A word of caution is needed here of course. Patents represent aspirational ideas. They don’t prove that a product exists or will ever exists – they are just inventors attempting to protect their intellectual property.

How Does Ivermectin Work?

The most easily found research on Ivermectin’s efficacy relate to its ability to eliminate demodex mites. Certainly the recently unearthed patents relating to Ivermectin all refer to the anti-parasitic effects as being important in their operation.

“The present invention also features formulation of ivermectin into pharmaceutical compositions useful for the treatment of ophthalmic pathologies, particularly ophthalmic pathologies due to Demodex folliculorum, and more particularly ocular rosacea.”

I have think that there is something else about Ivermectin that hasn’t surfaced yet. Surely all of the effort being invested in Topical and Ophthalmic Ivermectin based treatments aren’t all predicated on eradicating demodex mites are they? Stay tuned for further Ivermectin revelations!

What is Ivermectin?

Ivermectin is a mixture of two compounds belonging to the class of the avermectins, 5-O-demethyl-22,23-dihydroavermectin A_1a and 5-O-demethyl-22,23-dihydroavermectin A_1b. They are also known under the names of 22,23-dihydroavermectin B_1a and 22,23-dihydroavermectin B_1b.

Ivermectin comprises at least 80% of 22,23-dihydroavermectin B_1a and less than 20% of 22,23-dihydroavermectin B_1b. This active agent forms part of the class of the avermectins, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds J. E. F. (Ed), (1993) Martindale, The Extra Pharmacopoeia, 29th Edition, Pharmaceutical Press, London).

So there you go, aren’t you glad you asked

ADMINISTRATION OF AVERMECTIN/MILBEMYCIN COMPOUNDS FOR THE TREATMENT OF OPHTHALMIC PATHOLOGIES

Administration of at least one compound of the family of the avermectins or of the family of the milbemycins, notably ivermectin, is useful for the treatment of ophthalmic pathologies, including ocular rosacea.

United States Patent Application 20120053140

Publication Date: 03/01/2012

Filing Date: 06/14/2011

Assignee: Galderma S.A. (Cham, CH)

Inventors: Kaoukhov, Alexandre (Juan les Pins, FR), Villard, Christophe (Le Tignet, FR), Bouissou, Philippe (Roquefort Les Pins, FR)

[1] A method for the treatment of symptoms of ocular rosacea in the eye(s), said symptoms being selected from the group consisting of a feeling of burning of the eye, a feeling of smarting of the eye, a feeling of dryness of the eye, an increased sensitivity to light, blurred vision, and a complication of ocular rosacea in the cornea, said method comprising topically administering to the eye(s) of an individual in need of such treatment, a thus effective amount of ivermectin, formulated into an eyewash composition with a pharmaceutically acceptable vehicle therefor, wherein ivermectin is the sole active ingredient for treating said symptoms of ocular rosacea in said eyewash, said eyewash being sterile, non-irritating and compatible with eye tissue.

…

The term “avermectins” means in particular a compound selected from among ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin, emamectin and selamectin.

The term “milbemycins” means in particular a compound selected from among lepimectin, milbemectin, milbemycin oxime and moxidectin, nemadectin.

Another related patent, also by Kaoukhov and assigned to Galderma details Topical Ivermectin combined with Metrogel.

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Skin and Allergy News has an article today highlighting the recent positive research into the usage of Cyclosporin as a treatment for Ocular Rosacea.

Dr. Harper mentions that she likes to include Oracea as an oral treatment for the worst of her ocular rosacea patients, but also uses 20mg twice a day of doxycycline for those who cannot afford Oracea. The point is made, that 50mg a day of doxycline does cross over the line to be no longer strictly subantimicrobial but anti-bacterial.

Interestingly also the point is made by Dr. Fowler that Cyclosporine is off-label when used to treat ocular rosacea, and may always be so. Dr. Fowler says that this is because ophthalmologists find it difficult to quantify ocular rosacea and indeed to distinguish it from dry eye. Thus the implication is that approval for Cyclosporine as a treatment for chronic dry eye serves as a `close-enough’ indication for ocular rosacea symptoms as well.

This article continues an ongoing series of articles, highlighted by Rosacea News, that reveals Restasis (Cyclosporine) as an Ocular Rosacea Treatment.

