RESUMO
First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.
Assuntos
Antineoplásicos , Aprovação de Drogas , Neoplasias Hematológicas , Dose Máxima Tolerável , Neoplasias , United States Food and Drug Administration , Humanos , Neoplasias Hematológicas/tratamento farmacológico , Estados Unidos , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a DrogaRESUMO
Background: Trematode infections are of great importance as they affect the health of many species of mammals as cattle, sheep and goat. Fasciola hepatica represents the main trematode zoonosis and risks to human and cattle and paramphistomosis is one emerging parasitic diseases of ruminants widely distributed in the world. The economic expenses are incurred by the use of ineffective anthelmintics for trematode control. Besides to faecal egg count reduction test (FECRT) to determine the anthelmintic efficacy, can be used in vitro assays, by this the aim of the study was to determine the lethal doses (LD) with hatching egg test (EHT) of the main commercial anthelmintics used for the control of trematodes in cattle. Materials, Methods & Results: Liver and rumen were examined from cattle slaughtered in Tabasco, Chiapas and Campeche states from Mexico. F. hepatica eggs were recovered from gallbladder and rumen fluke eggs collected from adult parasites in saline solution. Subsequently, the hatching egg assays were performed placing 100 trematode eggs in distilled water in each one of 96 wells of polystyrene plates. After making the appropriate dilutions, several concentrations of commercial anthelmintics were evaluated, ranging from 0.04 to 80.63 mM for triclabendazole + 0.046 to 96.87 mM febendazole (TC+FBZ), from 0.04 to 91 mM for rafoxanide (RAFOX), from 0.02 to 43.74 mM for closantel (CLOS), from 0.036 to 76.18 mM for clorsulon + 0.002 to 3.31 mM ivermectin (CLORS+ IVM) and from 0.163 to 334.47 mM for nitroxynil (NITROX). A control group (water) was included in each plate. Lethal doses were obtained using the Probit procedure and analysis of the means with a one-way statistical design. Most drugs used against rumen fluke eggs presented a high LD50 and therefore were ineffective to cause egg mortality, such was the case of RAFOX that presented LD50 from 4,580 to 10,790 µg/mL (7 to 17 mM). CLOS presented the lowest LD50 (80 µg/mL or 0.12 mM) on rumen fluke eggs. TC+FBZ was found to be effective drug against the development of F. hepatica eggs in many samples. In the same way NITROX showed a low LD50 (37 to 63 µg/mL or 0.13 to 0.22 mM), but RAFOX presented a highest LD50 (1,450 µg/mL or 2.32 mM). Discussion: The present study focused on screen the ovicidal activity and determining in vitro lethal doses 50 of main commercial anthelmintics used to control F. hepatica and rumen fluke as rapid tests in a tropical region from Mexico. The FECRT is the main method to detect effectiveness of anthelmintic and other method is the coproantigen reduction test (CRT) by ELISA. Both tests require many infected animals depending the number of treatments and by this the egg hatch assay (EHA) represent a complementary diagnosis of effectiveness of anthelmintic products to compare between regions and even between farms, because few animals are required from the farm to collect trematode eggs, and it is possible to know the effectiveness against various anthelmintics at the same time. Efficacy studies on trematodes using egg hatching tests are scarce, although they have the advantage that they can be applied to both F. hepatica and rumen fluke. TC+FBZ was one of the most effective products in inhibiting the development of F. hepatica eggs. However, RAFOX showed low effectiveness against trematode eggs, with very high lethal doses. These results agree with a study that show low efficacy against the development of Paramphistomum cervi eggs and with the FECRT test reductions of 75% and 80.58% were obtained, in times from 7 to 84 days after treatment with RAFOX. NITROX and CLORS were drugs that had good efficacy on the development of F. hepatica eggs. A differential response between liver and rumen fluke was observed. The anthelmintics used against rumen fluke eggs show low ovicidal activity and in Fasciola hepatica TC+FBZ show the best activity
Assuntos
Animais , Bovinos , Trematódeos , Dose Máxima Tolerável , Fasciola hepatica , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/análise , Contagem de Ovos de Parasitas/veterináriaRESUMO
