RESUMEN
Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Reparación del ADN por Recombinación/genética , Neoplasias de la Mama Triple Negativas/terapia , Antraciclinas/farmacología , Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína BRCA1/genética , Proteína BRCA2/genética , Mama/patología , Mama/cirugía , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Carboplatino/farmacología , Supervivencia sin Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Seguimiento , Humanos , Mastectomía , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante/métodos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Pronóstico , Análisis de Supervivencia , Taxoides/farmacología , Taxoides/uso terapéutico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
PURPOSE: To evaluate the safest timing of pegfilgrastim administration in dose-dense anthracycline- and taxane-based chemotherapy, three different cohorts of patients enrolled in the Gruppo Italiano Mammella (GIM) 2 study and treated at the coordinating center received pegfilgrastim 24 h (cohort A) or 72 h (cohort B) or 96 h (cohort C) after chemotherapy. METHODS: A total of 41 patients were included. The safety of pegfilgrastim administration in terms of occurrence of early and late leukocytosis and the behavior of white blood cells (WBC) counts in the three cohorts across all chemotherapy cycles were evaluated. Anthracycline and taxane cycles were analyzed separately. RESULTS: The occurrence of early leukocytosis was a more common event in patients in cohort A in both anthracycline and taxane cycles (75 and 66.7%) as compared to cohort B (50 and 60%) and cohort C (66.7 and 33.3%). More patients in cohort C developed late leukocytosis in both anthracycline and taxane cycles (50 and 100%) as compared to cohort A (0 and 66.7%) and cohort B (35.7 and 86.7%). Patients in cohort A experienced the highest median value of WBC count 24 h after pegfilgrastim administration in both anthracycline and taxane cycles (61.2 × 10(3)/µl and 67.8 × 10(3)/µl). Patients in cohort C experienced the highest median value of WBC count at day 13 in both anthracycline and taxane cycles (19.4 × 10(3)/µl and 24.2 × 10(3)/µl). CONCLUSIONS: For the prevention of leukocytosis, the safest timing of pegfilgrastim administration based on WBC count in dose-dense anthracycline- and taxane-based regimens seems to be 72 h after chemotherapy. TRIAL REGISTRATION: This study is registered with https://clinicaltrials.gov/ct2/show/NCT00433420.
Asunto(s)
Antraciclinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Taxoides/uso terapéutico , Adulto , Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Estudios de Cohortes , Esquema de Medicación , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Italia , Persona de Mediana Edad , Polietilenglicoles , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. METHODS: In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. FINDINGS: Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock). INTERPRETATION: This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. FUNDING: Nektar Therapeutics.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Polietilenglicoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Capecitabina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Médicos , Taxoides/uso terapéuticoRESUMEN
BACKGROUND: Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment. METHODS: Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m(2)), cyclophosphamide (500 mg/m(2)), and 5-fluorouracil (500 mg/m(2)) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event. RESULTS: Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted. CONCLUSION: This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a treatment option for patients with MBC whose tumors progressed during or after taxane-based treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Polietilenglicoles/administración & dosificación , Retratamiento , Terapia Recuperativa , Análisis de Supervivencia , Taxoides/uso terapéutico , Resultado del TratamientoRESUMEN
Taxane chemotherapeutics have played a key role in the treatment of various types of cancer throughout the past years. However, the drawbacks inherent to the pharmaceutical formulation of taxanes are still a reality and mainly due to the low aqueous solubility of these medicines, as well as to the nontargeted therapy and consequent side effects. Nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) have sparked broad interest in this field and demonstrated capacity of improving taxanes' formulation. If, in one hand, the PLGA core of these NPs is able to solubilize drugs, on the other hand, the PEG shell promotes immune escape and presents chemical end groups for the attachment of targeting ligands. Advances in the design of these nanosystems resulted in the development of multitargeted PLGA/PEG NPs achieved by dual-ligand functionalization. The multitargeting offers a promising alternative to the delivery of taxanes across successive cell types or compartments and to the synergetic exploitation of more than one transporter on the cell surface. Besides the upgrade in the design of multitargeted PLGA/PEG NPs, their manufacturing has also evolved from bulk assembly to continuous-flow, high-throughput technologies such as microfluidics. This technology relies on microchannel platforms described to enable the production of large-scale batches of NPs in a better time-saving manner, with higher drug loading, reproducibility, and lower polydispersity. Herein, a detailed microfluidic method for the preparation of multitargeted, taxane-loaded PLGA/PEG NPs is described. Focus is given to the setting up of the microfluidic system and conditions required to manufacture these NPs by using polymers of PLGA and PEG previously elsewhere functionalized with two generic targeting ligands.