Topical Cyclosporine Proves Beneficial For Ocular Rosacea

By: BRUCE JANCIN, Skin & Allergy News Digital Network

WAIKOLOA, HAWAII – Topical cyclosporine 0.05% ophthalmic emulsion significantly outperformed artificial tears for the treatment of ocular rosacea in a double-blind, randomized, multicenter study.

“It’s a fairly small study, but I think it gives us some valuable information. This gives us a new option topically,” Dr. Julie C. Harper said in highlighting the study at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

…

“People definitely felt better with this product than with artificial tears,” observed Dr. Harper, a dermatologist at the University of Alabama at Birmingham.

In addition, the topical cyclosporine group fared significantly better in the other study end points, which focused on eye dryness and tear production.

Also, tear break-up time (a measure of how quickly an eye becomes dry) increased by a mean of 3.56 seconds in the cyclosporine group, a significantly more favorable effect than the 0.04-second decrease in the artificial tears arm.

…

The investigators speculated that topical cyclosporine’s clinical benefits in ocular rosacea are due to the drug’s anti-inflammatory effects, including a cyclosporine-mediated reduction in the number of activated lymphocytes in the conjunctiva, in combination with stimulation of increased tear production.

[Dr. Fowler disclosed that he has received research grants from Allergan, which markets Restasis. He also serves as a consultant to Galderma, which markets Oracea, as well as to numerous other pharmaceutical companies. Dr. Harper is on the speakers bureaus for Allergan, Galderma, and a handful of other companies.]

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• Ocular Rosacea Video Worth a Watch

Ocular Rosacea: Curse of the Celts and Celebs

The presentation is given by Heather Potter, MD, an Ophthalmologist from the University of Wisconsin School of Medicine and Public Health.

Highlights

Some of the points that I thought were interesting;

• rosacea is not purely related to demodex mites because eradicating them with Lindane (quite a dangerous drug it seems) does not help rosacea symptoms.
• some good slides and description of the life cycle of demodex
• tea tree oil shampoo for lid hygiene as in normal blepharitis treatment is a good option for demodex infestation of the eyelid.
• Tea Tree Oil is the best treatment we have for demodex
• Tea Tree Oil 20% combined with macadamia or walnut oil is another option
• Otophyma gets a mention, with a slide where you are directed to the visible pores in the enlarged ear
• Azelaic Acid 20% is mentioned at a 1st line topical treatment, but I think they actually meant Finacea which is only 15%
• Sodium Sulfacetamide wash as a lid scrub is mentioned as an alternative to baby shampoo
• “Burst and Taper” or just starting out with 40mg a day of doxycycline is mentioned as an oral treatment
• 3000 – 4000 mg Omega 3, tapering to 2000 mg a day maintenance has worked well for her ocular rosacea patients. It takes 6 weeks to have an effect.
• Ocular rosacea is found equally in males and females.
• Cyclosporin gets a mention as a topical treatment. Azasite Plus drops (a steroid plus azithromycin) is shown on the topical treatments slide.
• Need to raise the body temperature by 5 degrees before attempting warm compresses to liquify the meibomian gland secretions you are trying to clean.
• Cyclosporin gets another mention for dry eyes, along with punctal plugs
• Doxycycline gets a mention specifically as an ocular rosacea treatment
• An image from a “throw away journal” with what looks like a device to heat and massage the eyelids to help clear the glands.

The video is 25 minutes long, but you can squash it down to 16 minutes if you select the 1.5x link at the bottom of the video player.

Well worth a watch.

Best Bit for You?

What bit of the video was most worthwhile for you?

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Currently there is no definitive diagnostic test for ocular rosacea, it is based on clinical symptoms. One proposed diagnostic test is high abundance of oligosaccharides in the tear fluid of patients with rosacea.

Definitions

Schirmer Test: determines whether the eye produces enough tears to keep it moist.

TBUT: Tear Break up Time, the time required for dry spots to appear on the corneal surface after blinking.

Abstract

Clinical and laboratory study of ocular rosacea in northern Greece.

Lazaridou E, Fotiadou C, Ziakas N, Giannopoulou C, Apalla Z, Ioannides D., J Eur Acad Dermatol Venereol. 2011 Mar 2.

First Departments of Dermatology-VenereologyOphthalmology, Aristotle University Medical School, Thessaloniki, Greece.

