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Journal of Clinical Biochemistry and... Jul 2023This study aimed to illustrate the dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals . We...
This study aimed to illustrate the dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals . We have demonstrated that amide-type local anesthetics selectively and directly scavenge some free radicals. Three kinds of free radicals were eliminated by all the four local anesthetics examined. Mepivacaine, lidocaine, bupivacaine, and dibucaine scavenged hydroxyl radicals in dose-dependent manners. Ascorbyl free radicals were also scavenged in dose-dependent manners, and lastly singlet oxygen was scavenged in dose-dependent manners. Three other free radicals were not scavenged by all of the four local anesthetics; -butoxyl radical was scavenged by all the anesthetics examined but dibucaine, nitric oxide by mepivacaine but not by the other three, and tyrosyl radical by mepivacaine and lidocaine but not by the other two. Some free radicals (superoxide anion, -butyl peroxyl radical, DPPH) were not scavenged by any of the four local anesthetics. The local anesthetics were also shown to inhibit lipid peroxidation by TBARS assay. These results suggest that local anesthetics have antioxidant properties through their free radical scavenging activities.
PubMed: 37534092
DOI: 10.3164/jcbn.22-131 -
Science Advances Jan 2022Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus...
Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as fluoxetine and dibucaine, but how they inhibit 2C is unknown. Here, we present a crystal structure of the soluble and monomeric fragment of coxsackievirus B3 2C protein in complex with ()-fluoxetine (SFX), revealing an allosteric binding site. To study the functional consequences of SFX binding, we engineered an adenosine triphosphatase (ATPase)–competent, hexameric 2C protein. Using this system, we show that SFX, dibucaine, HBB [2-(α-hydroxybenzyl)-benzimidazole], and guanidine hydrochloride inhibit 2C ATPase activity. Moreover, cryo–electron microscopy analysis demonstrated that SFX and dibucaine lock 2C in a defined hexameric state, rationalizing their mode of inhibition. Collectively, these results provide important insights into 2C inhibition and a robust engineering strategy for structural, functional, and drug-screening analysis of 2C proteins.
PubMed: 34985963
DOI: 10.1126/sciadv.abj7615 -
Antimicrobial Agents and Chemotherapy Mar 2017The efficacy of antimicrobial drugs against , an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic...
The efficacy of antimicrobial drugs against , an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. However, inside infected macrophages, bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. Here, we describe how pH-dependent partitioning drives asymmetric antimicrobial drug distribution in infected macrophages. Specifically, weak bases with moderate activity against (fluoxetine, sertraline, and dibucaine) were shown to accumulate intracellularly due to differential permeability and relative abundance of their ionized and nonionized forms. Nonprotonatable analogs of the test compounds did not show this effect. Neutralization of acidic organelles directly with ammonium chloride or indirectly with bafilomycin A1 partially abrogated the growth restriction of these drugs. Using high-performance liquid chromatography, we quantified the degree of accumulation and reversibility upon acidic compartment neutralization in macrophages and observed that accumulation was greater in infected than in uninfected macrophages. We further demonstrate that the efficacy of a clinically used compound, clofazimine, is augmented by pH-based partitioning in a macrophage infection model. Because the parameters which govern this effect are well understood and are amenable to chemical modification, this knowledge may enable the rational development of more effective antibiotics against tuberculosis.
Topics: Ammonium Chloride; Anesthetics, Local; Antitubercular Agents; Biological Transport; Clofazimine; Dibucaine; Fluoxetine; Humans; Hydrogen-Ion Concentration; Macrolides; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Protons; Selective Serotonin Reuptake Inhibitors; Sertraline
PubMed: 28052847
DOI: 10.1128/AAC.01639-16 -
JAMA Dermatology Jan 2020Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital...
IMPORTANCE
Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital contact dermatitis and culprit allergens is limited. The last large-scale study on common, relevant allergens in patients with anogenital dermatitis was published in 2008.
