The primary goal of a phase I clinical trial is to find the maximum tolerable dose of a treatment. In this paper, we propose a new stepwise method based on confidence bound and information incorporation to determine t...The primary goal of a phase I clinical trial is to find the maximum tolerable dose of a treatment. In this paper, we propose a new stepwise method based on confidence bound and information incorporation to determine the maximum tolerable dose among given dose levels. On the one hand, in order to avoid severe even fatal toxicity to occur and reduce the experimental subjects, the new method is executed from the lowest dose level, and then goes on in a stepwise fashion. On the other hand, in order to improve the accuracy of the recommendation, the final recommendation of the maximum tolerable dose is accomplished through the information incorporation of an additional experimental cohort at the same dose level. Furthermore, empirical simulation results show that the new method has some real advantages in comparison with the modified continual reassessment method.展开更多
Shenqi Wuweizi tablet is a Chinese medicine preparation mainly composed of Codonopsis pilosula, Astragalus membranaceus, Kadsura longipedunculata and Ziziphus jujube with many curative effects. The maximum tolerance d...Shenqi Wuweizi tablet is a Chinese medicine preparation mainly composed of Codonopsis pilosula, Astragalus membranaceus, Kadsura longipedunculata and Ziziphus jujube with many curative effects. The maximum tolerance dose of Shenqi Wuweizi tablet in mice was studied, and its acute toxicity in mice was ex- plored. The results showed that Shenqi Wuweizi tablet did not cause the death of mice at the maximum dosage and mice did not show toxic reaction, so it could be used in livestock production and clinical veterinary treatment. The study provided a theoretical basis for application of Shenqi Wuweizi tablet in livestock production and clinical veterinary medication safety.展开更多
Allowable levels for pesticide residues in foods, known as tolerances in the US and as maximum residue limits （MRLs） in much of the world, are widely yet inappropriately perceived as levels of safety concern. A nove...Allowable levels for pesticide residues in foods, known as tolerances in the US and as maximum residue limits （MRLs） in much of the world, are widely yet inappropriately perceived as levels of safety concern. A novel approach to develop scientifically defensible levels of safety concern is presented and an example to determine acute and chronic pesticide food safety standard （PFSS） levels for the fungicide captan on strawberries is provided. Using this approach, the chronic PFSS level for captan on strawberries was determined to be 2 000 mg kg-1 and the acute PFSS level was determined to be 250 mg kg-1. Both levels are far above the existing tolerance and MRLs that commonly range from 3 to 20 mg kg-~, and provide evidence that captan residues detected at levels greater than the tolerance or MRLs are not of acute or chronic health concern even though they represent violative residues. The benefits of developing the PFSS approach to serve as a companion to existing tolerances/MRLs include a greater understanding concerning the health significance, if any, from exposure to violative pesticide residues. In addition, the PFSS approach can be universally applied to all potential pesticide residues on all food commodities, can be modified by specific jurisdictions to take into account differences in food consumption practices, and can help prioritize food residue monitoring by identifying the pesticide/commodity combinations of the greatest potential food safety concern and guiding development of field level analytical methods to detect pesticide residues on prioritized pesticide/commodity combinations.展开更多
Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with s...Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.展开更多
Objective The aim of this study was to define the maximum-tolerated dose (MTD) and observe the toxicity of escalating topotecan combined whole brain radiotherapy for brain metastasis in lung cancer.
Now we extend one method into a sequence of binomial data, propose a stepwise confidence interval method for toxic-ity study, and also in our paper, two methods of constructing intervals for the risk difference are pr...Now we extend one method into a sequence of binomial data, propose a stepwise confidence interval method for toxic-ity study, and also in our paper, two methods of constructing intervals for the risk difference are proposed. The first one is based on the well-known conditional confidence intervals for odds ratio, and the other one comes from Santner“small-sample confidence intervals for the difference of two success probabilities”, and it produces exact intervals, through employing our method.展开更多
Toxicity study,especially in determining the maximum tolerated dose(MTD)in phase I clinical trial,is an important step in developing new life-saving drugs.In practice,toxicity levels may be categorised as binary grade...Toxicity study,especially in determining the maximum tolerated dose(MTD)in phase I clinical trial,is an important step in developing new life-saving drugs.In practice,toxicity levels may be categorised as binary grades,multiple grades,or in a more generalised case,continuous grades.In this study,we propose an overall MTD framework that includes all the aforementioned cases for a single toxicity outcome(response).The mechanism of determining MTD involves a function that is predetermined by user.Analytic properties of such a system are investigated and simu-lation studies are performed for various scenarios.The concept of the continual reassessment method(CRM)is also implied in the framework and Bayesian analysis,including Markov chain Monte Carlo(MCMC)methods are used in estimating the model parameters.展开更多
文摘The primary goal of a phase I clinical trial is to find the maximum tolerable dose of a treatment. In this paper, we propose a new stepwise method based on confidence bound and information incorporation to determine the maximum tolerable dose among given dose levels. On the one hand, in order to avoid severe even fatal toxicity to occur and reduce the experimental subjects, the new method is executed from the lowest dose level, and then goes on in a stepwise fashion. On the other hand, in order to improve the accuracy of the recommendation, the final recommendation of the maximum tolerable dose is accomplished through the information incorporation of an additional experimental cohort at the same dose level. Furthermore, empirical simulation results show that the new method has some real advantages in comparison with the modified continual reassessment method.
