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Skin pigmentation may act as a “sponge” for some medications ranging from antibiotics to nicotine patches, potentially influencing the speed with which active drugs reach their intended targets, a pair of scientists report in a perspective article published in the journal Human Genomics.

There has been a growing awareness of genetic susceptibility or tolerance to medications. Redheads for example had been shown to need more inhalational anaesthetic than dark-haired individuals. The researchers argue that a sizable proportion of drugs and other compounds can bind to melanin pigments in the skin, leading to differences in how bioavailable and efficacious these drugs and other compounds are in people with varying skin tones.

“Our review paper concludes that melanin, the pigment responsible for skin colour, shows a surprising affinity for certain drug compounds,” said paper coauthor Simon Groen, an assistant professor of evolutionary systems biology at the University of California, Riverside. “Melanin’s implications for drug safety and dosing have been largely overlooked, raising alarming questions about the efficacy of standard dosing since people vary a lot in skin tones.”

According to Groen and coauthor Sophie Zaaijer, a consultant and researcher affiliated with UC Riverside who specialises in diversity, equity, and inclusion (DEI) in preclinical R&D and clinical trials, current FDA guidelines for toxicity testing fail to adequately address the impact of skin pigmentation on drug interactions.

“This oversight is particularly concerning given the push for more diverse clinical trials, as outlined in the agency’s Diversity Action Plan,” Zaaijer said. “But current early-stage drug development practices still primarily focus on drug testing in white populations of Northern European descent.”

In one example, the researchers found evidence of nicotine affinity for skin pigments, potentially affecting smoking habits across people with a variety of skin tones and raising questions about the efficacy of skin-adhered nicotine patches for smoking cessation.

“Are we inadvertently shortchanging smokers with darker skin tones if they turn to these patches in their attempts to quit?” Groen said.

Groen and Zaaijer propose utilising a new workflow involving human 3D skin models with varying pigmentation levels that could offer pharmaceutical companies an efficient method to assess drug binding properties across different skin types.

“Skin pigmentation should be considered as a factor in safety and dosing estimates,” Zaaijer said. “We stand on the brink of a transformative era in the biomedical industry, where embracing inclusivity is not just an option anymore but a necessity.” 

According to the researchers, skin pigmentation is just one example. Genetic variations among minority groups can lead to starkly different drug responses across races and ethnicities, affecting up to 20% of all medications, they said. 

“Yet, our molecular understanding of these differences remains very limited,” Zaaijer said.

For example, a study on acetaminophen – a drug that binds melanin – found no difference in total plasma levels of acetaminophen between individuals of African- and European-American ancestries. Oxidation clearance of acetaminophen did however show ancestry-based differences and was 37% lower in African–versus European-Americans, which could have been partially explained by polymorphisms in CYP2E1.

The researchers point out that a shift towards inclusive drug development is set to take place as instigated by a new law, the Food and Drug Omnibus Reform Act, enacted in 2022, which will mandate considering patient diversity in R&D and clinical trials. 

The researchers hope to activate the pharmaceutical industry and academia to start doing systematic experimental evaluations in preclinical research in relation to skin pigmentation and drug kinetics. They also encourage patients and advocacy groups to start asking about ancestry-related testing and efficacy of drugs.

Source: University of California – Riverside

Increased use of blood transfusions after major traumatic brain injury could help patients in intensive care units to regain greater functional independence and a better quality of life.

Six months after a major traumatic brain injury (TBI), patients who benefited from this approach regained more functional independence and had a better quality of life than those subjected to a more restrictive approach, even though the combined incidence of death and major disability was not significantly different between the two treatment groups.

This is the conclusion of an international research team led by Alexis Turgeon, professor at Université Laval, Canada Research Chair in Neurological Critical Care and Trauma, critical care physician and researcher at CHU de Québec-Université Laval, whose work is published today in the New England Journal of Medicine.  

“This randomized clinical trial, initiated in 2017, was carried out in 34 hospital centres in Canada, the United Kingdom, France and Brazil. Its aim was to compare two blood transfusion strategies – one so-called restrictive and the other liberal – employed to care for people hospitalized in an intensive care unit following a TBI. These approaches differ in the degree of anemia, or the minimum hemoglobin concentration that must be present in patients’ blood before a blood transfusion can be given,” explains Professor Turgeon. 

