Fighting with bacteria, decreasing the production of oil by the sebaceous glands, unplugging clogged follicular canals…
Why all these approaches are not effective? Maybe current paradigm of acne treatments is not completely correct? Resting mast cells are always physically located adjacent to the skin epidermis. Their role is patrolling i.e. an observation and the maintenance of security of skin barrier. Their pattern recognition molecules allow them to readily recognize and rapidly respond to bacteria, allergens and other pathogens that breach the skin barrier. However, MC itself can’t fight with pathogens, they can only send alarm signals that recruit other immune cells that will fight with the invasion.
Our working hypothesis: activated mast cells are the first chain link of the inflammation process. Novel drug that stops C. acnes proliferation and simultaneously interruptsmast cells activation is needed.
Rosacea is a chronic inflammatory skin disease that affects 16 million Americans (The National Rosacea Society, http://www.rosacea.org/).Rosacea is a mast cell–derived disease. This statement is accepted by lead dermatologists. There are several citations from this paper
“Rosacea is a complex disorder caused by immune dysfunction and neurovascular dysregulation involving many types of inflammatory cells.”
“Mast cells appear to play an intricate role in the pathophysiology of rosacea and could serve as potential targets for future therapies, according to recent study findings.”
“Once activated, the mast cells can promote the release of different mediators and have a considerable effect on the pathophysiology of diverse inflammatory diseases,” Dr. Wang et al. write.
These mediators include histamine, tryptase, and chymase, which are preformed mediators stored in granules that initiate the allergic cascade. Effector molecules including platelet activating factor and prostaglandins can be synthesized upon cell stimulation the authors say, and cytokines including interleukin-1, transforming growth factor-beta, TNF-alpha, and vascular endothelial growth factor can be released, further activating the mast cells.
“These effectors can participate in numerous inflammatory responses and endothelial dysfunction in the vasculature, altering neural activity and function,”
This paper also mentioned mast cells as target to treat rosacea: “Mast cells participate in the pathogenesis of rosacea through innate immune responses, neurogenetic inflammation, angiogenesis, and fibrosis. Mast cells can be important immune cells that connect innate immunity, nerves, and blood vessels in the development of rosacea, no matter what the subtypes.”
“If we are looking for a single way to treat rosacea, it may be time to go after the mast cell and its interactions with vascular smooth muscle and vasomotor nerves.”
“It is likely indisputable that better understanding of rosacea etiology could offer new targets for developing better treatments, says Guy F. Webster, M.D., Ph.D., who proposes a focus on controlling mast cell activity. This concept is based on findings from several lines of research that point to a role for histamine and other chemical mediators released by mast cells.
Some researchers were trying to use 4% cromolyn sodium (mast cell stabilizer) to alleviate rosacea symptoms. The results were not very impressive. 10 randomized adults with erythematotelangiectatic rosacea were chosen to apply a solution containing either the MC stabilizer (4% cromolyn sodium) or placebo, topically to their face, twice daily. Six tape strips were obtained from both right and left cheeks, at the time of first visit (v1) and last visit (v4). Facial erythema was clinically assessed by a blind investigator using the Clinician’s Erythema Assessment (CEA). None of the subjects presented with papules and pustules; therefore, after 8 weeks (v4), only facial erythema levels decreased in the cromolyn treatment group (data not shown). MMP activity was significantly decreased in the cromolyn treatment group (Figure 3f), whereas KLK activity (Figure 3g) and Cath LL-37 protein levels (Figure 3h) only showed a mild decrease.
The reason why 4% solution of cromolyn sodium was not effective is very simple - this polar and charged molecule just can't penetrate through human skin barrier (stratum corneum). Upper layer of human skin stratum corneum is very strong barrier for all hydrophilic, polar and charged molecules. But it's permeable for lipophilic molecules. Rosacea is associated with a profoundly diminished skin barrier and prominently impaired permeability that promotes bacterial colonization leading to rosacea phenotypes. So, maybe this diminished skin barrier allowed to penetrate some very small amount of cromolyn sodium and observe some effect for rosacea patients in this Phase 1 human trial.
It is obviously, that skin-permeable mast cell stabilizer will be more effective for rosacea treatment. We have developed lipophilic mutual prodrug that contain 2 parental drugs: safe and effective mast cell stabilizer (cromolyn) and anti-bacterial, anti-inflammatory drug (azelaic acid).
After application to the skin lipophilic mutual prodrug will diffuse through stratum corneum to viable skin layers where skin esterases will cut ester bonds and free parental drugs.
