Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer

Background: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.Methods: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.Results: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.Conclusions: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing

Risk classification in an emergency room: agreement level between a Brazilian institutional and the Manchester Protocol

The aim of this study was to assess the level of agreement between an institutional protocol and the Manchester protocol for the risk assessment of patients attended in an emergency room of a public hospital in Belo Horizonte - MG - Brazil. This is a descriptive and comparative study, in which 382 patients' reports were evaluated and the risk was classified, using the institutional protocol and the Manchester protocol. Rates were calculated through weighted and unweighted kappa, in order to determine the level of agreement between the protocols. The results showed that the correlation between the protocols is average when considering that classification errors occurred between neighboring colors (kappa=0.48), and good when considering that classification errors occurred between extreme colors (kappa=0.61). The Manchester protocol increased the patients' level of priority of patients and has been considered more inclusive.Este estudio tuvo por objetivo verificar el grado de concordancia entre un protocolo institucional y el protocolo de Manchester para la clasificación de riesgo de pacientes atendidos en primeros auxilios de un hospital público de Belo Horizonte - MG - Brasil. Se trata de estudio descriptivo comparativo en el cual 382 fichas fueron evaluadas y, realizada la clasificación de riesgo utilizando los protocolos mencionados encima, a partir del registro realizado por los enfermeros. Índices kappa ponderado y no ponderado fueron calculados para determinar el grado de concordancia entre los protocolos. Los resultados mostraron que la concordancia entre los protocolos es media, cuando considerados los errores de clasificación ocurridos entre colores vecinos (kappa=0,48) y buena, cuando considerados los errores de clasificación ocurridos entre colores extremos (kappa=0,61). Se concluye que el protocolo de Manchester aumentó el nivel de prioridad de los pacientes, demostrando ser un protocolo que incluye más.Este estudo teve por objetivo verificar o grau de concordância entre um protocolo institucional e o protocolo de Manchester, para a classificação de risco de pacientes atendidos no pronto-socorro de um hospital público de Belo Horizonte, MG, Brasil. Trata-se de estudo descritivo comparativo, no qual 382 prontuários foram avaliados e realizada a classificação de risco, utilizando os protocolos mencionados acima, a partir do registro realizado pelos enfermeiros. Índices Kappa ponderado e não ponderado foram calculados para determinar o grau de concordância entre os protocolos. Os resultados mostraram que a concordância entre os protocolos é média, quando considerados os erros de classificação, ocorridos entre cores vizinhas (Kappa=0,48) e boa, quando considerados os erros de classificação, ocorridos entre cores extremas (Kappa=0,61). Conclui-se que o protocolo de Manchester aumentou o nível de prioridade dos pacientes, demonstrando ser protocolo mais inclusivo

A NEW POSSIBILITY FOR SURVEILLANCE: DO WE IDENTIFY ALL CASES OF LEPTOSPIROSIS?

SUMMARY Leptospirosis is a febrile disease with a typically underestimated global incidence, especially in regions where dengue is endemic. Therefore, it is difficult to accurately determine the number of leptospirosis cases in these areas, which contributes to significant under-reporting this disease. In this study, we estimated the number of possible leptospirosis cases among dengue-like cases that were reported during 2008, 2010, and 2012 in the city of Fortaleza, northeast Brazil. Patients were evaluated for dengue and leptospirosis using immunoenzymatic tests for IgM antibodies that were specific to each pathogen. Among the suspected cases of dengue that resulted as negative in laboratory tests, 10.8% (2008), 19.2% (2010), and 30.8% (2012) were confirmed to be leptospirosis. Considering the cases reported by the surveillance authority as dengue that were subsequently discarded based on the laboratory test results, we estimate that the number of actual leptospirosis cases may be 26 to 49 times higher than those diagnosed and reported by the Health Services. Furthermore, we believe that approximately 20% of dengue-like cases may be leptospirosis cases in areas where the two diseases are endemic

One-loop effective actions and higher spins

The idea we advocate in this paper is that the one-loop effective action of a free (massive) field theory coupled to external sources (via conserved currents) contains complete information about the classical dynamics of such sources. We show many explicit examples of this fact for (scalar and fermion) free field theories in various dimensions d = 3,4,5,6 coupled to (bosonic, completely symmetric) sources with a number of spins. In some cases we also provide compact formulas for any dimension. This paper is devoted to two-point correlators, so the one-loop effective action we construct contains only the quadratic terms and the relevant equations of motion for the sources we obtain are the linearized ones