410,437 research outputs found
Dose calculations for [<sup>131</sup>I] <i>meta</i>-iodobenzylguanidine-induced bystander effects
No full textTargeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier - Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 - 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 - 0.75 Gy/h for UVW/NAT and 0.07 - 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 - 0.23 Gy for UVW and 0.03 - 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander dose-response profile similar to that generated by external beam gamma irradiation but with significantly greater cell death
On energy storage of Lu2O3:Tb,M (M=Hf, Ti, Nb) sintered ceramics: Glow curves, dose-response dependence, radiation hardness and self-dose effect
No full textThermoluminescent properties and energy storage characteristics of Lu2O3:Tb,M (M = Hf, Ti, Nb) sintered ceramics induced by ionizing radiation are presented and discussed. Dose-response dependence, radiation hardness and fading are studied. A linearity of the former exceeding seven orders of magnitude is confirmed for Lu2O3:Tb,Hf and Lu2O3:Tb,Nb ceramics. Lu2O3:Tb,Hf shows the best TL performance and also its fading is the lowest reaching 15% over 7 h and shows tendency to saturate. During the same period of time the Lu2O3:Tb,Ti, despite having TL at higher temperatures, losses about 25% of the stored energy and the TL signal of Lu2O3:Tb,Nb fades by almost 40% over 7 h. First order TL kinetics is confirmed for all three compositions. A self-dose effect in Lu2O3:Tb,Hf due to a natural content of the radioactive isotope (2.6%) is proved to be important for long-time reading of low doses.Accepted Author ManuscriptRST/Luminescence Material
A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: One stone for two birds?
No full textAim This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital. Methods A 1 year retrospective analysis of quality indicators of CPA (clinicians' adherence rate to CPA, pre-post rate of linezolid trough concentrations within the desired range and cost balance analysis) was conducted. Results Five hundred and forty-four CPAs were provided to clinicians during 2014 for personalizing linezolid therapy in 168 patients. Clinicians' adherence to CPAs was very high (94.7%). The pre-post rate of linezolid Cmin distribution showed a favourable impact of CPA on patient care (pre-post ratio of Cmin within the desired range + 23.4%, pre, 51.2% vs. post, 74.6%). Overall, linezolid dosage was mainly reduced (56.9% of cases), whereas dose augmentation was needed only in a minority of cases (7.7%). Cost balance analysis showed that overall 1258 standard doses of linezolid (unitary dose 600 mg) were spared for treating 168 patients with a personalized dosage for a median duration of 11 days (range 3-128 days) with a cost saving of 60038.05 €. Conclusion Active computerized advice elaborated by the clinical pharmacologist on the basis of TDM results and of patient's pathophysiological data and co-medications may be cost-effective for personalizing linezolid treatment
Immunomodulatory properties and molecular effects in inflammatory diseases of low-dose X-irradiation
No full textInflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degenerative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. During the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction, and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 and 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice
Practical considerations for optimal designs in clinical dose finding studies
No full textDetermining an adequate dose level for a drug and, more broadly, characterizing its dose response relationship, are key objectives in the clinical development of any medicinal drug. If the dose is set too high, safety and tolerability problems are likely to result, while selecting too low a dose makes it difficult to establish adequate efficacy in the confirmatory phase, possibly leading to a failed program. Hence, dose finding studies are of critical importance in drug development and need to be planned carefully. In this paper we focus on practical considerations for establishing efficient study designs to estimate target doses of interest. We consider optimal designs for both the estimation of the minimum effective dose (MED) and the dose achieving 100p% of the maximum treatment effect (EDp). These designs are compared with D-optimal designs for a given dose response model. Extensions to robust designs accounting for model uncertainty are also discussed. A case study is used to motivate and illustrate the methods from this paper. --dose finding,robust designs,model uncertainty,minimum effective dose,dose response,target dose estimation,sample size
A study of ovarian cancer patients treated with dose-intensive chemotherapy supported with peripheral blood progenitor cells mobilised by filgrastim and cyclophosphamide
No full textSummary We have shown that large numbers of haemopoietic progenitor cells are mobilised into the blood
after filgrastim [granulocyte colony-stimulating factor (G-CSF)] alone and filgrastim following cyclophosphamide
chemotherapy in previously untreated patients with ovarian cancer. These cells may be used to
provide safe and effective haemopoietic rescue following dose-intensive chemotherapy. Using filgrastim alone
(10 pg kg'-), the apheresis harvest contained a median CFU-GM count of 45 x 104 kg-' and 2 x 106 kg-
