Monday, November 13, 2023

Rare Diseases in the Era of High-Cost Drug Development

We are currently witnessing a remarkable era in medical innovation, marked by rapid advancements and transformative developments. Yet the medical community is often unable to tell what works and what doesn’t. As the complexity of medical treatments increases, the importance of distinguishing reliable therapies from ineffective ones becomes ever more crucial. In this context, robust data collection and sophisticated analysis are indispensable tools.
In recent years, the trend in clinical trials has shifted towards smaller studies focusing on diseases that either attract substantial health insurance reimbursements or predominantly affect affluent populations. This shift is largely driven by the expectation of high drug prices post-development. However, this leaves a significant gap in research and treatment for conditions like Metabolic Body Odor (MEBO) and "People are allergic to me" (PATM). These conditions disproportionately impact individuals who may find it challenging to achieve financial security due to the nature of their ailments.

In 2008, a community survey by pharmacist Arun Nagrath highlighted a lack of confidence in medical advice among patients. Fast forward to the present, and while medical practitioners may exhibit greater confidence, their assurance is not always underpinned by evidence. This is evident in the prescription of costly tests, which clinicians may struggle to interpret or follow up effectively.

The landscape of self-treatment is continuously evolving. Popular remedies change over time, and the effectiveness of these treatments varies widely. In 2008, probiotics and Chlorophyl/Copper Chlorophyllin products were at the forefront. However, some patients reported that their odor issues worsened after using these remedies (as indicated by the red area in the corresponding pie chart, compared to green for effectiveness and gray for uncertainty). Many patients found that perfumed products exacerbated their condition, including about half of reported deodorants, though the other half was suitable types. Remedies once popular, like Mushroom extracts such as ProM and Champex, Activated Charcoal, Baking Soda and Hydrogen Peroxide have faded from the discussion. Vitamin B2, although used by fewer than a quarter of respondents in 2008 and found effective by some, remains a favored treatment. Oldenlandia and Coconut oil were found useful by small fraction of respondents. Somebody even used Bleach to clean themselves and found it to make things worse.  Interestingly, certain drugs intended for other conditions were reported to have secondary effects on odor – beneficial in cases like Prilosec and Probathine, and detrimental with Anxiolytics, Antidepressants, and Antivirals, the latter aligning with recent findings related to the COVID-19 vaccine. Antifungals were used by a few and were never found to worsen condition. Neither did Folic acid, Zinc, Calcium and Magnesium.  There were cases when digestive enzymes, contraceptives, and baking soda treatments made things worse. 

Interest in resveratrol, a compound present in red wine, reached its zenith in the late 2000s and early 2010s. During this period, the MEBO community extensively used and promoted this compound. In the mid-2010s, DMB became a focal point of discussion for many, while Fluxovas entered the scene and began to be mentioned starting in 2020.

While the popularity of probiotics endures, there is a noticeable shift towards personalization. Individuals are increasingly acknowledging the significance of identifying probiotic strains that harmonize with their unique physiology and health objectives. Our microbiome study unveiled that individuals with higher cutaneous bacteria (and total bacteria) abundances in the gut benefited from reducing microbial diversity and overall bacterial counts. In contrast, those with lower abundances found advantages in increasing microbial diversity. This highlights the absence of a universal solution for probiotics.

This evolving self-treatment scenario emphasizes the pivotal role of precision medicine, considering individual genetic, environmental, and lifestyle influences for disease treatment and prevention. Conditions like TMAU, MEBO, and PATM, lacking standardized effective treatments, emphasize the pressing need for more nuanced and targeted approaches.
Precision medicine, gaining popularity, particularly in tandem with Artificial Intelligence approaches this year, marks a departure from one-size-fits-all strategies. It relies extensively on data, specifically genomic, microbiome, and metabolomic data, to tailor treatments to individual patient needs. This patient-centric approach promises to revolutionize treatment strategies, especially for those with previously under-researched and underserved medical conditions.