OBJECTIVES
To characterize patients with anogenital dermatitis referred for patch testing by the North American Contact Dermatitis Group, to identify common allergens, and to explore sex-associated differences between anogenital dermatitis and allergens.
DESIGN, SETTING, AND PARTICIPANTS
A retrospective, cross-sectional analysis was conducted of the North American Contact Dermatitis Group database among 28 481 patients who underwent patch testing from January 1, 2005, to December 31, 2016, at outpatient referral clinics in the United States and Canada.
EXPOSURE
Patch testing for allergens.
MAIN OUTCOMES AND MEASURES
Currently relevant allergic patch test reactions in patients with anogenital dermatitis.
RESULTS
Of 28 481 patients tested during the study period, 832 patients (336 men and 496 women; mean [SD] age, 50.1 [26.5] years) had anogenital involvement and 449 patients (177 men and 272 women; mean [SD] age, 49.6 [17.4] years) had anogenital dermatitis only. Compared with those without anogenital involvement, there were significantly more male patients in the group with anogenital dermatitis (177 [39.4%] vs 8857 of 27 649 [32.0%]; relative risk, 1.37; 95% CI, 1.14-1.66; P < .001). In the group with anogenital involvement, female patients were significantly less likely than male patients to have allergic contact dermatitis as a final diagnosis (130 [47.8%] vs 107 [60.5%]; relative risk, 0.78; 95% CI, 0.64-0.94; P = .01), whereas a final diagnosis of other dermatoses (eg, lichen planus, lichen sclerosus, or lichen simplex chronicus) was more frequent for female patients than for male patients (67 [24.6%] vs 28 [15.8%]; relative risk, 1.54; 95% CI, 1.02-2.31; P = .03). Of the 449 patients in the group with anogenital involvement only, 227 (50.6%) had 1 or more relevant reaction with patch testing. Allergens that were statistically significantly more common in patients with anogenital involvement compared with those without anogenital involvement included medicaments such as dibucaine (10 of 250 patients tested [4.0%] vs 32 of 17 494 patients tested [0.2%]; relative risk, 22.74; 95% CI, 11.05-46.78; P < .001) and preservatives such as methylchloroisothiazolinone and methylisothiazolinone (30 of 449 patients tested [6.7%] vs 1143 of 27 599 patients tested [4.1%]; relative risk, 1.61; 95% CI, 1.14-2.41; P = .008). A total of 152 patients met the definition for anogenital allergic contact dermatitis, which is defined as anogenital involvement only, allergic contact dermatitis as the only diagnosis, and 1 or more positive reaction of current clinical relevance.
CONCLUSIONS AND RELEVANCE
For patients with anogenital involvement only who were referred for patch testing, male patients were more likely to have allergic contact dermatitis, whereas female patients were more likely to have other dermatoses. Common allergens or sources consisted of those likely to contact the anogenital area. For individuals with anogenital involvement suspected of having allergic contact dermatitis, reactions to preservatives, fragrances, medications (particularly topical anesthetics), and topical corticosteroids should be tested.
Topics: Administration, Cutaneous; Adult; Aged; Allergens; Anesthetics; Anus Diseases; Cosmetics; Cross-Sectional Studies; Dermatitis, Allergic Contact; Female; Genital Diseases, Female; Genital Diseases, Male; Glucocorticoids; Humans; Male; Middle Aged; North America; Patch Tests; Quality of Life; Retrospective Studies; Young Adult
PubMed: 31774454
DOI: 10.1001/jamadermatol.2019.3844 -
Molecular Pharmaceutics Jun 2023In this study, we investigated the effects of drugs on membrane function in which lipid peroxidation was inhibited by the antioxidant Trolox (TRO) in liposomes...
