A product from Merck designated as MK-0524, also known as Laropiprant, is to be trialled as a treatment for the redness of rosacea.

This is great news for rosacea sufferers as MK-0524/Laropiprant will now join Sansrosa and Oxymetazoline which are already in development for this mostly ignored group of rosacea symptoms.

Trialists will take either Lapropiprant or placebo once daily for 4 weeks and be assessed on any reduction in the erythema, or redness associated with rosacea.

Laropiprant is a selective prostaglandin-2 receptor inhibitor, and is believed to specifically target the cascade of events causing flushing.

When taken in combination with Niacin, Laropiprant is used to treat high cholesterol. Niacin on its own would be generally considered unsuitable for rosacea sufferers because of the unwanted side effect of inducing facial flushing. Laropiprant itself has no cholesterol lowering effect, but it reduces facial flushes induced by niacin. The trial specifically excludes anyone who is currently taking more than 500mg a day of Niacin.

To date Merck have not had a product that could be called a rosacea treatment.

Clinical Trial NCT01451619

A Study of Laropiprant (MK-0524) in Participants With Moderate to Severe Erythematotelangiectatic Rosacea (MK-0524-155)

This study will assess the effect of MK-0524 relative to placebo, on signs and symptoms of rosacea and to determine the safety and tolerability profile of MK-0524 in participants with rosacea

A Randomized, Double-blind, Placebo-controlled, Multi-center, Parallel Group Study to Assess the Pharmacodynamics of MK-0524 in Subjects With Moderate to Severe Erythematotelangiectatic Rosacea. (Protocol No. 155)

Trial participants are expected to use effective forms of contraception during the trial and may not have more than 5 papules/pustules. The full list of exclusions further suggests that this drug can have significant side effects.

Related Articles

• How to Cure a Red Face (facial erythema or redness)

Steroid Induced Rosacea is, sadly, one hot topic.

I know this because the blog posting Treating Steroid Induced Rosacea is one of the most visited pages on this site, and is currently approaching 1000 comments. Unfortunately many who find themselves suffering from steroid rosacea have to endure a prolonged withdrawal and recovery period.

This just published abstract relating to Steroid Induced Rosacea is interesting for a few reasons;

• The average period of treatment for these steroid using patients was 20 months.
• The majority were using potent steroids (but we also know that OTC Steroids can cause Steroid Rosacea).
• The majority were using steroids for what the authors claim to be trivial dermatoses.

Could it be the case that vanity is driving some of the suffering that occurs from steroid rosacea?

I wonder if anyone who is suffering from the angry red face of steroid withdrawal would be so quick to use steroids if they had known where it could lead?

The paper ends with the conclusion that oral antibiotics and topical tacrolimus (Protopic) is the treatment of choice.

Steroid-induced rosacea: a clinical study of 200 patients, Indian J Dermatol. 2011 Jan;56(1):30-2, Bhat YJ, Manzoor S, Qayoom S.

Department of Dermatology, SKIMS Medical College Hospital, Srinagar, Jammu and Kashmir

BACKGROUND: Topical corticosteroids were first introduced for use in 1951. Since then uncontrolled use (abuse) has caused many different reactions resembling rosacea – steroid dermatitis or rosacea. Multiple pathways including rebound vasodilatation and proinflammatory cytokine release have been proposed as the mechanism for such reactions.

AIM: The aim was to study the adverse effects of topical steroid abuse and the response to various treatment modalities.

MATERIALS AND METHODS: Two hundred patients with a history of topical steroid use on face for more than 1 month were studied clinically and various treatments tried.

RESULTS: The duration of topical corticosteroid use varied from 1 month to 20 years with an average of 19.76 months. Majority of patients were using potent (class II) topical steroids for trivial facial dermatoses. The common adverse effects were erythema, telangiectasia, xerosis, hyperpigmentation, photosensitivity, and rebound phenomenon. No significant change in laboratory investigations was seen.

CONCLUSION: A combination of oral antibiotics and topical tacrolimus is the treatment of choice for steroid-induced rosacea.

It is Time to Taper!

If you are using steroid creams regularly then this abstract should serve as some good advice to think about tapering off. Don’t withdraw cold turkey style, but taper off instead. See if you can find a doctor to support you.