MEBO's causes remain largely unknown, and without clear diagnostic criteria, it is often referred to as idiopathic malodor. This uncertainty mirrors the earlier challenges in diagnosing conditions like IBS, which was once seen as a diagnosis of exclusion. Today, the importance of ruling out other diagnoses through tests is recognized.

MEBO is a poignant example of a rare condition that can severely impact an individual's ability to pursue a career and achieve financial success. This condition is not only socially debilitating but also lacks effective diagnostic and treatment options. Diagnostic studies for such rare conditions are prohibitively expensive, and the lack of effective therapies exacerbates the problem. Moreover, the large heterogeneity within the patient population makes finding a one-size-fits-all solution particularly challenging.

So, what should be done in this scenario? First and foremost, there's a need for increased funding and research attention towards rare diseases like MEBO. This could be facilitated by incentivizing pharmaceutical companies through tax breaks or grants to undertake research in less profitable but socially significant areas.

Secondly, fostering collaborations between research institutions, pharmaceutical companies, and patient advocacy groups can create a more holistic approach to understanding and treating these conditions. Such collaborations can also help in the collection of more comprehensive and diverse data, and better ways to collect itwhich is crucial given the heterogeneity of conditions like MEBO. 

Thirdly, the role of government and healthcare policymakers is critical. They can implement policies that encourage research and development in neglected areas, ensuring that the healthcare system is inclusive and caters to all, regardless of the financial implications or rarity of the condition.

Lastly, leveraging technology and innovation in medical research can also provide new avenues for diagnosis and treatment. For example, artificial intelligence and machine learning could be used to better understand complex conditions like MEBO, potentially leading to more effective and personalized treatments.

So far there’s never been any real emphasis on making clinical trials better or easier to conduct. Our goal, as a society, seems to be to manufacture more and more sports cars and to drive them faster and faster into the mud.

We hope that the healthcare industry and policymakers work together to ensure that all patients, regardless of their financial status or the rarity of their condition, have access to the treatments they need.


Gabashvili IS. The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study With Underrepresented Groups. JMIR Form Res. 2022 Nov 4;6(11):e41914. doi: 10.2196/41914. PMID: 36309347; PMCID: PMC9640199.

Gabashvili IS. Cutaneous bacteria in the gut microbiome as biomarkers of systemic malodor and People Are Allergic to Me (PATM) conditions: insights from a virtually conducted clinical trial. JMIR Dermatol. 2020 Nov 4;3(1):e10508. doi: 10.2196/10508. 

Gabashvili IS. Artificial Intelligence in Biomedicine: Systematic Review
medRxiv 2023.07.23.23292672; doi:

Friday, November 3, 2023

Cytochromes P450 and the World of Volatile Organic Compounds

Cytochrome P450, often abbreviated as CYP450 (CYP) or simply P450, is a vital group of enzymes found in the liver, and it plays a fundamental role in detoxifying the body and metabolizing various foreign compounds.

Metabolic enzymes employ different catalytic mechanisms. FMOs, for instance, directly receive electrons from nictinamide adenine dinucleotide phosphate (NADPH), while CYPs obtain their electrons via an intermediary protein known as CYP reductase. Furthermore, CYPs activate oxygen only after binding to an oxygenatable substrate, adding an extra layer of complexity to the metabolic puzzle. 

In the complex world of enzymatic metabolism, our comprehension of the comparative efficiency of different enzymes remains somewhat limited. The body's selection of which metabolic enzymes to use is governed by several factors such as substrate specificity, enzyme efficiency, temperature and the surrounding environment in the compartment where the enzyme and substrate are in, co-factors and co-enzymes,  concentration of substrates and competition for substrates. 

Cytochrome P-450 (CYP450) enzymes and Flavin-containing monooxygenases (FMOs), such as FMO3, often participate in the metabolic processes of the same compounds. For instance, substances like Nicotine, Caffeine, Tazarotenic acid, Benzydamine, and the antipsychotic drug Perazine (PER) encounter these enzymes during their metabolic journey.