Early clinical trials investigating antiPD(L)-1 agents rarely reached a maximum tolerated dose (MTD), and efficacy signals were observed even at the lowest dose levels. Most extended treatment intervals investigated indicated that these drugs do not follow a direct dose-toxicity or dose-efficacy relationship. Within this context and considering the high cost of antiPD(L)-1 agents, there is a significant debate on whether lower doses or the administration of such agents at an extended interval should be prospectively evaluated in already-approved agents, or at least be considered in novel combination trials involving antiPD(L)-1 drugs. Herein, we review the dosing, overall response rates, and incidence of treatment-related adverse events of antiPD(L)-1 agents in early dose-escalation trials and discuss the appropriateness of recommended Phase 2 dose selection as well as the final regulatory approved doses of such agents. Efficacy and safety data from randomized dose-range Phase 2 trials and real-world data (RWD) on the usage of lower doses and/or non-standard extended treatment intervals are also examined. As the accumulating evidence suggests lower doses or extended dosing intervals of antiPD(L)-1 may achieve a similar clinical benefit in comparison to the currently approved doses, we address the clinical and financial toxicity implications of using potentially higher doses than necessary. Last, we discuss ways to resolve the current dosing conundrum of antiPD-(L)1 agents such as performing near-equivalence studies and propose a framework for future development of immunotherapeutics to find the lowest efficacious dose instead of MTD.
Assuntos
Inibidores de Checkpoint Imunológico , Humanos , Dose Máxima TolerávelRESUMO
CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.
Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , NF-kappa B/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Peptídeos Penetradores de Células/efeitos adversos , Peptídeos Penetradores de Células/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
Having demonstrated the ability of monosialoganglioside GM1 micelles as oncology drug transporter, this work focuses on evaluating its application in an in vivo system, studying the toxicity and antitumoral effect of GM1-Ptx micellar formulation. The maximum tolerated dose (MTD) obtained after intravenous administration of GM1-Ptx in mice was 55 mg/kg and the 50% lethal dose (LD50) was 70 mg/kg. This value is higher than those described for the commercial formulations TAXOL and ABRAXANE, with LD50 of 30 and 45 mg/kg respectively. The antitumor activity, mortality and incidence of metastasis were studied on a murine model of mammary gland cancer. The GM1-Ptx formulation was administered i.v. at different doses for 9 weeks using empty GM1 micelles and saline as treatment controls. Once the treatments were completed, biochemical markers were quantified and histological tissue tests were performed. The most promising results were obtained with the treatment at a dose of 15 mg/kg/twice a week, condition in which a longer survival and significant reduction in the incidence of animals with metastasis, since only one 25% of the mice showed presence of pulmonary micro metastases.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Gangliosídeos/farmacologia , Paclitaxel/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Polietilenoglicóis/químicaRESUMO
BACKGROUND: P2X7 receptors (P2X7R) are ligand-gated ion channels activated by adenosine 5'-triphosphate (ATP), which are involved in processes that are dysfunctional in stress response and depression, such as neurotransmitter release, and neuroimmune response. Genetic and pharmacological inhibition of the P2X7R induce antidepressant-like effects in animals exposed to stress. However, the effect of P2X7R antagonism in an animal model of depression based on selective breeding has not previously been studied, and the mechanism underling the antidepressant-like effect induced by the P2X7R blockade remains unknown. AIMS: The present study aimed to: (1) determine whether P2X7R blockade induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats and, (2) investigate whether brain-derived neurotrophic factor (BDNF) signalling in the frontal cortex and hippocampus is involved in this effect. METHODS: FSL and the control Flinders Resistant Line (FRL) rats were treated with vehicle or the P2X7R antagonist A-804598 (3, 10 or 30 mg/Kg/day) for 1 or 7 days before being exposed to the forced swim test (FST). After the behavioural test, animals were decapitated, their brains were removed and the frontal cortex, ventral and dorsal hippocampus were dissected for BDNF signalling analysis. RESULTS: We found that repeated treatment with A-804598 (30 mg/Kg) reduced the immobility time in the FST and activated the BDNF signalling in the ventral hippocampus of FSL rats. CONCLUSIONS: P2X7R blockade induces an antidepressant-like effect associated with increased levels of BDNF-AKT-p70 S6 kinase in the ventral hippocampus, which may be mediated by tropomyosin-related kinase B (TRKB) receptor activation supporting the notion of P2X7R antagonism as a potential new antidepressant strategy.