Related Articles

• Treating Steroid Induced Rosacea
• Combining Azithromycin with Protopic (tacrolimus) topical
• Over the Counter Steroids can cause Steroid Induced Rosacea
• Promiseb even better than Desonide 0.05%
• Community Forum: Proper use of topical steroids

A Press Release today (Vicept are happy to generate publicity at every step of their development) touting more Phase II Study results for their Oxymetazoline based V-101 product. V-101 is a topical slated to treat the redness of rosacea.

The first Phase II trial results for V-101 were announced just 3 months ago.

It isn’t yet clear what Vicept Therapeutics have done with the commonly available active ingredient oxymetazoline to package it as palatable to the sensitive skin of rosacea sufferers.

This most recent study `was designed to optimize the concentration of V-101 Cream in preparation for Phase III clinical testing in patients with erythematous rosacea and to further characterize the duration of the clinical effect’.

The previous Phase II trial examined 4 concentrations but this latest trial evaluated 2 concentrations of the active ingredient in V-101.

Vicept Therapeutics are now pushing for a meeting with the FDA to seek permission to enter into Phase III evaluations.

Vicept Therapeutics Announces Positive Results from a Second Phase II Study of V-101 for the Treatment of Type I Rosacea (Erythematotelangiectatic Rosacea)

Malvern, PA – April 19, 2011

Vicept Therapeutics, Inc. announced today positive results from a second Phase II clinical trial evaluating the dose-response relationship of two concentrations of V-101 cream, a topical cream for the treatment of Type I Rosacea (Erythematous Rosacea).

The results demonstrated a statistically significant improvement (p= <0.01) in the primary endpoint, a reduction in facial erythema or redness, over a twelve hour period versus placebo cream in patients with erythematous rosacea.

Further, V-101 demonstrated a safety profile similar to placebo cream. This is the second of two V-101 Phase II studies to achieve statistical significance in the primary endpoints.

Related Patents

See Vicept Therapeutics gets funding for V-101 for coverage of the Patents owned by Vicept relating to their Oxymetazoline based treatment.

What About Rebound Redness?

There is still a question in my mind about how in-development treatments like V-101 will deal with the possibility of rebound redness.

Related Articles

• Oxymetazoline good for 6 hours and safe for 3 months
• Patents abound for treating rosacea with alpha agonists
• Oxymetazoline may be good for 2 years
• Xylometazoline (Otrivin) is another red face treatment

A brief extract today covering a paper detailing how the topical Xylometazoline can be used to treat the redness of rosacea.

Similar to oxymetazoline, xylometazoline is marketed as a nasal decongestant under many brand names. Brands you may come across include Otrivine, Otrivin, Sinutab Nasal Spray, Cirovin and Novorin.

Oxymetazoline is the active ingredient in over the counter products such as Afrin, Vicks Sinex and Visine. The potential side effects of oxymetazoline when applied topically include rebound redness, hypertension and palpitation.

We know that both oxymetazoline and xylometazoline are fast acting topical decongestants and that their effects are similar. Oxymetazoline was developed from Xylometazoline in 1961.

Caution

Even though the active ingredient discussed in this paper is readily available as a nasal decongestant, it doesn’t follow that applying Otrivin topically is a good idea. There are many other ingredients in these topicals that may be irritating to rosacea skin. Also you cannot be sure that you are applying the correct amount when you use a spray topically. Finally, the long term effects of the metazolines on skin won’t be known until a lot more research and trials are completed.

Some Good News

What is encouraging, though, is the fact that more researchers are looking at the metazoline family and that new treatments for the redness of rosacea are on the horizon.

Rosacea (erythematotelangiectatic type) effectively improved by topical xylometazoline.

J Dermatol. 2010 Nov 3. doi: 10.1111/j.1346-8138.2010.00999.x.

Kim JH, Oh YS, Ji JH, Bak H, Ahn SK., Department of Dermatology Institute of Basic Medical Science, Yonsei University Wonju College of Medicine, Wonju Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Related Articles

• Oxymetazoline good for 6 hours and safe for 3 months
• V-101 (Oxymetazoline) starting Dose-Finding Trials
• Oxymetazoline: what about rebound redness ?
• Sansrosa’s sister to enter redness race
• Dermatology Times highlights Afrin and Sansrosa
• Red Face: when flushing isn’t Rosacea

We were tipped off by a comment on the blog posting about Cutanix going offline, to the possible future availability of a Cutanix like product. The commenter, who works for SkinMedica told us that;

skincarejunkie

Bioform was sold to Merz Aesthetics.
In that sale Cutanix was sold to SkinMedica.
They will launch the product this Jan so stay tunned!