The figure illustrated the mechanism of action (MOA) of mutual prodrug (figure was modified from this paper). Azelaic acid already approved for rosacea treatment (Finacea Gel contains 15% azelaic acid in an aqueous gel base). However, human trial results showed that azelaic acid alone is not very effective in clinical trials. For example, Finacea reduced the number of facial lesions in people with rosacea. For example, in one trial: people who used Finacea gel had their number of facial lesions reduced by nearly 58%, people who used a placebo gel (gel with no active drug) had their number of facial lesions reduced by nearly 40%
Combination of safe and effective mast cell stabilizer and azelaic acid should have synergistic effect - effects when 2 drugs applied together resulting in an overall effect that is greater than the sum of individual effects of any of them. Our mutual prodrug will deliver 2 drugs exactly where they needed to treat rosacea.
According to NIH, skin inflammation diseases Chronic urticaria (CU) and Chronic idiopathic urticaria (CIU) also known as chronic spontaneous urticaria (CSU) has 3 million US cases per year. CIU/CSU is a subtype of chronic urticaria (CU) and is differentiated from inducible forms of CU (CindU) in that CIU/CSU has no known external trigger. The incidence of CU in the general population has been estimated at 1.4% per year with a prevalence ranging from 0.5% to 5%. CU and CIU/CSU most often occurs in people between the ages of 20 and 40. Women are disproportionately affected by approximately 2:1.
Both CU and CIU/CSU are fundamentally mast cell-driven disease, in which pruritus is a key symptom in addition to wheals and/or angioedema (Zuberbier et al., 2018). In urticaria, the degranulation of hyperactive subcutaneous mast cells and release of their mediators (histamine, bradykinin, kallikrein, and other vasoactive substances) in the superficial dermis cause the symptoms by activating sensory nerves, capillary and venous vasodilatation, leukocyte infiltration that lead to skin severe inflammation. CU and CIU/CSU are unpredictable, systemic skin diseases, characterized by the spontaneous and recurrent appearance of itchy, painful hives (wheals) on the skin, angioedema or both for at least 6 weeks. CU and CIU/CSU are the diseases with major negative impact on the patients' daily activities and can therefore worsen their quality of life. Antihistamines are drug of choice in chronic urticaria and CIU/CSU. However they are relatively slow acting. Approximately 60% of patients do not achieve complete control with first-line treatment antihistamines like Cetirizine (Zyrtec), Benadryl and loratadine (Claritin), fexofenadine (Allegra), desloratadine (Clarinex) and levocetirizine (Xyzal). The anti-inflammatory steroids (prednisolone) help in faster relief of symptoms. When rapid control of urticaria is needed, a short tapering course of steroids may be used, but in any other situation their role is limited. Invariably, prolonged use of steroids like Prednisone leads to numerous adverse effects and severe rebound in urticaria when withdrawal is attempted.
Both Chronic urticaria and Chronic spontaneous urticaria are a debilitating diseases that may significantly impact a patient’s life. Currently there are limited options available for patients with CU and CIU/CSU and they are not address adequately disease symptoms. In approximately 50% of patients, urticaria and angioedema coexist, while 40% experience urticaria alone and 10% will have isolated angioedema. The hallmark of urticaria is transient (less than 24 hours duration) pruritic wheals. Current standard-of-care treatment involves non-sedating antihistamines (nsAH) (mostly H1 receptor blockers) as a first line, often at multiples of typical doses. However, on average, only 50% of CSU patients have an adequate response to a standard or even up to fourfold doses, and this percentage is even lower when angioedema is also present. For those who require additional treatment, physicians prescribe a variety of medications including oral corticosteroids (OCS), leukotriene receptor antagonists (LTRA), methotrexate, topical Prednisolone despite none of these medications has been US Food and Drug Administration (FDA) approved for use in CU and CIU/CSU. In 2014, antibody omalizumab (Xolair) developed by Novartis became the first drug to gain a FDA label to treat CIU/CSU in adults and adolescents 12 years of age and older patients with inadequate response to H1 antihistamines. However, until now antihistamines remain the first-line treatment for CU and CIU/CSU with omalizumab currently recommended as Step 4 by the Joint Task Force on Practice Parameters in the United States [1,14]. Currently, Novartis already lost patent protection on the original formulation of Xolair in both the U.S. and EU. Recently, Novartis developed a next generation monoclonal anti-immunoglobulin E (IgE) antibody Ligelizumab (QGE031) that is thought to work by blocking the IgE/FcεRI pathway, a key driver of the inflammatory process in CSU. Ligelizumab was investigated in two Phase III clinical trial programs PEARL 1 and PEARL 2 that recruited more than 2,000 patients with chronic spontaneous urticaria, in patients whose symptoms were not adequately controlled with H1-antihistamines. globally across 48 countries. However, recently provided top-line results from both PEARL 1 and PEARL 2 studies showed that the studies met their primary endpoints of superiority for ligelizumab versus placebo at Week 12, but not versus omalizumab.
