Oral DMSO Treatment for Lipoid Proteinosis: Efficacy, Side Effects, and Long-Term Outcomes

11.07.202317.07.2023 by alexxlab

How does oral DMSO treatment affect patients with lipoid proteinosis. What are the potential benefits and side effects of this therapy. Is DMSO an effective long-term treatment option for lipoid proteinosis. What alternatives exist for managing this rare genetic disorder.

Содержание

Understanding Lipoid Proteinosis: A Rare Genetic Disorder

Lipoid proteinosis, also known as Urbach-Wiethe disease, is an uncommon autosomal recessive disorder characterized by the deposition of hyaline material in various tissues throughout the body. This condition typically manifests with skin and mucous membrane involvement, often accompanied by hoarseness due to laryngeal infiltration.

What are the key features of lipoid proteinosis? The hallmark symptoms include:

Thickening and scarring of the skin
Beaded papules along the eyelid margins
Waxy deposits on the tongue and oral mucosa
Progressive hoarseness starting in early childhood
Neurological manifestations in some cases

Given its rarity, finding effective treatments for lipoid proteinosis has been challenging. Researchers have explored various therapeutic approaches, with oral dimethyl sulfoxide (DMSO) emerging as a potential option in recent years.

The Promise of Oral DMSO Treatment: Initial Findings

Dimethyl sulfoxide (DMSO) gained attention as a possible treatment for lipoid proteinosis following reports of its efficacy in individual cases. How did DMSO come to be considered for this condition? Its anti-inflammatory and antioxidant properties, combined with its ability to penetrate biological membranes, made it an intriguing candidate for addressing the underlying pathology of lipoid proteinosis.

One notable case report published in the British Journal of Dermatology in 1988 described a “remarkable response” to oral DMSO therapy in a patient with lipoid proteinosis. This early success generated interest in further exploring DMSO as a potential treatment option.

Long-Term Outcomes: A Clinical Study of Oral DMSO Therapy

To better understand the long-term efficacy of oral DMSO treatment for lipoid proteinosis, a clinical study was conducted and reported in the German journal “Der Hautarzt” in 1997. The study followed three patients with lipoid proteinosis who received oral DMSO therapy over an extended period.

What were the key details of this long-term DMSO treatment study?

Participants: Two sisters and one unrelated male patient with confirmed lipoid proteinosis
Dosage: 60 mg/kg/day of oral DMSO
Duration: Average treatment time of 3 years
Monitoring: Assessment of skin lesions, mucosal involvement, and vocal symptoms

Disappointing Results: Lack of Efficacy in Long-Term Use

Despite the initial promise shown in earlier case reports, the long-term study revealed disappointing outcomes for oral DMSO treatment in lipoid proteinosis. What were the main findings of this clinical investigation?

After an average of three years of continuous DMSO therapy, the researchers observed:

No significant improvement in skin lesions
Persistent mucosal involvement
Lack of improvement in hoarseness
Disease progression in one patient, including worsening vocal symptoms

These results led the researchers to conclude that long-term oral DMSO treatment failed to produce any beneficial effects in the three patients studied. The therapy was ultimately discontinued due to its lack of efficacy.

Potential Side Effects and Complications of Oral DMSO Treatment

While the study focused primarily on the lack of therapeutic benefit, it’s important to consider the potential side effects and risks associated with long-term oral DMSO use. What adverse effects should patients and clinicians be aware of when considering DMSO treatment?

Common side effects of oral DMSO administration may include:

Gastrointestinal upset (nausea, vomiting, diarrhea)
Skin irritation or rash
Headache
Dizziness
Garlic-like breath and body odor

More serious complications, though rare, can occur with prolonged use or high doses of DMSO. These may include liver toxicity, kidney problems, and neurological effects. The long-term safety profile of oral DMSO, especially in the context of lipoid proteinosis treatment, requires further investigation.

Alternative Treatment Approaches for Lipoid Proteinosis

Given the ineffectiveness of long-term oral DMSO therapy observed in this study, what other treatment options are available for individuals with lipoid proteinosis? While there is no cure for the condition, several approaches have been explored to manage symptoms and improve quality of life:

1. Retinoids

Oral retinoids, such as acitretin, have shown promise in some cases of lipoid proteinosis. These medications may help reduce the deposition of hyaline material and improve skin symptoms. A case report published in the Journal of Dermatological Case Reports in 2014 described successful treatment of two Egyptian patients with acitretin.

