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1.
Clin Transl Sci ; 17(3): e13753, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38465519

RESUMO

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.


Assuntos
Qualidade de Vida , Sialorreia , Adulto , Criança , Humanos , Voluntários Saudáveis , Sialorreia/tratamento farmacológico , Área Sob a Curva , Soluções Oftálmicas/efeitos adversos , Derivados da Atropina , Administração Oral
2.
J Am Chem Soc ; 137(38): 12249-60, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26352795

RESUMO

Selective inhibition of α-helix-mediated protein-protein interactions (PPIs) with small organic molecules provides great potential for the discovery of chemical probes and therapeutic agents. Protein Data Bank data mining using the HippDB database indicated that (1) the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix had few orientations when interacting with the second protein and (2) the hot spot pockets of PPI complexes had different sizes, shapes, and chemical groups when interacting with the same hydrophobic projecting hot spots of α-helix. On the basis of these observations, a small organic molecule, 4'-fluoro-N-phenyl-[1,1'-biphenyl]-3-carboxamide, was designed as a generic scaffold that itself directly mimics the binding mode of the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix. Convenient decoration of this generic scaffold led to the selective disruption of α-helix-mediated PPIs. A series of small-molecule inhibitors selective for ß-catenin/B-cell lymphoma 9 (BCL9) over ß-catenin/cadherin PPIs was designed and synthesized. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This new class of inhibitors can selectively disrupt ß-catenin/BCL9 over ß-catenin/cadherin PPIs, suppress the transactivation of canonical Wnt signaling, downregulate the expression of Wnt target genes, and inhibit the growth of Wnt/ß-catenin-dependent cancer cells.


Assuntos
Desenho de Fármacos , Proteínas de Neoplasias/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , beta Catenina/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas de Neoplasias/química , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Fatores de Transcrição , beta Catenina/química
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