The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.
Rationale:
Recurrent wheezing in children represents a severe public health concern. Wheezing attacks (WA), mainly associated with viral infections, lack effective preventive therapies.
Objectives:
To evaluate the efficacy and safety of mucosal sublingual immunotherapy based on whole inactivated bacteria (MV130) in preventing WA in children.
Methods:
A Phase 3 randomized, double-blind, placebo-controlled, parallel-group trial including a cohort of 120 children <3 years old with ⩾3 WA during the previous year was conducted. Children with a positive skin test to common aeroallergens in the area where the clinical trial was performed were excluded from the trial. Subjects received MV130 or placebo daily for 6 months. The primary endpoint was the number of WA within 1 year after the first dose comparing MV130 and placebo.
Measurements and Main Results:
There was a significant lower number of WA in MV130 versus the placebo group, 3.0 (interquartile range [IQR], 2.0–4.0) versus 5.0 (IQR, 3.0–7.0) (
P
< 0.001). As secondary outcomes, a decrease in the duration of WA and a reduction in symptoms and medication scores in the MV130 versus placebo group were found. No adverse events were reported related to the active treatment.
Conclusions:
Mucosal bacterial immunotherapy with MV130 shows safety and clinical efficacy against recurrent WA in children.Clinical trial registered with
www.clinicaltrials.gov
(NCT 01734811).
Single recombinant latex allergens permit the study of the pattern of sensitization to individual allergens. We aimed to quantify the IgE-response to individual latex allergens in children sensitized to latex. The study group included 31 latex-sensitized children: 26 operated at least twice, 20 of them with spina bifida; two children with one operation and three atopic non-operated children. IgE antibodies to rHev b 1, rHev b 3, rHev b 5, rHev b 6.01, rHev b 7.02 and rHev b 8, coupled to ImmunoCAPs, were measured in each serum. IgE responses to rHev b 1, rHev b 5 and rHev b 6.01 were found in 17 children each, and their mean +/- s.d. levels were 5 +/- 7.4, 16.8 +/- 14 and 10 +/- 18 kU/l, respectively. IgE responses to rHev b 3 (4 +/- 5.4 kU/l) were found in eight children. Two children had IgE to rHev b 7 (1.7 and 3.2 kU/l), and none to rHev b 8. Four sera were negative to all tested recombinant allergens. We divided the patients in three groups: sensitized only to rHev b 1, sensitized only to rHev b 5 and/or rHev b 6.01, and sensitized to both rHev b 1 and to rHev b 5 and/or rHev b 6.01. The three groups had the same profile of clinical features. Hev b 5 induces the quantitatively higher IgE responses in children with multiple surgeries sensitized to latex. Responses to Hev b 6.01 equal those of Hev b 1.
It seems that profilin is a relevant allergen for both groups of patients from a frequency point of view, but with scarce presence in natural latex extracts and raw sources, with a subsequent low IgE induction capacity.
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