Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer.

Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 microM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, CI 5-39%, s.e.P 0.079). The remissions lasted 3, 8, 11 and 11+ months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity

Mass production of Bacillus subtilis and Trichoderma viride for the control of Phyllosticta citricarpa (Teleomorph: Guignardia citricarpa).

The work was aimed at studying the production of cells and metabolites of Bacilius subtilis (ACB-69) and of Trichoderma viride conidia (ACB-14) on different substrates, since they can potentially control Phyllosticta citricarpa. Our results showed that the medium consisting of cotton meal added of hydrolized protein provided the highest yield of B. subtiiis cells (2.44 x IO9 cells/mL), after the culture had been incubated for three days. This liquid substrate also provided conditions for the bacterium to produce thermostable metabolites, in sufficient amounts to inhibit the plant pathogen's micelial growth. The production of B. subtilis under the solid fermentation system performed better on the brewers rice substrate; the number of bactéria; cells decreased as the substrate concentration increased. In general, the liquid medium yielded a higher amount of B. subtilis than the solid medium. With regard to the large scale production of T. viride, it was verified that the substrates tested had a low spore production; the best substrate among those tested (com cob + hydrolized protein) only yielded 2.17 x IO6 conidia/mL. O objetivo foi estudar a produção de células e de metabólitos de Bacillus subtilis (ACB-69) e de conídios de Trichoderma viride (ACB-14) em diferentes substratos, pois apresentam potencial para o controle de Phyllosticta citricarpa. O meio constituído de farelo de algodão acrescido de proteína hidrolisada foi o que proporcionou maior produção de células de B. subtilis (2,4 x 109 células/mL), após três dias de incubação da cultura. Esse substrato líquido também propiciou condições para que a bactéria produzisse metabólitos termoestáveis e, em quantidades suficientes para inibir o crescimento micelial do fitopatógeno. A produção de B. subtilis pelo sistema de fermentação sólida foi melhor no substrato quirera de arroz sendo que o número de células da bactéria diminuiu à medida que aumentou a concentração do substrato. De um modo geral, o meio líquido foi superior ao sólido para a produção de B. subtilis. Com relação à produção de T. viride, verificou-se que os substratos testados apresentaram baixa produção de esporos, sendo que o melhor substrato testado (sabugo de milho + proteína hidrolisada) produziu apenas 2,2 x 106 conídios/mL

Effect of tissue fit on corneal shape after transplantation

Postkeratoplasty astigmatism is now a major problem preventing visual recovery. Certain postopertive topographic characteristics are felt to be dictated by the fit of the donor corneal button in its recipient bed. Deficient tissue at the wound is predicted to contribute to the location of the steep meridian and excess tissue to the location of the flat meridian. In an eight-cat sample using our Fit Assessment Method and Photogrammetric Index Method, the authors tested the relationship between button fit in recipient bed and resulting corneal curvature at approximately 42, 161, and 289 postoperative days. Corneal symmetry improved between the first and second postoperative periods. Deficient tissue led to steepened curvature and ample tissue to flattened curvature in the first measurement period. When buttons fit poorly, deficient tissue led to steepness in the first postoperative period, but led to flattened curvature 90 deg away from the deficient tissue meridian in the second and third periods. The relationship between ample tissue and flattest postoperative curvature did not depend on the magnitude of button-bed disparity in any period. Corneal elasticity appeared to influence the way tissue disparity affected postoperative topography. Our findings support Troutman's balloon mode. When there was a large amount of uncompensated tissue disparity, the tissue deficiency exerted a force that shortened the translimbal chord. This produced both steepened curvature parallel to this chord soon after surgery and flattened curvature at 90 deg to the chord in the stable postoperative cornea

A new photogrammetric method for quantifying corneal topography

Attempts to describe normal corneal shape and to represent corneal topography by an array of discrete points have limited usefulness. A quantitative photogrammetric method that produces indices to describe corneal shape was developed. Four indices depict the departure of keratographic rings from circularity, and two indices express the trends and consistencies of all the rings from one keratograph. This photogrammetric index method (PIM) was evaluated against established measurement techniques. Values for the six indices were computed for groups (10 corneas each) of symmetrical, regularly astigmatic, and keratoconic corneas that had been defined by keratometry and clinical criteria. Predictions of the differences among groups were formulated for each index based on group descriptions and anticipated manual tracing and/or digitization error. Parametric and nonparametric tests of significance supported most predictions. The asymmetry of irregularly astigmatic keratoconic corneas, the variability of their orthogonal principal meridians, and an increasing symmetry toward their peripheries were documented clearly. The circularity of symmetrical group rings and the ellipticity of regularly astigmatic group rings were also evident. Preliminary norms are offered to illustrate the usefulness of the PIM in defining groups of corneas with the same histories and in classifying individual corneas

Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study.

INTRODUCTION: Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise. METHODS: Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3. RESULTS: Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation. CONCLUSIONS: Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation. TRIAL REGISTRATION: NCT00448383, NCT0023488

Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice

Objective. To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. Methods. ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients selfadministered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). Results. Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 < 2.6, indicating clinical remission, and 13% achieved a HAQ DI score < 0.5. The allergic adverse event rate, regardless of relationship to adalimumab, was 6.5/100-patient-years (PYs) in previously TNF antagonist-exposed patients and 4.3/100-PYs in TNF antagonist naive patients. A multiple regression analysis indicated no statistically significantly increased risk of serious infections in patients who received prior TNF antagonists compared with TNF antagonist naive patients. Conclusion. In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab

Produção de agentes de biocontrole de guignardia citricarpa, agente causal da mancha preta dos frutos cítricos.

O trabalho teve por objetivo estudar a produção de células e de metabólitos de Bacilius subtilis (ACB-69) em diferentes substratos por meio de dois sistemas de fermentação: liquida e sólida. Adicionalmente, foi estudada a produção de conídios de Trichoderma viride (ACB-14) em diversos meios sólidos com diferentes fontes de carbono e nitrogênio. Esses agentes de biocontrole apresentam potencial para o controle de Guignardia citricarpa. Os resultados mostraram que o meio constituído de farelo de algodão acrescido de proteína hidrolisada foi o que proporcionou maior produção de células bacterianas, após três dias de incubação da cultura. Tal substrato também propiciou condições para que a bactéria produzisse metabólitos termoestáveis e, em quantidades suficientes para inibir o crescimento do fitopatógeno. A produção de B. subtilis pelo sistema de fermentação sólida foi melhor no substrato quirela de arroz sendo que, o número de células da bactéria diminuiu à medida que aumentou a concentração do substrato. Com relação à produção de T. viride, verificou-se que o melhor substrato foi sabugo de milho, acrescentado de proteína hidrolizada, como fonte de nitrogênio

Isotope thermometery in nuclear multifragmentation

A systematic study of the effect of fragment$-$fragment interaction, quantum statistics, $\gamma$-feeding and collective flow is made in the extraction of the nuclear temperature from the double ratio of the isotopic yields in the statistical model of one-step (Prompt) multifragmentation. Temperature is also extracted from the isotope yield ratios generated in the sequential binary-decay model. Comparison of the thermodynamic temperature with the extracted temperatures for different isotope ratios show some anomaly in both models which is discussed in the context of experimentally measured caloric curves.Comment: uuencoded gzipped file containing 20 pages of text in REVTEX format and 12 figures (Postscript files). Physical Review C (in press