Background: The prevalence of ophthalmic involvement in rosacea is probably higher than previously presumed and varies considerably among several studies. Objective This study aimed to determine the incidence of ocular disease among a population of rosacea patients in Northern Greece, to objectively determine the presence of eye dryness in rosacea patients with and without clinical ophthalmic involvement and correlate the severity of ocular disease with the severity of cutaneous rosacea.

Methods: One hundred patients with rosacea were assessed for the stage of their disease and examined for ocular symptoms and signs. In 24 of them the tear break up time (TBUT) and Schirmer test were performed in each eye, along with 24 controls.

Results: A total of 33 patients (33%) were positive for ophthalmic findings. The most frequent symptoms and signs were burning sensation and tearing, and conjunctivitis and blepharitis, respectively. Eleven patients with ophthalmic manifestations had mild to moderate erythematotelangiectatic rosacea, 17 had moderate papulopustular rosacea and four exhibited findings of phymatous rosacea. The total mean value of patients’ Schirmer tests was significantly lower compared with the healthy controls (P < 0.0001). Mean TBUT was shorter in the rosacea group than that in the age-matched controls (P < 0.0001).

Conclusion: Ocular involvement in rosacea is a common phenomenon with eye dryness being an early sign. Tear function tests, like Schirmer test and TBUT, although not specific, could contribute to the screening and early diagnosis of the disease, to prevent the potential development of sight-threatening conditions.

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Itchy, sandy feeling in eyelids may be blepharitis

Question: What causes my eyelids to be itchy and sandy in the mornings?

Answer: The most likely cause of your symptoms is something called blepharitis, or inflammation of the eyelids, and is the most common ocular disease we see. This type of inflammation is sometimes, but not always, associated with a bacterial infection, dry eyes, or a skin condition such as acne rosacea.

…

Common symptoms may include the scratchy sensation of a foreign body, or burning, flaking, tearing, crusting, itching, inflammation and redness of the lid margins.

Dry eye syndrome may be associated with either type and may make the symptoms worse. Allergic sources, smoke, dust or a dry environment, while not a cause of this problem, can also contribute to the severity of symptoms. The uncertain cause, chronic nature of the associated conditions, and inadequate treatments make this condition difficult to manage.

Given the number of possible causes and symptoms, the actual diagnosis in your case requires a good eye examination by your ophthalmologist.

…

Taking fish oil capsules may be helpful by making the oily secretions less thick and allowing them to flow out of the glands more freely.

It is important to understand that blepharitis is often a chronic condition requiring ongoing attention in order to reduce symptoms over time. However, good eyelid hygiene and prescription medications are often effective at managing the symptoms of this disease.

Dr. Donald Lewellen Jr. is a board-certified ophthalmologist at Eye Clinic of Manitowoc and the Two Rivers Eye Clinic.

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Timolol has been used orally in the treatment for hypertension and opthalmic solutions have been used to reduce intraocular pressure in glaucoma.

Clinical Trial NCT01250457: Topical Timolol for the Treatment of Benign Vascular Periocular Lesions

Pre-treatment and post-treatment lesion size will then be compared to determine whether twice-daily topical application of timolol 0.5% solution alters the morphometry of benign vascular periocular lesions.

…

Benign vascular tumors of the eyelid are common causes of ocular morbidity. Capillary hemangiomas in children cause refractive and occlusive amblyopia. In adults, Rosacea-associated eyelid telangiectasis and sclerosis can result in keratitis and corneal neovascularization.

Corticosteroid therapy of benign vascular lesions risks sight-threatening complications including central retinal artery occlusion and significant systemic morbidity.

Alternatively, oral and intravenous beta-blockers have been reported to induce regression of benign vascular lesions. One recent report documented efficacy of topical timolol in treating a large capillary hemangioma of the eyelid in a child.

Topical application reduces systemic side effects of beta-blockers including bradycardia, hypotension, heart block, and bronchospasm. This one-year prospective case-control series will investigate whether topical Timolol 0.5% solution applied twice daily causes significant regression of benign vascular periocular lesions.

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Mites and Eye Symptoms

A new study has found there may be a link between ocular rosacea and bacteria associated with Demodex mites, microscopic inhabitants of normal skin that tend to occur in much greater numbers in those with rosacea.

In the recently published study of 59 rosacea patients, Dr. Jianjing Li and colleagues at the Ocular Surface Center in Miami found a significant correlation between facial rosacea, infestation of the eyes with Demodex mites and reaction to certain mite-related organisms previously shown to stimulate an immune response in rosacea sufferers.