2. Surgical Interventions

For patients experiencing severe vocal cord involvement and respiratory symptoms, surgical removal of laryngeal deposits may be necessary. This approach can help improve voice quality and alleviate breathing difficulties.

3. Dermabrasion and Laser Therapy

These techniques may be useful for managing cutaneous manifestations of lipoid proteinosis, particularly facial lesions and scarring. They can help improve the appearance of affected skin and potentially enhance patient self-esteem.

4. Cryosurgery

A case report published in the Journal of Dental Research, Dental Clinics, Dental Prospects in 2008 described the successful use of cryosurgery with liquid nitrogen to remove lip lesions in a patient with lipoid proteinosis. This technique may offer a less invasive option for managing localized mucosal involvement.

Future Directions in Lipoid Proteinosis Research and Treatment

While the long-term study of oral DMSO treatment yielded disappointing results, it underscores the need for continued research into effective therapies for lipoid proteinosis. What avenues show promise for future investigation?

Genetic therapies: As our understanding of the genetic basis of lipoid proteinosis improves, targeted gene therapies may become a possibility in the future.
Novel drug development: Research into compounds that can prevent or reverse hyaline deposition may lead to more effective treatments.
Combination therapies: Exploring synergistic effects of multiple treatment modalities could yield better outcomes for patients.
Personalized medicine approaches: Given the variability in disease presentation, tailoring treatments to individual patient characteristics may optimize therapeutic responses.

Implications for Clinical Practice and Patient Care

The findings of the long-term DMSO study have important implications for the management of lipoid proteinosis. How should clinicians approach treatment decisions in light of this information?

Key considerations include:

Careful evaluation of potential benefits and risks before initiating any experimental therapy
Regular monitoring of disease progression and treatment response
Multidisciplinary care involving dermatologists, otolaryngologists, and other specialists as needed
Patient education about the chronic nature of the condition and the limitations of current treatment options
Psychological support to address the emotional impact of living with a rare, visible disorder

By adopting a comprehensive, patient-centered approach, healthcare providers can help individuals with lipoid proteinosis manage their symptoms effectively and maintain the best possible quality of life.

In conclusion, while oral DMSO treatment initially showed promise for lipoid proteinosis, long-term studies have failed to demonstrate sustained benefits. As research continues, a multifaceted approach combining symptomatic management, emerging therapies, and supportive care remains the cornerstone of lipoid proteinosis treatment. Ongoing collaboration between researchers, clinicians, and patients will be crucial in advancing our understanding of this rare disorder and developing more effective interventions in the future.

[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-Bayazit¹, 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-Bayazit¹, 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.

Cited by

Two Egyptian cases of lipoid proteinosis successfully treated with acitretin.
Bakry OA, Samaka RM, Houla NS, Basha MA.
Bakry OA, et al.
J Dermatol Case Rep. 2014 Mar 31;8(1):29-34. doi: 10.3315/jdcr.2014.1168. eCollection 2014 Mar 31.
J Dermatol Case Rep. 2014.
PMID: 24748909
Free PMC article.
Cryosurgery (N2O) Application to Remove Lip Lesions of Lipoid Proteinosis Syndrome: A Case Report.
Shirani AM.
Shirani AM.
J Dent Res Dent Clin Dent Prospects. 2008 Spring;2(2):68-70. doi: 10.5681/joddd.2008.014. Epub 2008 Aug 15.
J Dent Res Dent Clin Dent Prospects. 2008.
PMID: 23289062
Free PMC article.
Acitretin treatment for lipoid proteinosis.
Gündüz O, Sahiner N, Atasoy P, Senyücel C.
Gündüz O, et al.
Case Rep Dermatol Med. 2012;2012:324506. doi: 10.1155/2012/324506. Epub 2012 Aug 9.
Case Rep Dermatol Med. 2012.
PMID: 23259080
Free PMC article.

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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.

