The US Food and Drug Administration (FDA) regulates medical devices primarily through the law known as the Federal Food, Drug, and Cosmetic Act, as Amended (“the FD&C Act,” or “the Act”). Regulations promulgated by FDA in Title 21 of the Code of Federal Regulations (CFR) spell out the broad provisions contained in the Act.

United States food and drug administration

TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4). ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe(3+)-bound transferrin receptors, or after lysosomal degradation of ferritin-iron complexes and autophagic ingestion of iron-containing macromolecules, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe(2+) transporter known at present and it is highly expressed in erythroid precursors. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe(2+) transport protein. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe(2+) permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe(2+) at varying degrees, which correlate well with the disease severity. A comparison of TRPML1(-/- )ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe(2+) levels, an increase in intralysosomal Fe(2+) levels and an accumulation of lipofuscin-like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients.

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The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel

Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study

Pharmacologically active compounds including both legally used pharmaceuticals and illicit drugs are potent environmental contaminants. Extensive research has been undertaken over the recent years to understand their environmental fate and toxicity. The one very important phenomenon that has been overlooked by environmental researchers studying the fate of pharmacologically active compounds in the environment is their chirality. Chiral drugs can exist in the form of enantiomers, which have similar physicochemical properties but differ in their biological properties such as distribution, metabolism and excretion, as these processes (due to stereospecific interactions of enantiomers with biological systems) usually favour one enantiomer over the other. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. Furthermore, degradation of chiral drugs during wastewater treatment and in the environment can be stereoselective and can lead to chiral products of varied toxicity. The distribution of different enantiomers of the same chiral drug in the aquatic environment and biota can also be stereoselective. Biological processes can lead to stereoselective enrichment or depletion of the enantiomeric composition of chiral drugs. As a result the very same drug might reveal different activity and toxicity and this will depend on its origin and exposure to several factors governing its fate in the environment. In this critical review a discussion of the importance of chirality of pharmacologically active compounds in the environmental context is undertaken and suggestions for directions in further research are made. Several groups of chiral drugs of major environmental relevance are discussed and their pharmacological action and disposition in the body is also outlined as it is a key factor in developing a full understanding of their environmental occurrence, fate and toxicity. This review will be of interest to environmental scientists, especially those interested in issues associated with environmental contamination with pharmacologically active compounds and chiral pollutants. As the review will outline current state of knowledge on chiral drugs, it will be of value to anyone interested in the phenomenon of chirality, chiral drugs, their stereoselective disposition in the body and environmental fate (212 references).

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Pharmacologically active compounds in the environment and their chirality

Importance Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma. Objective To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma. Data Sources and Study Selection The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting β-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest. Data Extraction and Synthesis Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers. Main Outcomes and Measures Asthma exacerbations. Results The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, −6.4% [95% CI, −10.2% to −2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, −2.8% [95% CI, −5.2% to −0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, −12.0% [95% CI, −22.5% to −1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, −23.2% [95% CI, −33.6% to −12.1%]). Conclusions and Relevance In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting β-agonist) and short-acting β-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.

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Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.

Background
Venous thromboembolism (VTE) is the second most common medical complication and a cause of excess length of hospital stay. Its incidence and economic burden are expected to increase as the population ages. We reviewed the recent literature to provide updated cost estimates on VTE management.

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Review of the cost of venous thromboembolism.

Background The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment. Objective We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials. Methods A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed. Results Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting β-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements. Conclusion The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses.

https://www.jacionline.org/article/S0091-6749(15)00427-3/pdf

Magnitude of effect of asthma treatments on Asthma Quality of Life Questionnaire and Asthma Control Questionnaire scores: Systematic review and network meta-analysis

The annals of pharmacotherapy

OBJECTIVETo summarize the available evidence on the issues in health economics related to oral anticoagulation for stroke prevention in atrial fibrillation (AF) in the US.DATA SOURCESA literature review was performed using PubMed, EMBASE, Cochrane Library, and International Pharmaceutical Abstracts, as well as the websites of professional organizations.STUDY SELECTION AND DATA EXTRACTIONThe search was conducted according to a prespecified protocol, limiting articles to those published in English from 2001 to October 2012 and focused on the economics associated with AF and AF-related stroke in the US. Data from 27 studies were extracted and included in the review.DATA SYNTHESISStrokes in patients with AF are more debilitating and have higher recurrence rates and mortality compared with strokes unrelated to AF. However, data describing the long-term cost of AF-related stroke and stroke subtypes remain limited. The costs of major gastrointestinal (GI) bleeding and intracranial bleeding related to warfarin ar...

Review of Economics and Cost-Effectiveness Analyses of Anticoagulant Therapy for Stroke Prevention in Atrial Fibrillation in the US

Background: The Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) are commonly used in clinical trials to assess patient disease-specific health status and asthma control. Objectives: We investigated the magnitude of effect observed in trials of different treatments with the AQLQ and ACQ instruments. A systematic literature review identified randomised controlled trials (RCTs) reporting changes from baseline in AQLQ and/or ACQ overall scores in adult patients with uncontrolled/symptomatic asthma at baseline. Results: Fifty-five RCTs (35,863 patients) met the inclusion criteria. The mixed treatment comparison (MTC) model for the AQLQ (48 RCTs) included statistically significant (P ≤0.05) covariates for study treatment, whether inhaled corticosteroid (ICS) was administered during a run-in phase, whether study treatment was administered on top of an ICS, AQLQ instrument type, and interaction between study and background treatment (Figure). Findings for ACQ (6 RCTs) were broadly similar, but less robust because of small trial numbers. Conclusions: For both AQLQ and ACQ, the minimal important difference (MID) of 0.5 was achieved with most established asthma therapies vs. study baseline, but not for most between-groups comparisons against placebo. The magnitude of AQLQ score changes was also sensitive to trial design. Funding: This study was funded by Boehringer Ingelheim.

https://erj.ersjournals.com/content/erj/42/Suppl_57/P4972.full.pdf

Maria Fernandez

Papers

Review of the cost of venous thromboembolism.

Magnitude of effect of asthma treatments on Asthma Quality of Life Questionnaire and Asthma Control Questionnaire scores: Systematic review and network meta-analysis

The annals of pharmacotherapy

Review of Economics and Cost-Effectiveness Analyses of Anticoagulant Therapy for Stroke Prevention in Atrial Fibrillation in the US

Systematic review and meta-analysis of the magnitude of the effect on AQLQ and ACQ in asthma clinical trials