Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

A joined analysis of two European Organization for the Research and Treatment of Cancer (EORTC) studies to evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of elderly patients with metastatic breast cancer.

We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3-4 toxicity or antitumor activity and patients' baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m(2) every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.

TROMBOSE VENOSA EXPERIMENTAL NA COBAIA: EFEITO DA HEPARINA E DE DROGAS QUE ALTERAM A FUNCAO PLAQUETARIA

Thrombosis was induced in the jugular vein of guinea pigs by damage of the epithelium with a sclerosing solution. The effect of heparin, Dextran 70, acetylsalicylic acid, dipyridamole and phenylbutazone in preventing the development of the thrombus was investigated. Only heparin in high doses showed this effect.

Paracoccidioidomycosis: A comparative study of the evolutionary serologic, clinical and radiologic results for patients treated with ketoconazole or amphotericin B plus sulfonamides

A comparative study of two groups of patients with paracoccidioidomycosis was carried out with the objective of comparing the evolutionary serologic, clinical and radiologic results after 6, 12, 15 and 18 months of treatment with ketoconazole (22 patients) or amphotericin B plus sulfonamides (32 patients). The serologic data analyzed as a whole showed a tendency to sharper drops in antibody titers in the patients treated with ketoconazole. Clinically patients treated with ketoconazole fared better but the differences were not statistically significant. No statistical difference was detected between groups in terms of the results of radiologic evolution. © 1985 Martinus Nijhoff/Dr W. Junk Publishers.

Bayesian doubly optimal group sequential designs for randomized clinical trials

When conducting a randomized comparative clinical trial, ethical, scientific or economic considerations often motivate the use of interim decision rules after successive groups of patients have been treated. These decisions may pertain to the comparative efficacy or safety of the treatments under study, cost considerations, the desire to accelerate the drug evaluation process, or the likelihood of therapeutic benefit for future patients. At the time of each interim decision, an important question is whether patient enrollment should continue or be terminated; either due to a high probability that one treatment is superior to the other, or a low probability that the experimental treatment will ultimately prove to be superior. The use of frequentist group sequential decision rules has become routine in the conduct of phase III clinical trials. In this dissertation, we will present a new Bayesian decision-theoretic approach to the problem of designing a randomized group sequential clinical trial, focusing on two-arm trials with time-to-failure outcomes. Forward simulation is used to obtain optimal decision boundaries for each of a set of possible models. At each interim analysis, we use Bayesian model selection to adaptively choose the model having the largest posterior probability of being correct, and we then make the interim decision based on the boundaries that are optimal under the chosen model. We provide a simulation study to compare this method, which we call Bayesian Doubly Optimal Group Sequential (BDOGS), to corresponding frequentist designs using either O'Brien-Fleming (OF) or Pocock boundaries, as obtained from EaSt 2000. Our simulation results show that, over a wide variety of different cases, BDOGS either performs at least as well as both OF and Pocock, or on average provides a much smaller trial. ^

FDA Medical Library serials holdings list /

Mode of access: Internet.

BEM-ESTAR SUBJETIVO E AUTOEFICÁCIA EM DEPENDENTES DE COCAÍNA/CRACK

Este estudo teve por objetivo identificar e descrever associações entre bem-estar subjetivo, construto formado por satisfação geral com a vida e afetos positivos e negativos,e autoeficáciapara abstinência de drogas em dependentes de cocaína/crack em processo de abstinência. Utilizou, para avaliar as variáveis, as Escalas de Afetos Positivos e Negativos, de Satisfação Geral com a Vida, de Autoeficácia para Abstinência de Drogas, de Avaliação para Mudança da Universidade de Rhode Island e um questionário de dados sócio-demográficos e socioculturais. Participaram 70 homens, dependentes de cocaína/crack, jovens e de baixa escolaridade.Eram pessoas de rendimentos de até três salários mínimos (63%), que foram internadas mais de uma vez (65%), autodeclaradas abstinentes no momento da coleta dos dados. Os participantes possuíam níveis médiosde autoeficácia para abstinência de drogas, níveis baixos de bem-estar subjetivo, e estavam satisfeitos com suas vidas. Cálculos de correlação de Pearson revelaram que não há associação entre bem-estar subjetivoe autoeficácia para abstinência de drogas, entre prontidão para mudança no consumo de drogas e bem-estar subjetivo, nem entre prontidão para mudança no consumo de drogas eautoeficácia para abstinência de drogas. Resultados de análise de variância revelaram que não houve diferençasnos níveis de bem-estar subjetivo entreos diferentes os agrupamentos de prontidão para mudanças nem entre as médias de autoeficácia para abstinência de drogas entre os diferentes agrupamentos de prontidão para mudanças no consumo de drogas. A discussão abordou os resultados diante do fato de a internação dos participantes ter sido involuntária ou voluntária, do tempo de internação, do seu estágio de prontidão para mudar seu comportamento de consumo de drogas e das características de seu grupo de abstinência diante da literatura da área. Finalmente, apontou, em conclusão, limitações e agenda de pesquisa futura.