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Guanidinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Quinolinas/farmacologia , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Guanidinas/administração & dosagem , Masculino , Dose Máxima Tolerável , Antagonistas do Receptor Purinérgico P2X/farmacologia , Quinolinas/administração & dosagem , Ratos , Receptor trkB/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Estresse Psicológico/tratamento farmacológico , Natação , Fatores de TempoRESUMO
Although fish is a healthy alternative for meat, it can be a vehicle for mercury (Hg), including in its most toxic organic form, methylmercury (MeHg). The objective of the present study was to estimate the risk to human health caused by the consumption of sushi and sashimi as commercialized by Japanese food restaurants in the city of Campinas (SP, Brazil). The total Hg content was determined by atomic absorption spectrometry with thermal decomposition and amalgamation, and the MeHg content calculated considering that 90% of the total Hg is in the organic form. The health risk was estimated from the values for the provisional tolerable weekly ingestion (PTWI) by both adults and children. The mean concentrations for total Hg were: 147.99, 6.13, and 3.42 µg kg-1 in the tuna, kani, and salmon sushi samples, respectively, and 589.09, 85.09, and 11.38 µg kg-1 in the tuna, octopus and salmon sashimi samples, respectively. The tuna samples showed the highest Hg concentrations. One portion of tuna sashimi exceeded the PTWI value for MeHg established for children and adults. The estimate of risk for human health indicated that the level of toxicity depended on the type of fish and size of the portion consumed.
Assuntos
Contaminação de Alimentos/análise , Mercúrio/análise , Mercúrio/toxicidade , Restaurantes , Alimentos Marinhos/análise , Adolescente , Adulto , Animais , Brasil , Criança , Peixes , Humanos , Dose Máxima Tolerável , Compostos de Metilmercúrio/análise , Octopodiformes , Saúde Pública , Medição de Risco/métodos , Alimentos Marinhos/efeitos adversos , Espectrofotometria AtômicaRESUMO
PURPOSE: In the VELOUR study, aflibercept + FOLFIRI regimen resulted in improved survival in metastatic colorectal cancer (mCRC) patients who progressed after oxaliplatin. The use of aflibercept outside the clinical trial framework needs to be further assessed in terms of effectiveness and tolerability. METHODS: Early access to aflibercept through a named patient programme (NPP) was provided to mCRC patients receiving FOLFIRI as second-line treatment in Spain. The effectiveness of aflibercept was assessed as progression-free survival (PFS) achieved within the NPP population. Post hoc analyses on PFS were done according to certain baseline characteristics (K-RAS mutation, prior targeted therapy) or prognostic factors. RESULTS: Registries from 71 mCRC patients included in the NPP were reviewed retrospectively. The median age for the NPP population was 64 years (19.7 % aged ≥70 years) and 63.4 % patients had ≥2 metastases. A median PFS of 5.3 months (95 % CI, 3.6-8.5 months) was achieved, which did not depend on K-RAS mutation status or prior targeted therapy received. The risk of progression or death increased in patients with a poor prognosis as per the GERCOR score (performance status [PS] 1-2 and increased baseline lactate dehydrogenase [LDH] level) compared with patients with a good prognosis (PS 0 and normal LDH level) (median PFS: 2.6 vs. 8.3 months, respectively; p = 0.0124). Aflibercept was well tolerated, with a manageable toxicity profile. CONCLUSIONS: Bearing in mind the differences in sample size, the PFS achieved with the aflibercept + FOLFIRI regimen in the real-life practice setting is comparable to that observed in the clinical trial setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Peritoneais/secundário , Prognóstico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Estudos Retrospectivos , Espanha , Taxa de SobrevidaRESUMO
