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The species of the Lamiaceae family produce essential oils in the glandular trichomes, leaf surfaces, and in inflorescences, and can also produce many secondary compounds, which indicates great potential for study. The aim of this paper was to describe the chemical composition and the biological, antioxidant, antimicrobial, and antitumor activities of the essential oil of Cantinoa althaeifolia for the first time. The essential oil was obtained from the leaves by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC/MS). The antioxidant activity was established by the phosphomolybdenum method. The minimum inhibitory concentration against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans was determined. The lethality test of Artemia salina was performed. The cytotoxicity against murine fibroblasts (3T3), non-tumor cells (McCoy), murine melanoma (B16F10), and human breast carcinoma (MCF-7) cells was assessed. Five major compounds were isolated: himachalene (11.62%), spathulenol (10.08%), caryophylline oxide (9.93%), (E)-caryophylene (9.21%), and pogostol (6.31%). The phosphomolybdenum complex method showed positive results. The minimum inhibitory concentration was greater than 1000 μg/mL for the tested microorganisms. The mortality rate of Artemia salina was low. The tested cancer cell lines showed an IC50 of 12.5 and 25 μg/mL. These findings indicate that the essential oil of Cantinoa althaeifolia has antioxidant, antimicrobial, and antitumor activities. Las especies de la familia Lamiaceae producen aceites esenciales en los tricomas glandulares, la superficie de las hojas y las inflorescencias, y también pueden producir muchos compuestos secundarios, lo que indica un gran potencial de estudio. El objetivo de este trabajo fue describir la composición química y las actividades biológicas, antioxidantes, antimicrobianas y antitumorales del aceite esencial de Cantinoa althaeifolia por primera vez. El aceite esencial se obtuvo de las hojas por hidrodestilación y se analizó mediante cromatografía de gases y espectrometría de masas (CG/EM). La actividad antioxidante se estableció mediante el método del fosfomolibdeno. Se determinó la concentración mínima inhibitoria contra Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa y Candida albicans. Se realizó la prueba de letalidad de Artemia salina. Se evaluó la citotoxicidad contra fibroblastos murinos (3T3), células no tumorales (McCoy), melanoma murino (B16F10) y carcinoma de mama humano (MCF-7). Se aislaron cinco compuestos principales: himachaleno (11,62%), espatulenol (10,08%), óxido de cariofileno (9,93%), (E)-cariofileno (9,21%) y pogostol (6,31%). El método del complejo de fosfomolibdeno mostró resultados positivos. La concentración inhibitoria mínima fue superior a 1000 μg/mL para los microorganismos probados. La tasa de mortalidad de Artemia salina fue baja. Las líneas celulares de cáncer probadas mostraron una CI50 de 12,5 y 25 μg/mL. Estos hallazgos indican que el aceite esencial de Cantinoa althaeifolia tiene actividades antioxidantes, antimicrobianas y antitumorales. As espécies da família Lamiaceae produzem óleos essenciais nos tricomas glandulares, superfícies foliares e em inflorescências, podendo também produzir diversos compostos secundários, o que indica grande potencial de estudo. O objetivo deste trabalho foi descrever a composição química e as atividades biológica, antioxidante, antimicrobiana e antitumoral do óleo essencial de Cantinoa althaeifolia pela primeira vez. O óleo essencial foi obtido das folhas por hidrodestilação e analisado por cromatografia gasosa e espectrometria de massas (CG/EM). A atividade antioxidante foi determinada pelo método do fosfomolibdênio. A concentração inibitória mínima contra Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa e Candida albicans foi determinada. Foi realizado o teste de letalidade de Artemia salina. A citotoxicidade contra fibroblastos murinos (3T3), células não tumorais (McCoy), melanoma murino (B16F10) e células de carcinoma de mama humano (MCF-7) também foi avaliada. Cinco compostos principais foram isolados: himachaleno (11,62%), espatulenol (10,08%), óxido de cariofileno (9,93%), (E)-cariofileno (9,21%) e pogostol (6,31%). O método do complexo de fosfomolibdênio apresentou resultados positivos. A concentração inibitória mínima foi superior a 1000 μg/mL para os microrganismos testados. A taxa de mortalidade de Artemia salina foi baixa. As linhas de células cancerosas testadas mostraram uma CI50 de 12,5 e 25 μg/mL. Esses achados indicam que o óleo essencial de Cantinoa althaeifolia possui atividades antioxidante, antimicrobiana e antitumoral.