CD34+ cells. Treatment with filgrastim (5 pg kg-1) following cyclophosphamide (3 g m-2) resulted in a
harvest containing 66 x 104 kg-' CFU-GM and 2.4x 106 kg-' CD34+ cells. There was no statistically
significant difference between these two mobilising regimens. We have also demonstrated that dose-intensive
carboplatin and cyclophosphamide chemotherapy can be delivered safely to patients with ovarian cancer when
supported by peripheral blood progenitor cells and filgrastim. Carboplatin (AUC 7.5) and cyclophosphamide
(900 mg m-2) given at 3 weekly intervals with progenitor cell and growth factor support was well tolerated in
terms of haematological and systemic side-effects. Double the dose intensity of chemotherapy was delivered
compared with our standard dose regimen when the treatment was given at 3 weekly intervals. Median dose
intensity could be further escalated to 2.33 compared with our standard regimen by decreasing the interval
between treatment cycles to 2 weeks. However, at this dose intensity less than a third of patients received their
planned treatment on time. All the delays were due to thrombocytopenia
Optimal designs for dose finding studies
No full textIdentifying the "right" dose is one of the most critical and difficult steps in the clinical development process of any medicinal drug. Its importance cannot be understated: selecting too high a dose can result in unacceptable toxicity and associated safety problems, while choosing too low a dose leads to smaller chances of showing sufficient efficacy in confirmatory trials, thus reducing the chance of approval for the drug. In this paper we investigate the problem of deriving e?cient designs for the estimation of the minimum effective dose (MED) by determining the appropriate number and actual levels of the doses to be administered to patients, as well as their relative sample size allocations. More specifically, we derive local optimal designs that minimize the asymptotic variance of the MED estimate under a particular dose response model. The small sample properties of these designs are investigated via simulation, together with their sensitivity to misspeciffication of the true parameter values and of the underlying dose response model. Finally, robust optimal designs are constructed, which take into account a set of potential dose response profiles within classes of models commonly used in practice. --minimum effective dose,c-optimal design,dose response,Elfving's theorem
The Price of Anarchy in Routing Games as a Function of the Demand
No full textThe price of anarchy has become a standard measure of the efficiency of
equilibria in games. Most of the literature in this area has focused on
establishing worst-case bounds for specific classes of games, such as routing
games or more general congestion games. Recently, the price of anarchy in
routing games has been studied as a function of the traffic demand, providing
asymptotic results in light and heavy traffic. The aim of this paper is to
study the price of anarchy in nonatomic routing games in the intermediate
region of the demand. To achieve this goal, we begin by establishing some
smoothness properties of Wardrop equilibria and social optima for general
smooth costs. In the case of affine costs we show that the equilibrium is
piecewise linear, with break points at the demand levels at which the set of
active paths changes. We prove that the number of such break points is finite,
although it can be exponential in the size of the network. Exploiting a scaling
law between the equilibrium and the social optimum, we derive a similar
behavior for the optimal flows. We then prove that in any interval between
break points the price of anarchy is smooth and it is either monotone
(decreasing or increasing) over the full interval, or it decreases up to a
certain minimum point in the interior of the interval and increases afterwards.
We deduce that for affine costs the maximum of the price of anarchy can only
occur at the break points. For general costs we provide counterexamples showing
that the set of break points is not always finite.Comment: 22 pages, 7 figure
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Radiation dose estimates for radiopharmaceuticals
No full textTables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms
Optimal designs for dose-response models with restricted design spaces
No full textIn dose response studies, the dose range is often restricted due to concerns over drug toxicity and/or efficacy. We present restricted and unrestricted interval locally optimal designs with respect to a very general class of optimality criteria for estimating the underlying dose response curve. The underlying curve belongs to a diversified set of link functions suitable for the dose response studies and having a common canonical form. These include the fundamental binary response models – the logit and the probit as well as the skewed versions of these models. The results are illustrated through the re-design of a dose ranging trial conducted at the Merck Research Laboratories (Zeng and Zhu, 1997). This work is a generalization of the results of Dai and Zhu (2002) in terms of the design interval, the underlying dose response curve and the optimality criterion. --Binary response model,Dose ranging,Dose response,Link function,General Equivalence Theorem,Locally compound optimal design
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