In this study, we investigated the effects of drugs on membrane function in which lipid peroxidation was inhibited by the antioxidant Trolox (TRO) in liposomes containing egg yolk lecithin. Local anesthetics (LAs), such as lidocaine (LID) and dibucaine (DIB), were used as model drugs. The effect of LAs on the inhibitory activity of TRO was evaluated by calculating the p from the inhibition constant calculated by curve fitting. p indicates the strength of TRO membrane protective function. p indicates the strength of LA activity. LAs inhibited lipid peroxidation in a dose-dependent manner and decreased p. The effect of DIB on p was 1.9 times more than that of LID. This result indicated that LA may improve the fluidity of the membrane, which may facilitate the migration of TRO from the membrane to the liquid phase. As a result, TRO is less likely to suppress lipid peroxidation within the lipid membrane, possibly resulting in a decrease in p. The effect of TRO on p was found to be similar in both, indicating that it did not depend on the type of the model drug. These results suggest that our developed procedure successfully quantified the effects of LAs on lipid membrane functions. We were able to obtain the characteristics of model drugs independent of TRO by simultaneously measuring and analyzing the lipid peroxidation inhibitory activities of TRO and model drugs in liposomes.
Topics: Anesthetics, Local; Liposomes; Lipid Peroxidation; Antioxidants; Dibucaine; Lidocaine; Lipids
PubMed: 37104048
DOI: 10.1021/acs.molpharmaceut.2c01053 -
Acta Anaesthesiologica Scandinavica Feb 2021Variants of butyrylcholinesterase are frequently associated with prolonged response to suxamethonium or mivacurium. Butyrylcholinesterase (BChE) can be characterized by...
INTRODUCTION
Variants of butyrylcholinesterase are frequently associated with prolonged response to suxamethonium or mivacurium. Butyrylcholinesterase (BChE) can be characterized by phenotyping and determination of genotype. Inappropriate timing of blood sampling might interfere with phenotyping methods. However, guidelines regarding delay between exposure to anaesthesia and testing are not clearly defined. In this study, the BChE activity and phenotype in an early (T1) and late (T2) phase were compared and the phenotype/genotype correlation was assessed.
METHODS
Patients with a prolonged paralysis after mivacurium or suxamethonium were selected after ethical committee approval and written consent. BChE activity was based on butyrylthiocholine hydrolysis rate and phenotyping on differential inhibition of BChE activity with dibucaine and fluoride. DNA sequencing allowed genotypic characterization.
RESULTS
We included the results of 20 patients with prolonged neuromuscular block (NMB) induced by mivacurium or suxamethonium. In these patients, BChE activity was different at T1 and T2 (2120 [1506-2733] U L and 4055 [2810-5301] U L , respectively; P = 0.0014; values are mean [95% CI]). When phenotyping was possible, phenotyping at T1 and T2 yielded identical results. Phenotyping failed to identify one new variant (p.Tyr146Cys) and the K variant in 14 of 16 patients.
CONCLUSION
Anaesthesia interfered with BChE activity, but not with phenotyping. Phenotyping can be performed on blood drawn during or immediately after recovery of mivacurium or suxamethonium to screen for clinically relevant variants of BChE. However, accurate diagnosis of BChE deficiency needs further confirmation by determination of genotype.
Topics: Apnea; Butyrylcholinesterase; Humans; Mivacurium; Neuromuscular Blockade; Succinylcholine
PubMed: 33010031
DOI: 10.1111/aas.13718 -
Journal of Pharmacy & Bioallied Sciences Jun 2021To compare and analyze the clinical adequacy of two topical anesthetic gels, Precaine (8% lidocaine + 0.8% dibucaine) and Precaine B (20% benzocaine) in children before...
AIM
To compare and analyze the clinical adequacy of two topical anesthetic gels, Precaine (8% lidocaine + 0.8% dibucaine) and Precaine B (20% benzocaine) in children before intraoral local anesthetic injections.
