Products and Procedures under the microscope:

Products & Procedures under the microscope

With Gaynor Wooldridge

Chair of the Medicines and Procedures Panel (MaPP) at the Institute of Chiropodists and Podiatrists

UREA – THE MAGIC SUBSTANCE?

INTRODUCTION

As podiatrists and foot health practitioners we are in a prime position to assess patients’ skin, and to also advise on the most appropriate course of action for maintaining skin integrity and the treatment of dry skin conditions. This article will have a closer look at the history of urea, it’s properties, the wider global uses, and current applications in skin care of this amazing substance.

Fig. 1

What is it?

All of our patients know what urea is, don’t they? When we recommend cream

containing urea, they all have something amusing to say! “I went to the doctor after drinking a litre of food colouring. I was diagnosed with having a case of dye urea.”

But what actually is the physiology of urea?

Urea, (molecular formula NH2CONH2, Fig. 1),

is also known as a carbamide, and is a polar, hygroscopic molecule produced by the human body. It is the chief nitrogenous end product of the metabolic breakdown of proteins in all mammals, and some fish, and occurs in their urine, blood, bile, milk and perspiration (Kerrapati and Mehendale, 2014); this urea, or ornithine, cycle, (Fig. 2), is also known as the Krebs-Henseleit cycle (Oxford dictionary, 2006). Grether-Beck et al. (2012) hypothesised that urea was not merely a passive metabolite, but also a small-molecule regulator of epidermal structure and function.

Early discoveries

In Asia, Africa and Europe the therapeutic use of urine (urotherapy) has been documented for centuries (Savica et al. 2011). Pliney the Elder discussed the use of urine for treating sores and burns, as well as skin rashes and more, in his Naturalis Historia (AD 77) It is the largest single work to have survived from the Roman Empire to modern day. The book of Proverbs (5:15), purportedly written and complied approximately 700 BC and attributed to King Solomon, advised:

Fig. 2

“...drink water from your own cistern, flowing water from your own well...” (Motola, 2016).

Urea was first isolated from urine in 1727 by Herman Boerhaave (Kyle, 2018). Rouelle is commonly cited as its discoverer in 1773 (Verzi, 2020), but Boerhaave beat him by almost 50 years. The first ground -breaking laboratory synthesis was produced by Friedrich Wohler in 1828, which followed William Prout’s extraction of pure urea from urine (1817); Prout also identified that hydrochloric acid was contained in gastric juices and classified food components as water, fats, carbohydrates and proteins (Rosenfeld, 2003).

The first use of urea in modern medicine was the topical treatment of wounds due to its proteolytic and antibacterial properties (Verzi, 2020). Robinson (1936) discussed the healing effects of urea on chronic, purulent wounds. He reported that a 2% solution of urea in water, on saturated gauze dressings which were applied to the wound, had remarkable cleansing and healing properties.

These healing effects of urea on chronic, purulent wounds were also discussed by Robinson (1936). Robinson was a senior entomologist, and he demonstrated how local granulation tissue was stimulated by allantoin; this is produced during the breakdown of uric acid produced by maggots. He also carried out successful clinical tests to show that the ammonia/urea produced by the maggots was sufficient to increase wound pH to neutral, or slightly alkaline; this promoted the healing of purulent and indolent wounds. Elmore (1938) also discussed the use of urine to improve wound healing in horses.

Modern medicine

Piquero-Casals et al. (2021) reviewed the properties of urea, and reported that it was hygroscopic, present in the epidermis as a component of the natural moisturising factor (NMF) and essential for adequate hydration and integrity of the stratum corneum. There have been multiple clinical trials in the use of urea-containing formulations. The results have all shown significant improvement in atopic dermatitis, ichthyosis, xerosis, seborrheic dermatitis and psoriasis; it has also been shown to improve skin penetration and optimise the action of topical drugs (Pan et al. 2013). Neuropathy can also refer to autonomic compromise, as well as sensory and motor dysfunction, as in anhidrosis. The Rochester Diabetic Neuropathy Study (Dyck et al. 1992) found that 6% of the study population presented with autonomic neuropathy, and that this autonomic defect was evident in the eccrine sweat glands of the skin. The study compared the efficacy of 10% and 25% urea cream on participants (male and female) with type 1 and type 2 DM. The results indicated that both creams significantly hydrated the skin, but 25% hydrated it more significantly.

