Sex differences in drug- and non-drug-induced analgesia

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

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Sex Differences in Drug-Induced Arrhythmogenesis

Frontiers in Physiology ◽

10.3389/fphys.2021.708435 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mathias Peirlinck ◽

Francisco Sahli Costabal ◽

Ellen Kuhl

Keyword(s):

Sex Differences ◽

Safety Evaluation ◽

New Drugs ◽

Specific Response ◽

Drug Induced ◽

Tissue Conductivity ◽

Male And Female ◽

Drug Safety Evaluation ◽

Qt Intervals ◽

Drug Concentrations

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

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Multi-site study of an in vivo phototoxicity evaluation in Sprague-Dawley rats: skin site and sex differences in sensitivity to drug-induced phototoxicity

Fundamental Toxicological Sciences ◽

10.2131/fts.6.171 ◽

2019 ◽

Vol 6 (5) ◽

pp. 171-179 ◽

Cited By ~ 1

Author(s):

Kazuhiro Kuga ◽

Yutaka Yonezawa ◽

Hitoshi Katou

Keyword(s):

Sex Differences ◽

Sprague Dawley ◽

Drug Induced ◽

Skin Site ◽

Sprague Dawley Rats

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Unravelling Sex Differences in Drug-Induced Liver Injury

General and Applied Toxicology ◽

10.1002/9780470744307.gat226 ◽

2011 ◽

Cited By ~ 1

Author(s):

Weida Tong ◽

Qiang Shi ◽

William Salminen ◽

Minjun Chen ◽

Hong Fang ◽

...

Keyword(s):

Sex Differences ◽

Liver Injury ◽

Drug Induced ◽

Drug Induced Liver Injury

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Sex differences in drug-induced changes in ventricular repolarization

Journal of Electrocardiology ◽

10.1016/j.jelectrocard.2015.08.004 ◽

2015 ◽

Vol 48 (6) ◽

pp. 1081-1087 ◽

Cited By ~ 5

Author(s):

Jose Vicente ◽

Lars Johannesen ◽

Jay W. Mason ◽

Esther Pueyo ◽

Norman Stockbridge ◽

...

Keyword(s):

Sex Differences ◽

Ventricular Repolarization ◽

Drug Induced ◽

Induced Changes

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Sex differences in drug-induced rotation in two strains of rats

Brain Research ◽

10.1016/0006-8993(81)90830-1 ◽

1981 ◽

Vol 223 (1) ◽

pp. 229-234 ◽

Cited By ~ 41

Author(s):

Clifford A. Brass ◽

Stanley D. Glick

Keyword(s):

Sex Differences ◽

Drug Induced

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Diazepam-binding inhibitor/acyl-CoA-binding protein mRNA and peripheral benzodiazepine receptor mRNA in endocrine and immune tissues after prenatal diazepam exposure of male and female rats

Journal of Endocrinology ◽

10.1677/joe.0.1660163 ◽

2000 ◽

Vol 166 (1) ◽

pp. 163-171 ◽

Cited By ~ 9

Author(s):

B Burgi ◽

W Lichtensteiger ◽

M Schlumpf

Keyword(s):

Sex Differences ◽

Mrna Expression ◽

Binding Protein ◽

Benzodiazepine Receptor ◽

Female Offspring ◽

Female Rats ◽

Drug Induced ◽

Immune Organs ◽

Male And Female Rats ◽

Immune Tissues

Peripheral benzodiazepine (BDZ) receptor (PBR) and diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP) characterized as a ligand at central BDZ receptors, at PBR with involvement in the regulation of steroidogenesis, and as an intracellular acyl-CoA transporter, are both known to interact with BDZ in adult systems. We investigated their expression after prenatal exposure to BDZ. Diazepam (1.25 mg/kg per day s.c.) was administered to time-pregnant Long Evans rats from gestational day (GD) 14 to 20. Expression of mRNAs encoding for PBR and for DBI/ACBP was studied in the same animals with (33)P-labeled 60 mer oligonucleotides (oligos) by in situ hybridization at GD20, and with (32)P-labeled oligos by Northern blot in steroidogenic and immune organs at postnatal day (PN) 14 and in adult offspring. Prenatal diazepam increased DBI/ACBP mRNA expression in male fetal adrenal and in fetal and PN14 testis. Thymus exhibited increased DBI/ACBP mRNA in male fetuses and in adult female offspring, and reduced organ weight at PN14 in both sexes. In female spleen, an increase in DBI/ACBP mRNA and a decrease in PBR mRNA was seen at PN14. Apart from the finding in spleen, no drug-induced changes in PBR mRNA were observed. The effects of prenatal diazepam were superimposed on treatment-independent sex differences in DBI/ACBP mRNA and PBR mRNA expression. Our data indicate that expression of DBI/ACBP mRNA in steroidogenic and immune organs can be affected by exposure to BDZ during ontogeny, while PBR mRNA expression appears to be less sensitive. They further reveal marked sex differences in the developmental patterns of the two proteins during pre- and postpubertal ontogeny.

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