Thursday, September 4, 2008

Drug news: Rebamipide resuscitation?

Back in March, Novartis listed Rebamipide in its financials as a terminated project, so I assumed that clinically, it really had bitten the dust.

But apparently only according to Novartis. Otsuka (with whom Novartis had a licensing arrangement dating to 2005) is going to continue developing it, this time with new partner Acucela, a small Japanese company focused - until now - on retinal disease treatments.

I wish them all the best of luck. I used to hear some good things about rebamipide results from some doctors and patients participating in the trials, but then it all went dark except for some rumours about mismanagement of the trials. Hopefully it will all fare better this time around.

Acucela and Otsuka Pharmaceutical Enter Co-Development Agreement for Rebamipide Ophthalmic Suspension for Dry Eye

BOTHELL, Wash. & TOKYO, Sep 04, 2008 (BUSINESS WIRE) -- Acucela Inc. and Otsuka Pharmaceutical Co., Ltd. today announced that they have entered into a definitive agreement to co-develop Rebamipide ophthalmic suspension (hereinafter, Rebamipide), Otsuka's proprietary compound for the treatment of dry eye which is currently in Phase III clinical development in the United States.

Dry eye triggers versus causes

I frequently hear people saying, or posting on DryEyeTalk, "XXX caused my dry eye."

Often, a review of their history gives even a layperson like me good reason to question whether what they are so sure of is actually correct. And even in some apparently black-and-white situations where dry eye symptoms are sudden and severe - commencing immediately after or during some identifiable event - reliably establishing cause and effect is not always that simple.

My personal belief (theory, I guess) is that in many cases, there are one or more underlying conditions - perhaps mild blepharitis/MGD, perhaps ocular allergies or rosacea, perhaps something else - but with no symptoms. Then, along comes a single traumatic event of some kind and punts you right over the edge into a fullflown severe dry eye episode. So as reasonable as it seems to blame the event that "started" it all... I think we're looking at the difference between a trigger and a cause.

Not that there's any simple straightforward line to be drawn between triggers and causes, of course. LASIK is both. And so are many of the things you'll see on the classic "Causes of dry eye" lists... surgeries, drugs, environmental factors and so on. But the point is that your "tipping point" is not necessary the beginning and the end of your dry eye story.

I was reminded of this today while speaking with a gentleman who traces his dry eye to paint exposure. From the story, it seemed compelling: No history of dry eye whatsoever, and almost immediately after a brief exposure to paint in the air he began having severe symptoms. And here he is four years later, still with dry eye (and incidentally unusually sensitive to paint). But while we were talking I happened to mention instances I know of where dry eye was attributable to mold attacking the meibomian glands. It turns out that this gentleman had had problems with mold in the house. Was that related? I have no idea. But could it be? Possibly.

Then of course there's all the people who have a drying drug or surgery... BUT did they already have bleph, rosacea, lagophthalmos, etc. beforehand?

So for those of you whose doctors seem skeptical of your claims, please don't forget that there could be a decent reason for their skepticism. Unfortunately, dry eye patients have a rough time because of the lack of validation of the life impact of their symptoms. As a result there is a tendency to take things personally and even to lump a doctor's resistance to one's claims about causation in that same "He/she does not get it!" category. Step back and put yourself in their shoes. Dry eye is a complex, usually multifactorial disease and sorting out causes can take some serious detective work.

On the other hand, if you're doing your best to be a good open-minded compliant patient and your doctor is simply not up to the task - is not willing to be a detective in the cause of helping you get some relief - don't waste your time. Move on.

Another Omega 3 player joins the crowd

Just letting you know there's yet another company trying to cash in on the dry eye omega 3 craze.

Dry Eye Omega Benefits from LifeGuard Health LLC

Fifty bucks for a two-month supply puts it right in the neighborhood of the other proprietary dry eye supplements (most of which run $20 to $30 ish per month). Personally I'll stick with my Barleans oils - I spend $10 or less a month and still get top quality. If I feel like splurging I'll get a couple bottles of the high epa/dha fish oil.

If somebody out there with SEVERE dry eye sees a massive difference from any supplement, please let me know. Oh yes and please make sure you've been taking it for a considerable period, have made no changes whatsoever to your eyecare regimen during that time, and have not experienced any other significant changes such as allergies, new job, etc.

I'm not pooh-poohing Omega 3s. I love them, I think they are vital for general health, and I faithfully stir my cinnamon Barlenas into yoghurt each morning with some berries (yum). But they sure aren't a cureall for dry eye.

Abstract: Antibiotic toxicity

So in test tubes, topical antibiotics showed some toxicity, especially Vigamox. It will be interesting to see what happens when they do some in vivo testing.