Ivan Bristow (2013) also discussed the use of emollients in the care of the diabetic foot, and supported the benefits of urea and emollients in maintaining skin integrity. He also suggested how the creaming also serves as a means of daily foot inspection for people with diabetes and at-risk feet.

Until the early part of the 19th century, it was believed that the synthesis of urea required a living organism, or some part of a living organism, such as a kidney (Ramberg, 2000). In 1828, Friedrich Wöhler, as previously mentioned, challenged this view by synthesising urea in a laboratory, thus disproving the concept of Aristotle’s vitalism theory (Coulter et al. 2019). Wöhler is now known as a pioneer of organic chemistry - even though he never actually intended to make urea!

Because urea is a naturally occurring substance found on the surface of the skin, it is an active part of our natural moisturising factor (NMF), and makes up 7% of these water binding, skin substances (Fowler, 2012). Over time, urea decreases with age, trauma from harsh ingredients and environmental factors, all of which makes the skin more susceptible to dryness, aging and inflammation (Fig. 3, reproduced from clinic photographs, 2022). As podiatrists, we frequently see alterations in barrier function, often associated with several skin diseases. At a lower dose (≤ 10%), urea containing topical formulations act as a skin moisturiser, whilst higher concentrations (≥ 10%), urea based preparations exert a keratolytic action (Cellano, 2018). See Fig. 3

Other current uses

There are many varied uses of urea. It is now prepared commercially in vast amounts from liquid ammonia and liquid carbon dioxide. These two materials are combined under high pressures and elevated temperatures, to form ammonium carbamate; this then decomposes at much lower pressures to yield urea and water (Sigurdasen et al. 2018). Kumar (2013) investigated how urea can now be used as a source of electric power, as urine eating bacteria are able to create a current strong enough to power a mobile phone. In 2013, Cai et al. published their results demonstrating that stem cells harvested from reprogrammedFig. 3 into human urine were able to be neurones, and then used to grow tooth-like structures. Globally, 90% of synthetically produced urea, with production at approximately 220m tonnes/year, is now used in fertilisers and as an additive (AdBlue) for diesel fuel emissions. Demand and supply has continued to push up fertiliser prices 3-fold between 2021 and 2022 (Outlaw et al. 2022). Continued overleaf

Products & Procedures under the microscope

(continued)

The United Nations Food and Agriculture Organisation’s index of food prices is already at its highest level since 2011. China and Russia are the biggest producers of industrial urea, and they have restricted exports to ensure supply to their own farmers. An energy crunch in China has also led to fertiliser production to be slashed, and the food-grade carbon dioxide, which is a by-product of the ammonia production process, was also dramatically affected during the COVID pandemic (Nelson, 2022).

And finally…

Urea is a small, but vitally important, compound in the body. As practitioners working within foot care, we are constantly looking to improve and maintain the quality and integrity of patients’ skin. Urea plays a fundamental role in regulating keratinocyte proliferation, the skin’s barrier function and antimicrobial defence (Piquero-Casals, 2021).

The key to healthy skin must surely be hydration, and urea seems to be this ‘magic’ ingredient.

