Overview

1. The anatomy of the human nail
2. The organism behind nail fungus
3. How topical treatments work

1. The anatomy of the human nail

Overview

The skin is the largest organ in the body and its most important function is to provide a selectively permeable barrier to the outside environment. The outermost layer of skin is called the stratum corneum (SC), Latin for horned layer, which is a dynamic structure that functions to protect deep layers of the skin from infection and injury [1]. This layer is comprised of dense skin cells (15 layers deep) called corneocytes [2] that originate deep within the skin and migrate to the surface of the skin as they mature. Complete replacement of these cells in the epidermis takes approximately 1-2 weeks, as it takes about 24 hours to form a single layer of the SC. One of the most important structures of the SC is the nail, which is a flat, hardened covering at the tips of the fingers or toes that has evolved to function as a protectant for the tips of our digits. The nail covers and protects a part of the finger called the matrix (see below), which is a layer of skin under the nail from which all of the cells that become the nail arise [3].

Nail Structure

The nail itself is comprised of three main layers. From the outer structure in, they are the nail plate, the nail bed, and the nail matrix. The nail plate, also called the dorsal outer layer, is dense and hard, consisting of keratin [4]. The nail plate is a thin (0.25 -0.6mm for fingernails and up to 1.3mm for toenails), hard, yet slightly elastic, translucent, convex structure that is made up of approximately 25 layers of dead keratinized and flattened cells. These cells are tightly bound to one another via numerous intercellular links, membrane-coating granules and desmosomes, which are cell structures specialized for cell-to-cell adhesion [4].

The nail bed is the skin beneath the nail plate [5]. Like all skin, the nail bed is made of two types of tissues: deep dermis, (the living tissue fixed to the bone which includes capillaries and glands), and the superficial epidermis (the layer just beneath the nail plate, which moves forward with the plate). The epidermis is attached to the dermis by tiny longitudinal “grooves” known as matrix crests.

The nail matrix (sometimes called the matrix unguis, keratogenous membrane, or onychostroma) is the tissue that the nail protects [6]. This part of the nail bed rests beneath the nail and contains nerves, lymph and blood vessels. The matrix is responsible for producing cells that become the nail plate. The width and thickness of the nail plate is determined by the size, length, and thickness of the matrix, while the shape of the fingertip itself shows if the nail plate is flat, arched or hooked [6]. The nail matrix continuously produces nail. The matrix at the base of fingernails consists of the most rapidly dividing skin cells in the body, which grow four times faster than toenails at a rate of about 3mm a month. This tissue consists of rapidly proliferating skin cells that soon fill with the protein keratin. This is the protein that gives strength to the nail [7].

The nail-plate (corpus unguis) is the actual nail that we usually refer to as the “fingernail” or “toenail.” This part of the nail is made of a clear protein called keratin. Several layers of dead, flattened cells make the nail strong and able to protect the end of the finger, yet partially flexible. The nail-plate is comprised of dorsal, intermediate, and ventral layers. The dorsal outer layer is dense and hard, consisting of keratin. However, despite its hardness, this layer of the nail is only a few cells thick (approximately 0.5mm) [8]. The dorsal and ventral layers of the nail plate have the highest concentration of lipids in the nail, and affect penetrability of treatments (see below) [9]. In intermediate layer of the nail plate contains highly compressed, flattened cells, in comparison with the other two layers, which contain softer, less compressed cells [10].

The Protein Keratin: Giving Strength to Nails

Keratin refers to a family of fibrous structural proteins that give nails their hardness. Keratin is the key structural material that comprises the outer layer of human skin, hair and nails. Single pieces of keratin, or monomers, assemble into bundles to form intermediate filaments, which are tough and insoluble. These filaments are the building blocks of the nail.

Keratin filaments are comprised of keratinocytes, which are keratinized cells [11]. Keratinocytes serve many important functions, most important of which is the production of the structural protein keratin. Keratinocytes are formed deep in the skin and progresses up through the epidermis to the dorsal outer layer of the nail. During this migration, the cell is transformed right before reaching the SC into a mature keratinocyte, called a corneocyte (or squames, from the Latin word squama for scale or armor) [12].

This transformation causes the cell to change in a number of important ways. For example, the cell loses both its nucleus and cytoplasm, forms a tough outer structure called the cell envelope, expels a large amount of lipids into extracellular spaces, and aggregates large amounts of keratin inside itself. The resultant corneocyte is comprised of about 80% keratin by dry weight. By this stage the corneocyte is in reality a dead cell, as it lacks a nucleus and is no longer actively conducting biological processes. However, it now serves a structural purpose in the nail. Following maturation, this cell is shed in the normal skin cell turnover process.