Some pharma companies (for example, Celldex and Jasper Therapeutics) developed another approach to alleviate CU symptoms – they develop anti-KIT antibodies that bind with KIT receptor on mast cells. KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells. MC activity is mainly regulated by its membrane tyrosine kinase receptor, the c-Kit receptor (c-Kit-R), identified and classified in the cluster of differentiation 117 (CD-117) and binding the stem cell factor (SCF) as its natural ligand.
Barzolvolimab (CDX-0159) is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. As a result, binding of CDX- 0159 to KIT on mast cells led to dose- dependent, profound suppression of plasma tryptase, a MC- specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. In simple words, CDX-0159 just kills mast cells. The companies state that since mast cell activation plays a central role in the onset and progression of chronic urticaria and other skin inflammatory diseases, their elimination or ablation will alleviate the symptoms of these diseases. Well. no subcutaneous mast cells - no problems with chronic urticaria and other skin inflammatory diseases.
Our opinion that this approach is absolutely unacceptable.
Just read the review: “Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?” Authors stated: “consequently, skin MCs are strategically positioned and equipped for the defense against invading pathogens, response to allergen encounters, and interaction with a resident or infiltrating immune effector cells. However, these interactions may be beneficial or detrimental, and MCs are heavily involved in inflammatory skin disorders. The purpose of this review is to delineate the fascinating role of MCs in skin barrier function, all the way from maintenance of skin homeostasis to infections and inflammatory disorders.”
Just remember the story of how geese saved Rome.
According to legend, a flock of geese saved Rome from the Gauls by alerting the Roman guards to an attempted sneak attack:.
• The story
The Gauls were attempting to sneak into Rome under cover of night to conquer the city, except for the Capitoline Hill, which was defended by the Romans. The Gauls disturbed a sacred flock of geese that lived in the temple of Juno, and the geese' honking woke the Roman guards. The guards then threw the invaders off the hill.”
Subcutaneous mast cells are our “sacred flock of geese”. They are being on guard all the time. Now imagine if Roman guards just killed all geese because they are sometimes sending false alarm signal during the night and woke them. Most likely that during this Gauls incursion Rome could have erased from history.
The question is: what can happen with chronic urticaria patients when their subcutaneous mast cells will be completely eliminated? Yes, may be chronic urticaria symptoms will be completely or partially disappear. But there are numerous and very dangerous bacterial skin infections that can start during this period. The question is: who will send alarm signal to the guards i.e. neutrophils, leucocytes, macrophages and other innate immune cells? To get the answer you can read the review "Roles of Mast Cells in
Cutaneous Diseases" - below picture from this review.
Mast cells reside in various tissues that can be colonized or infected by Candida spp., including Candida (C.) albicans (24). A human mast cell line (HMC-1) degranulated and produced IL-8 in response to C. albicans, contributing to enhanced migration of neutrophils.
The companies like Celldex and Jasper Therapeutics (they have Briquilimab that blocks stem cell factor from binding to the cell-surface receptor c-Kit, also known as CD117, thereby inhibiting signaling through the receptor. This inhibition disrupts the critical survival signal, leading to the depletion of the mast cells via apoptosis which removes the underlying source of the inflammatory response in mast cell driven diseases such as chronic urticaria.) currently have some promising results in Phase 2 trials. Question is: what will happen during Phase 3 trial when patient number will be 2000-3000 thousand (while Phase 2 number was 200)? Big numbers usually crash any attempts to cheat like to do patients stratification for Phase 2 clinical trials. Again the question: Why soo many Phase 2 trials are succesful but following Phase 3 failed? You can read the review "Estimation of clinical trial success rates and related parameters". However, the reason of Phase 3 failure can be enough simple - the eligibility criteria for Phase 2 and Phase 3 are different. So, Phase 2 eligibility criteria allows patient stratification - to choose patients that will respond well and at the same time they will have low probability to have dangerous side effects. In case of mast cell ablation by antibodies, some patients in Phase 3 trial can get very dangerous and even life-threatening skin infections. In this case FDA data monitoring committee (DMC) (also known as a data and safety monitoring board (DSMB), a data and safety monitoring committee (DSMC), or an independent data monitoring committee (IDMC)) will put a clinical hold on this trial for reason like "Participants are exposed to unreasonable or significant risk".
