Medical Bulletin 14/ October/ 2024

A pioneering clinical trial by the Indian Council of Medical Research (ICMR) has uncovered the significant role of ultra-processed and fried foods, rich in Advanced Glycation End-products (AGEs), in contributing to India’s escalating diabetes crisis. This landmark study, conducted by the Madras Diabetes Research Foundation, an ICMR Centre for Advanced Research in Diabetes, indicates that adopting low- Advanced Glycation End-products diets could be a promising strategy to mitigate diabetes risk.

The research, funded by the Department of Biotechnology and published in the International Journal of Food Sciences and Nutrition, identified high- Advanced Glycation End-products foods including red meat, french fries, bakery products, parathas, samosas, and sugary treats. Advanced Glycation End-products are harmful compounds formed through glycation, where sugars modify proteins or lipids, leading to various health complications like inflammation, oxidative stress, insulin resistance, and cellular damage.

Over 12 weeks, 38 overweight and obese participants (BMI of 23 or higher) followed either a high- Advanced Glycation End-products or low- Advanced Glycation End-products diet. Results showed that those on the low- Advanced Glycation End-products diet experienced improved insulin sensitivity and lower blood sugar levels, while participants on the high- Advanced Glycation End-products diet exhibited increased Advanced Glycation End-products levels and inflammation.

To reduce diabetes risk, researchers advocate for a low- Advanced Glycation End-products diet that includes green leafy vegetables, fruits, fish, boiled foods, and brown rice. The study emphasized that cooking methods such as frying, roasting, and grilling elevate Advanced Glycation End-products levels, whereas boiling helps keep them in check.

Dr. V Mohan, chairman of the Madras Diabetes Research Foundation, noted that obesity, physical inactivity, and consumption of unhealthy diets rich in Advanced Glycation End-products are the primary factors behind India’s diabetes epidemic.

Can Skin Tone Affect Your Meds?

Skin pigmentation may act as a “sponge” for some medications, 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.

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 color, shows a surprising affinity for certain drug compounds,” said Simon Groen, an assistant professor of evolutionary systems biology in the Institute of Integrative Genome Biology at the University of California, Riverside, and a coauthor on the paper. “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 specializes 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.

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.

Groen and Zaaijer propose utilizing 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.

“It's a monumental task, requiring clear lines of communication between academics, industry researchers, clinicians, and regulators,” Zaaijer said. “The future of medicine relies on our capacity to connect these currently isolated operational teams.”

They also encourage patients, their advocacy groups, and clinical trial participants to ask questions related to ancestry-specific drug efficacy and safety, such as, “Has this drug been tested to see if it's safe for people from different ancestral backgrounds, including mine?” Clinicians and pharmaceutical representatives should be able to provide an easy-to-understand document outlining the results of the various tests, the researchers said.

They acknowledge that in the current state of drug development this will be hard.

“In terms of risk profile testing, drugs are most often tested on one or a few human cell models that mostly come from donors of Northern European descent,” Zaaijer said. “Drugs are then tested in a rodent model. If these tests are successful, drug companies push the drug through to clinical trials. But are drugs ready to be given to a diverse patient group if they haven’t first been tested, for example, on human cell models of different ancestries? Would you bungee jump off a bridge if you know the ropes have not been tested for your weight category? Unlikely. So why is this currently acceptable with drugs?”

Groen explained that in different ancestral backgrounds certain genetic variants are more prevalent. Those variants can affect how a drug is metabolized and how it behaves in a body, he said.

Reference: Zaaijer, S., Groen, S.C. Implementing differentially pigmented skin models for predicting drug response variability across human ancestries. Hum Genomics 18, 113 (2024). https://doi.org/10.1186/s40246-024-00677-7

Gaps in Cancer Drug Access Between Developed and Developing Nations: BMJ Global Health

New cancer drugs launched each year increased from 0.5 in the 1990s to over eight in 2022 among high-income countries, whereas they increased from 0.1 to 1.5 a year among upper-middle-income countries, according to a global analysis revealing "significant" and "widening" disparities.