OBJECTIVES: To investigate the safety, tolerability, and pharmacokinetics of liraglutide in adolescents with obesity. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial. Twenty-one subjects, aged 12-17 years and Tanner stage 2-5, with obesity (body mass index [BMI] corresponding to both a BMI ≥95th percentile for age and sex and to a BMI of ≥30 kg/m2 for adults; additionally, BMI was ≤45 kg/m2) were randomized (2:1) to receive 5 weeks of treatment with liraglutide (0.6 mg with weekly dose increase to a maximum of 3.0 mg for the last week) (n = 14) or placebo (n = 7). The primary endpoint was number of treatment-emergent adverse events (TEAEs). Secondary endpoints included safety measures, and pharmacokinetic and pharmacodynamic endpoints. RESULTS: All participants receiving liraglutide, and 4 receiving placebo (57.1%), had at least 1 TEAE. The most common TEAEs were gastrointestinal disorders. No severe TEAEs, TEAE-related withdrawals, or deaths occurred. Twelve hypoglycemic episodes occurred in 8 participants receiving liraglutide and 2 in 1 participant receiving placebo. No severe hypoglycemic episodes were reported. Liraglutide exposure in terms of trough concentration increased with dose, although dose proportionality was confounded by unexpectedly low trough concentration values at the 2.4 mg dose. Exposure in terms of model-derived area under the plasma concentration time curve from 0 to 24 hours after dose in steady state was similar to that in adults with obesity. CONCLUSIONS: Liraglutide had a similar safety and tolerability profile compared with adults when administered to adolescents with obesity, with no unexpected safety/tolerability issues. Results suggest that the dosing regimen approved for weight management in adults may be appropriate for use in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01789086.
Assuntos
Hipoglicemia/induzido quimicamente , Liraglutida/farmacocinética , Liraglutida/uso terapêutico , Obesidade Infantil/tratamento farmacológico , Adolescente , Área Sob a Curva , Índice de Massa Corporal , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hipoglicemia/epidemiologia , Injeções Subcutâneas , Liraglutida/efeitos adversos , Masculino , Dose Máxima Tolerável , Segurança do Paciente , Obesidade Infantil/diagnóstico , Valores de Referência , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. METHODS: In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day -7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. RESULTS: Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs-1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. CONCLUSIONS: The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Braquiterapia/métodos , Everolimo/administração & dosagem , Neoplasias do Colo do Útero/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Cisplatino/administração & dosagem , Progressão da Doença , Relação Dose-Resposta a Droga , Everolimo/efeitos adversos , Everolimo/farmacocinética , Feminino , Seguimentos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. MATERIALS AND METHODS: Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. RESULTS: Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 µM. Nine of these were potent antiproliferative agents (IC50 <10 µM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. CONCLUSIONS: The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.
Assuntos
Antineoplásicos/farmacologia , Colina Quinase/antagonistas & inibidores , Adenocarcinoma/metabolismo , Animais , Antineoplásicos/química , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos , Linhagem Celular Tumoral , Proliferação de Células , Células HT29 , Humanos , Indolquinonas/química , Concentração Inibidora 50 , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Fosfatidilcolinas/química , Proteínas Recombinantes/química , Triterpenos/químicaRESUMO
OBJETIVO Avaliar a distribuição da ingestão de ácido fólico e a segurança de diferentes doses de suplementos em mulheres em idade reprodutiva. MÉTODOS Foram utilizados dados de consumo a partir de dois dias não consecutivos de registro alimentar de 6.837 mulheres em idade reprodutiva (19 a 40 anos) participantes do Inquérito Nacional de Alimentação, módulo da Pesquisa de Orçamentos Familiares 2008-2009. Médias e percentis de consumo habitual de folato natural e ácido fólico foram estimados utilizando o método do National Cancer Institute . Cinco cenários foram simulados somando-se diferentes doses diárias de fortificação (400 mcg, 500 mcg, 600 mcg, 700 mcg e 800 mcg) ao ácido fólico oriundo dos alimentos consumidos pelas mulheres. Comparou-se o total de ácido fólico (dieta + suplemento) com o nível máximo de ingestão tolerável (UL = 1.000 mcg) para definir a dose segura de suplementação. RESULTADOS Mulheres com ingestão habitual de ácido fólico acima do nível máximo de ingestão tolerável foram observadas para doses de suplemento de 800 mcg (7,0% das mulheres). Abaixo desse valor, qualquer dose de suplementação mostrou-se segura. CONCLUSÕES O uso de suplementos de até 700 mcg de ácido fólico mostrou-se seguro. .