Rosacea News covered this paper in April and resulted in a similar summary;

Ocular symptoms match Demodex Bacteria reaction too

This paper is one more small achievement using statistics to try to build a picture of how demodex mites might be involved with rosacea symptoms. We have learnt from recent research that rosacea sufferers are sensitive to 2 particular types of bacteria that have been isolated in demodex mites.

This study further establishes that a reaction to the bacteria correlates to ocular symptoms as well as facial symptoms.

So the small step forward is that for those with rosacea linked to demodex bacteria, ocular symptoms may also be exacerbated by a reaction to the bacteria.

As the NRS Blog notes, more research may help draw out exactly how strongly demodex bacteria and facial and ocular rosacea symptoms are related to each other.

Related Articles

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• demodex mite bacteria causes the inflammation ?
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This study further establishes that a reaction to the bacteria correlates to ocular symptoms as well as facial symptoms.

So the small step forward is that for those with rosacea linked to demodex bacteria, ocular symptoms may also be exacerbated by a reaction to the bacteria.

Correlation between Ocular Demodex Infestation and Serum Immunoreactivity to Bacillus Proteins in Patients with Facial Rosacea, Ophthalmology. 2010 Jan 14, Li J, O’Reilly N, Sheha H, Katz R, Raju VK, Kavanagh K, Tseng SC..

PURPOSE: To investigate correlation between ocular Demodex infestation and serum.

DESIGN: A prospective study to correlate clinical findings with laboratory data.

PARTICIPANTS: We consecutively enrolled 59 patients: 34 men and 25 women with a mean age of 60.4+/-17.6 years (range, 17-93).

METHODS: Demodex counting was performed based on lash sampling. Serum immunoreactivity to two 62-kDa and 83-kDa proteins derived from B oleronius was determined by Western blot analysis. Facial rosacea, lid margin, and ocular surface inflammation were documented by photography and graded in a masked fashion.

MAIN OUTCOME MEASURES: Statistical significance based on correlative analyses of clinical and laboratory data.

RESULTS: These 59 patients were age matched, but not gender matched, regarding serum immunoreactivity, ocular Demodex infestation, or facial rosacea. There was a significant correlation between serum immunoreactivity and facial rosacea (P = 0.009), lid margin inflammation (P = 0.040), and ocular Demodex infestation (P = 0.048), but not inferior bulbar conjunctival inflammation (P = 0.573). The Demodex count was significantly higher in patients with positive facial rosacea (6.6+/-9.0 vs. 1.9+/-2.2; P = 0.014). There was a significant correlation of facial rosacea with lid margin inflammation (P = 0.016), but not with inferior bulbar conjunctival inflammation (P = 0.728). Ocular Demodex infestation was less prevalent in patients with aqueous tear-deficiency dry eye than those without (7/38 vs. 12/21; P = 0.002).

CONCLUSIONS: The strong correlation provides a better understanding of comorbidity between Demodex mites and their symbiotic B oleronius in facial rosacea and blepharitis. Treatments directed to both warrant future investigation

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Dr. Mannis in his interview for the RSRP had this to say about IPL and ocular rosacea.

Q: Do you think IPL treatment of the face usually improves ocular rosacea? What about patients who feel that it has made their ocular rosacea worse, eg more veins showing in the white of the eye, lids more sensitive, eyelashes falling out, hot compresses now cause the eyes to swell?

A: Unfortunately, as ophthalmologists, we have very little experience with IPL. That’s something that’s done by and large by dermatologists. I am not aware of any definite ocular side effects from facial treatments with IPL.

Q: Does ocular rosacea increase the likelihood of cataracts or other eye diseases such as macular degeneration, or central serrous corinopathy (retinopathy)?

A: No. But, if IPL is done, there needs to be eye protection. Any kind of laser treatment done on the skin around the eye requires the practitioner to use eye shields to be sure that the globe is not exposed to the intense light in any way. As long as it’s not, then the likelihood of any of those problems occurring is very small.

