Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice

Nitrogen Pollution Is Linked to US Listed Species Declines

Nitrogen (N) pollution is increasingly recognized as a threat to biodiversity. However, our understanding of how N is affecting vulnerable species across taxa and broad spatial scales is limited. We surveyed approximately 1400 species in the continental United States listed as candidate, threatened, or endangered under the US Endangered Species Act (ESA) to assess the extent of recognized N-pollution effects on biodiversity in both terrestrial and aquatic ecosystems. We found 78 federally listed species recognized as affected by N pollution. To illustrate the complexity of tracing N impacts on listed species, we describe an interdisciplinary case study that addressed the threat of N pollution to California Bay Area serpentine grasslands. We demonstrate that N pollution has affected threatened species via multiple pathways and argue that existing legal and policy regulations can be applied to address the biodiversity consequences of N pollution in conjunction with scientific evidence tracing N impact pathways

Nitrogen Pollution Is Linked to US Listed Species Declines

Nitrogen (N) pollution is increasingly recognized as a threat to biodiversity. However, our understanding of how N is affecting vulnerable species across taxa and broad spatial scales is limited. We surveyed approximately 1400 species in the continental United States listed as candidate, threatened, or endangered under the US Endangered Species Act (ESA) to assess the extent of recognized N-pollution effects on biodiversity in both terrestrial and aquatic ecosystems. We found 78 federally listed species recognized as affected by N pollution. To illustrate the complexity of tracing N impacts on listed species, we describe an interdisciplinary case study that addressed the threat of N pollution to California Bay Area serpentine grasslands. We demonstrate that N pollution has affected threatened species via multiple pathways and argue that existing legal and policy regulations can be applied to address the biodiversity consequences of N pollution in conjunction with scientific evidence tracing N impact pathways

Biomarkers, metabonomics, and drug development: Can inborn errors of metabolism help in understanding drug toxicity?

Application of “omics” technology during drug discovery and development is rapidly evolving. This review evaluates the current status and future role of “metabonomics” as a tool in the drug development process to reduce the safety-related attrition rates and bridge the gaps between preclinical and clinical, and clinical and market. Particularly, the review looks at the knowledge gap between the pharmaceutical industry and pediatric hospitals, where metabonomics has been successfully applied to screen and treat newborn babies with inborn errors of metabolism. An attempt has been made to relate the clinical pathology associated with inborn errors of metabolism with those of drug-induced pathology. It is proposed that extending the metabonomic biomarkers used in pediatric hospitals, as “advanced clinical chemistry” for preclinical and clinical drug development, is immediately warranted for better safety assessment of drug candidates. The latest advances in mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy should help replace the traditional approaches of laboratory clinical chemistry and move the safety evaluation of drug candidates into the new millennium