2. Onychomycosis: nail fungus

Onychomycosis is a term that describes a number of different infections of keratinized tissues of the nail due to a fungus [13, 14]. A number of different fungi can cause onychomycosis, including Candida, dermatophytic molds, and nondermatophytic molds. Of these, dermatophytes are the fungi most commonly responsible for onychomycosis [13]. The most common dermatophyte species that causes onychomycosis infections is Trichophyton rubrum [15].

Onychomycosis can be picked up form the outside environment in a number of ways, but some of the most common factors that can lead to a infection include: an injury to the nail or skin near the nail, getting a manicure or pedicure with utensils that have been exposed to an infective fungi, having moist skin for a long time (for example, wearing closed-in shoes for an extended period of time), walking around in moist environments that harbor the fungi (for example, a gym locker-room) or having a nail deformity or disease. Essentially, fungi prefer warm, moist environments. Therefore, lengthy exposure of the nail to these conditions can increase one’s chances of picking up a fungal infection from the outside environment.

An onychomycosis infection begins as a small, white spot of fungi underneath the fingernail or toenail, typically in a region of the nail called the hyponychium. This is the part of the nail immediately under the nail plate but above the nail bed that is located at the tip of the finger or toe, and is the most common location for initial nail infection. The fungi responsible for causing onychomycosis reproduce and increase in numbers by making copies of itself – a process called clonal reproduction [15]. This process can happen very quickly. As the fungal infection multiplies, it can invade deeper layers of the nail, and can eventually involve virtually any part of the nail anatomy, including the matrix, nail bed or nail plate. The extent of infection can vary greatly from individual to individual.

3. How Topical Treatments Work

Topical drugs are the usual course of action of treatment of Onycomycosis because drugs can travel between cells via intercellular channels, and there exist a diverse array of topical treatments available both on the market and over the counter. Depending on the extent of the infection, these treatments must penetrate the nail and even the nail bed and matrix in order to reach the infection.

Topical treatments are treatments that are applied directly to the nail, and then soak through the nail into the nail bed and matrix. Thus, the ability of a drug to get through the nail is of utmost importance. The nail is made up of both fat-like (“lipid”) and water-like elements. Intercellular lipids are part of the barrier system of the skin; thus, it is not surprising that the stratum corneum (SC) contains a large amount of intercellular lipids. These lipids are found in extracellular space between corneocytes. It is generally accepted that these lipids play a key role in limiting the diffusion of topical onychomycosis treatments through the SC. This was a problem originally in the development of treatments for onychomycosis, as most topical fungal treatments were originally designed for non-nail application; thus, they were lipophilic and not suitable for topical application to the nail.

What are lipids? Lipids are fat molecules that have a polar head and two non-polar tails. The polarity in the head results from a molecular interaction between oppositely charged phosphate and nitrogen groups. This results in one side of the molecule being hydrophilic, or water loving, while the other side of the molecule is hydrophobic, or water hating. These molecules can bind together based on their water-hating and water-loving properties to form chains of lipids called membranes. The polar, water-soluble heads of the membrane point toward the water on the inside and outside of the cell, while the non-polar, fatty-acid tails point away from water and toward the interior of the membrane. The resulting bi-layer of lipid molecules thus contains an oily inner core. This core functions as a selective barrier that prevents water-soluble substances from moving past them.

The nail itself is comprised of approximately 7-12% water [4], and its many layers of dense, flattened keratin are considered hydrophilic (water-loving) [16, 17]. Water-soluble treatments, therefore, are much more effective as topicals than are lipid-soluble treatments, given the water-loving properties of the nail. In fact, the nail has been found to be more permeable to water than skin is [17]. Given the fact that keratin forms a hard, compressed covering over the tip of the finger, how exactly do topical treatments that are water-based get through the nail into the nail bed? There exist water-filled channels or pores spanning the membrane through which these substances diffuse.

Some exceptions to the water-fat rule do apply. For example, Vitamin E is a fat-soluble vitamin. Although it can be “water solubilized” in the lab to help its absorption through the intestinal wall, once it is absorbed into the body it would appear to behave as a fat-soluble vitamin does. Thus, the properties of some treatments must be studied carefully to determine how they will interact with the nail anatomy when applied topically, rather than orally.