The last news from Cutanix was in April 2007 when they disappeared off the internet and a warning letter from the FDA surfaced. At that stage DRL was a part of my regular regime, it kept my facial redness under pretty good control. I, along with many others was sad to hear that this product was no longer available.

Now SkinMedica has announced the availability of their formulation of the Cutanix DRL, as a new product called Redness Relief Calmplex Treatment Moisturizer.

This product is available in 1.6 ounces (50ml / 45gm) for $80 at skinmedica.com.

By comparison we have been used to paying $45.00, or less with a discount, for 1.7 oz of Cutanix DRL.

How to Purchase

SkinMedica products are available at physician offices across the US. You can use their Physician Finder to find one close to you. Alternatively you can purchase RR CalmPlex from their web site and designate any physician when you place your order.

Ordering outside the US is to be possible via the international distributors for SkinMedica.

Does it Work ?

The Redness Relief Camplex contains the same active ingredient from the Cutanix Dynamic Relief Lotion, namely 4-Ethoxybenzaldehyde. SkinMedica call this ingredient CalmPlex. Cutanix’s moniker was Quadrinone.

SkinMedica tell us that they have commissioned Dr. Zoe Draelos to undertake pilot studies into the effectiveness of Redness Relief CalmPlex and that the results of these studies are on file at SkinMedica. Of course not being able to read this studies does mean that we can’t see for ourselves how effective is has proven to be. Perhaps in the future more research will become available.

The publicity for RR CalmPlex also tells us that in in-vitro (i.e. in the lab, not on skin) CalmPlex was found  to be an inhibitor of Prostaglandin E2 (PGE2), claimed to be a key natural vasodilator.

A small pilot study published in 2005 concluded that this benzaldehyde-derived anti-inflammatory agent may be useful in reducing facial erythema in a rosacea model.

Redness Relief CalmPlex Ingredients

Water/Aqua/Eau, Glycerin, Ethoxydiglycol, Squalene, Isocetyl Stearate, Simmondsia Chinensis (Jojoba) Seed Oil, Isostearyl Palmitate, Mineral Oil, Glyceryle Stearate, PEG-100 Stearate, Niacinamide, Glycereth-7, PEG-7 Glyceryl Cocoate, 4-Ethoxybenzaldehyde (CalmPlex), Cetyl Ricinoleate, Polysorbate 20, Polyacrylamide, C13-14 Isoparaffin, Laureth-7, Phenoxyethanol, Methylparaben, Propylparaben, Butylparaben.

Defunct Cutanix DRL Ingredients

By comparison, here are the Cutanix DRL Ingredients. Note that Cutanix referred to 4-Ethoxybenzaldehyde  as Quadrinone.

Purified Water, Glycerin, Ethoxydiglycol, Glyceryl Stearate (and) PEG 100 Stearate, Squalane (vegetal), Isocetyl Stearate, Isostearyl Palmitate, Simmondsia Chinesis (Jojoba) Seed Oil, Lipovol MOS-130, Niacinamide, Glycereth-7, PEG-7 Glyceryl Cocoate, Polyacrylamide (and) C13-14 Isoparaffin (and) Laureth-7, Quadrinone, Cetyl Ricinoleate, Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and) Butylparaben (and) Propylparaben (and) Isobutylparaben, Polysorbate-20

Are you Excited?

I can well remember the sad thoughts when Cutanix was no longer available. Will you be tempted back to try RR CalmPlex?

Related Articles

• Cutanix goes offline, gets letter from FDA
• Benzaldehyde reduces Facial Erythema
• Cutanix DRL (Quadrinone) reduces redness
• Red Face: when flushing isn’t Rosacea

One of the up and coming treatments for the redness of rosacea is the use of oxymetazoline based formulations.

Oxymetazoline is the active ingredient in decongestant products like Afrin, Sudafed OM and Vicks Sinex as well as in eye drops like Visine LR.