MATERIALS AND METHODS
This clinical study included thirty children who needed an inferior alveolar nerve block. They were divided into three groups: Group A: Precaine topical gel group, Group B: Precaine B topical gel Group, Group C: no anesthetic topical gel group (control group). These two effective topical gels were applied before giving intraoral local anesthesia, and afterward, the child's pain response was surveyed utilizing the Wong-Baker Faces Pain Rating Scale. The scores obtained were subjected to statistical analysis.
RESULTS
Intergroup comparison showed a significant mean difference between the control group and Precaine group ( > 0.05) as well as Precaine B group ( > 0.05). However, there is no significant difference obtained between Group A and Group B ( < 0.05).
CONCLUSION
It is psychologically and clinically beneficial to apply a topical anesthetic agent before injecting any intraoral anesthesia. In this study, both anesthetic gels showed a nonsignificant difference in reducing inferior alveolar injection pain, but Precaine B shows more promising results than Precaine.
PubMed: 34447172
DOI: 10.4103/jpbs.JPBS_772_20 -
Antimicrobial Agents and Chemotherapy May 2016Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We...
Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We screened the Prestwick Chemical Library, a library of approved drugs, for inhibitors of coxsackievirus B3, identified pirlindole as a potent novel inhibitor, and confirmed the inhibitory action of dibucaine, zuclopenthixol, fluoxetine, and formoterol. Upon testing of viruses of several EV species, we found that dibucaine and pirlindole inhibited EV-B and EV-D and that dibucaine also inhibited EV-A, but none of them inhibited EV-C or rhinoviruses (RVs). In contrast, formoterol inhibited all enteroviruses and rhinoviruses tested. All compounds acted through the inhibition of genome replication. Mutations in the coding sequence of the coxsackievirus B3 (CV-B3) 2C protein conferred resistance to dibucaine, pirlindole, and zuclopenthixol but not formoterol, suggesting that 2C is the target for this set of compounds. Importantly, dibucaine bound to CV-B3 protein 2C in vitro, whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.
Topics: Antiviral Agents; Carbazoles; Carrier Proteins; Clopenthixol; Dibucaine; Enterovirus; Fluoxetine; Formoterol Fumarate; HeLa Cells; Humans; Rhinovirus; Viral Nonstructural Proteins; Viral Proteins; Virus Replication
PubMed: 26856848
DOI: 10.1128/AAC.02182-15 -
Revista Brasileira de Ginecologia E... May 2021The diagnosis of genital ulcers remains a challenge in clinical practice. Lipschütz ulcer is a non-sexually transmitted rare and, probably, underdiagnosed condition,...
The diagnosis of genital ulcers remains a challenge in clinical practice. Lipschütz ulcer is a non-sexually transmitted rare and, probably, underdiagnosed condition, characterized by the sudden onset of vulvar edema along with painful necrotic ulcerations. Despite its unknown incidence, this seems to be an uncommon entity, with sparse cases reported in the literature. We report the case of an 11-year-old girl who presented at the emergency department with vulvar ulcers. She denied any sexual intercourse. The investigation excluded sexually transmitted infections, so, knowledge of different etiologies of non-venereal ulcers became essential. The differential diagnoses are extensive and include inflammatory processes, drug reactions, trauma, and malignant tumors. Lipschütz ulcer is a diagnosis of exclusion. With the presentation of this case report, the authors aim to describe the etiology, clinical course, and outcomes of this rare disease, to allow differential diagnosis of genital ulceration.
Topics: Administration, Topical; Anti-Infective Agents, Local; Child; Diagnosis, Differential; Dibucaine; Epstein-Barr Virus Infections; Female; Humans; Rare Diseases; Treatment Outcome; Ulcer; Vulvar Diseases
PubMed: 34077985
DOI: 10.1055/s-0041-1729147 -
Contact Dermatitis Feb 2018
Topics: Anesthetics, Local; Buttocks; Dermatitis, Allergic Contact; Dibucaine; Erythema; Hemorrhoids; Humans; Male; Middle Aged; Ointments; Syndrome; Tetracaine
PubMed: 29341181
DOI: 10.1111/cod.12880