Asunto(s)
Antineoplásicos/administración & dosificación , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Portadores de Fármacos/química , Microfluídica/métodos , Nanopartículas/química , Polietilenglicoles/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Taxoides/administración & dosificación , Antineoplásicos/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Ligandos , Taxoides/uso terapéutico , Flujo de TrabajoRESUMEN
Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Nanopartículas/uso terapéutico , Receptor EphA2/metabolismo , Animales , Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Docetaxel/sangre , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/uso terapéutico , Humanos , Liposomas , Ratones Endogámicos NOD , Ratones SCID , Taxoides/farmacología , Taxoides/uso terapéutico , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: It has been shown that antiproliferative drugs such as paclitaxel lower the amount of intimal hyperplasia after stent implantation. We report the first clinical experience of 7-hexanoyltaxol (QP2)-eluting polymer stent system (QuaDS) implantation for in-stent restenosis. METHODS AND RESULTS: Fifteen consecutive patients with elective indication to percutaneous coronary intervention for in-stent restenosis were treated with the QuaDS-QP2 stent implantation. The QuaDS-QP2 stent was successfully implanted in all but 2 target lesions. In one lesion, the restenotic segment could not be completely covered by the stent, and in another lesion, a bare metal stent was implanted distally to the QuaDS-QP2 stent. One patient suffered from postprocedural non-Q-wave myocardial infarction (NQWMI). No other adverse events were observed during hospital stay. Six- and 12-month angiographic and clinical follow-up was scheduled for all patients. At 6 months, 3 patients had target lesion revascularization (20%). Two patients had restenosis (13.3%); one experienced restenosis in a gap between 2 drug-eluting stents, and the other had stent occlusion leading to NQWMI. Minimal intimal hyperplasia was observed in all the segments covered by drug-eluting stents (late loss=0.47+/-1.01 mm with a loss index=0.17+/-0.39). At 12 months, 1 patient suffered from NQWMI, and 8 of 13 patients (61.5%) had angiographic restenosis (late loss=1.36+/-0.94 mm with a loss index=0.62+/-0.44). CONCLUSION: This first experience with QuaDS-QP2 stent implantation for in-stent restenosis revealed minimal intimal hyperplasia at the 6-month follow-up. However, the antiproliferative effect was not maintained at the 12-month follow-up, resulting in delayed occurrence of angiographic restenosis.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/uso terapéutico , Oclusión de Injerto Vascular/tratamiento farmacológico , Stents , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Angiografía Coronaria , Implantes de Medicamentos , Femenino , Estudios de Seguimiento , Oclusión de Injerto Vascular/diagnóstico por imagen , Oclusión de Injerto Vascular/etiología , Inhibidores de Crecimiento/administración & dosificación , Inhibidores de Crecimiento/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Polímeros/administración & dosificación , Polímeros/uso terapéutico , Stents/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer. PATIENTS AND METHODS: Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m(2) every 28 days); or comparator-vinorelbine (30 mg/m(2) weekly) or mitomycin C (10 mg/m(2) day 1 and every 28 days) plus vinblastine (5 mg/m(2) day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only. RESULTS: Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P =.11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P =.71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P =.01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%). CONCLUSION: PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Doxorrubicina/uso terapéutico , Mitomicina/uso terapéutico , Taxoides/uso terapéutico , Vinblastina/análogos & derivados , Vinblastina/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/patología , Doxorrubicina/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Liposomas , Persona de Mediana Edad , Mitomicina/efectos adversos , Metástasis de la Neoplasia , Terapia Recuperativa , Vinblastina/efectos adversos , VinorelbinaRESUMEN
OBJECTIVES: The Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial was a multicenter, randomized, open-label trial comparing the safety and performance of 13- and 17-mm QuaDDS stents (n = 126) (Quanam Medical Corp., Santa Clara, California/Boston Scientific Corp., Natick, Massachusetts) versus uncoated control stents (n = 140) in focal, de novo coronary lesions. BACKGROUND: The pioneering drug-delivery QuaDDS stent used four to six acrylate polymer sleeves, each loaded with 800 microg of the paclitaxel derivative 7-hexanoyltaxol. METHODS: Clinical end points were assessed at 1, 6, and 12 months post procedure. Quantitative coronary angiography and intravascular ultrasound were performed post procedure and at six-month follow-up. RESULTS: In the QuaDDS group, early stent thrombosis and myocardial infarction (MI) rates were significantly higher, leading to premature cessation of enrollment. For the QuaDDS group, the stent thrombosis rate increased from 3.2% to 10.3% between 1 and 12 months, associated with increased non-Q-wave MI and death rates. The angiographic restenosis rate at six months was reduced from 32.7% (control) to 7.4% (p < 0.0001). However, the primary end point was not met with six-month target vessel revascularization (TVR) rate as well as the composite major adverse cardiac event rates (cardiac death, MI, and TVR) comparable between groups. CONCLUSIONS: Despite angiographic indications of potential anti-restenotic benefit, increased rates of stent thrombosis, MI, and cardiac death associated with the QuaDDS stent show an unacceptable safety profile.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/uso terapéutico , Enfermedad Coronaria/terapia , Reestenosis Coronaria/prevención & control , Stents , Anciano , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/efectos adversos , Materiales Biocompatibles Revestidos , Angiografía Coronaria , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/mortalidad , Reestenosis Coronaria/mortalidad , Trombosis Coronaria/etiología , Muerte Súbita Cardíaca/etiología , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Polímeros , Stents/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The recent progress in antiviral chemotherapy against respiratory syncytial virus (RSV) infections was reviewed. RSV infections among high risk individuals, such as premature babies, infants with congenital disease of cardiopulmonary system or immune system and the aged, hospitalised patients with immunosuppressed status are threatened, with high mortality rates and thus need anti-viral chemotherapy. Clinical efficacy of ribavirin and humanized monoclonal antibody (mAb) against RSV infections as well as experimental reports of novel anti-RSV compounds under investigation such as membrane fusion inhibitors were introduced.