Recent publicity from Vicept Therapetics suggests that their product in development V-101 contains the active ingredient oxymetazoline.

A well known side effect of Visine is rebound redness, where continued use leads to the redness that you were originally treating. Extended usage of Afrin can also lead to rebound nasal congestion.

Rebound redness with eyedrop use

PEOPLE’S PHARMACY

Oxymetazoline is a long-acting topical drug that constricts, or shrinks, blood vessels. That is how it relieves congestion in the nose. But people who use nasal decongestants for allergies, colds or sinus problems are warned to use such products for only three to five days. After that they may experience rebound congestion as the medicine wears off.

The same thing can happen in the eyes. Rebound redness occurs when the blood vessels dilate after the effects of the medicine fade. It can take several days (or sometimes longer) for this effect to gradually disappear. You may be better off with artificial tears rather than anti-red drops.

For any oxymetazoline based treatment to succeed as a treatment for a chronic condition like rosacea (i.e. rosacea isn’t a condition that goes away after just a couple of days), the promoters will need to prove that their formulations are safe for use in the medium to long term.

A 2007 paper Successful Treatment of the Erythema and Flushing of Rosacea Using a Topically Applied Selective α1-Adrenergic Receptor Agonist, Oxymetazoline attempted to answer this questions thus;

Neither of our patients exhibited either problem with the application of oxymetazoline to the skin. While the laboratory induction of receptor desensitization cannot yet be perfectly correlated with actual physiologic response, recent laboratory studies indicate that agonists that are more selective for α1D-adrenoceptors are less prone to induce receptor desensitization than are α1A- or α1B-agonists. The clinical significance of this may be an important consideration in contemplating any potential future use of these drug classes on the skin because agonists with certain receptor subtype binding profiles may retain their clinically desirable effects while minimizing their adverse effect.

(emphasis mine)

You can download a full copy of this article from the Archives of Dermatology website; Successful Treatment of the Erythema and Flushing of Rosacea Using a Topically Applied Selective α1-Adrenergic Receptor Agonist, Oxymetazoline

So we all wait to see how the trials of V-101 prove performance with extended and intermittent usage of oxymetazoline.

Related Articles

• Sansrosa’s sister to enter redness race
• V-101 (Oxymetazoline) starting Dose-Finding Trials
• Rosacea Support Community: "Afrin" cure? 

The trial will study the efficacy of V-101 Cream, applied once per day, at a low dose of 0.01%, 2 lots of mid-dose of 0.06% and 0.1%, as well as a high dose of 0.15%.

The active ingredient in the formulation has not been officially disclosed, but a reasonable guess is that the active is oxymetazoline. The patents held by the company suggest that oxymetazoline is a primary active of interest, and further confirming the active ingredient is an exclusion criteria for this trial that precludes the “use of products containing oxymetazoline within 14 days of baseline”.

Oxymetazoline is the active ingredient in over the counter products such as Afrin, Vicks Sinex and Visine. The potential side effects of oxymetazoline when applied topically include rebound redness, hypertension and palpitation.

It will be interesting to see how well oxymetazoline performs in a double blind trial as well as get an understanding of any rebound redness and also whether any rebound redness occurs when continuing to use oxymetazoline after having a break.

Here is a short extract of the just announced trial;

Dose Response Study of Patients With Erythematous Rosacea

The purpose of this study is to evaluate the dose-response relationship (effect) of four concentrations of V-101 Cream in patients with erythematous (redness) rosacea.

Related Links

• Vicept Therapeutics positive Phase I study of V-101 for redness of Rosacea
• Vicept Therapeutics gets funding for V-101
• Sansrosa’s sister to enter redness race
• oxymetazoline good for 6 hours and safe for 3 months
• oxymetazoline may be good for 2 years
• AAD Poster Sessions: oxymetazoline
• Dermatology Times highlights Afrin and Sansrosa

Now that a company name has surfaced we can put the pieces together back to 2007 when Rosacea News featured a publication that suggested that a viable alternative to Sansrosa was about to compete in the anti-redness race. The author of that paper, Dr. D. Shanler is a holder of multiple patents relating to alpha adrenoceptor agonists and treating skin conditions.

While it can’t be said for sure that V-101 is oxymetazoline, it is encouraging to see a product of this sort slowly making its way through the drug development cycle.

