 and 14 days using a stability-indicating reversed phase high-performance liquid chromatography (HPLC) assay with ultraviolet detection. RESULTS: Ifosfamide and mesna were both physicochemically stable (>94%) for 14 days in all tested infusion solutions (10, 20 and 30 mg/mL). CONCLUSIONS: Our stability data indicate that ifosfamide and mesna (1:1) combination can be administered as a prolonged continuous infusion with portable pump in an outpatient setting without replacement of the infusion bag. We suggest 20 mg/mL as a reasonable concentration for infusion rates of about 2-4 cc/hr over prolonged periods of time.


Assuntos
Ifosfamida/química , Mesna/química , Soluções Farmacêuticas/química , Fenômenos Químicos , Combinação de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Ifosfamida/administração & dosagem , Infusões Intravenosas , Mesna/administração & dosagem , Pacientes Ambulatoriais , Soluções Farmacêuticas/administração & dosagem
20.
J Oncol Pharm Pract ; 20(2): 120-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23676510

RESUMO

BACKGROUND: Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. METHODS: Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. RESULTS: Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. CONCLUSIONS: Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Taxoides/efeitos adversos , Taxoides/farmacocinética , Adulto , Idoso , Neoplasias da Mama/patologia , Docetaxel , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Projetos Piloto
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