Clinical Trial, Phase III; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy. Yes

Orientador: Profª. Drª. Iara José de Messias Reason Coorientador: Prof. Dr. Najeh Maissar Khalil Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna. Defesa : Curitiba, 26/08/2016 Inclui referências : f. 117-139 Resumo: O câncer é uma das doenças que mais preocupa a população mundial atualmente e as projeções futuras são alarmantes. A dificuldade no desenvolvimento de tratamentos com menor custo, efetivos e baixo efeito colateral preocupa a devido o risco de pacientes ficarem sem o atendimento adequado. Apostar em produtos naturais com potenciais terapêuticos talvez seja a solução mais viável a curto prazo. Uma das substâncias que vem obtendo boas respostas clínicas é a capsaicina. Ela é um metabólito secundário utilizado como analgésico e anti-inflamatório, porém, com relatos de respostas antitumorais e cancerígenas. A fim de avaliar o potencial terapêutico da capsaicina e melhorar o direcionamento do fármaco apenas para células tumorais, o presente estudo teve o objetivo de desenvolver nanoformulação de albumina bovina com capsaicina. Entretanto, antes de desenvolver a formulação foi necessário validar o método analítico para identificação e quantificação da capsaicina. O mesmo foi realizado por cromatografia líquida de alta eficiência com volume de injeção de 100?L, fase móvel de metanol:água (15:85, v/v), temperaturas da coluna e amostra em 25 oC, coluna fase reversa C18 (25cm X 4mm), tempo de corrida de 8 minutos e leitura da absorbância em 280 nm. A formulação foi desenvolvida por método de dessolvataçãocoacervação utilizando meio com pH 7, adição do agente dessolvatante (etanol) em 1 mL/min e concentração do reticulante (glutaraldeído) a 8%. Após desenvolver a formulação, a mesma foi validade através de vários métodos analíticos, o que confirmou a estabilidade da formulação (90 dias em ambiente refrigerado) e a reprodutibilidade do método de síntese. As nanopartículas apresentaram forma quasi-esférica, diâmetro de aproximadamente 200 nm e baixo índice de polidispersão. Os testes in vivo analisaram as alterações ocasionadas sobre parâmetros bioquímicos, hematológicos, histológicos e da expressão de citocinas. Diferentemente dos resultados da literatura, houve um discreto aumento da glicemia para capsaicina livre, no entanto, os outros parâmetros bioquímicos ficaram dentro da normalidade. O hemograma da capsaicina livre apresentou alteração na contagem de % de linfócitos, 67 ±4%, contra 37 ±7 e 49±7% do controle e nanopartículas, respectivamente. Por outro lado, os granulócitos da droga livre tiveram redução (21 ± 2%), enquanto o controle (49 ±4%) e nanopartículas de capsaicina (40 ±9%) não tiveram diferença significativa, o que pode representar algum processo inflamatório ou infeccioso. Entretanto, ainda são necessários outros estudos para confirmar alguma hipótese. A análise histológica revelou infiltrados de leucócitos em tecidos pulmonares, sendo esta resposta inflamatória mais intensa com a droga livre. Dentre as citocinas, apenas a expressão de TNF-alfa foi influenciada. Esta citocina apresentou menor expressão plasmática nos grupos com capsaicina livre e nanoencapsulada. Os testes in vivo demonstraram perfil de segurança devido a ausência de alterações nos exames. Sobre a resposta antitumoral in vitro, a nanoformulação obteve excelentes resultados com inibição do crescimento de mais 80% das células B16F10 (modelo de melanoma) na concentração de 250 ug/mL. A IC50 calculada ficou em 31,25 ug/mL durante incubação de 72h. Ao fim desta etapa de estudo, pode-se concluir que o desenvolvimento da nanopartícula de albumina com capsaicina para fins terapêuticos (anti-tumorais) ocorreu com sucesso. A formulação possui controle no diâmetro, liberação da droga, menor toxicidade ao ser comparada com a droga livre e boa resposta antitumoral in vitro. Palavras-chave: Nanopartículas. Capsaicina. Antitumoral. Toxicidade. Albumina. Abstract: Cancer is currently one of the diseases that most concerns the world population and its future projections are alarming. The difficulty in developing effective, with lower costs and side effects treatments is due to the risk of patients being without adequate attendance. To consider natural products with therapeutic potentials may be the most viable solution at short-term. One of the substances that has been obtaining great clinical responses is capsaicin. It is a secondary metabolite utilized as analgesic and anti-inflammatory, however, with reports of antitumor and anti-carcinogenic responses. In order to