OBJETIVO Evaluar la distribución de ingesta de ácido fólico y la seguridad de diferentes dosis de suplementos en mujeres en edad reproductiva. MÉTODOS Se utilizaron datos de consumo a partir de dos días no consecutivos de registro alimentario de 6.837 mujeres en edad reproductiva (19 a 40 años) participantes en la Investigación Nacional de Alimentación, módulo de la Investigación de Presupuestos Familiares 2008-2009. Promedios y percentiles de consumo habitual de folato natural y ácido fólico fueron estimados utilizando el método del National Cancer Institute. Cinco escenarios fueron simulados sumándose diferentes dosis diarias de fortificación (400 mcg, 500 mcg, 600 mcg, 700 mcg y 800 mcg) al ácido fólico oriundo de los alimentos consumidos por las mujeres. Se comparó el total de ácido fólico (dieta + suplemento) con el nivel máximo tolerable de ingestión (UL= 1.000 mcg) para definir la dosis segura de suplementación. RESULTADOS Mujeres con ingestión habitual de ácido fólico por encima del nivel máximo tolerable de ingestión fueron observadas para dosis de suplemento de 800 mcg (70% de las mujeres). Por debajo de ese valor, cualquier dosis de suplementación se mostró segura. CONCLUSIONES El uso de suplementos hasta 700 mcg de ácido fólico se evidenció seguro. .
OBJECTIVE To evaluate the distribution of folic acid intake and the safety of different doses of supplements in women of childbearing age. METHODS Data were used from two non-consecutive days of food records of 6,837 women of childbearing age (19-40 years old) participants of the National Food Survey, a module of the Household Budget Survey 2008-2009. Means and percentiles of usual consumption of natural folate and folic acid were estimated using the National Cancer Institute method. Five scenarios were simulated by adding different daily doses of fortification (400 mcg, 500 mcg, 600 mcg, 700 mcg and 800 mcg) to folic acid derived from food consumed by the women. To define a safe dose of the supplement, the total folate (dietary + supplement) was compared with the tolerable upper intake level (UL = 1,000 mcg). RESULTS Women with usual intake of folic acid above the tolerable upper intake levels were observed only for doses of supplement of 800 mcg (7.0% of women). Below this value, any dose of the supplement was safe. CONCLUSIONS The use of supplements of up to 700 mcg of folic acid was shown to be safe. .
Assuntos
Adulto , Feminino , Humanos , Adulto Jovem , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Brasil , Ácido Fólico/efeitos adversos , Dose Máxima Tolerável , Inquéritos Nutricionais , Necessidades NutricionaisRESUMO
BACKGROUND: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. CONCLUSION: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Células Matadoras Induzidas por Citocinas/transplante , Células Dendríticas/transplante , Imunoterapia Adotiva , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carboplatina/administração & dosagem , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/secundário , Carcinoma Lobular/terapia , Terapia Combinada , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Docetaxel , Feminino , Seguimentos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem , Tiotepa/administração & dosagemRESUMO
OBJECTIVE: To evaluate the distribution of folic acid intake and the safety of different doses of supplements in women of childbearing age. METHODS: Data were used from two non-consecutive days of food records of 6,837 women of childbearing age (19-40 years old) participants of the National Food Survey, a module of the Household Budget Survey 2008-2009. Means and percentiles of usual consumption of natural folate and folic acid were estimated using the National Cancer Institute method. Five scenarios were simulated by adding different daily doses of fortification (400 mcg, 500 mcg, 600 mcg, 700 mcg and 800 mcg) to folic acid derived from food consumed by the women. To define a safe dose of the supplement, the total folate (dietary + supplement) was compared with the tolerable upper intake level (UL = 1,000 mcg). RESULTS: Women with usual intake of folic acid above the tolerable upper intake levels were observed only for doses of supplement of 800 mcg (7.0% of women). Below this value, any dose of the supplement was safe. CONCLUSIONS: The use of supplements of up to 700 mcg of folic acid was shown to be safe.
