What are the potential benefits of oral DMSO treatment for lipoid proteinosis. How effective is DMSO in managing symptoms of this rare genetic disorder. What risks and side effects are associated with long-term DMSO use for lipoid proteinosis.

Understanding Lipoid Proteinosis: A Rare Genetic Disorder

Lipoid proteinosis, also known as Urbach-Wiethe disease, is an extremely rare autosomal recessive disorder characterized by the deposition of hyaline material in the skin, mucous membranes, and internal organs. This condition typically manifests in early childhood with hoarseness as one of the first symptoms, followed by skin lesions and other complications as the disease progresses.

Key features of lipoid proteinosis include:

• Hoarseness due to laryngeal involvement
• Thickening of the skin and mucous membranes
• Beaded papules along the eyelid margins
• Waxy yellow plaques on the skin
• Neurological symptoms in some cases

Given the rarity of this condition, treatment options are limited and largely experimental. One such experimental approach that has been explored is the use of oral dimethyl sulfoxide (DMSO).

Oral DMSO Treatment: Mechanism of Action and Potential Benefits

Dimethyl sulfoxide (DMSO) is an organosulfur compound with a variety of potential therapeutic applications. In the context of lipoid proteinosis, DMSO has been investigated as a potential treatment due to its unique properties:

• Penetration enhancement: DMSO can facilitate the transport of other substances across biological membranes
• Anti-inflammatory effects: It may help reduce inflammation associated with the condition
• Antioxidant properties: DMSO can scavenge free radicals, potentially reducing oxidative stress
• Collagen dissolution: It may help break down abnormal protein deposits characteristic of lipoid proteinosis

Are there any documented benefits of oral DMSO treatment for lipoid proteinosis? While some case reports have suggested potential improvements, the overall evidence remains limited and inconclusive. A notable case report by Wong and Lin (1988) described a “remarkable response” to oral DMSO in a patient with lipoid proteinosis. However, subsequent studies have failed to consistently replicate these positive results.

Long-Term Efficacy of Oral DMSO: Insights from Clinical Experience

The study by Ozkaya-Bayazit et al. (1997) provides valuable insights into the long-term efficacy of oral DMSO treatment for lipoid proteinosis. The researchers treated three patients (two sisters and an unrelated man) with oral DMSO at a dose of 60 mg/kg/day for an average of 3 years.

What were the outcomes of this long-term DMSO treatment? Unfortunately, the results were disappointing:

• No beneficial effects were observed on skin lesions
• Mucosal lesions showed no improvement
• Hoarseness, a hallmark symptom of lipoid proteinosis, did not improve
• One patient experienced disease progression, with worsening hoarseness and onset of dyspnea

Based on these findings, the researchers concluded that long-term oral DMSO treatment failed to provide any significant benefits for patients with lipoid proteinosis. This study highlights the challenges in developing effective treatments for rare genetic disorders and underscores the need for continued research into novel therapeutic approaches.

Potential Risks and Side Effects of Long-Term DMSO Use

While the study by Ozkaya-Bayazit et al. did not report significant adverse effects from long-term DMSO use, it’s important to consider the potential risks associated with prolonged DMSO treatment:

• Gastrointestinal disturbances: Nausea, vomiting, and diarrhea
• Skin irritation: Redness, itching, or burning sensation at the site of application (for topical use)
• Breath and body odor: A characteristic garlic-like smell
• Hepatotoxicity: Potential liver damage with long-term use
• Ocular effects: Changes in lens refractivity (reversible upon discontinuation)
• Drug interactions: DMSO may enhance the effects of certain medications

How can these potential side effects be managed? Close medical supervision and regular monitoring of liver function and other relevant parameters are essential for patients undergoing long-term DMSO treatment. Additionally, patients should be counseled about the potential for body odor and other quality-of-life impacts.

Alternative Treatment Approaches for Lipoid Proteinosis

Given the limited efficacy of oral DMSO treatment, what other therapeutic options are available for patients with lipoid proteinosis? While there is no cure for this condition, several approaches have been explored:

1. Retinoids: Oral acitretin has shown promise in some case reports, improving skin lesions and voice quality
2. Surgical interventions: Removal of vocal cord infiltrates or other problematic lesions
3. Dermabrasion: For cosmetic improvement of facial lesions
4. Laser therapy: CO2 laser treatment for beaded eyelid papules
5. Cryotherapy: Liquid nitrogen application for localized lesions
6. Supportive care: Speech therapy, psychological support, and management of specific symptoms

Which of these approaches is most effective? The optimal treatment strategy often depends on the individual patient’s presentation and the specific manifestations of their disease. A multidisciplinary approach involving dermatologists, otolaryngologists, and other specialists is typically required to provide comprehensive care for patients with lipoid proteinosis.

The Role of Genetic Counseling in Lipoid Proteinosis Management

Given the autosomal recessive inheritance pattern of lipoid proteinosis, genetic counseling plays a crucial role in the management of this disorder. How can genetic counseling benefit patients and families affected by lipoid proteinosis?