Heat Shock Protein 90 as a Drug Target against Protozoan Infections Biochemical characterization of HSP90 From plasmodium falciparum and trypanosoma evansi and evaluation of its inhibitor as a candidate drug

Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.

Preclinical evaluation of proteasome inhibition for the treatment of prostate cancer

Prostatic carcinoma is the most prevalent cancer detected in men. Bortezomib is the first proteasome inhibitor to undergo clinical trials for several forms of cancer. Although we know this class of agent preferentially kills cancer cells, our knowledge of proteasome inhibition mechanisms of induced death is far from complete. We investigated the effects of bortezomib on the LNCaP-Pro5 (Pro5) and PC-3-Pro4 (Pro4) human prostatic adenocarcinoma cells lines. We showed a reduction in proliferation and an increase in DNA fragmentation, caspase 3 activity, and cell surface phosphatidyl serine exposure. The bortezomib-treated tumors from both cell lines were dramatically reduced, and apoptosis was induced. There was also a reduction in proliferation in the treated tumors from both cells lines. We looked at changes in the levels of the proangiogenic factors VEGF, IL-8 and bFGF in vitro and in vivo. Although there was a reduction in the levels of VEGF produced by the Pro5 cell line and tumor due to bortezomib, no similar observations were made for the other angiogenic factors or in the Pro4 cells. We investigated the effects of bortezomib on p53 in the Pro5 cell line. Bortezomib induced strong stabilization of p53. It did not promote phosphorylation on serines 15 and 24 and p53 remained bound to its inhibitor, mdm2. Nonetheless, confocal microscopy revealed that bortezomib stimulated p53 translocation to the nucleus and enhanced p53 DNA binding, accumulation of p53-dependant transcripts, and activation of a p53-responsive reporter gene. Furthermore, stable transfectants of LNCaP-Pro5 expressing the p53 inhibitor, HPV-E6, displayed reduced bortezomib-induced p53 activation and cell death. Our data shows bortezomib to induce antitumor effects in the human Pro4 and Pro5 prostatic adenocarcinoma cell lines by the direct induction of apoptosis. The drug also causes a reduction in cell proliferation and mean vessel density while modulating the secretion of proangiogenic factors. Although we show that proteasome inhibition stimulates p53 activation via a novel mechanism in Pro5 cells, it is also toxic to p53 null cells as is seen in the Pro4 line. ^

Drug law enforcement : a review of the evaluation literature

This article describes the results of a systematic review of drug law enforcement evaluations. The authors describe the search procedures and document the results in five main categories: international/national interventions (e.g., interdiction and drug seizure), reactive/ directed interventions (e.g., crackdowns, raids, buy-busts, saturation patrol, etc.), proactive/ partnership interventions (e.g., third-party policing, problem-oriented policing, community policing, drug nuisance abatement, etc.), individualized interventions (e.g., arrest referral and diversion), or interventions that used a combination of reactive/directed and proactive/ partnership strategies. Results indicate that proactive interventions involving partnerships between the police and third parties and/or community entities appear to be more effective at reducing both drug and nondrug problems in drug problem places than are reactive/ directed approaches. But the general quality of research in drug law enforcement is poor, the range of interventions that have been evaluated is limited, and more high-quality research is needed across a greater variety of drug interventions.