V-101 was found to offer a benefit to the redness of rosacea, and was not detectable in the blood of users.

Vicept Therapeutics Announces Positive Clinical Study Results of V-101 for the Treatment of the Erythema of Rosacea

MALVERN, Pa., Aug. 5 /PRNewswire/ — Vicept Therapeutics, Inc., a privately held specialty biopharmaceutical company, announced positive results today from a pharmacodynamic and pharmacokinetic clinical trial of the Company’s lead product V-101, a topical cream under investigation for the treatment of erythema in patients with rosacea.

The double-blinded, placebo-controlled, crossover clinical trial of 22 patients with rosacea was designed to evaluate the bioavailability of V-101 and provide preliminary evidence of efficacy as measured by improvement in moderate to severe erythema, the bright redness of the skin associated with rosacea.  V-101 had a side effect profile similar to placebo and V-101′s active ingredient was not detectable in study participants’ plasma, a strong indication of the product’s overall tolerability and safety profile.  Additionally, the study results were positive for all endpoints, demonstrating a clinically and statistically significant improvement in treating the erythema associated with rosacea.

“This important study demonstrated that V-101 has a good safety profile and provides statistically significant evidence of effectiveness in treating the erythema of rosacea,” said Dr. Neal Walker, president and chief executive officer of Vicept. “We look forward to advancing our clinical program into Phase II and continuing our efforts to develop this product for the 16 million people in the United States who live with this common, chronic skin condition every day.”

Related Articles

• Vicept Therapeutics gets funding for V-101
• Sansrosa’s sister to enter redness race
• oxymetazoline good for 6 hours and safe for 3 months
• oxymetazoline may be good for 2 years
• AAD Poster Sessions: oxymetazoline
• patents abound for treating rosacea with alpha agonist

Vicept Therapuetics is based in Malvern in Pennsylvania and is a privately held company.

From Fidelity Biosciences Joins $10M Series A for Vicept Therapeutics

“We are delighted by the strong investor interest in this round of financing which will allow us to continue to advance the development of our product pipeline utilizing our novel, patent protected α-adrenergic receptor technology for the treatment of diseases of the skin,” added Dr. Walker. “With this investment, we will have the necessary resources to continue progress with our lead candidate through Phase II for rosacea as well as pursuing other dermatologic conditions including actinic purpura and peri-procedural bruising of the skin.”

Great to see another company getting funding to develop new treatments for rosacea. Obviously there is a belief by venture capitalists that rosacea is a growth market, especially for the treatment for erythema.

The following patent looks likely to be related to the company and their product development.

COMPOSITIONS AND METHODS FOR TREATING PURPURA

(WO/2009/065116)

PCT/US2008/083774

VICEPT THERAPEUTICS, INC

SHANLER, Stuart D; ONDO, Andrew

Embodiments of the present invention are directed to compositions and methods for the treatment of purpura. Preferred compositions comprise an α adrenergic receptor agonist selected from selective α₁ adrenergic receptor agonist, selective α₂ adrenergic receptor agonist, non-selective α₁/α₂adrenergic receptor agonist, agents with α₂ adrenergic receptor agonist activity and combinations thereof, in a pharmaceutically acceptable carrier in order to treat and improve the cosmetic appearance of hemorrhagic (purpuric) lesions in the skin.

The authors of this 2009 patent describe some trials where the following formulations were trialled;

• Oxymetazoline hydrochloride from Afrin Original 12 Hour Nasal Spray
• Naphazoline hydrochloride from Clear Eyes Maximum Redness Relief
• Tetrahydrozoline hydrochloride from Visine Original
• Phenylephrine hydrochloride from Neo-Synephrine Extra Strength Spray
• Brimonidine tartrate from Bausch & Lomb
• Oxymetazoline hydrochloride and brimonidine tartrate combined.

The results of this trial claimed;

… that this demonstrates that selective αi adrenergic receptor agonists and selective α₂ adrenergic receptor agonists, used separately or in combination, when topically applied to and around a treatment site after a procedure that can/will induce purpura, will reduce the size and appearance of the purpuric macules/ patches and is an effective treatment to hasten their resolution.

The source of the purpura in this instance was a pulse dye laser at 585nm.