基金Supported by"Veterinary Biological Technology"Innovation Team Project of Colleges and Universities in Tianjin(TD12-5019)Teaching Reform Project of Experimental Teaching Demonstration Center at Tianjin Agricultural University(2015SY102)+2 种基金Innovative Team Training Program Fund of Colleges and Universities in Tianjin(TNTD2015015)Science and Technology Development Fund of Tianjin Agricultural University(2013N09)Innovative Entre-preneurial Training Program of College Students(201510061166)
文摘Shenqi Wuweizi tablet is a Chinese medicine preparation mainly composed of Codonopsis pilosula, Astragalus membranaceus, Kadsura longipedunculata and Ziziphus jujube with many curative effects. The maximum tolerance dose of Shenqi Wuweizi tablet in mice was studied, and its acute toxicity in mice was ex- plored. The results showed that Shenqi Wuweizi tablet did not cause the death of mice at the maximum dosage and mice did not show toxic reaction, so it could be used in livestock production and clinical veterinary treatment. The study provided a theoretical basis for application of Shenqi Wuweizi tablet in livestock production and clinical veterinary medication safety.
基金the Chilean Government and the National Commission for Scientific and Technological Research (CONICYT) for supporting this work through the Becas Chile Scholarships
文摘Allowable levels for pesticide residues in foods, known as tolerances in the US and as maximum residue limits （MRLs） in much of the world, are widely yet inappropriately perceived as levels of safety concern. A novel approach to develop scientifically defensible levels of safety concern is presented and an example to determine acute and chronic pesticide food safety standard （PFSS） levels for the fungicide captan on strawberries is provided. Using this approach, the chronic PFSS level for captan on strawberries was determined to be 2 000 mg kg-1 and the acute PFSS level was determined to be 250 mg kg-1. Both levels are far above the existing tolerance and MRLs that commonly range from 3 to 20 mg kg-~, and provide evidence that captan residues detected at levels greater than the tolerance or MRLs are not of acute or chronic health concern even though they represent violative residues. The benefits of developing the PFSS approach to serve as a companion to existing tolerances/MRLs include a greater understanding concerning the health significance, if any, from exposure to violative pesticide residues. In addition, the PFSS approach can be universally applied to all potential pesticide residues on all food commodities, can be modified by specific jurisdictions to take into account differences in food consumption practices, and can help prioritize food residue monitoring by identifying the pesticide/commodity combinations of the greatest potential food safety concern and guiding development of field level analytical methods to detect pesticide residues on prioritized pesticide/commodity combinations.
文摘Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.
文摘Objective The aim of this study was to define the maximum-tolerated dose (MTD) and observe the toxicity of escalating topotecan combined whole brain radiotherapy for brain metastasis in lung cancer.
文摘Now we extend one method into a sequence of binomial data, propose a stepwise confidence interval method for toxic-ity study, and also in our paper, two methods of constructing intervals for the risk difference are proposed. The first one is based on the well-known conditional confidence intervals for odds ratio, and the other one comes from Santner“small-sample confidence intervals for the difference of two success probabilities”, and it produces exact intervals, through employing our method.
文摘Toxicity study,especially in determining the maximum tolerated dose(MTD)in phase I clinical trial,is an important step in developing new life-saving drugs.In practice,toxicity levels may be categorised as binary grades,multiple grades,or in a more generalised case,continuous grades.In this study,we propose an overall MTD framework that includes all the aforementioned cases for a single toxicity outcome(response).The mechanism of determining MTD involves a function that is predetermined by user.Analytic properties of such a system are investigated and simu-lation studies are performed for various scenarios.The concept of the continual reassessment method(CRM)is also implied in the framework and Bayesian analysis,including Markov chain Monte Carlo(MCMC)methods are used in estimating the model parameters.