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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).
fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label
Wengström Y, et al. (2008). European oncology nursing society extravasation guidelines.
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What is interstitial cystitis(IC)/bladder pain syndrome? (n.d.).
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.

Current Version

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

What does dimexide treat? | Zdorovye

Dimexide has a number of features that will help to consider this remedy as one of the key products in the treatment of oncological diseases. This compound is a true free radical fighter and detox product. Dimexide is able to penetrate through cell tissues, delivering the necessary substances in preparations, has an anti-cancer effect and, in combination with other anti-cancer drugs, gains more strength.

Dimexide (Dimethylsulfoxide, DMSO, (CH₃)₂SO) has a number of features that make it one of the key products in cancer therapy. This compound is a true free radical fighter and detox product. Dimexide is able to penetrate through cell tissues, delivering the necessary substances in preparations. Dimexide has an anti-cancer effect and, in combination with other anti-cancer drugs, gains more strength.

Dimexide is a safe product. It has been used by a large number of patients in the United States and beyond, and not a single case of death or any serious injury has been recorded.

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Side effects

if 60-90% dimexide is applied to the palm, the skin may be wrinkled for several days.
Garlic-like body odor and mouthfeel are all a specific metabolite of dimexide: dimethyl sulfide, a constituent of onion and garlic flavor. Drinking a significant amount of drinking water will help dissipate unwanted odor.
indigestion, headaches, nausea are detox reactions. If dimexide is diluted with water, heat is released. This reaction is not dangerous.

Be careful! Industrial dimethyl sulfoxide solution contains acid and acetone impurities. Similar DMSO is strongly discouraged . Acetone is extremely harmful to the body. Prolonged contact with acetone leads to disruption of the liver and death in some cases. Dimethyl sulfoxide should be purchased for medical manipulations exclusively from trusted manufacturers.

An undiluted solution of dimethyl sulfoxide has a solid state of aggregation if it is in the refrigerator (not in the freezer) for two hours. Undesirable impurities do not have the opportunity to freeze during this period. Turning the vial over, you can see how streams of poisonous liquid will seep through the ice. It is necessary to use only ice in a bottle.

In order to return dimexide to a liquid state, it is necessary to carefully heat the vial with the contents in a water bath (t water – about 60 ° C). When about half of the contents are unfrozen, the vial should be removed from the bath. It is dimethyl sulfoxide, almost odorless. The agent at a concentration of 26% inhibits the development of various microorganisms in the blood of cancer patients. In oncology practice, the ability of DMSO to deliver drugs with an antitumor effect to the tumor and accumulate in it is exploited.

Sulfur (S)

When salt-laden ocean water becomes gaseous, it oxidizes to dimethyl sulfoxide. Further, obeying the water cycle in nature, it passes into the composition of atmospheric moisture and later clouds form from it and from them water falls to the Earth’s surface in the form of precipitation. Dimethyl sulfoxide is present in every cell.

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Sulfur (S) as a chemical element is involved in a wide range of chemical reactions involving the detoxification of drugs and other toxic compounds. Dimexide has up to forty pharmacological possibilities that are potentially useful in the treatment of a number of diseases. Garlic is an active agent precisely because of the presence of sulfur in this plant. Therefore, dimethyl sulfoxide is also effective.

The body uses sulfur, constantly generating cells instead of old ones.
Sulfur (S) is needed to maintain the permeability of cell membranes.
Sulfur (S) works in the formation of connective tissue, victory over inflammatory processes, support of immune defense.
Lack of sulfur (S) is a problem because this element is lost during the cooking process.

Sulfur deficiency symptoms are prolonged wound healing, brittle nails and hair, digestive dysfunction, inflammation, lung problems, weakened immune system, arthritis, acne, depression, memory loss.

Therapeutic possibilities of dimethyl sulfoxide

Dimexide has the most diverse therapeutic effect.

Anti-pain, anti-inflammatory, anti-virus, anti-fungal, vasodilator, effective against free radicals, immune defense optimization, diuretic. The agent transports drugs through cell membranes, against blood clots, works as a tranquilizer, activates wound healing, takes part in the synthesis of interferon (proteins that fight viruses), enhances the action of antibacterial substances.