• Risk assessment: Helping families understand the likelihood of having an affected child
• Prenatal testing: Offering options for prenatal diagnosis in at-risk pregnancies
• Family planning: Discussing reproductive options and potential risks
• Psychosocial support: Addressing the emotional and psychological impacts of living with a rare genetic disorder
• Education: Providing up-to-date information about the condition and emerging research

Genetic counseling can empower patients and families to make informed decisions about their health and future. It also plays a vital role in identifying at-risk family members who may benefit from early screening and intervention.

Future Directions in Lipoid Proteinosis Research and Treatment

While current treatment options for lipoid proteinosis remain limited, ongoing research offers hope for future therapeutic advancements. What are some promising areas of investigation?

• Gene therapy: Targeting the ECM1 gene responsible for lipoid proteinosis
• Novel drug development: Exploring compounds that can inhibit or reverse hyaline material deposition
• Personalized medicine approaches: Tailoring treatments based on individual genetic profiles
• Improved diagnostic techniques: Developing non-invasive methods for early detection and monitoring
• International collaborations: Facilitating research on this rare disorder through global partnerships

As our understanding of the molecular mechanisms underlying lipoid proteinosis continues to grow, new therapeutic targets may emerge. Collaborative efforts between researchers, clinicians, and patient advocacy groups will be crucial in driving progress in this field.

The Importance of Patient Registries and Natural History Studies

One of the challenges in researching rare disorders like lipoid proteinosis is the limited number of affected individuals available for study. How can this obstacle be addressed? Patient registries and natural history studies play a vital role in advancing our understanding of rare diseases:

• Collecting longitudinal data on disease progression and variability
• Identifying potential biomarkers for disease severity and treatment response
• Facilitating patient recruitment for clinical trials
• Providing insights into the long-term outcomes and quality of life impacts of the disorder
• Informing the development of clinical practice guidelines and standards of care

By participating in these initiatives, patients with lipoid proteinosis can contribute to the advancement of scientific knowledge and potentially benefit from improved treatments in the future.

The Role of Patient Support Groups and Advocacy

Living with a rare disorder like lipoid proteinosis can be isolating and challenging. Patient support groups and advocacy organizations play a crucial role in improving the lives of affected individuals and their families. How do these groups contribute to the lipoid proteinosis community?

• Providing emotional support and connecting patients with others who share similar experiences
• Disseminating information about the latest research and treatment options
• Advocating for increased research funding and improved access to care
• Raising awareness about lipoid proteinosis among healthcare providers and the general public
• Facilitating participation in research studies and clinical trials

By fostering a sense of community and empowerment, these organizations help patients and families navigate the challenges of living with a rare genetic disorder.

Addressing the Psychosocial Impact of Lipoid Proteinosis

The visible manifestations of lipoid proteinosis, such as skin lesions and hoarseness, can have significant psychosocial impacts on affected individuals. How can healthcare providers and support systems address these challenges?

• Offering psychological counseling to help patients cope with the emotional aspects of the disorder
• Providing resources for managing social interactions and relationships
• Addressing potential issues related to self-esteem and body image
• Facilitating access to occupational therapy and vocational support if needed
• Encouraging participation in support groups and peer mentoring programs

A holistic approach to care that addresses both the physical and psychological aspects of lipoid proteinosis is essential for improving overall quality of life for affected individuals.

The Potential of Telemedicine in Rare Disease Management

Given the rarity of lipoid proteinosis and the limited number of specialists with expertise in this condition, telemedicine offers promising opportunities for improving patient care. How can telemedicine benefit patients with lipoid proteinosis?

• Increasing access to specialists regardless of geographic location
• Facilitating regular follow-up and monitoring without the need for frequent travel
• Enabling multidisciplinary care coordination through virtual case conferences
• Providing a platform for patient education and self-management support
• Allowing for remote assessment of visible symptoms and lesions

As telemedicine technologies continue to advance, they have the potential to significantly improve the care and management of patients with rare disorders like lipoid proteinosis.

[Oral DMSO therapy in 3 patients with lipoidproteinosis. Results of long-term therapy]

Case Reports

. 1997 Jul;48(7):477-81.

doi: 10.1007/s001050050613.

[Article in

German]

E Ozkaya-Bayazit 
¹
, G Ozarmağan, C Baykal, T Uluğ

Affiliations

Affiliation

• ¹ Dermatologische Abteilung, Medizinischen Fakultät Istanbul der Universität, Istanbul.

• PMID:

  9333627

• DOI:

  10.1007/s001050050613

Case Reports

[Article in

German]

E Ozkaya-Bayazit et al.

Hautarzt.

1997 Jul.

. 1997 Jul;48(7):477-81.

doi: 10.1007/s001050050613.

Authors

E Ozkaya-Bayazit 
¹
, G Ozarmağan, C Baykal, T Uluğ

Affiliation

• ¹ Dermatologische Abteilung, Medizinischen Fakultät Istanbul der Universität, Istanbul.

