We need to start thinking about gender when prescribing drugs

Different genders respond to drugs differently. This would require a careful approach to differences, although the path towards more inclusive experimentation is proceeding slowly

(photo: Getty Images) that the next morning the risk of being involved in a car accident on the way to work was very high. Her name is zolpidem, an active ingredient in widely prescribed drugs for insomnia and no, it is no coincidence that the phrase refers to women (and not men) behind the wheel. It is in fact also thanks to episodes of reduced ability to drive in women who took the drug that a few years ago the Fda (or Food & drug administration), the US regulatory body that regulates the use of medicines, came to recommend reduce the dosage to women, after having ascertained that they metabolize it much more slowly than men.

How is it possible that all this happened after more than twenty years that the medicine was on the market? "These are the consequences of how drug testing was conducted, all focused both in the preclinical phase - that is, the laboratory and on animals - and in the clinical phase - that is, the human being - centered on a single model: the male one. ". At the latest edition of Trieste Next, Silvia De Francia, researcher at the University of Turin and expert in gender pharmacology, responds to a transversal approach in medical science that investigates the efficacy and safety profile of drugs taking into account the differences defined by sex and gender. Differences that permeate the entire history of medicine, reach up to the present day, those of the Covid-19 pandemic, and that De Francia has recently summarized in the book The medicine of differences - Stories of women, men and discrimination (Neos Edizioni).

A series of bad stories

That of zolpidem is (unfortunately) neither unique nor rare. Dwelling on even the most striking examples, we can rewind the tape back to the fifties and sixties, where the failure to include women in the evaluation of an anti-nausea drug, thalidomide, very popular at the time to counteract the disorder during pregnancy, caused a real and its own health disaster. Since its release in Europe, more than 12 thousand children were born without or with very serious limb malformations and many spontaneous abortions before it came to light which, if taken during the first trimester of pregnancy, had a teratogenic effect. "The drug had not been tested on pregnant rats before it was indicated for use on pregnant women: the tests were only conducted retrospectively," comments De Francia. Ten years earlier, it had been the case of diethylstilbestrol, a hormonal drug at the time used to prevent abortion, which however revealed serious consequences on the progeny, such as genital malformations and carcinomas.

The first report on the gender difference in pharmacology concerns the "unbalanced" effects of barbiturates in animal models and dates back to 1932. "Nonetheless, the first steps towards a reform of research and clinical practice in this perspective date back only to the end of the last century," says De Francia. We have to wait until 1993 for the FDA to include the mandatory recruitment of both genders in the guidelines for drug testing, with repercussions on new drugs put on the market since the end of the nineties. Until that time, the only reference for clinical research was the young white male, weighing 70 kilos.

Today, almost 90 years after the first evidence of this need, there is an enrollment of the female model of between 20 and 25%. "In short, equality is still a long way off", comments the researcher.

Why this gender bias

For a long time, medical science was based on the assumption that men and women, except for the characteristics related to reproduction, were the same. "Beyond this, the exclusion of women from research simplifies, and a lot, the analysis", explains De Francia: "The female organism is more complex and more difficult to manage from the point of view of the return of results ". Let's think, for example, of how it changes over time, and therefore in the different age groups, from the fertile period to the menopause, passing through pregnancy and breastfeeding, acquiring different characteristics and with the possibility of a different response to treatments in basis of the hormonal baggage of each specific moment.

"By retrospectively analyzing the drugs already in use for some time also on the female population and tested only on a male sample, we begin to notice the first adverse events, that is, unexpected reactions, already on girls who are entering the period of puberty, as if instead before, up to 8-10 years, males and females were much, much more similar ", explains De Francia:" From that moment of development the gap becomes enormous, but not only: it is clear that in many cases not only does the hormonal baggage affect the effect of the drugs but can, at the same time, be itself influenced by the administration of the drugs ".

Different organisms

In addition to hormonal variability, the male and female bodies also have significant anatomical differences: the latter has (on average) smaller organs, a different composition, a different distribution of fat and lean mass, a different liquid content. All factors that affect both pharmacokinetics (the process by which a drug is transported, absorbed and metabolized by our body) and pharmacodynamics (which instead concerns the biological and biochemical effects of drugs).

Enzymes with a role in drug metabolism can be expressed differently between men and women, as well as another front to consider is that depending on sex and gender, people have a different immune response and suffer from diseases differently. "Women have a more powerful defense system that protects them from viruses, bacteria and even cancer better than what happens in men - explains De Francia - and they tend to respond better to vaccines, developing more antibodies". The price to pay is that, on the other hand, they are much more affected by autoimmune diseases.

Inclusion at 360 degrees

To overcome the gender bias and be able to talk about inclusion and equity, it is not enough to think of eliminating the knowledge gap that characterizes research on men and women and indeed , “The need, and the urgency, to study all possible models is increasingly clear”, explains De Francia. We think of transgender people, for whom there are practically no studies, but also of the elderly or pediatric population, which are also underrepresented. "An eight-year-old child is not a less heavy adult but an individual with different hormonal characteristics and organ maturation", the researcher goes on: "Nevertheless, therapies for children are very often 'adjusted' compared to those of adults and there there are very few ad hoc studies ".

Gender, drugs and Covid-19

The pandemic, beyond the catastrophe it has brought about, has provided a great impetus to the gender approach in the clinical and pharmacological study and has been the first major global health issue where the principles of gender medicine have been taken into consideration, also because various supranational agencies have insisted on gender-disaggregated data collection. Nevertheless, there is still a long way to go.

An open front is that of drugs for the treatment of infection. The lack of approved therapies for Covid-19 makes repurposing, i.e. the reuse or repositioning of old, already approved medicines, a relevant approach. We are talking about drugs already used for other pathologies that have been investigated in recent months, such as hydroxychloroquine, anti-inflammatory, antiviral, "for which preclinical and clinical tests, including safety and pharmacokinetic profiles, have been performed in the past, but only on the male model, and that before being tested for the treatment against Covid-19 have not undergone any study with a view to gender differences ”, explains De Francia.

"Filling these gaps is an urgent question", the researcher goes on: "If in the search for solutions against Covid-19 even repurposing is conducted in such a way as to strengthen sexual neutrality with exclusion, one more time, of women or other segments of the population, the risk is to exacerbate health inequalities in care ”.


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Topics

Coronavirus Women Health therapies Covid-19 Vaccines Vaccine coronavirus globalData.fldTopic = "Coronavirus, Women, Health, Covid-19 Therapies, Vaccines, Coronavirus Vaccine"

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