Evaluation of toxicity of commercial ophthalmic fluoroquinolone antibiotics as assessed on immortalized corneal and conjunctival epithelial cells.
Cornea. 2008 Sep;27(8):930-4.
Sosa AB, Epstein SP, Asbell PA.

PURPOSE: To evaluate the toxicity of a variety of the fluoroquinolone antibiotics on the ocular surface by using tissue culture models of corneal epithelial cells and conjunctival epithelial cells.

METHODS: Immortalized conjunctival (CCC) and human corneal (HCE) epithelial cells were grown and when confluent the cells allowed to air dry for 1 hour. Medium was then replaced with 100 microL of one of the following: 1) Vigamox [moxifloxacin (0.5%: MX)]; (2) Zymar [gatifloxacin (0.3%: GA)]; 3) Quixin [levofloxacin (0.5%: LE)]; 4) Ocuflox [ofloxacin (0.3%: OF)]; 5) Ciloxan [ciprofloxacin (0.3%: CP)]; 6) medium (viable control); 7) "normal"/physiologic saline; 8) formalin (dead control). After one hour, 150 microL of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazonium bromide was added and incubated for 4 hours. After decanting, precipitate was dissolved in 150 microL of isopropanol. Absorbance was determined at 572 nm.

RESULTS: The lowest amount of cell death was associated with the viable control. All ophthalmic preparations showed both corneal and conjunctival cell toxicity. Aside from the viable control, normal saline showed the next lowest amount of toxicity. Of the topical ocular antibiotics tested, MX showed the least amount of toxicity. All of the other antibiotics tested were statistically indistinguishable from each other.

CONCLUSIONS: All of the topical ocular antibiotics tested showed evidence of both corneal and conjunctival toxicity (MX < OF < or = LE < or = CP < or = GA), although only MX was statistically significant. Whether this finding reflects on in vivo wound healing remains to be determined. This model provides a rapid and cost-effective method to screen for surface toxicity of topical agents.

Abstract: Preventing dry eye from some cancer treatments

Prevention of radiochemotherapy-induced toxicity with amifostine in patients with malignant orbital tumors involving the lacrimal gland: a pilot study.
Radiat Oncol. 2008 Sep 1;3(1):22.
Goldblum D, Ghadjar P, Curschmann J, Greiner R, Aebersold D.

ABSTRACT: BACKGROUND: To use amifostine concurrently with radiochemotherapy (CT-RT) or radiotherapy (RT) alone in order to prevent dry eye syndrome in patients with malignancies located in the fronto-orbital region.

METHODS: Five patients (2 males, 3 females) with diagnosed malignancies (Non-Hodgkin B-cell Lymphoma, neuroendocrine carcinoma) involving the lacrimal gland, in which either combined CT-RT or local RT were indicated, were prophylactically treated with amifostine (500mg sc). Single RT fraction dose, total dose and treatment duration were individually adjusted to the patient's need. Acute and late adverse effects were recorded using the RTOG score. Subjective and objective dry eye assessment was performed for the post-treatment control of lacrimal gland function.

RESULTS: All patients have completed CT-RT or RT as indicated. The median total duration of RT was 29 days (range, 23 - 39 days) and the median total RT dose was 40 Gy (range, 36 - 60 Gy). Median lacrimal gland exposure was 35.9 Gy (range, 16.8 - 42.6 Gy). Very good partial or complete tumor remission was achieved in all patients. The treatment was well tolerated without major toxic reactions. Post-treatment control did not reveal in any patient either subjective or objective signs of a dry eye syndrome. CONCLUSIONS: The addition of Amifostine to RT/CT-RT of patients with tumors localized in orbital region was found to be associated with absence of dry eye syndrome.

Abstract: Chlamydia infection and dry eye

Discussing possible link between conjunctival chlamydia infection and dry eye.

Vestn Oftalmol. 2008 Jul-Aug;124(4):16-9.
[To the role of Chlamydia infection in the development of dry eye]
[Article in Russian / No authors listed]

The study deals with the possible etiological role of Chlamydia, Mycoplasma, Ureaplasma, and bacteroid infections in the development of chronic conjunctivitis and dry eye (DE). A hundred and fifty patients with DE and chronic conjunctivitis were examined. Conjunctival scrapes were examined by direct immunofluorescence for evidence of Chlamydia, Mycoplasma, Ureaplasma, and bacteroid infections. DE was verified by the Schirmer test and the Norn test. Ninety-five (63.3%) persons were found to be infected. GE was diagnosed in 84 (56%) of the 150 patients. Analysis of infection rates revealed Chlamydia, Mycoplasma, Ureaplasma as mono- and mixed infection in 63.3, 50.6, and 35.3, respectively, and bacteroids as mixed infection in 32.6%. Chlamydia was detected in the conjunctiva in the vast majority of patients with DE (90.5%). Chlamydia infection of the conjunctiva is one of the causes of artificial DE. Conjunctival Chlamydia affliction is manifested by the clinical picture of chronic slowly progressive inflammation with the progression of DE after a latent period of about 2-3 years.