Free radicals and dimethyl sulfoxide

DMSO, as already mentioned, is one of the effective means of fighting free radicals. Certain molecules in the human body are unstable and this causes them to destroy cells. Dimexide is attached to these molecules and removes them from the body. DMSO replaces cellular water and thus heals diseased cells by killing free radicals. All this helps to use dimexide in the treatment of cancer and a number of other diseases.

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Transport and strengthening

Dimethyl sulfoxide acts as a transport for other chemical compounds, medicines, enhances their effect. Some drugs, when diluted with DMSO, can be used at lower dosages without weakening their therapeutic effect.

Immunity and Dimethyl Sulfoxide

DMSO strengthens the immune defense by activating the production of white blood cells and macrophages. The tool stimulates macrophages in such a way that they turn into the most destructive for harmful microorganisms and malignant cells. DMSO reduces allergic manifestations by opening cell membranes and acts to attach antigens to cell receptors that stimulate the production of antibodies. This mechanism forms immunity to infections and the development of neoplasms.

Anti-freeze capability

Dimethyl sulfoxide exhibits anti-freeze properties. It protects against damage caused by low air temperatures. Prior to the discovery of dimexide, there was no way to preserve organs without forming ice crystals that destroyed tissues. Thus, the storage of organs for the purpose of transplantation is a type of Dimexide application.

Detoxification

Once in the body, heavy metals are extremely difficult to remove and pose a threat to health. Dimexide acts in this case as a means of detoxification. Sulfur is a micronutrient, which has already been mentioned, a key component of some amino acids, which binds to heavy metals and removes them with urine, defecation and sweat. DMSO (intravenous) clears amyloid proteins that trigger Alzheimer’s disease.

How to use Dimethyl Sulfoxide

It is recommended to use Dimexide (DMSO) only under the supervision of experienced professionals. Thoroughly wash the area on the skin where the product will be applied. The concentration of the agent and dosage vary. White-skinned, fair-haired people are most sensitive to DMSO. For these individuals, any concentration should be 50% or less, especially in the area around the face and neck. The agent applied to the skin is finally absorbed after 4-8 hours. Taken orally, DMSO has a peak in the blood after 4 hours.

Surface application: Liquid form is the most common form of Dimexide application. It makes sense to start surface manipulations of DMSO from low concentrations. The skin must be prepared: clean, dry and undamaged. Concentrations of about 50% are applied to the face and neck area. In areas with reduced circulation, the concentration of the agent is below 70%.

Oral: Oral dosage is 1-2 teaspoons per day. Dimeksid can be mixed with tomato/grape juice. You need to start taking with 1/2 teaspoon of dimexide and gradually build up.

Intramuscular administration of dimexide solutions, intravenous injections, intravenous drips are also possible.

Good to know! DMSO has properties that make it an indispensable agent in the treatment of persons affected by accidents, sudden heart attacks. The tool reduces swelling, activates the supply of oxygen to the tissues.

Dimexide in the form of 30-50% solutions is used for a wide range of problems of the musculoskeletal system (this includes rheumatoid arthritis, arthrosis, sciatica, sprains, myositis) and dermatological inflammations (furunculosis, purulent wounds, burns, thrombophlebitis).
*published by econet.ru.

*Ekonet.ru articles are for informational and educational purposes only and do not replace professional medical advice, diagnosis or treatment. Always consult your doctor for any questions you may have about a medical condition.

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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, infected 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.

Oral DMSO Treatment for Lipoid Proteinosis: Efficacy, Side Effects, and Long-Term Outcomes

Understanding Lipoid Proteinosis: A Rare Genetic Disorder

The Promise of Oral DMSO Treatment: Initial Findings

Long-Term Outcomes: A Clinical Study of Oral DMSO Therapy

Disappointing Results: Lack of Efficacy in Long-Term Use

Potential Side Effects and Complications of Oral DMSO Treatment

Alternative Treatment Approaches for Lipoid Proteinosis

1. Retinoids

2. Surgical Interventions

3. Dermabrasion and Laser Therapy

4. Cryosurgery

Future Directions in Lipoid Proteinosis Research and Treatment

Implications for Clinical Practice and Patient Care

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

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