• PMID:

  9333627

• DOI:

  10.1007/s001050050613

Abstract

Lipoid proteinosis is a rare autosomal recessive disorder with a chronic, benign course. There is no generally accepted systemic therapy apart from the experimental oral use of dimethyl sulphoxide (DMSO) and etretinate in two single cases. We treated two sisters and an unrelated man with lipoid proteinosis with longterm oral DMSO (60 mg/kg/d). At the end of an average treatment time of 3 years, DMSO was withdrawn because it produced no beneficial effects with regard to their skin, mucosal lesions or hoarseness. Additionally, one patient showed progression of her disease with worsening hoarseness and onset of dyspnea, requiring surgical removal of vocal cord infiltrates. Three patients with lipoid proteinosis failed to show any beneficial response to long term treatment with DMSO.

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  PMID: 3191019

• [Lipoid proteinosis in 2 sisters].

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DMSO (Dimethyl Sulfoxide): Uses, Benefits, Risks, and More

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Medically reviewed by Angelica Balingit, MD — By Jessica DiGiacinto and Joe Bowman — Updated on May 16, 2023

DMSO is a colorless chemical solvent that may have many medical uses but is currently only approved by the FDA to treat interstitial cystitis.

The story of dimethyl sulfoxide (DMSO) is an unusual one. This by-product of the paper making process was discovered in Germany in the late 19th century. It’s a colorless liquid that gained notoriety for its ability to penetrate the skin and other biological membranes.

Scientists discovered that they could use DMSO as a transportation device to pass small molecules through skin in the 1960s. Since then, scientists have researched the potential benefits and risks of using DMSO to treat a variety of conditions. This research is ongoing.

DMSO was approved by the Food and Drug Administration (FDA)to treat interstitial cystitis (a chronic bladder issue) under the brand name RIMSO-50.

The compound has no other approved uses, but it’s been purported to be a treatment for:

• arthritis
• cancer
• chemotherapy side effects
• general pain

Because it absorbs easily into the skin, it’s also been studied as a vehicle for administering topical drugs.

In the late 70s, the FDA approved DMSO to help treat interstitial cystitis. It remains the only FDA-approved bladder installation (or bladder wash) for this condition. For individuals living with interstitial cystitis, DMSO has been shown to:

• ease pain due to the condition
• help relax the bladder
• increase bladder capacity

When it comes to off-label uses, DMSO is often employed as an alternative treatment to reduce inflammation and pain.

Because it absorbs easily into the skin, DMSO may be a beneficial alternative to other pain medications. However, further investigation into this area is needed before any conclusions can be drawn.

DMSO has also been touted for its ability to reduce the amount of leakage during chemotherapy administration, but more studies, and real-world usage, need to be done before it can be labeled as a trusted method.

Additionally, there has been some research into DMSO’s benefits when it comes to inhibiting cancer cells. A 2020 study published in the Journal of Medical Discovery found evidence of benefit. However, research is just beginning in this area, so many more studies need to be done before any conclusions can be made.

While many of the reported side effects of taking DMSO are mild, the amount of DMSO someone takes is directly correlated to the severity of the reaction.

One common side effect is the taste of garlic in the mouth and throat.

More severe side effects include:

• headache
• nausea
• vomiting
• stomach ache
• diarrhea
• fever
• chills
• a lowered heart rate
• itching
• rash
• rough or thickened skin

Risks

Because it’s seen as a more alternative treatment, DMSO is easy to find and buy online. However, buying this product and using it without a healthcare professional’s supervision could increase the likelihood of overuse.

DMSO may also increase the effect of a few medications, which could produce serious reactions in some people. A few medications DMSO may affect include:

• sedatives
• blood thinners
• steroids

DMSO can be administered

• topically, via a gel or solution
• as a bladder wash, via a catheter (for interstitial cystitis)

As with any alternative treatment, it’s always advised to talk with a doctor before deciding to purchase any product that contains DMSO. Dosage is directly connected to the severity of possible side effects.

Dimethyl sulfoxide (DMSO) is a chemical solvent that is sometimes used to help reduce inflammation and pain, and may also be beneficial in reducing leakage during chemotherapy treatment.

It has been FDA approved to treat only one condition: interstitial cystitis.

Because of possible interactions with other common medications, and lack of definitive research into its benefits, DMSO should not be used without medical supervision.

Last medically reviewed on February 1, 2022

How we reviewed this article:

Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations. We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy.

• Capriotti K, et al. (2012). Dimethyl sulfoxide: History, chemistry, and clinical
  utility in dermatology.
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• DMSO. (2009).
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• Elisia I, et al. (2016). DMSO represses inflammatory cytokine production from human blood cells and reduces autoimmune arthritis.
  ncbi.nlm.nih.gov/pmc/articles/PMC4816398/
• Madsen BK, et al. (2018). Adverse reactions of dimethyl sulfoxide in humans: A systematic review.
  ncbi.nlm.nih.gov/pmc/articles/PMC6707402/
• Molecule of the week archive: Dimethyl sulfoxide. (2021).
  acs.org/content/acs/en/molecule-of-the-week/archive/d/dimethyl-sulfoxide.html?cid=home_motw
• Tang H, et al. (2020). DMSO inhibits growth and induces apoptosis through extrinsic pathway in human cancer cells.
  https://www.proquest.com/openview/06527232a660b6867effa2ff8f68deed/1?pq-origsite=gscholar&cbl=2050635
• Understanding unapproved use of approved drugs “off-label.” (2018).
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• Wengström Y, et al. (2008). European oncology nursing society extravasation guidelines.
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  urologyhealth.org/urology-a-z/i/interstitial-cystitis

Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

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May 16, 2023

Written By

Jessica DiGiacinto, Joe Bowman

Edited By

Jessica DiGiacinto

Copy Edited By

Delores Smith-Johnson

Feb 1, 2022

Medically Reviewed By

Angelica Balingit, MD

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Medically reviewed by Angelica Balingit, MD — By Jessica DiGiacinto and Joe Bowman — Updated on May 16, 2023

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What Dermatologists Treat: Topical Skin Therapy

Methods

Ending. Beginning in #3/2015, #4/2015

Author: Ruppel VV, PhD, veterinary dermatologist. Veterinary Clinic of Neurology, Traumatology and Intensive Care, St. Petersburg.

Topical anti-inflammatory agents

Topical glucocorticoids

Physical exposure to cold is considered the simplest and safest method to help reduce itching. But more often, local glucocorticoids are used to eliminate itching (and inflammation). In high concentrations, when applied to inflamed and injured skin, glucocorticoids are absorbed into it. This rarely leads to serious adverse clinical effects if glucocorticoids are used for a short time.
Scientists have conducted a significant number of studies confirming that long-term topical use of corticosteroids can lead to systemic changes: for example, adversely affect the response of the adrenal cortex to exogenous corticotropin and lead to an increase in liver enzymes. And therefore, despite the significant number of products containing various glucocorticoid compounds in their composition, the search for safe agents for topical application to the skin continues to this day.
So, relatively recently, Virbac offered a Cortavance spray containing hydrocortisone aceponate, which belongs to the diester class of glucocorticoids. Diesters are lipophilic components that provide enhanced penetration into the skin. Hydrocortisone aceponate, which accumulates in the skin of dogs, is effective locally at low doses. Topical application of diesters results in a high therapeutic index – high local activity with reduced systemic secondary effects. In addition, the product has a minimal effect on the cells of the epidermis and on the synthesis of collagen, which is a condition that prevents pronounced atrophogenicity when used. But, despite this, the drug should be applied with caution to those areas where the skin is physiologically thinned (scrotum, groin, armpits, sides).
If we talk about possible side effects that occur against the background of the use of glucocorticoids, then their list includes atrophy, peeling, comedones, alopecia and pyoderma, as well as skin calcification, which can occur on their own, without concomitant systemic effects.
The most powerful are fluoride steroids. They penetrate the skin better and are therefore more effective. Even a single application to the skin during the day may be sufficient to achieve the expected effect. However, their use may be associated with a large number of side effects (see above).
Topical glucocorticoid therapy should follow the same principles as systemic therapy. That is, strong drugs at the initial stage should be used twice a day to relieve inflammation, then once a day, and finally, subject to the expected long-term therapy, they should be replaced with softer glucocorticoids. In the future, maintenance therapy with these local agents should be continued, if possible, on a daily basis.
In some cases, with maintenance therapy with local glucocorticoids, it is enough to use them twice a week. Pet owners should wear gloves to avoid adverse consequences.

Local immunomodulators

Tacrolimus
Tacrolimus (Protopic) is a 23-mer macrolide that is similar in action to cyclosporine and results in calcineurin inhibition. It inhibits the production of cytokines by T-lymphocytes, has an effect on antigen-presenting cells and keratinocytes.
Tacrolimus reduces the clinical symptoms of manifestation in atopic dermatitis, in some cases it can be effective in discoid lupus erythematosus, perianal fistulas, ulcerative nasal dermatitis of Bengal cats, metatarsal fistulas of German shepherds.
In some cases, the authors have also used it in the treatment of vasculitis, vitiligo, alopecia areata, allergic contact dermatitis, erythema multiforme, and other inflammatory skin conditions.
More effective form of the drug with a content of 0.1% tacrolimus. Owners are advised to wear gloves when applying this product to the skin of animals.

Pimecrolimus
Pimecrolimus (Elidel) is an ascomycin macrolactam derivative that acts similarly to tacrolimus. Pimecrolimus is worse than tacrolimus at penetrating the skin of patients, so it is less effective.
Precautions for handling it are the same as for tacrolimus (use of gloves).

Imiquimod
Imiquimod (Aldara) is a relatively new drug with great potential for use in veterinary dermatology.
Imiquimod is a synthetic amine-based imidazoquinoline immune response modifier with potent antiviral and antitumor effects in animals and humans.
Antiviral and antitumor effects primarily result from activation of Toll-like receptors (TLR)-7, leading to the secretion of cytokines from monocytes/macrophages (interferon [IFN]-α, interleukin [IL]-12, tumor necrosis factor [TNF]-α ).
The local immune response leads to the predominance of Th2 and the development of the so-called cellular immune response. The latter is important for the treatment of viral infections, such as human papillomavirus, herpes simplex virus, actinic keratosis,
superficial basal cell carcinoma, human and feline squamous cell carcinoma in situ. The drug has also been used to treat feline herpesvirus dermatitis with varying efficacy.
For most conditions, imiquimod is applied two to three times per week in varying courses of duration; but usually, as noted, results are observed after a 4-week course of therapy.
The frequency of application may depend on whether skin irritation occurs at the site of imiquimod application. And if such reactions occur, then the drug can be used with longer intervals.