The publishers of this patent have an additional similar patent that was mentioned by Rosacea News  in 2007;  Sansrosa’s sister to enter redness race

Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using a1-adrenoceptor agonists

United States Patent Application 20050165079

Shanler, Stuart D.; (New York, NY) ; Ondo, Andrew; (Las Cruces, NM)

The present invention is directed to the treatment of skin erythema as exhibited in rosacea and other conditions characterized by increased erythema (redness) of the skin. These conditions exhibit dilation of blood vessels due to a cutaneous vascular hyper-reactivity. In particular, the present invention is directed to a novel composition and method for the treatment of skin erythema using .alpha..sub.1-adrenergic receptor (.alpha..sub.1-adrenoceptor) agonists incorporated into cosmetic, pharmacological or dermatological compositions for topical application to the skin.

Whilst it appears that no new molecules have been discovered, these patents, if allowed, will protect the usage of these formulations to treat the redness of several skin conditions including rosacea. As we have seen with the Sanrosa product it can take many years and a large investment in R&D to progress from a discovery to a sellable product. It is great news that Vicept has secured funding to begin this drug approval process.

[update]:From a press release dated January 10, 2011, Vicept Therapeutics Announces Positive Phase 2 Data of V-101 for the Treatment of Type I Rosacea (Erythematotelangiectatic Rosacea)

Vicept Therapeutics, Inc. announced today positive study results from a Phase 2 clinical trial evaluating the dose-response relationship of 4 concentrations of V-101 cream, a topical cream for the treatment of Type I Rosacea (Erythematotelangiectatic Rosacea). The results demonstrated a highly statistically significant (p=0.006) improvement in the primary end point, which was a reduction in facial erythema, over an eight hour period in patients with erythematotelangiectatic rosacea (ETR), versus placebo. Further, V-101 demonstrated a safety profile similar to placebo cream and no evidence of “rebound” or tachyphylaxis was observed.

“These positive data showed that V-101 significantly reduced the redness associated with Type I rosacea (ETR) and demonstrated a favorable side effect profile, further confirming its potential to be the first effective topically applied therapy directed specifically toward the erythema of rosacea,” said Dr. Neal Walker, President and Chief Executive Officer of Vicept. “This is a major milestone for the Company and we intend to continue to advance the V-101 development program.”

Study V-101-ROSE-202 is a prospectively randomized, multi-centered, double-blinded, placebo-controlled, Phase II clinical trial designed to evaluate the dose-response relationship of four concentrations of V-101 cream vs. vehicle (placebo) for the treatment of the erythema associated with rosacea. A total of 183 patients with moderate to severe erythema participated at seven investigational centers across the United States. Patients were divided among five groups and self-administered one of four concentrations of V-101 cream or vehicle (placebo) cream once daily for 28 days. The study also demonstrated that V-101 cream was extremely well-tolerated in these patients with ETR, a population of patients with facial skin that is highly sensitive to topical preparations. The safety profile of all the active preparations was similar to that of placebo.

Related Articles

• oxymetazoline good for 6 hours and safe for 3 months
• oxymetazoline may be good for 2 years
• AAD Poster Sessions: oxymetazoline
• patents abound for treating rosacea with alpha agonists

La Roche-Posay are not particularly well known in the rosacea world but they do sponsor the National Rosacea Society and have a range of products, called Rosaliac, that targets rosacea sufferers.

The company is taking the opportunity of the rosacea awareness month and their support of the NRS to promote a new product – Rosaliac UV Fortifying Anti-Redness Moisturizer with SPF 15.

The ingredients of this product are hard to find, all I can see is the generic “a patented combination of ingredients including Vitamin CG, Xanthine and thermal spring water to help neutralize visible redness” as well as a “patented broad spectrum filtering system to help protect against UVA and UVB rays”.

The ingredients for the related Rosaliac Skin Perfecting Anti-Redness Moisturizer are listed here: Rosaliac with xanthine, vitamin CG & B3. We would need to know what La Roche-Posay have included to add broad spectrum sun protection before giving it a tick for rosacea sufferers.

Rosaliac (apparently the range with the highest loyalty in the La Roche-Posay offering) is said to provide an instant relief of visible redness due to a light green tint. This sort of approach might not be to all rosacea sufferers’ liking. How do you find this product ?

Featured Product

Related Articles

• Rosaliac with xanthine, vitamin CG & B3
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