REFERENCES

[1] https://en.wikipedia.org/wiki/Stratum_corneum
[2] https://en.wikipedia.org/wiki/Corneocyte
[3-ed was 12] https://en.wikipedia.org/wiki/Nail_matrix
[4] https://en.wikipedia.org/wiki/Nail_plate
[5] https://en.wikipedia.org/wiki/Nail_bed
[6] https://en.wikipedia.org/wiki/Nail_matrix
[7] https://en.wikipedia.org/wiki/Keratin
[8] https://www.nyscc.org/cosmetiscope/archive/tech1101.html
[9] https://www.ncbi.nlm.nih.gov/pubmed/10344627
[10] https://www.ijdvl.com/article.asp?issn=0378-6323;year=2012;volume=78;issue=3;spage=263;epage=270;aulast=Grover
[11] https://en.wikipedia.org/wiki/Keratinocyte
[3] K. A. WALTERS and G. L. FLYNN, Permeability characteristics of the human nail plate, International Journal of Cosmetic Science 5, 231-246 (1983)
[12] https://www.cosmeticsandtoiletries.com/research/biology/130232783.html
[13] https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002306/
[14] https://www.mayoclinic.com/health/nail-fungus/DS00084
[15] https://jcm.asm.org/content/37/11/3713.abstract
[16] https://www.anacor.com/pdf/Exp%20Opin%20%20Investig%20%20Drugs.pdf
[17] https://deepblue.lib.umich.edu/bitstream/2027.42/72442/1/j.1467-2494.1983.tb00348.x.pdf

The post The Science Behind Topical Toenail Fungus Treatments appeared first on ToenailFungusTreatments.com.

Nail fungus (onychomycosis) is the most common affliction of the nails, characterized by abnormal nail color, texture, and thickness. Nail fungus is caused by an infection of one of several possible species of fungi, with humidity, improper footwear, nail trauma, genetic predisposition, and immunosuppression considered contributing factors4. Both continuous and pulse itraconazole treatment regimens have demonstrated efficacy against nail fungus. A clinical response can be observed after several months of systemic treatment with orally administered itraconazole in over 80% of patients. Long-term remissions are observed in the majority of patients, although a small percentage of patients that have been successfully treated do ultimately relapse. Factors affecting treatment outcome include the site of infection (fingernail vs. toenail) and the species underlying the infection5,6. The efficacy of itraconazole in achieving clinical response and long-term cures of nail fungus is likely attributable to its ability to be absorbed into the nail and remain there at therapeutic levels for at least 6 months after completion of treatment5,7.

In addition to its use in the eradication of nail fungus, itraconazole has been used for treatment and prevention of systemic fungal infections in immunocompromised cancer patients8. However, recent studies have suggested that azole anti-fungal compounds may also be directly effective against certain types of cancer and prolong patient survival. Econazole kills leukemia, breast cancer, and colorectal cancer cell lines in a dose-dependent manner and slows the growth of colorectal cancer in mice9-11. Ketoconazole also suppresses the growth of colorectal cancer in mice, and potentiates the activity of nocodazole, a known chemotherapeutic agent12. Moreover, combination chemotherapy including ketoconazole increased the response length and overall survival of patients with androgen-independent prostate cancer13.
Intriguingly, accumulating evidence suggests that itraconazole may in fact be an even more potent chemotherapeutic agent than econazole or ketoconazole. Several recent studies have demonstrated that itraconazole specifically targets key molecular pathways involved in cancer. Itraconazole was shown to inhibit the mammalian target of rapamycin (mTOR) pathway, a signaling network regulating cellular growth and proliferation that is frequently activated in tumors. Inhibition of mTOR signaling by itraconazole is dependent on the aforementioned ability of itraconazole to block metabolism of lanosterol, which is also a precursor of cholesterol in humans. Proper synthesis and transport of cholesterol within the cell is required for mTOR pathway activation14.

The Hedgehog (Hh) pathway, normally involved in embryonic development and stem cell regulation, is another signaling cascade that is aberrantly activated in a variety of human tumors. Itraconazole was recently identified in an unbiased screen for small-molecule antagonists of the Hh pathway, with inhibitory activity over 10 times more potent than any other azole anti-fungal. Interestingly, unlike the mTOR pathway, the role of itraconazole in Hh pathway inhibition is not dependent on its role in cholesterol biosynthesis, but on its ability to compete with natural activators of the essential Hh pathway component Smoothened (SMO). Experiments in mouse models of medulloblastoma and basal cell carcinoma harboring activating mutations in the Hh pathway further demonstrated that itraconazole could suppress the growth of Hh-dependent tumors15.
Another key feature of tumors is their ability to induce angiogenesis, or the formation of blood vessels, to obtain their own blood supply. Itraconazole was also identified in a screen for small molecules that block proliferation of the cells that constitute the inner lining of blood vessels. As with the Hh pathway, the inhibitory activity of itraconazole was unique among all azole anti-fungals. In addition to inhibiting cell cycle progression of endothelial cells in vitro, itraconazole was shown to suppress growth factor-dependent angiogenesis in mouse models of blood vessel formation, indicating its potential use as an anti-angiogenic compound16.
Itraconazole has also been linked to regulation of cellular processes that protect against cancer. Cytokines are small molecules that serve diverse functions within the body’s immune system and during cancer progression. Certain types of cytokines that are released in response to infection and inflammation can activate immune cells capable of killing tumor cells. However, other types of cytokines that promote proliferation and survival of normal blood cells can be exploited or produced by cancer cells. Itraconazole is a modulator of cytokine activity that can both increase production of cytokines involved in host defense and lower levels of cytokines that promote leukemic cell growth17,18.
Another important component of the body’s defense against cancer is the production of antioxidants that protect tissues from the potentially cancer-inducing effects of carcinogens, mutagens, and naturally occurring free radicals. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been shown to be a direct target of itraconazole. The major role of NQO1 is the maintenance of cellular levels of antioxidants, but NQO1 also contributes to the stabilization of tumor suppressor proteins. Itraconazole treatment increases NQO1 levels, and therefore may promote both cellular detoxification and tumor suppression19.
Together, these studies suggest that itraconazole, an anti-fungal compound currently used to treat nail fungus, may also be a novel chemotherapeutic and chemoprotectant agent. Because the anti-fungal effects of itraconazole have been extensively studied for over 25 years, its safety and potential side effects are already well characterized. Excitingly, the doses of itraconazole already used to treat nail fungus and other types of systemic fungal infections result in blood serum levels well within the range needed to achieve the observed anti-cancer effects15,16. Clinical trials to determine the effect of itraconazole in treating lung cancer, skin cancer, prostate cancer, breast cancer, and leukemia are now underway20.