“Most patients hospitalised after a TBI suffer from anemia, defined as low haemoglobin concentration, which could reduce oxygen transport to the brain during a period when it is most vulnerable,” points out François Lauzier, also a professor at Université Laval and who co-led the study with Professor Dean Fergusson of the Ottawa Hospital Research Institute. 

The restrictive approach consists in tolerating a low haemoglobin level before giving a transfusion, while a liberal approach aims to maintain high haemoglobin levels, thus giving more blood transfusion.  

“By improving oxygen transport to the brain during the acute phase of care, it may be possible to save more nerve cells in the days following a TBI, thereby preventing additional brain damage,” says Professor Turgeon. 

To conduct the study, the research team recruited 742 critically ill patients with moderate or severe TBI and anaemia defined as a haemoglobin level of 10g/dL or less during hospitalisation. Randomly divided into two groups, these individuals were subjected to one or other of the transfusion strategies during their stay in the intensive care unit. To maintain these thresholds, the care teams administered blood transfusions whenever necessary. 

Six months after TBI, the research team assessed the level of overall recovery for each group, including neurovegetative status, dependence on activities of daily living and impairments preventing resumption of activities that had been performed prior to TBI. “The combined incidence of death and major disability was not statistically different between the two groups, but seemed favouring the liberal strategy in all analyses,” says Professor Turgeon. What’s more, those treated using the liberal approach showed a higher functional independence measure and quality of life index than those treated using the restrictive approach.  

“In light of the overall results of our study and considering the safety of current blood transfusions, the liberal strategy is probably the option that should be preferred in the acute phase of care to improve long-term prognosis following TBI,” concludes Professor Turgeon. 

Source: Université Laval

For years, Prof Bozhi Tian’s lab has been learning how to integrate the rigid, metallic and bulky world of electronics with the soft, flexible and delicate world of the body. In their latest work, published in Science, they have created a prototype for what they call “living bioelectronics”: a combination of living cells, gel, and electronics that can integrate with living tissue and treat psoriasis.

The patches are made of sensors, bacterial cells, and a gel made from starch and gelatin. Tests in mice found that the devices could continuously monitor and improve psoriasis-like symptoms, without irritating skin.

“This is a bridge from traditional bioelectronics, which incorporates living cells as part of the therapy,” said Jiuyun Shi, the co-first author of the paper and a former PhD student in Tian’s lab (now with Stanford University).

“We’re very excited because it’s been a decade and a half in the making,” said Tian.

The researchers hope the principles can also be applied to other parts of the body, such as cardiological or neural stimulation.

A third layer: cells

Pairing electronics with the human body has always been difficult. Though devices like pacemakers have improved countless lives, they have their drawbacks; electronics tend to be bulky and rigid, and can cause irritation.

But Tian’s lab specialises in uncovering the fundamental principles behind how living cells and tissue interact with synthetic materials; their previous work has included a tiny pacemaker that can be controlled with light and strong but flexible materials that could form the basis of bone implants.

In this study, they took a new approach. Typically, bioelectronics consist of the electronics themselves, plus a soft layer to make them less irritating to the body.

But Tian’s group wondered if they could add new capabilities by integrating a third component: living cells themselves. The group was intrigued with the healing properties of certain bacteria such as S. epidermidis, a microbe that naturally lives on human skin and has been shown to reduce inflammation.

They created a device with three components. The framework is a thin, flexible electronic circuit with sensors. It is overlaid with a gel created from tapioca starch and gelatin, which is ultrasoft and mimics the makeup of tissue itself. Lastly, S. epidermidis microbes are tucked into the gel.

When the device is placed on skin, the bacteria secrete compounds that reduce inflammation, and the sensor monitors the skin for signals like skin temperature and humidity. In tests with mice prone to psoriasis-like skin conditions, there was a significant reduction in symptoms.

Their initial tests ran for a week, but the researchers hope the system, which they term the ABLE platform, for Active Biointegrated Living Electronics, could be used for a half-year or more. To make the treatment more convenient, they said, the device can be freeze-dried for storage and easily rehydrated when needed.

Since the healing effects are provided by microbes, “It’s like a living drug – you don’t have to refill it,” said Saehyun Kim, the other co-first author of the paper and a current PhD student in Tian’s lab.

In addition to treating psoriasis, the scientists can envision applications such as patches to speed wound healing on patients with diabetes.

They also hope to extend the approach to other tissue types and cell types. “For example, could you create an insulin-producing device, or a device that interfaces with neurons?” said Tian. “There are many potential applications.”

Source: University of Chicago