Other local agents

Sulfur
Sulphurous (sulphated) lime is prepared by boiling a suspension of sublimated sulfur, lime (Ca[OH]2) and water, which produces calcium pentasulfide and calcium thiosulfate. Sulfur is a degreasing agent. Sulfur is keratoplastic at low concentrations and keratolytic at high concentrations (h3S breaks down keratin). In this case, it acts synergistically with salicylic acid. Sulfur is antifungal and antibacterial mainly due to the conversion of pentathionic acid and h3S (this conversion can be supplemented by skin bacteria and keratinocytes).
Lime sulfide inhibits the growth of Microsporum canis more effectively than chlorhexidine, captan, povidone-iodine, and ketoconazole shampoo.
Lime sulfide is inexpensive and non-toxic and is now available in Russia. Side effects include rare excessive dryness or irritation of the skin.
The disadvantages of its use include an unpleasant odor (reminiscent of the smell of rotten eggs) and staining of light wool and skin in yellow.

Vitamin A
Retinoic acid at a concentration of 0.05%, tretinoin (Retin-A) , is popular in humane dermatology abroad (used to treat acne, pimples and ichthyosis). Although quite expensive, this concentration has been used by the authors in dogs and cats for the treatment of acne and some localized keratinizing diseases.
Usually, at the initial stage, a gel with a concentration of 0.01% is used, since it is less irritating than, for example, if the concentration of the active substance is 0.025%.
Retinoic acid increases the turnover time of the epidermis, reduces the cohesiveness of keratinocytes, normalizes the maturation of the follicular epithelium, and also has comedolytic properties. It has also been used in animals to prevent skin atrophy caused by corticosteroids. Retinoic acid can cause local skin irritation, which is a significant problem for many people and many animals (cats). Such side effects have been observed by scientific publications with Retina-A.
The preparation in the form of microspheres (Retin-A MICRO) is also available for sale abroad, which causes skin irritation in humans to a much lesser extent, as noted in the literature.
Synthetic retinoids are also available as local preparations (and in Russia). Adapalene is a topical retinoid with specific receptor activity for intranuclear retinoic acid receptors and is less irritating than retinoic acid. It also inhibits the activation of neutrophils and lipoxygenase enzymes. Tazarotene is a relatively new acetylene retinoid topical agent that is available in 0.1% cream and gel form. As a topical treatment, it is likely to have minimal absorption and no side effects have been reported so far. Tazarotene acts on retinoic acid receptors, which leads to the regulation of keratinocyte differentiation processes and inhibition of inflammation mechanisms in the skin (for example, by antagonizing the effects of IFN-γ).
Bexarotene is a relatively new synthetic retinoid X receptor (RXR) – a selective retinoid that inhibits proliferation, stimulates terminal differentiation, activates caspase-3, and also induces apoptosis. It also inhibits IL-2 secretion, prevents T cells from escaping from vessels into tissues, controls epidermal differentiation, and suppresses inflammation. It is available in dosage forms as a 1% gel for oral and topical use. Human medicine uses include the treatment of hand dermatitis, lymphomatoid papulosis, alopecia areata, follicular mucinosis, and mycosis fungoides. It is assumed that it can be used as one of the components in the complex treatment of T-cell lymphoma in dogs.
Zinc
Zinc has been valued in human medicine for its effects in wound healing, treating viral infections such as the herpes simplex virus. It is found in some veterinary shampoo products and has antimicrobial and antiseborrheic effects.
Urea
Urea has hygroscopic and keratolytic properties that contribute to the normalization of the epidermis, especially the quality of the stratum corneum. The application of urea as part of a cream or ointment to the stratum corneum has a softening and moisturizing effect, and the basis of the drug is perceived as less oily. It acts as a humectant at concentrations between 2% and 20%, but above this level, urea is a keratolytic. This action is the result of the dissolution of prekeratin and keratin, as well as the possible destruction of hydrogen bonds that keep the stratum corneum intact. It is a powerful keratolytic agent used to treat nasal hyperkeratosis, calluses, dermatosis of the auricle margins and acne.
a-hydroxy acids 2%-10%
a-hydroxy acids include lactic, malic, citric, tartaric, glutamic, glycolic and tartaric acids. They are effective in regulating keratinization, being keratoplastic substances, delaying final differentiation and weakening the forces of intercellular cohesion of the stratum corneum.
Ethyl lactate
The action of ethyl lactate is similar to that of benzoyl peroxide at a reduced skin pH. It is hydrolyzed in the skin by bacterial lipases to ethanol and lactic acid. Ethyl lactate is lipid soluble and has the ability to penetrate hair follicles and sebaceous glands.
Fatty acids
Fatty acids are important in moisturizing and controlling transepidermal water loss and epidermal barrier function.
Several new products have recently been developed that function by direct topical application of fatty acids to the skin and coat. These products have worked well for seborrheic skin conditions and allergic diseases. Among the available products in Russia, one can consider such as Dermoscent Essential 6 Spot-on (Laboratoire de Dermo-Cosmetique Animale) and Allerderm Spot-on (Virbac).