For more information on Dry Eye see the following articles: Dry Eye: Awareness, Diagnosis, and Management and Dry Eye Syndrome from Sunday Times Sri Lanka

Zapping Dry Eye

Posted: 12:23 pm EDT October 8, 2009

Christopher Coad, M.D., Ophthalmologist at Chelsea Eye & Cosmetic Surgery Associates in New York City, is using a technique for some dry eye patients called intense pulsed light therapy (IPL). IPL is sometimes used to reduce facial skin redness caused by growth of abnormal blood vessels in patients with rosacea. Doctors noticed that some rosacea patients reported easing of dry eye symptoms after getting IPL. That finding led physicians to try it for patients with dry eye.

First, eye shields and a cooling ultrasound gel are placed around the eyes to protect the eyes and surrounding skin. Then, the IPL is aimed under the lower lid, moving across the eyes. Two passes of the light are made. Then the gel and eye shields are removed.

Coad says IPL has three main effects on dry eye. First, the heat acts like a warm compress to liquefy the blocked oil that’s plugging the meibomian gland. Second, the small blood vessels that carry inflammatory cells to the site are sealed. Third, the light treatment improves the health and function of the meibomian gland, reducing the risk of further inflammation.

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Elidel no better than Metrogel for lumps and bumps of rosacea.

A comparison of metronidazole 1% cream and pimecrolimus 1% cream in the treatment of patients with papulopustular rosacea: a randomized open-label clinical trial. Clin Exp Dermatol. 2009 Jul 6

Patients were randomly assigned treatment with either pimecrolimus 1% cream or metronidazole 1% cream for 12 weeks. Pimecrolimus cream is no more efficacious than metronidazole cream in the treatment of PR.

Another bacterial link found ?

Is rosacea another disorder of gut microbes? Curr Gastroenterol Rep. 2009 Aug;11(4):253-4

This paper sounds like it might be heading in the direction to add to some research that looks at small intestinal bacterial overgrowth as a source of rosacea symptoms. Alas all we can see at the moment is the title. Also note that the author has published several other papers that at least in their title link intestinal disorders with diseases such as fibromyalgia as obesity.

Facial blood vessels correlate to Ocular Rosacea Symptoms

This paper, who’s full text is available via the link, suggests that the presence of facial visible blood (telangiectasia) is more of a clue that ocular rosacea may also be present, compared to other facial symptoms like papules and pustules.

Correlation of the severity of cutaneous rosacea with ocular rosacea,  Indian J Dermatol Venereol Leprol 2009;75:405-6.

In our series, ocular involvement did not correlate with the severity of papular, pustular, nodular lesions and flushing but, surprisingly, we found a significant relationship between the severity of telangiectasia and ocular involvement. This finding was not in agreement with the previous studies claiming that the ophthalmologic complications of rosacea are completely independent of the severity of facial rosacea. On the other hand, it seems that the significant relationship between the severity of telangiectasia and eye lesions in our study might be an incidental experience. We agree with the general assumption that skin and eye lesions in rosacea are separate al together.

IAP the link from intestine to Rosacea Skin ?

This paper is proposing that the activity of the enzyme intestinal alkaline phosphatase (IAP) could be the link between an inflammatory response to intestinal bacteria and rosacea skin symptoms.

Intestinal alkaline phosphatase: The molecular link between rosacea and gastrointestinal disease?, Med Hypotheses. 2009 Jun 30 (UMR 168 CNRS/Institut Curie, 11 rue Pierre et Marie Curie, 75005 Paris, France Rosacea Research and Development Institute, Pahala HI 96777, USA)

Rosacea is a common inflammatory condition of the facial skin of unknown etiology, which frequently occurs in combination with gastrointestinal disorders. Many dietary and hormonal factors are known to affect the severity of rosacea symptoms, several of which also modulate the activity of the enzyme intestinal alkaline phosphatase (IAP). The role of IAP in inhibiting an inflammatory response to intestinal bacteria suggests a mechanism by which intestinal pathologies may be linked to the skin inflammation characteristic of rosacea. Analysis of alkaline phosphatase activity is routinely performed on blood samples, and methods to quantify enzyme activity of the intestinal isoform specifically have been described. Correlations between IAP activity and rosacea symptoms in patients and controls can thus be screened by noninvasive and inexpensive means. If IAP activity is found to be low in rosacea patients, acute symptoms could be treated with oral IAP supplementation, and trials of IAP-activating medications currently used in gastrointestinal disease could be initiated in rosacea patients. More importantly, the safe and long-term control of rosacea could be undertaken by patients themselves through dietary modification to naturally increase IAP activity.

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