Abstract: Silicone plug aftermath

Only 17 eyes so I'm not personally inclined to take the stenosis bits as gospel truth. But the overall message seems to be that "silicone punctal plugs are good", i.e. reliably improving symptoms and not causing complications (other than spontaneously falling out sometimes). I sure won't argue with that. Probably everyone here knows how I feel about intracanalicular plug risks.

Long-term Follow-up of Punctal and Proximal Canalicular Stenoses After Silicone Punctal Plug Treatment in Dry Eye Patients.
Am J Ophthalmol. 2008 Aug 22.
Boldin I, Klein A, Haller-Schober EM, Horwath-Winter J.

PURPOSE: To determine the clinical value and relevance of punctal and proximal canalicular stenoses after punctal plug therapy in moderate to severe dry eye syndrome. DESIGN: Retrospective, observational case series.

METHODS: Seventeen eyes were determined to have punctum or proximal canalicular stenoses after spontaneous loss of a collared silicone punctal plug. After initial diagnosis all patients had 12 months or more of follow-up (mean, 39; range, 12 to 87 months). The clinical data collected included gender and age of patients, localization of the stenosis, plug size, duration of punctal occlusion, subjective symptoms, objective ocular surface disease parameters, and occurrence of complications.

RESULTS: A statistically significant correlation between localization of the stenosis and plug size, and localization of the stenosis and duration of punctal occlusion could not be found. At follow-up, subjective symptoms (P < .01) and frequency of artificial tear application (P < .001) were significantly reduced compared to data before plug insertion. Schirmer I test results (P < .001), corneal fluorescein staining (P < .01), and rose bengal staining (P < .001) improved significantly, whereas tear break-up time (P < .2) and impression cytology scores of the conjunctival surface (P = .2) remained almost unchanged. Complications could not be found.

CONCLUSION: Within the observation period of up to seven years, all stenoses remained asymptomatic. Additionally, subjective symptoms and most dry eye parameters in our study population improved.

Abstract: Dry eye among Japanese high school students


Very worrying. I sure would like to see a study like this done on high school students the US! I have worried for quite some time about the twenty-somethings and even teenagers on DryEyeTalk who have no obvious disease or dry eye cause. We really need better education of youngsters on eyecare so that at least they can be forewarned about things that could make this worse, such as abusing contact lenses or using vasoconstrictors frequently.

Japan Ministry of Health Study on Prevalence of Dry Eye Disease Among Japanese High School Students.
Am J Ophthalmol. 2008 Aug 22.
Uchino M, Dogru M, Uchino Y, Fukagawa K, Shimmura S, Takebayashi T, Schaumberg DA, Tsubota K.

PURPOSE: To determine the prevalence of dry eye disease and contact lens (CL) use among Japanese private high school students.

DESIGN: Cross-sectional prevalence survey. METHODS: We carried out a cross-sectional survey in 3,433 Japanese high school students who completed questionnaires designed to ascertain a prior diagnosis of dry eye disease and current symptoms of dry eye disease, as well as information on CL use and type of CL. We used logistic regression analysis to examine the associations between dry eye disease and CL use.

RESULTS: Of the 3,443 high school students, 3,433 (100%) completed the questionnaires. A total of 2,848 boys and 585 girls joined and the age range was from 15 to 18 years. Clinically diagnosed dry eye disease was present in 123 boys (4.3%) and 47 girls (8.0%). Severe symptoms of dry eye disease were observed in 599 subjects in boys (21.0%) and 143 in girls (24.4%). Soft contact lens (SCL) and hard contact lens (HCL) use was 36.1% and 1.7%, respectively.

CONCLUSION: Dry eye disease leading to a clinical diagnosis or severe symptoms is prevalent in the studied Japanese private high school students. The condition is more prevalent among female subjects and CL wearers. Relevant measures directed against these risks could provide a positive impact on public health and quality of life of high school students.

Abstract: New diagnostic for examining the lipid layer

Doesn't sound like the quickest & easiest clinical test I've ever heard of, but it does sound interesting. Anything to add to TBUT results could be a good thing.

New test to quantify lipid layer behavior in healthy subjects and patients with keratoconjunctivitis sicca.
Cornea. 2008 Sep;27(8):866-70. Links
Rolando M, Valente C, Barabino S.

