Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children.

BACKGROUND: Studies on the efficacy of peanut sublingual immunotherapy (SLIT) are limited. The durability of desensitization after SLIT has not been well described. OBJECTIVE: We sought to evaluate the efficacy and safety of 4-mg peanut SLIT and persistence of desensitization after SLIT discontinuation. METHODS: Challenge-proven peanut-allergic 1- to 11-year-old children were treated with open-label 4-mg peanut SLIT for 48 months. Desensitization after peanut SLIT was assessed by a 5000-mg double-blind, placebo-controlled food challenge (DBPCFC). A novel randomly assigned avoidance period of 1 to 17 weeks was followed by the DBPCFC. Skin prick test results immunoglobulin levels, basophil activation test results, TH1, TH2, and IL-10 cytokines were measured longitudinally. Safety was assessed through patient-reported home diaries. RESULTS: Fifty-four participants were enrolled and 47 (87%) completed peanut SLIT and the 48-month DBPCFC per protocol. The mean successfully consumed dose (SCD) during the DBPCFC increased from 48 to 2723 mg of peanut protein after SLIT (P < .0001), with 70% achieving clinically significant desensitization (SCD > 800 mg) and 36% achieving full desensitization (SCD = 5000 mg). Modeled median time to loss of clinically significant desensitization was 22 weeks. Peanut skin prick test; peanut-specific IgE, IgG4, and IgG4/IgE ratio; and peanut-stimulated basophil activation test, IL-4, IL-5, IL-13, IFN-γ, and IL-10 changed significantly compared with baseline, with changes seen as early as 6 months. Median rate of reaction per dose was 0.5%, with transient oropharyngeal itching being the most common, and there were no dosing symptoms requiring epinephrine. CONCLUSIONS: In this open-label, prospective study, peanut SLIT was safe and induced clinically significant desensitization in most of the children, lasting more than 17 weeks after discontinuation of therapy.

Overview of FDA Drug Approval and Labeling.

The U.S. Food and Drug Administration (FDA) regulates a variety of products, including medical, food, and tobacco products. Prior to the creation of the FDA, there were few protections to the public around the contents and sale of food and pharmaceuticals. Over time, legislation was passed and amended that ensured drugs and biologics undergo extensive review by multidisciplinary teams to provide assurance that marketed products are safe and effective for their intended use. The FDA-approved drug labeling is the primary tool for communicating essential information regarding the safe and effective use of a drug product. As such, providers should be familiar with the format of the prescribing information because it is a valuable source of information, particularly prior to prescribing a new drug for the first time. Although there are clinical circumstances in which off-label drug use may be warranted, prescribing drugs off-label involves a context of use that has not undergone the FDA's rigorous evaluation of the benefit-risk assessment.

Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo.

Anticoagulant therapeutics are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent - heparin. Herein we report the first synthesis, characterization, and performance of sulfated poly-amido-saccharides (sulPASs) as heparin mimetics. sulPASs inhibit the intrinsic pathway of coagulation, specifically FXa and FXIa, as revealed by ex vivo human plasma clotting assays and serine protease inhibition assays. sulPASs activity positively correlates with molecular weight and degree of sulfation. Importantly, sulPASs are not degraded by heparanases and are non-hemolytic. In addition, their activity is reversed by protamine sulfate, unlike small molecule anticoagulants. In an in vivo murine model, sulPASs extend clotting time in a dose dependent manner with bleeding risk comparable to heparin. These findings support continued development of synthetic anticoagulants to address the clinical risks and shortages associated with heparin.

A Boxed Warning for Montelukast: The FDA Perspective.

The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.

Friction-lowering capabilities and human subject preferences for a hydrophilic surface coating on latex substrates: implications for increasing condom usage.