Essential 6 Spot-on contains a combination of fatty acids and emollients. It hydrates the skin, controls transepidermal water loss, and helps reduce inflammation as it also contains antioxidants. Overall, this product contains natural botanical ingredients including hemp seed and neem seed oils to achieve high concentrations of essential fatty acids with a 4:1 omega-6/omega-3 ratio. Additionally, other essential oils (rosemary, lavender, melaleuca, cedarwood, oregano, cloves, camphor, wintergreen, peppermint, turmeric) are included in the product along with vitamin E to restore the water-lipid film, moisturize the skin and control odor. Essential 6 Spot- on helps improve coat quality and control itching in dogs with atopic dermatitis, which can be used as part of the treatment of atopic dermatitis in dogs.
Allerderm Spot-on has similar properties. It contains a dermal lipid complex composed of a mixture of ceramides and fatty acids similar to those found in healthy skin of dogs and cats. It is believed that treatment with Allerderm Spot-on may also stimulate the production of endogenous stratum corneum lipids.
Polypropylene Glycol
Polypropylene glycol was originally used as a solvent and filler in the dosage form. At higher concentrations (>75%) it sometimes causes irritation or sensitization. It may also increase contact sensitization to other drugs or chemicals combined with it. It is an excellent lipid solvent and degreaser of the skin, but the main value of propylene glycol is probably its ability to increase the penetration of drugs through the skin. Propylene glycol is a powerful and reliable antibacterial agent, also possessing antidermatophyte and anticonidial properties. For most dermatological cases, it is used in concentrations of 30% to 40%. Propylene glycol is an excellent humectant (desiccant) and can induce keratolysis. Thus, higher concentrations are practically helpful in hyperkeratotic conditions, and 75% propylene glycol spray is effective in treating sebaceous adenitis.
Dimethyl Sulfoxide (DMSO)
DMSO is a simple hygroscopic organic solvent. Since it is easily miscible with lipids, organic solvents and water, it is an excellent dosage form excipient. Upon contact with air, concentrated solutions take on water and become hydrated at 67%. Higher concentrations tend to penetrate the skin barrier better. DMSO penetrates the skin (within 5 minutes), mucous membranes and the blood-brain barrier, as well as cells, organelles and membranes of microorganisms. Unlike most solvents, DMSO does not damage membranes upon penetration. It promotes membrane absorption of many other substances, especially corticosteroids. At the cellular level, DMSO and steroids show a synergistic effect.
DMSO has the properties of a cryoprotective, radioprotective, anti-ischemic, anti-inflammatory agent (binds free radicals, reduces prostaglandin synthesis, stabilizes lysosome membranes). Although its mechanism of action is not fully understood, the systemic toxicity and teratogenicity of this solvent in its pure form is considered to be low. Toxicity may be a concern depending on dose, route of administration, species and individual response of the animal. Admixtures or combinations with other agents can make DMSO dangerous due to its ability to enhance transepidermal absorption. Well-known minor side effects with DMSO include garlic odor, local fever (due to exothermic reaction with water) and/or itching (due to histamine release), and dehydration (very hygroscopic).
Possible uses may include topical application to skin ulcers, burns, insect bites, interdigital granulomas, open wounds, and skin grafts; reduction of excess granulation tissue and skin calcification; and treatment of acral dermatitis due to licking. The commercial name of the drug in Russia is Dimexide.
Aloe Vera
The bulk of the information regarding aloe vera is anecdotal. There are more than 300 species of Aloe plants, which vary in chemical composition depending on the species, climate and growing conditions. The terms “aloe”, “aloe vera” and “aloe extract” refer to the end products of juice extraction by various methods from aloe plants. The result of this heterogeneity in collection or extraction is a large difference between the composition, consistency and appearance of different products. Therefore, interpretation and comparison of different studies is often impossible, as the authors point out.
Aloe vera is used to treat pain, itching, fungal and bacterial infections, insect bites, burns, wound healing, and excessive growth of granulation tissue.
Melaleuca oil
Melaleuca oil is extracted from the leaves of the tea tree (Melaleuca alternifolia). It is antibacterial (eg against coagulase-positive staphylococci) and fungicidal (eg against Candida albicans,
T. mentagrophytes) properties.
Excessive application of melaleuca oil to the skin can lead to toxicosis, symptoms that include hypersalivation, incoordination, weakness, hypothermia, and liver toxicity.

Literature:

Muller and Kirk’s Small Animal Dermatology, 7th Edition, P.114-134.
Other articles of the rubric

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– Blockade of peripheral nerves with a neurostimulator

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– Congenital diaphragmatic hernia. Features of anesthesia and mechanical ventilation

– Post-resuscitation activities and post-resuscitation monitoring

– Features of anesthesia in puppies and kittens. Part 2.