evaluate the therapeutic potential of capsaicin and improve the drug's targeting to tumor cells, the present study aimed to develop a bovine albumin nanoformulation with capsaicin. Nonetheless, before developing the formulation it was necessary to validate the analytical method to identify and quantify the capsaicin. This procedure was performed by high-performance liquid chromatography (HPLC) with injection volume of 100 ?L, mobile phase of methanol: water (15:85, v/v), column and sample temperature of 25 oC, reversed-phase column C18 (25cm X 4mm), trial time of 8 minutes and absorbance reading in 280 nm. The formulation was developed by desolvation/ coacervation method using mean with pH 7, 1 mL/min addition of dissolvent agent (ethanol) and reticulant agent concentration (glutaraldehyde) of 8%. After developing the formulation, it was validated through many analytical methods, which confirmed the stability of the formulation (90 days in a refrigerated environment) and reproducibility of the synthesis method. The nanoparticles presented a quasi- spherical form, diameter of approximately 200 nm and a low polydispersity index. In vivo tests analyzed the alterations caused over biochemical, hematological, histological parameters and over the cytokines expression. Differently from the literature, a small rise in glucose level occurred in the group of free capsaicin, however, the other biochemical parameters remain within the reference range. The hemogram of this free capsaicin group presented alterations in lymphocytes % count 67 ±4%, against 37 ±7 and 49±7% of control and nanoparticles groups, respectively. In contrast, the granulocytes of the free drug group reduced (21 ± 2%), while the control group (49 ±4%) and the nanoparticle one (40 ±9%) presented no significant difference, what may represent some inflammatory or infectious process. Still, other studies are necessary to confirm any hypothesis. The histological analysis revealed leukocytes infiltrates in pulmonary tissues, being this inflammatory response more intense with the free drug. Among the cytokines, only the expression of TNF-alfa was influenced. This cytokine showed a lower plasmatic expression in the groups with free and nano encapsulated capsaicin. In vivo tests demonstrated a safe profile due to the absence of alterations in the analyses. About the antitumor response in vitro, the nanoformulation obtained excellent results, inhibiting 80% of B16F40 cells (melanoma mode) in the concentration of 250 ug/mL. The IC50 calculated was 31.5 ug/mL during incubation of 72h. In the end of this study stage, it can be concluded that the development of a nanoparticle of albumin with capsaicin to therapeutic purposes (antitumor) occurred with success. The formulation has control in diameter and drug release, lower toxicity when compared to the free drug and a good antitumor response in vitro. Key-words: Nanoparticles. Capsaicin. Antitumor. Toxicity. Albumin.

Journal Article; Research Support, Non-U.S. Gov't; Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer. Yes

Paclitaxel (Taxol®) was the first effective antineoplastic in the management of refractory neoplasias to the conventional chemotherapy. It induces clinically to myelosuppression and sensory peripheral neuropathy boundary and cumulative dose, well documented at literature already. Less often the patients exhibited myalgias and arthralgias. As to concern to the inflammatory pain, there is nothing described do date, aiming to correlate the involvement from pro-inflammatory cytokines with the hyperalgesia genesis associated to PCX since the drug induces the alpha-TNF expression gene. It has already been demonstrated, experimentally by several authors, the essential role of alpha-TNF triggering a set of cytokines which active two components of the inflammatory pain (eicosanoid and sympathetic). Findings of our group showed that zymosan (ZY) administrated intraperitoneal (ip) in mice, induces the release of these cytokines by resident macrophages at the wriggling abdominal model (CA) and that their injection intra-articular rat knees produces a feature periarthritis as a sign of hyperalgesia at articular incapacitation model (IA). Based on these findings, the aim of the present work was to evaluate PCX effect at the modulation of nociceptive response induced by zymosan in two animal models of the inflammatory pain. Then, was injected via ip PCX (8mg/kg/an) before two hours of ZY (1mg/cav;ip) in mice on the CA test. Rats were treated with ip PCX (4,8 mg/kg/an) after one hour ZY intra-articular (250mcg/animal;i-art) for IA