Personal lubricants can increase user satisfaction with male condoms by reducing friction and yielding a slippery sensation. However, lubricants pose disadvantages of dilution in physiologic fluids and sloughing away over repeated articulations. To address these drawbacks, a latex surface modification, which becomes lubricious in the presence of physiologic fluid, has been developed and evaluated. This study assesses (i) the frictional performance of the lubricious coating compared to non-coated latex and latex lubricated by personal lubricant, (ii) the level of agreement between human-perceived slipperiness and machine-measured friction, and (iii) human preference for a hypothetical male condom containing the lubricious coating. Friction coefficient of the lubricious coating was 53% lower than that of non-coated latex and approximately equal to that afforded by personal lubricant. A touch test and survey of a small population sample (N = 33) revealed a strong correlation (R 2 = 0.83) between human-perceived slipperiness and machine-measured friction. A majority of participants (73%) expressed a preference for a condom containing the lubricious coating, agreeing that an inherently slippery condom that remained slippery for a long duration would increase their condom usage. Such a coating shows potential to be an effective strategy for decreasing friction-associated pain, increasing user satisfaction and increasing condom usage.

Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides.

Poly-amido-saccharides (PAS) are carbohydrate-based, enantiopure synthetic polymers in which sugar repeat units are joined by amide linkages. This unique and relatively rigid pyranose backbone contributes to their defined helical secondary structure and remarkable chemical properties. Glucose- (glc-) and galactose- (gal-) PAS 10-mer structures are synthesized and investigated with molecular dynamics (MD) simulations and experimental measurements. Quantum mechanical DFT energy minimization calculations, as well as experimental observables including circular dichroism, (1)H,(13)C-HSQC, and (1)H,(1)H-NOESY 2D-NMR studies, validated the all-atom simulation models produced using a modified CHARMM force field. Water radial distribution functions show distinct differences in the glc- and gal-PAS systems that correlate well with observed differences in solubility between gal-PASs and glc-PASs. The computational analysis and MD simulations are in good agreement with experimental results, validating the proposed models as reliable representations of novel glc- and gal-PASs.

Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose Lower Than That for Chronic Obstructive Pulmonary Disease.

Anticholinergic drug products are not part of the current treatment paradigm for asthma, despite their widespread availability for chronic obstructive pulmonary disease (COPD) and interest in their use for asthma. Published study results, mostly of short duration and primarily with ipratropium and tiotropium, have revealed inconsistent efficacy results. Consequently, the role of inhaled anticholinergic drugs in the treatment of asthma has been unclear. This commentary discusses and comments on data from five clinical trials in adults that were submitted by Boehringer Ingelheim to the U.S. Food and Drug Administration to support approval of tiotropium delivered by the Respimat device (Spiriva Respimat) for the treatment of asthma. These trials provided substantial evidence that supported the approval of Spiriva Respimat at a recommended dose of 2.5 µg once daily for asthma. Notably, in trials that evaluated two doses of tiotropium, 2.5 µg and 5 µg (the dose approved for COPD), pulmonary function measures for Spiriva Respimat 2.5 µg once daily were better overall than those obtained for the 5-µg once-daily dose, thus justifying selection of the lower dose for asthma. Spiriva Respimat represents the first new class of drug approved by the U.S. Food and Drug Administration for the treatment of asthma in more than a decade. The availability of Spiriva Respimat for asthma along with other novel therapies currently under development has the potential to impact asthma treatment guidelines.

Synthesis and Characterization of Poly(glyceric Acid Carbonate): A Degradable Analogue of Poly(acrylic Acid).