References

1 Drugs@FDA – FDA Approved Drug Products website https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

2 Odds FC. Intraconazole – a new oral anti-fungal agent with a very broad spectrum of activity in superficial and systemic mycoses. Journal of Dermatological Science 5(2): p. 65-72 (1993).

3 Vanden Bossche H, et al. Anti-Candida drugs – the biochemical basis for their activity. Critical Reviews in Microbiology 15(1): p. 57-72 (1987).

4 Welsh O, et al. Onychomycosis. Clinics in Dermatology 28(2): p. 151-159 (2010).

5 Gupta AK, et al. Itraconazole for the treatment of onychomycosis. International Journal of Dermatology 37(4): p. 303-308 (1998).

6 Hay RJ, et al. An evaluation of itraconazole in the management of onychomycosis. British Journal of Dermatology 119(3): p. 359-366 (1988).

7 Matthieu L, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed – an investigation in onychomycosis. Clinical and Experimental Dermatology 16(5): p. 374-376 (1991).

8 Cronin S and Chandrasekar PH. Safety of triazole anti-fungal drugs in patients with cancer. Journal of Antimicrobial Chemotherapy 65(3): p. 410-416 (2010).

9 Ho YS, et al. Molecular mechanisms of econazole-induced toxicity on human colon cancer cells: G0/G1 cell cycle arrest and caspase 8-independent apoptotic signaling pathways. Food and Chemical Toxicology 43(10): p. 1483-1495 (2005).

10 Soboloff J, et al. Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging. Experimental Hematology 30(10): p. 1219-1226 (2002).

11 Zhang Y, et al. Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death. Breast Cancer Research and Treatment 72(3): p. 265-278 (2002).

12 Wang YJ, et al. Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice. Molecular Carcinogenesis 34(4): p. 199-210 (2002).

13 Scholz M, et al. Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone. Journal of Urology 173(6) p. 1947-1952 (2005).

14 Xu J, et al. Cholesterol trafficking is required for mTOR activation in endothelial cells. Proceedings of the National Academy of Sciences 107(10): p. 4764-4769 (2010).

15 Kim J, et al. Itraconazole, a Commonly Used Anti-fungal that Inhibits Hedgehog Pathway Activity and Cancer Growth. Cancer Cell 17(4): p. 388-399 (2010).

16 Chong CR, et al. Inhibition of angiogenesis by the anti-fungal drug itraconazole. ACS Chemical Biology 2(4): p. 263-270 (2007).

17 Bruserud Ø. Effects of azoles on human acute myelogenous leukemia blasts and T lymphocytes derived from acute leukemia patients with chemotherapy-induced cytopenia. International Immunopharmacology 1(12): p. 2183-2195 (2001).

18 Inoue H, et al. Modulation of the human interleukin-12p40 response by a triazole anti-fungal derivative, itraconazole. Scandinavian Journal of Infectious Disease 36(8): p. 607-609 (2004).

19 Korashy HM, et al. Induction of the NAD(P)H:quinone oxidoreductase 1 by ketoconazole and itraconazole: a mechanism of cancer chemoprotection. Cancer Letters 258(1): p. 135-43 (2007).

20 ClinicalTrials.gov: A service of the National Institutes of Health.

https://clinicaltrials.gov/ct2/results?term=itraconazole+cancer

The post From Toenails to Tumors: Itraconazole in the Treatment of Nail Fungus and Cancer appeared first on ToenailFungusTreatments.com.