Asunto(s)
Antivirales/uso terapéutico , Catequina/análogos & derivados , Drogas en Investigación , Ácido N-Acetilneuramínico/análogos & derivados , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Amidas , Animales , Anticuerpos Monoclonales/uso terapéutico , Biopolímeros/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Catequina/uso terapéutico , Compuestos Heterocíclicos/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Lípidos/uso terapéutico , Ácido N-Acetilneuramínico/uso terapéutico , Norbornanos , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Pirazoles , Virus Sincitiales Respiratorios/patogenicidad , Ribavirina/uso terapéutico , Ribonucleósidos/uso terapéutico , Ribosa , Factores de Riesgo , Tiocarbamatos , Tionas/uso terapéuticoRESUMEN
Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Carcinoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Taxoides , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Docetaxel , Portadores de Fármacos , Femenino , Humanos , Liposomas , Neoplasias Pulmonares , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivados , Paclitaxel/uso terapéuticoRESUMEN
Out of 1500 patients suffering from tremor of diverse origin, reliable data on 521 were selected for analysis. The drug was given for over two months (mean daily dose 8 mg) and effectively reduced all kinds of tremor by an average 50%. The only side-effects occurring with any frequency were dryness of the mouth and constipation. The data collected show bornaprine to have a beneficial effect on all types of tremor.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/uso terapéutico , Temblor/tratamiento farmacológico , Anciano , Hidrocarburos Aromáticos con Puentes/efectos adversos , Estreñimiento/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Temblor/clasificación , Xerostomía/inducido químicamenteRESUMEN
The objective is to assess the cost-effectiveness of pegfilgrastim for the prevention of hospitalization due to febrile neutropenia (FN) in patients with epithelial ovarian carcinoma (EOC) receiving taxane/platinum-based chemotherapy. A decision analysis model evaluated a hypothetical cohort of 10,000 patients receiving six cycles of taxane/platinum-based chemotherapy for EOC. Three strategies were analyzed for the prevention of hospitalization due to FN: 1) dose modifications and delays after a hospitalization for FN without the use of granulocyte-colony stimulating factors (G-CSF) (NO G-CSF); 2) all patients receive G-CSF with each chemotherapy cycle (1 degrees PROPHYLAXIS); 3) patients receive G-CSF for all subsequent chemotherapy cycles after a hospitalization for FN (2 degrees PROPHYLAXIS). The model was applied to two patient populations: 1) an average-risk population (FN hospitalization rate = 5%); 2) a high-risk population (FN hospitalization rate = 16%). Using baseline assumptions in an average-risk population, NO G-CSF was the least expensive strategy with a cost of $68 million and resulted in 2,860 hospitalizations for FN. 2 degrees PROPHYLAXIS resulted in 141 fewer hospitalizations than NO G-CSF at a cost of $76,288 per hospitalization prevented. 1 degrees PROPHYLAXIS was the most effective and resulted in 1,689 fewer hospitalizations for FN compared to NO G-CSF at a cost of $47,343 per hospitalization prevented. When this model is applied to a high-risk patient population, 1 degrees PROPHYLAXIS is more effective and less expensive than both NO G-CSF and 2 degrees PROPHYLAXIS. We conclude that in average-risk patients receiving chemotherapy for EOC the use of pegfilgrastim is effective at reducing hospitalizations due to FN, but at a significant cost. However, in high-risk patients, primary prophylaxis is the only cost-effective strategy and should be strongly considered.
Asunto(s)
Antineoplásicos/efectos adversos , Hidrocarburos Aromáticos con Puentes/efectos adversos , Carcinoma/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/economía , Hospitalización/economía , Neutropenia/prevención & control , Neoplasias Ováricas/tratamiento farmacológico , Taxoides/efectos adversos , Antineoplásicos/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Estudios de Cohortes , Análisis Costo-Beneficio , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Neutropenia/etiología , Polietilenglicoles , Proteínas Recombinantes , Taxoides/uso terapéuticoRESUMEN
The study covers 30 patients with idiopathic Parkinson disease, 13 men and 17 women, aged between 50 and 70, on stabilized L-Dopa and/or bromocriptine, which failed to ensure adequate control of the symptoms, especially tremor. To this regimen was added Bornaprine/placebo in randomized sequence. The patients were tested according to the Webster Rating Scale before, during and after each stage of the treatment. Statistical analysis of the results showed the superiority of Bornaprine over the placebo in reducing tremor (p less than 0.01) and, to a lesser degree, some other parkinsonian symptoms. No noteworthy side effects were found apart from dryness of the mouth, which was more frequent with Bornaprine.