The synthesis and characterization of a degradable version of poly(acrylic acid), poly(glyceric acid carbonate), are reported. Specifically, atactic and isotactic poly(benzyl glycidate carbonate)s are obtained via the ring-opening copolymerization of rac-/(R)-benzyl glycidate with CO2 using a bifunctional rac-/(S,S)-cobalt salen catalyst in high carbonate linkage selectivity (>99%) and polymer/cyclic carbonate selectivity (∼90%). Atactic poly(benzyl glycidate carbonate) is an amorphous material with a T(g) (glass transition temperature) of 44 °C, while its isotactic counterpart synthesized from enantiopure epoxide and catalyst is semicrystalline with a T(m) (melting temperature) = 87 °C. Hydrogenolysis of the resultant polymers affords the poly(glyceric acid carbonate). Poly(glyceric acid carbonate) exhibits an improved cell cytotoxicity profile compared to poly(acrylic acid). Poly(glyceric acid carbonate)s also degrade remarkably fast (t(1/2) ≈ 2 weeks) compared to poly(acrylic acid). Cross-linked hydrogels prepared from poly(glyceric acid carbonate) and poly(ethylene glycol) diaziridine show significant degradation in pH 8.4 aqueous buffer solution compared to similarly prepared hydrogels from poly(acrylic acid) and poly(ethylene glycol) diaziridine.

Carboxylated glucuronic poly-amido-saccharides as protein stabilizing agents.

The synthesis of novel carbohydrate-based polymers allows the structure to be tailored at the monomer level for a specific property and expands the range of available structures beyond those found in nature. Using a controlled anionic polymerization, a new type of carbohydrate polymer is synthesized in which glucose-derived monomers are joined by an α-1,2 amide linkage to give enantiopure poly-amido-saccharides (PASs). To investigate the effect of adding ionizable carboxylic acid groups, such as those found in natural polysaccharides containing glucuronic acid, the oxidation of the primary alcohol at the C6-position of the repeat unit to a carboxylic acid is reported. TEMPO-mediated oxidation provides control over the degree of oxidation in excellent yield. Based on circular dichroism, the oxidized polymers possess an ordered helical secondary structure in aqueous solution. Finally, oxidized PASs stabilize lysozyme toward dehydration and freezing stresses better than a current, widely used protein stabilizing agent, trehalose.

Synthetic Enantiopure Carbohydrate Polymers that are Highly Soluble in Water and Noncytotoxic.

The first synthesis of poly-amido-saccharides (PASs) from a galactose(gal)-derived ß-lactam sugar monomer is reported. The polymers are prepared using a controlled anionic ring-opening polymerization and characterized by NMR, optical rotation, IR, and GPC. Galactose-derived PASs display high solubility in aqueous solutions and are noncytotoxic to HepG2, CHO, and HeLa cell lines. To evaluate whether gal-derived PASs are recognized by the gal-specific lectin present on human hepatocytes, cellular uptake of rhodamine-labeled polymers is assessed using flow cytometry and fluorescence microscopy. Based on these results, the polymers are taken into cells via endocytosis that is not dependent on the gal-specific receptor on hepatocytes. Neutral, hydrophilic polymers, such as gal-derived PASs, are desirable materials for a range of biomedical applications, such as drug delivery, surface passivation, and hydrogel formation.

Pathogenesis of food allergy in the pediatric patient.

In the US and other developed countries, food allergy is a growing epidemic in pediatric populations with a substantial impact on health-related quality of life. As such, there are great efforts underway to unravel the mechanisms of oral mucosal tolerance and to better define the factors related to host and allergen exposure that contribute to the aberrant immune response leading to sensitization and clinical food allergy. Although more research is needed to eventually develop targeted treatment and prevention strategies, this review highlights our current understanding of the pathogenesis of IgE-mediated food allergy.

Pathophysiology of food allergy.

In this article we review the pathophysiology of food allergy, which affects 4% of US children and 2% of adults, and is increasing in prevalence. Most food allergens share certain specific physicochemical characteristics that allow them to resist digestion, thus enhancing allergenicity. During allergic sensitization, these allergens are encountered by specialized dendritic cell populations in the gut, which leads to T-cell priming and the production of allergen-specific IgE production by B cells. Tissue-resident mast cells then bind IgE, and allergic reactions are elicited when mast cells are reexposed to allergen. Adjacent IgE molecules bound to the surface of the mast cell become cross-linked, causing mast cell degranulation and release of powerful vasoactive compounds that cause allergic symptoms.