Assuntos
Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Adulto , Brasil , Feminino , Ácido Fólico/efeitos adversos , Humanos , Dose Máxima Tolerável , Inquéritos Nutricionais , Necessidades Nutricionais , Adulto JovemRESUMO
The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Adulto , Alanina Transaminase/metabolismo , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Aspartato Aminotransferases/metabolismo , Benzamidas/efeitos adversos , Neoplasias da Mama/metabolismo , Diarreia/induzido quimicamente , Esquema de Medicação , Feminino , Humanos , Cinesinas/antagonistas & inibidores , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). METHODS: ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. RESULTS: The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC(50)] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD(50) 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. CONCLUSION: LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used.
Assuntos
Lipídeos/administração & dosagem , Lipídeos/química , Metotrexato/administração & dosagem , Metotrexato/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Contagem de Células Sanguíneas , Sistemas de Liberação de Medicamentos , Emulsões/administração & dosagem , Emulsões/química , Feminino , Células HL-60 , Humanos , Células K562 , Estimativa de Kaplan-Meier , Dose Máxima Tolerável , Metotrexato/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de ToxicidadeRESUMO
PURPOSE Our primary endpoint is to determine the effect of L-glutamine Resource (Nestlé Healthcare Nutrition) in the prevention of induced enteritis after pelvic radiotherapy (RT). METHODS We observed the incidence of diarrhoea during and after pelvic radiation therapy in patients receiving L-glutamine Resource (Nestlé Healthcare Nutrition) supplementation. To assess results, patients were stratified according to prior treatment (prior surgery and/or concomitant chemotherapy, or no prior or concomitant treatment). RESULTS Incidence of diarrhoea observed is similar to published series in which glutamine is not administered. Grade 1 intestinal toxicity was observed in 4 patients (15.4%), grade 2 in 10 patients (38.4%) and grade 3 in 5 patients (19.2%). Mean dose of RT at the start of enteritis was 23.55 Gy (12-40). No grade 4 toxicity occurred and in 7 patients (27%) no toxicity was reported. No differences in toxicity incidence were observed between RT dose levels. CONCLUSIONS Administration of glutamine to patients during pelvic RT does not appear to prevent the incidence of enteritis (diarrhoea). No differences were observed between patients who underwent concomitant chemotherapy (where you would expect an increase in toxicity) and those who did not.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Diarreia/prevenção & controle , Glutamina/uso terapêutico , Neoplasias Pélvicas/complicações , Doença Aguda , Cisplatino/administração & dosagem , Diarreia/tratamento farmacológico , Diarreia/etiologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Pélvicas/terapia , Prognóstico , Estudos Prospectivos , Qualidade de VidaRESUMO
Center for Genetic Engineering and Biotechnology (CIGB)-M3 is a trivalent recombinant single-chain Fv antibody fragment specific for carcinoembryonic antigen (CEA). Preclinical studies with radiolabeled CIGB-M3 have showed that the antibody fragment accumulates in human colon tumor xenografts growing in nude mice. A Phase I clinical trial was carried out to determine safety, biodistribution, and pharmacokinetics of the radiolabeled CIGB-M3 in two groups of patients with CEA+ colorectal cancers. Group I (10 patients) received a single intravenous injection of 0.3 mg of (131)I-CIGB-M3 (16.7-23.3 mCi/mg). Group II (7 patients) received 1 mg (5-7 mCi/mg). No adverse events related to the injected product were recorded, and no immunology response was detected up to 6 months after the injection. Tumors were detected in 15 of the 17 studied cases. The pharmacokinetic profile showed beta half-times of 14.1 and 6.3 hours for Groups I and II, respectively. Seventy-two (72) hours after the administration of the product, 85% of the total injected activity was excreted in urine in the form of free (131)I. The kidneys were identified as the organs that can limit the maximum tolerated dose. The (131)I-CIGB-M3 was safe in patients with colorectal cancer. The biodistribution and pharmacokinetic data suggest that the product can be further tested for molecular radiotherapy of CEA+tumors.