We are not going to kill/eliminate subcutaneous mast cells. We just going only temporarily to calm down them with effective and safe mast cell stabilizer. At the same time we are going to stop itching by transdermal delivering of highly selective antagonist of the histamine H1 receptor Cetirizine (Zyrtec).
Samdolite Pharmaceuticals has a novel breakthrough solution for a more effective treatment for Chronic Urticaria.. We have developed novel first-in-class mutual prodrug Cetirizine diethyl cromoglicate (MW 895 and calculated Log P = 4.5) that will deliver transdermally two parental drugs linked by ester bonds: effective and safe mast cell stabilizer (cromolyn sodium) and highly selective antagonist of the histamine H1 receptor Cetirizine (Zyrtec). The traditional administration of both cetirizine hydrochloride and cromolyn sodium is oral administration. The transdermal permeability of these compounds is poor because of their high water solubility.
Both Cromolyn sodium and Cetirizine molecules are charged, polar and have Log P that unfavorable for effective transdermal delivery (Cromolyn sodium Log P = - 4.8 and Cetirizine Log P = 0.86). If they applied as water solutions to human skin they will not penetrate through stratum corneum that is very strong barrier for all polar, charged and water-soluble molecules.
Cetirizine diethyl cromoglicate is a first-in-class mutual prodrug that uses a unique mechanism of action: when topically applied to human skin as a lipophilic compound it will penetrate through stratum corneum to viable skin layers (epidermis and dermis). There t will be cleaved by endogenous esterases to hydrophilic parental drugs Cetirizine (Zyrtec) and Cromolyn Sodium. Cromolyn Sodium will inhibit the release of chemical mediators (histamine, bradykinin, tryptase etc.) from sensitized mast cells. Cetirizine will act as a highly selective antagonist of the histamine H1 receptors on sensory nerves (activation leads to itching), on capillaries and venules – an activation leads to vasodilatation, painful hives (wheals) on the skin and angioedema, on leukocyte – an activation induces leukocyte infiltration in epidermis and dermis and severe skin inflammation.
Chronic Urticaria and CSU affects 1–2% of the population (3-5 millions for US).The CU related cost has been reported to be as high as $2050 per year per patient in the United States, having a huge personal and familiar impact (calculations for 2008 (https://pubmed.ncbi.nlm.nih.gov/18209166/). Because CU and CIU is primarily an outpatient disease, medication costs alone accounted for 62.5% ($1280) of the total annual cost. Indirect costs accounted for 15.7% ($322) of the total costs. Patients with CIU/CSU have worse health-related quality of life than those with psoriasis or atopic dermatitis. Their degree of impairment is comparable to that observed in patients with severe ischemic heart disease. CIU/CSU patients had a mean of 15.1 all-cause office visits annually. Other calculations gave even higher numbers - the mean annual healthcare cost for a patient with CIU/CSU is over US$9,000. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529877/)
High medication costs, followed by total indirect costs, result in the largest economic burden among patients with CU and CIU/CIS. High medication costs may place low-income patients at risk for suboptimal treatment and increased burden due to poorly controlled disease.
Topical formulations are more convenient for patients than injectable ones and can provide immediate relief when applied directly to disease-induced skin lesions. Therefore, proposed mutual prodrug has a potential to provide a substantial benefit over existing available treatments. Since there are limited approved therapies for patients with CSU/CIU with an inadequate response to H1-antihistamines, a proposed topical remedy has a choice to receive FDA Breakthrough Therapy designation in patients with moderate-to-severe chronic spontaneous urticaria that is inadequately controlled with H1-antihistamines at approved or increased doses (only 50% of CSU patients have an adequate response to non-sedating antihistamines (nsAH) at standard or up to fourfold doses).
Currently, topical treatments for chronic urticaria (hives) include:
Anti-itch creams: Creams or lotions containing menthol, pramoxine, or calamine can help relieve itching. Ointments with menthol or pramoxine can also help numb the area.
Topical corticosteroids: Mild cases of hives can be treated with topical corticosteroids.
Hydrocortisone: An over-the-counter cream that can be applied to the affected areas.
Other treatments for chronic urticaria include:
Antihistamines
Can help control itching and swelling. Some antihistamines can also flatten hives, shorten how long you have hives, or reduce the number of hives you get.
Home remedies
Keep your skin hydrated, wear loose clothing, use a cool compress, take a cool bath, and use mild soaps.