FMO3, in particular, stands out for its remarkable ability to convert trimethylamine (TMA) into trimethylamine N-oxide (TMAO). However, even TMA navigates a maze of metabolic pathways and could encounter cytochromes P-450.

Similar to FMO3, genetic variations in CYP2E1, such as the SNP g.50657948 T>G, have been linked to odor (lamb odor and flavor in sheep), indicating a broader role beyond metabolism, potentially affecting odorant and pheromone clearance. Ubiquitous amino acid derived from food  - tryptophan serves as the precursor for skatole, and the conversion of tryptophan to skatole involves the action of enzymes, including CYP2E1, in a series of metabolic reactions. CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, diabetes, fasting, and obesity. 

Poor dietary choices, medications, exposure to external factors such as air pollution, cigarette smoke, radiation (e.g., UV radiation from the sun), and certain environmental toxins, inflammatory processes, whether due to infection, injury, or chronic inflammatory conditions, even normal metabolic processes can generate reactive oxygen species (ROS) as byproducts. Examples are superoxide anion (O2·-), hydrogen peroxide (H2O2), hydroxyl radical (·OH), and singlet oxygen (1O2), among others. Excessive production or impaired elimination of ROS can lead to oxidative stress.

To counteract the harmful effects of oxidative stress, the body activates the detoxification process, in which cytochrome P450 takes center stage. Cytochrome P450 catalyzes the addition of an oxygen atom to foreign compounds, making them more water-soluble. This transformation results in the formation of alcohols and, as byproducts, aldehydes. The detoxification process is a critical defense mechanism that helps the body eliminate harmful substances.

High-fat and high-protein diets have gained popularity but can have adverse effects on our health. Research has shown that these diets may induce organ damage, abnormal serum biochemical indexes, and inflammation. Interestingly, the production of malodorous gas compounds in the body because of these diets can be influenced by the interaction between the intestinal microbiota and liver cytochrome P450. 

from Zhang et al, 2022

Chemicals that alter xenobiotic metabolizing enzymes, such as CYPs, may also alter endogenous hormone levels since some of these enzymes control levels of endogenous hormones. Many of the pesticides that caused mammary gland tumors or other mammary effects also alter steroidogenesis in the H295R adrenocortical carcinoma cell line, activate nuclear receptors or CYP enzymes, or are estrogenic.

CYP family of heme monooxygenase enzymes is known for its ability to catalyze enantioselective hydroxylation and epoxidation reactions. Epoxidation reactions have been hypothesized to proceed via multiple mechanisms involving different reactive intermediates. A study of the bacterial enzyme CYP199A4 from Rhodopseudomonas palustris demonstrated a significant reduction in epoxidation activity when the D251N mutation was introduced. Remarkably, despite these mutations, the chemoselectivity and stereoselectivity of the epoxidation reaction remained intact.

Innovations in biotechnology have led to the development of specialized cytochrome P450 enzymes, such as the Cytochrome P450 BM-3 mutant (139-3). This mutant exhibits high activity towards the epoxidation of non-natural substrates, including propylene, which can be converted to propylene oxide. 

In summary, cytochrome P450 is a fascinating and essential component of our body's biochemistry, with implications that extend beyond detoxification. Understanding its functions and interactions can pave the way for advancements in both medicine and biotechnology.


Zhang T, Xie B, Liu H. High-fat and high-protein diets from different sources induce different intestinal malodorous gases and inflammation. Food Research International. 2022 Apr 1;154:110989.

Padwa A, Murphree SS. Epoxides and aziridines-a mini review. Arkivoc. 2006 Jan 1;3(6).

Störmer E, Brockmöller J, Roots I, Schmider J. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Psychopharmacology. 2000 Sep;151:312-20.

Harahap RS, Noor RR, Gunawan A. Effect of CYP2E1 gene polymorphisms on lamb odor and flavor in Indonesian sheep. InIOP Conference Series: Earth and Environmental Science 2021 Jun 1 (Vol. 788, No. 1, p. 012022). IOP Publishing.