REFERENCES

Bristow, I. 2013. Emollients in the care of the diabetic foot. The Diabetic Foot Journal. Vol 16 No. 2 Cai, J et al. 2013. Regeneration of tooth-like structures from integrationfree human urine induced pluripotent stem cells. Cell Regeneration Journal volume 2 no. 1 Cellano, L. 2018. Topical urea in skincare: A review. Dermatol Therapy. Nov Coulter, I et al. 2019. Vitalism – A world view revisited: a critique of vitalism and it’s implications for integrative medicine. Integrative Medicine: A Clinicians Journal. 18(3): 60-73 Dyck, PJ et al. 1991. The Rochester Diabetic Neuropathy Study Design. Criteria for types of neuropathy, selection bias and reproducibility of neuropathic tests. Neurology Journal 41(6) Elmore, CJ. 1938. Urea for wound healing. JAMA 110(10): 758 Fowler, J. 2012. Understanding the role of natural moisturising factor in skin hydration. Practical Dermatology Grether-Beck, S et al. 2012. Urea uptake enhances barrier function and antimicrobial defence in humans by regulating epidermal gene expression. The Journal of Investigative Dermatology 132(6): 1561-1572 Kligman, A. 1957. Dermatologic uses of urea. Acta Dermato-Venereologica Korrapati, MC and Mehendale, HM. 2014. Urea. Encyclopedia of Toxicity. 3rd ed: pp 885-888 Kumar, M. 2013. From gunpowder to teeth whitener: the science behind historic uses of urine. Science Smithsonian Magazine Kyle, RA and Steensma, DP. 2018. Herman Boerhaave – Master Clinician and Humanist. Mayo Clin Proc. Nov; 93(11): 119-120 Motola, J. 2016. The history of urine as healing. The journal of Urology. Vol.195, Iss 4S

Nelson, A. 2022. CO2: will there be another carbon dioxide gas shortage in the UK, and how it could impact on supplies. National World. Outlaw, JL et al. 2022. Economic pact of higher fertiliser prices in AFPCs. Representative Crop Farms Briefing Paper 22-01 Oxford Dictionary of Biochemistry and Molecular Biology (2nd Ed). 2006. Edited by Cannock, R et al. Oxford University Press. Pan, M et al. 2013. Urea, a comprehensive review of the clinical literature. Dermatol Online Journal; 19: 20392 [PubMed] Accessed 15th February 2022 Piquero-Casals, J et al. 2021. Urea in dermatology: a review of its emollient, moisturising, keratolytic, skin barrier enhancing and antimicrobial properties. Dermatol Ther (Heielb); 11(6): 1905-1915

“It often happens in the search for new therapeutic agents that some old stand-by is overlooked, whose lustre has worn off, but which may have useful applications in moments where miracle drugs falter. In the world of topical therapy, urea is such a drug. Youthful skin with a visible glow – it’s the holy grail of skincare.”

(Kligman, 1957).

Pliney the Elder. AD77. Natural History LCL392: 50-51. Book XX. Natural Art Library. Robinson, W. 1936. Use of urea to stimulate healing in chronic, purulent wounds. The American Journal of Surgery. Vol 33, Iss 2 pp 192-197 Ramberg, PJ. 2000. The death of vitalism and the birth of organic chemistry: Wohler’s urea synthesis and the disciplinary identity of organic chemistry. Ambix 47(3): 170-95

Rosenfeld, L. 2003. William Prout: Early 19th century physician - chemist. Clinical Chemistry 49: 699-705 Savica, V et al. 2011. Urine through the centuries. Journal of Nephrology 24 Suppl 17: S123-5 Sigurdasen, JJ et al. 2018. The molecular processes of urea hydrolysis in relation to ammonia emissions from agriculture. Reviews in Environmental Science and Biotechnology 17; 241-258 Verzi, AE et al. 2020. History of urea as a dermatological agent in clinical

practice. Int J Clin Practice

FIGURES

Fig.1 National Centre for Biotechnology Information (2022). PubChem compound summary for CID 1176, Urea. Retrieved February 15 2022 from https://PubChem.ncbi.nlm.nih.gov compound/Urea

Fig.2 Krebs, H and Hanseleit, K. 1932a. Untersuchungen uber die.

Harnstoffbildung I’m Tierkorper I, Klinische Wocheschrift 11(27): 1137-1139