New drug launches remained minimal in lower-middle-income and low-income countries, it found.

Published in the British Medical Journal (BMJ) Global Health, the analysis highlighted significant disparities in both availability and timeliness of these medicines worldwide, according to researchers.

The inequities could explain the poor cancer outcomes across many countries, especially the low- and middle-income ones, where mortality-to-incidence ratios have been studied to be higher, despite overall cases being lower, the researchers, including those from The Pennsylvania State University, US, said.

The disparities are likely to worsen with low- and middle-income countries expected to bear the major brunt of the projected surge in global cancer cases in the years to come, the researchers added.

Over the study period, from 1990 to 2022, 568 new anti-cancer drugs were found to have been launched. The researchers included nearly 4,200 drug launches and regulatory approvals from across 111 countries in their analysis.

The data was taken from Pharmaprojects, a commercial database tracking global pharmaceutical research and development (R & D) activities in over 150 countries. Data from World Bank and Global Cancer Observatory was also used in the study.

Of the 568 new cancer drugs, the US saw the most launches at 345, followed by Japan and Canada at 224 and 221, respectively, the researchers found.

Over 190 of the new drugs were launched in the UK and 169 in China during 1990-2022.

Most of the new drugs were launched in the world's high-income regions such as North America, Western Europe, East Asia, and Australia, while the fewest were launched in low- and middle-income regions, including Africa and Southeast Asia, the researchers found.

Further, while over half of the new drugs became available in the past decade, 35 per cent of the 568 were available in only one country, 22 per cent in two to five countries and 43 per cent in over five countries, the team found.

"The average number of new cancer drug launches per country each year increased from 0.5 per year in the early 1990s to 8.7 per year in 2022 in high-income countries, from 0.1 to 1.5 per year in upper-middle-income countries, while remaining minimal among lower-middle-income and low-income countries," the authors wrote.

Reference: Li M, Ka D, Chen Q. Disparities in availability of new cancer drugs worldwide: 1990-2022. BMJ Glob Health. 2024 Oct 8;9(9):e015700. doi: 10.1136/bmjgh-2024-015700. PMID: 39379168.

Study Warns Against Use of AI Chatbots for Drug Information

Artificial Intelligence (AI) powered search engines and chatbots may not always provide accurate and safe information on drugs, and patients shouldn’t rely on these, warned a study. Researchers from Belgium and Germany conducted the study after finding many answers were wrong or potentially harmful.

Reference: Andrikyan W, Sametinger SM, Kosfeld F, et al Artificial intelligence-powered chatbots in search engines: a cross-sectional study on the quality and risks of drug information for patients. BMJ Quality & Safety Published Online First: 01 October 2024. doi: 10.1136/bmjqs-2024-017476

New Cancer Therapy from Indian Scientists Target Patients Resistant to Current Treatments

Scientists at the Indian Association for the Cultivation of Science (IACS), Kolkata, an autonomous institute of the Department of Science and Technology, have developed a novel therapy that could be a potential precision medicine especially for those resistant to current cancer remedies. The team identified a promising new target for cancer treatment by activating a DNA repair enzyme called TDP1, suggesting a combination therapy. To find an alternative treatment, the team probed how cancer cells repair DNA during cell division and respond to chemotherapy that targets the enzyme Top1, often leading to drug resistance.

The research published in The EMBO Journal highlights two key proteins --- Cyclin-dependent kinase 1 (CDK1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1). The study showed that cancer cells can counteract the effect of existing drugs by activating TDP1 -- a DNA repair enzyme -- allowing them to survive, said the team led by Benu Brata Das from the varsity. "By targeting both Cyclin-dependent kinase 1 and Tyrosyl-DNA Phosphodiesterase 1, we can potentially overcome resistance and improve treatment effectiveness," Das said.

The study suggests that using CDK1 inhibitors -- such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib -- alongside Top1 inhibitors could enhance cancer cell killing. The study points to a promising avenue for precision medicine in treating cancers, especially those resistant to current therapies.