– Central venous pressure monitoring

– Epidural anesthesia

– Epidural anesthesia (continued)

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Efficacy of some antiviral agents against COVID-19: in vitro studies

Efficacy of some antiviral agents against COVID-19: in vitro studies

Authors: Xi Wang, Ruiyuan Cao, Huanyu Zhang, Jia Liu, Mingyue Xu, Hengrui Hu, Yufeng Li, Lei Zhao, Wei Li, Xiulian Sun, Xinglou Yang, Zhengli Shi, Fei Deng, Zhihong Hu, Wu Zhong, Manli Wang

Translation: Cancer Prevention Foundation

Since December 2019, the new COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread to more than 200 countries, infecting more than 1. 5 million people, caused 92,798 deaths (data as of April 10, 2020). The World Health Organization (WHO) declared the COVID-19 pandemic on March 11 and called for accelerated development of diagnostic procedures, vaccines and drugs to combat this new disease. In addition to the novel coronavirus infection, influenza viral infections have been a persistent threat to global public health for many years. In the United States only, as estimated by the Centers for Disease Control and Prevention (CDC), during the 2019 winter season-2020, there were at least 39 million cases, 400,000 hospitalizations, and 24,000 influenza deaths (https://www.cdc.gov/flu/weekly/index.htm). Considering that the current circulation of SARS-CoV-2 is accompanied by other influenza viral infections, the study of available and effective drugs for the treatment of both diseases is of great interest.

Indeed, in the early stages of the COVID-19 outbreak, some influenza drugs (eg, oseltamivir) were used to treat patients with COVID-19[12]. We previously reported that favipiravir (T705), an anti-influenza drug approved in Japan and China, showed some efficacy against SARS-CoV-2 in in vitro studies [3]. In addition, umifenovir, an anti-influenza drug with the main antiviral component hemagglutinin (HA), is being used in a clinical trial against COVID-19 (ChiCTR2000029573) and has recently been added to the COVID-19 Diagnosis and Treatment Guidelines (sixth and seventh editions) in China. A recent retrospective study showed that treatment with umifenovir increased the number of recoveries and reduced mortality rates in patients with COVID-19[4]. However, to the best of our knowledge, no systematic analysis of the efficacy of influenza drugs against SARS-CoV-2 has been performed.

In this study, we evaluated the efficacy of six currently available and licensed influenza drugs in the treatment of SARS-CoV-2. These drugs include umifenovir, baloxavir, laninamivir, oseltamivir, peramivir, and zanamivir [5, 6]. M2 inhibitors (amantadine and rimantadine) are not included in this study as they were not recommended by the WHO for the treatment of influenza due to drug resistance. In a first step, the cytotoxicity of compounds in the African green monkey kidney cell line Vero E6 (ATCC-1586) was measured using the standard kit-8 (CCK8) cell scoring method. Cells were then infected with SARS-CoV-2 with a MOI of 0.05 in the presence of test compound or dimethyl sulfoxide (DMSO) control. Dose-response lines were constructed by quantifying the copy number of viral RNA in the infected cell supernatant 48 hours after infection (p. i.). As shown in Figure 1A, umifenovir effectively inhibited viral infection in in vitro studies; The 50% maximum effective concentration (EC 50 ) and 50% cytotoxic concentration (CC 50 ) of umifenovir were 4.11 (3.55-4.73) and 31.79(29.89-33.81) µm, respectively, and the selectivity index (SI = CC50/EC50) is 7.73. Baloxavir partially inhibited SARS-CoV-2 infection (~29%) at a high concentration of 50 μM (Figure 1A). In contrast, laninamivir, oseltamivir, peramivir, and zanamivir did not inhibit SARS-CoV-2 even at the highest drug concentrations (Figure 1A). The antiviral activity of the compounds was also assessed by observing cytopathic effects (CPE) and immunofluorescent staining of infected cells. As shown in Supplementary Figure S1, 48 hours post-infection, only in umifenovir-treated cells but not the other five drugs, viral genome expression and observed cytopathic effect (CPE) to SARS-CoV-2 were significantly reduced. It should be noted that we have also tested some human lung cell lines, such as MRC-5 human embryonic lung fibroblasts and the Calu-3 lung cancer cell line, however, they were not very efficient for SARS-CoV-2 replication and therefore were not used for this. research.

In addition to the influenza virus, umifenovir has been reported to inhibit a wide range of viruses by interfering with several steps in the viral replication cycle [7]. The effect of umifenovir on the stage of SARS-CoV-2 replication was investigated by conducting a preliminary experiment with time-based checkpoints with a frequency of infection (MOI) of 0. 05. Umifenovir was incubated with cells at the beginning of virus entry (Entry), post-entry (Post-entry) and during the entire infection process (Full-time), and the result of the virus was quantified by qRT-PCR. The data obtained showed that umifenovir effectively blocks the virus both at the stage of penetration and immediately after penetration. It has a strong effect on the rate of virus entry (~75% inhibition) with less effect on post-entry events (~55% inhibition) (Figure 1B). In addition, Western blotting (Figure 1C) and immunofluorescence microscopy (Supplementary Figure S2) confirmed that viral genome expression was drastically down-regulated throughout the full-time period (13% of the DMSO group, Figure 1C), and showed a more significant inhibitory effect at the stage of penetration (41%) than at the stage after the beginning of penetration (61%).