test. Both tests, the animals were pre-treated subcutaneous via with COX-1 and COX-2 inhibitors, sympathetic blockade and citokines inhibitors. It was demonstrated that PCX (8mg/kg/an) dose potentiates the inflammatory hyperalgesia at CA model, increasing in 183%, being statistical significant at the level p< 0.001, versus experimental group. Such effect was inhibited at level of significance, p< 0.001 and dependent-dose by indomethacin (ED50 0.05mg/kg), celoxib (ED5013.68mg/kg), atenolol(ED50 0.13mg/kg), talidomide (ED50 23.36mg/kg), penthoxyphylin (ED50 8.40mg/kg) and dexamethasone (ED50 0,71mg/kg). This potential effect of at the IA test was justified at IA model in dose 4mg/kg (p< 0,001) by significant increase of time of suspension the paws through arthritis at third and fourth hours versus experimental group. By same way there was significant inhibition at the level p< 0.001 of this magnification of the pre-treated rats. Latter, PCX (Taxol®) magnified significantly the inflammatory hyperalgesia induced by ZY at CA and IA models, justifying one sided myalgias and artralgias of the patients by using PCX, suggesting the involvement of the hyperalgesic citokines - alpha-TNF, prostanoids and sympathetic mediators of the genesis of this hyper-nociceptive effect. Paclitaxel(Taxol®), foi o 1º antineoplásico efetivo no tratamento de cânceres refratários a quimioterapia convencional. Clinicamente, induz mielossupressão e neuropatia periférica sensorial dose-limitante e cumulativa, já bem documentada na literatura. Menos freqüentemente os pacientes tratados apresentam mialgias e artralgias. No que diz respeito à dor inflamatória, nada foi descrito até o momento, visando correlacionar o envolvimento das citocinas pró-inflamatórias, com a gênese da hiperalgesia associada ao PCX, já que a droga induz a expressão do gene TNF-alpha. Experimentalmente já foi demonstrado por vários autores, o papel fundamental do TNF-alpha desencadeando uma cascata de citocinas que ativam os dois componentes da dor inflamatória (eicosanóide e simpático). Dados do nosso laboratório registram que o zymosan (ZY) administrado ip em camundongos, induz a liberação dessas citocinas por macrófagos residentes no modelo de contorção abdominal (CA), e que sua injeção intra-articular em joelhos de ratos produz uma periartrite característica tida como sinal de hiperalgesia no modelo de incapacitação articular (IA). Com base nestes achados, constituiu-se objetivo do presente trabalho, avaliar o efeito do PCX na modulação da resposta nociceptiva induzida pelo ZY em dois modelos animais de dor inflamatória. Para tanto, injetou-se via ip PCX (8mg/kg/an) 2h antes do ZY (1mg/cav;ip) em camundongos no teste CA. Ratos foram tratados ip com PCX 4 e 8mg/kg/an) 1 h após da administração intra-articular ZY (250mcg/an) no teste IA. Em ambos os testes os animais foram pré-tratados via Sc com inibidores de COX-1 e COX-2, bloqueador simpático e inibidores de citocinas. Ficou demonstrado que PCX na dose de 8mg/kg potencializa a hiperalgesia inflamatória no modelo de CA, aumentando de maneira significativa (p< 0.001) o n° de CA em 183%, em relação ao controle. Tal efeito foi inibido de maneira significativa (p

Introdução. Embora muitas crianças com câncer possam ser curadas, um número significativo têm resposta insatisfatória por ineficácia da terapêutica tornando necessário identificar agentes anticâncer mais efetivos contra tumores refratários ou recaídos. Estudos com Etoposide revelaram uma clara relação entre o tempo de exposição e os seus efeitos citotóxicos, mostrando resultados superiores com o uso de doses fracionadas quando comparado ao uso de uma dose única. Estudos de farmacocinética sugerem que as concentrações plasmáticas ativas de Etoposide se situa entre 1 e 5 μg/ml e que níveis acima de 5 μg/ml determinam uma mielotoxicidade importante. O Etoposide apresenta um bom espectro antitumoral mesmo em pacientes que já foram tratados por via parenteral e uma adequada biodisponibilidade pela via oral, podendo ser administrado com segurança em regime ambulatorial. Portanto, torna-se atraente a busca de esquemas de administração deste agente, os quais produzem níveis de concentração plasmática seguras pelo maior tempo possível. Objetivos. Os objetivos deste estudo de fase I é avaliar o perfil de toxicidade, a toxicidade dose-limitante, a dose máxima tolerada, a farmacocinética plasmática e a dose segura do Etoposide oral recomendada para estudos de fase II em pacientes pediátricos portadores de tumor sólido refratário. Materiais e Métodos. Todos os pacientes eram portadores de tumor