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Cutaneous and Ocular Toxicology 2015Topical medications are frequently neglected as the potential cause of systemic drug reactions. In this case report, a patient with a maculopapular eruption attributed...
Topical medications are frequently neglected as the potential cause of systemic drug reactions. In this case report, a patient with a maculopapular eruption attributed to a drug hypersensitivity reaction was submitted to skin patch tests in order to clarify the drug implicated. Incidentally, a positive reaction to cinchocaine was observed. With the ulterior confirmation of the application of an antihemorrhoidal ointment containing cinchocaine, which was omitted during the initial anamnesis, the diagnosis of systemic contact dermatitis to cinchocaine was made.
Topics: Dermatitis, Contact; Dibucaine; Female; Humans; Middle Aged; Patch Tests
PubMed: 25198408
DOI: 10.3109/15569527.2014.952375 -
PloS One 2014Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in...
Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 µM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels.
Topics: Alleles; Apnea; Base Sequence; Biocatalysis; Butyrylcholinesterase; DNA Mutational Analysis; Family Health; Female; Humans; Infant, Newborn; Isoquinolines; Kinetics; Male; Mivacurium; Molecular Dynamics Simulation; Mutation, Missense; Neuromuscular Depolarizing Agents; Pedigree; Succinylcholine
PubMed: 25054547
DOI: 10.1371/journal.pone.0101552 -
Journal of Controlled Release :... Sep 2014Lipid nanoemulsions and -suspensions are being intensively investigated as carriers for poorly water soluble drugs. The question on where model compounds or probes are...
Lipid nanoemulsions and -suspensions are being intensively investigated as carriers for poorly water soluble drugs. The question on where model compounds or probes are localized within the dispersions has been the subject of several studies. However, only little data exists for pharmaceutically relevant molecules in dispersions composed of pharmaceutically relevant excipients. In this work, the localization of drugs and drug-like substances was studied in lipid nanoemulsions and -suspensions. Conclusions about the drug localization were drawn from the relations between lipid mass, specific particle surface area and drug load in the dispersions. Additionally, the achievable drug loads of the liquid and the solid lipid particles were compared. Nanoemulsions and -suspensions comprised trimyristin as lipid matrix and poloxamer 188 as emulsifier and were prepared with different well-defined particle sizes. These pre-formed dispersions were passively loaded with either amphotericin B, curcumin, dibucaine, fenofibrate, mefenamic acid, propofol, or a porphyrin derivative. The physico-chemical properties of the particles were characterized; drug load and lipid content were quantified by UV spectroscopy and high performance liquid chromatography, respectively. For all drugs the passive loading procedure was successful in both emulsions and suspensions. Solid particles accommodate drug molecules preferably at the particle surface. Liquid particles can accommodate drugs at the particle surface as well as in the core; the distribution between the two sites is drug specific. It is also drug specific whether solid or liquid particles yield higher drug loads. As a general rule, smaller particles led to higher drug loads than larger ones. Propofol and the porphyrin derivative displayed eutectic interaction with the lipid and crystal growth after loading, respectively.
Topics: 1-Octanol; Amphotericin B; Chemistry, Pharmaceutical; Curcumin; Dibucaine; Drug Carriers; Emulsifying Agents; Emulsions; Fenofibrate; Mefenamic Acid; Nanoparticles; Particle Size; Poloxamer; Porphyrins; Propofol; Solubility; Triglycerides; Water
PubMed: 24933601
DOI: 10.1016/j.jconrel.2014.06.007