Next, a detailed study was carried out on how umifenovir blocks the entry of SARS-CoV-2 into cells. The virus (MOI = 0.05) was allowed to bind to Vero E6 cells at 4°C for 1 hour in the presence of umifenovir (10 μM) or DMSO control. Virus particles bound to the cell (bound virions) and in the supernatant (unbound virions) were analyzed by qRT-PCR. The results showed that treatment with umifenovir resulted in a significant decrease in binding efficiency (67%) compared with the control group (P < 0.05) (Fig. 1d). Accordingly, the proportion of unbound virions increased significantly to 156% of the control group after treatment with umifenovir (P < 0.001) (Figure 1d).

Next, the intracellular movement of the virus was analyzed. As we recently reported, inside infected cells, SARS-CoV-2 underwent vesicle transport, which was first carried out by early endosomes (EEs) and then further transported to endolysosomes (ELs) [8]. Co-localization of virions with endosomes (EEs) or endolysosomes (ELs) was visualized by immunofluorescence microscopy and analyzed statistically (n > 150 cells). As shown in Figure 1e and Supplementary Figure S3, at each time point monitored, there was no significant difference in the number of virions co-localized with EEs when comparing DMSO and umifenovir groups, although as infection progressed (30, 60 and 90 min p. i.), co-localization levels were significantly reduced in both DMSO (24.0%, 5.1% and 3.2%) and umifenovir groups (21.4%, 4.1% and 2.8%), indicating that some virions have already been transported from EEs to the next stage of vesicle transport. In contrast, at 60 min p.i. in the umifenovir group, a slightly higher percentage of virions were transported to ELs (22.4%) than in the DMSO group (18.3%) (P < 0.05) (Figure 1e, f). At 90 min after the start of treatment, significantly fewer virions (~13.5%) were found in the DMSO group, while significantly more virions remained in the umifenovir group (~23.6%), indicating that the drug captured the virus in the DMSO group (P < 0.001) (Fig. 1e, f). Taken together, these results indicated that umifenovir not only interfered with viral attachment, but also with the release of SARS-CoV-2 from intracellular vesicles (ELs).

Among the drugs tested, laninamivir, oseltamivir, peramivir, and zanamivir are the neuraminidase (NA) inhibitors most widely prescribed for the prevention and treatment of influenza. Despite the fact that SARS-CoV-2 does not contain NA analogues, NA inhibitors such as oseltamivir are nevertheless used clinically in the treatment of patients with COVID-19 [1, 2]. Our data indicate that these NA inhibitors were not active against SARS-CoV-2 (Figure 1A), consistent with the conclusion that oseltamivir and zanamivir were ineffective in inhibiting SARS-CoV-2. Baloxavir marboxil is a novel anti-influenza drug that selectively inhibits the endonuclease activity of the viral polymerase responsible for capturing droplet-coated primers from the host mRNA to initiate transcription of the viral mRNA. However, this capillary capture mechanism of endonuclease is not shared by coronaviruses, which encode their own enzymes for the formation of 5′-mRNA structures [10]. This may explain why baloxavir failed to block SARS-CoV-2 infection (Fig. 1a). During this study, Choi et al. also showed that oseltamivir and baloxavirne were able to inhibit SARS-CoV-2 in in vitro studies [11].

Umifenovir, an indole derivative, has been licensed in Russia and China as an antiviral for influenza for several decades. It is a broad-spectrum drug against a wide range of enveloped and non-enveloped viruses. Umifenovir interacts predominantly with aromatic amino acids, and affects several stages of the viral life cycle, either directly affecting viral proteins or virus-associated host factors [7]. For example, in the influenza virus, crystal structures have shown that umifenovir is introduced into the hydrophobic fusion pocket of the HA subunit, thereby preventing the low-temperature conformational change of HA and blocking the fusion process [12]. In hepatitis C virus, umifenovir disrupted both viral attachment and intracellular movement of vesicles [13]. In addition, we found that umifenovir plays a role in the interference between SARS-CoV-2 binding (Fig. 1d) and intracellular vesicle turnover (Fig. 1e, f). Umifenovir can also bind to lipid membranes and change the configuration of cytoplasmic or endosome membranes, which are critical for virus attachment and fusion [7]. Whether umifenovir infects virus and/or cells could be further investigated using a published method [14].

Thus, of the six influenza drugs, only umifenovir effectively suppressed SARS-CoV-2. Functionally, it blocks the spread of the virus, preventing it from attaching and spreading through the ELs. Although the SI of umifenovir is relatively low (SI = 7.73), as with any repurposed drug, its pharmacokinetic profile, including maximum concentration (Cmax), is more important in predicting efficacy. It is believed that if the maximum concentration of Cmax reaches EC 90 , the drug is likely to be effective; while if the Cmax reaches the EC 50 , the drug may be effective in in vivo studies. In humans, a single oral administration of 800 mg umifenovir results in a Cmax of ~4.1 µm [15], and this dosage is effective and safe against various influenza viruses with EC 50 values ​​ranging from 2.5 to 20 µm [7, 16]. Umifenovir also exhibited anti-inflammatory activity, which may increase its efficacy in in vivo studies [16].

Given that the EC 50 (4.11 µm) of umifenovir against SARS-CoV-2 is comparable to or even lower than that of influenza viruses, we therefore suggest that umifenovir is potentially effective in the treatment of patients with COVID-19.