sólido não responsivo aos tratamentos estabelecidos. A dose inicial do Etoposide foi de 20mg/m2/dose, a cada 8 horas durante 14 dias seguido de um intervalo de 7 dias antes de iniciar o próximo ciclo. A farmacocinética plasmática do Etoposide foi estudada durante o primeiro dia de tratamento e os níveis de Etoposide determinados pelo método de HPLC. Resultados. Dezessete pacientes foram incluídos no estudo, sendo que em 13 foram realizados o estudo de farmacocinética. O número total de cursos de quimioterapia foi de 64. Nove pacientes foram incluídos no Nível de dose I, sendo que leucopenia grau 2-3 foi observada em 5. A dose foi então escalonada para 25 mg/m2 (Nível de dose II) e fornecida a 8 pacientes subsequentes o que determinou leucopenia grau 3-4 em 4 deles. Este Nível de dose foi então considerado como DMT (Dose Máxima Tolerada). A TDL foi neutropenia. As concentrações plasmáticas máximas de Etoposide nos pacientes incluídos no Nível de dose I e II foram de 2,97 e 8,59 μg/ml, respectivamente, e os níveis da droga >1 μg/ml foi mantido durante cerca de 6,3 horas após a administração da droga em ambos os níveis de dose. Resposta parcial foi observada em 1 paciente e 4 apresentaram doença estável. Conclusões. A administração prolongada de Etoposide oral nas doses de 20 mg/m2 a cada 8 horas durante 14 dias consecutivos, seguidos de 7 dias de repouso, foi bem tolerada e determinou uma toxicidade manejável em crianças e adolescentes portadores de doenças malignas refratárias. A dose de 20 mg/m2 aparentemente preencheu os requisitos farmacocinéticos que objetivam melhorar o índice terapêutico do Etoposide, ou seja, a obtenção de níveis plasmáticos citotóxicos sustentados e abaixo do limite de toxicidade clínica da droga. Background. Although the majority of children with cancer can be cured, there is still a need for new agents to treat patients with relapsed or refractory tumors. Etoposide is highly schedule-dependent for its antitumor activity, showing superior results when a multiple drug administrations is compared with single high dose administration. Pharmacokinetic analysis suggested that this could be related to the greater anti-tumor effect obtained when etoposide plasma concentrations between 1 and 5 μg/ml are sustained, avoiding the myelotoxicity observed with high plasma levels (> 5 μg/ml). Considering that the therapeutic plasma levels can be achieved with oral route, the patients can be treated in the outpatient clinic which minimizes the inconvenience and the costs associated with hospitalization. Therefore, it is essential identify an appropriate dose that produce safe therapeutic plasma levels for a longer period of time than that obtained using a high concentration over short period of time and may enhance Etoposide antineoplastic efficacy. Objectives. The objectives of this phase I study were to evaluate the toxicity profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), plasma pharmacokinetics and to recommend a safe fractionated dose of oral etoposide for phase II trials in pediatric patients with refractory solid tumors. Procedure. All patients had refractory solid tumor no longer amenable to established forms of treatment. The initial dose of etoposide was 20mg/m2 three-times daily for 14 days every 21 days (dose-level I). Etoposide plasma pharmacokinetics were studied on day 1 of treatment and determined by HPLC. Results. Seventeen children were enrolled, 13 of whom were included in the pharmacokinetic study. The total number of courses was 64. Nine patients were included at dose-level I and grade 2-3 leucopenia was observed in 5. The dose was escalated to 25mg/m2 (dose-level II) thereafter in another 8 patients and grade 3-4 leucopenia was observed in 4. This dose-level was therefore considered the MTD. The DLT was neutropenia. In patients at dose-level I and II the maximum plasma etoposide concentrations was 2.97 and 8.59μg/ml, respectively; and drug levels >1μg/ml were maintained for about 6.3 hours following drug administration at both dose-levels. Partial response was observed in 1 patient and 4 patients showed a stable disease. Conclusions. Prolonged oral Etoposide at dose of 20mg/m2 three-times daily for 14 days every 21 days was well tolerated in children and adolescents with refractory solid tumor. The pharmacokinetic study showed that patients included at this dose-level achieved an adequate (1 - 5 μg/ml) plasma concentration of Etoposide for a prolonged time.

Here we describe the first case, to our knowledge, of CNS [Central nervous system] toxicity in a patient treated with irinotecan. Yes