PURPOSE: Diagnostic procedures currently available to evaluate tear film lipid layer alterations are of limited application and do not provide quantitative results. The purpose of this prospective, case-control study was to develop a noninvasive test to measure tear lipid behavior in healthy subjects and patients with dry eye.

METHODS: The dynamic lipid layer interference patterns (DLIP) test was performed on 21 patients with dry eye and 21 age-matched controls. Subjects in the study and control groups were asked to perform 5 forced blinks and 10 consecutive nonforced blinks every 2 seconds to load lipids from the palpebral reservoir into the tear film. After recording the lipid layer interference patterns obtained with the Tearscope, a masked investigator counted the number of blinks to observe significant changes of shape, position, and number of waves of the interference patterns. Patients with dry eye were identified on the basis of the typical symptoms measured by a validated questionnaire (Ocular Surface Disease Index questionnaire score >10), Schirmer I test scores <10 mm/5 min, tear breakup time (TBUT) <7 seconds, and lissamine green conjunctival staining >4.

RESULTS: Significant differences in Schirmer test, TBUT, and lissamine green were recorded between groups. The DLIP test in the dry eye group (2.4 +/- 3.1 blinks) was statistically decreased compared with the control group (18.1 +/- 5.9 blinks; P < 0.0001, t test). A significant Pearson correlation (r = 0.788) was found between the DLIP test and TBUT. The receiver operating characteristic curve defined a cutoff value of 6.5 blinks to separate healthy from dry eyes (sensitivity of 100%, specificity of 95%).

CONCLUSIONS: The DLIP is a new test that can be used in clinical practice to quantify tear film lipid layer behavior and to diagnose dry eye.

Abstract: Doxy drops and epithelial cell loss

For those of you following developments of doxycycline drops, here's a new study examining the effects of dessicating stress in mice and the ability of doxy drops to mitigate the damage.

Desiccating stress decreases apical corneal epithelial cell size--modulation by the metalloproteinase inhibitor doxycycline.
Cornea. 2008 Sep;27(8):935-40.
Beardsley RM, De Paiva CS, Power DF, Pflugfelder SC.

PURPOSE: We investigated the effects of desiccating stress on murine corneal apical epithelial cell area and desquamation by using 4 defined parameters and evaluated the effects of the metalloproteinase inhibitor doxycycline on this process.

METHODS: C57BL/6 mice were subjected to experimental dry eye (EDE) for 5 days without or with topical therapy with doxycycline 0.025% or 0.0025% or vehicle 4 times a day. C57BL/6 mice that were not exposed to desiccating stress served as controls. Whole mount corneas from each group were immunostained for occludin and visualized by laser scanning confocal microscopy. The images were analyzed in a masked fashion, and mean individual cell area, apical cell density, average cell number loss, and average percent loss were recorded.

RESULTS: EDE caused a significant decrease in apical corneal cell area (1073 +/- 135.9 microm2), an increase in apical cell density (895.8 +/- 115.4 cells per mm2) and a greater percent of epithelial loss (21.29% +/- 13.40%) than controls (1341 +/- 95.28 microm2, 714.4 +/- 55.60 cells per mm2, 2.897% +/- 3.452%, P < 0.001 for all, respectively). Treatment with 0.025% doxycycline preserved cell area (1337 +/- 144.6 microm2) and the apical cell density (721.0 +/- 91.62 cells per mm2) and decreased percentage loss (5.117% +/- 6.757%) compared with the vehicle control group (1154 +/- 88.10 microm2, 830.2 +/- 49.76 cells per mm2, 22.14 +/- 9.616%, P < 0.001 for all, respectively).

CONCLUSIONS: Desiccating stress decreases apical corneal epithelial cell area, increases apical cell density, and promotes epithelial cell loss. Treatment with the metalloproteinase inhibitor doxycycline during desiccating stress preserves cell area and apical cell density and prevents EDE-induced corneal epithelial cell loss. These findings suggest that metalloproteinases mediate apical corneal epithelial loss during desiccating stress.

Wednesday, September 3, 2008

Dry Eye Shop news

Seems like the blog has slimmed down into simply Medline searches and summaries... boring for you and me both! I'll see what I can do to spice things up a bit.

First, a shameless plug for my business. If you get my weekly bulletins you probably are aware of all these things but for those of you who don't like email spam, here's some of the most recent updates to the Shop:

Tranquileyes Economy Buster Prepack ($35)
This is a limited-time offer from Eye Eco... for $35, a moisture goggle and 6 pairs of replacement foam. The catch? The foam is less fancy and less durable than the standard foam, but it still works fine and is comfortable, and it makes this pack the best Tranquileyes deal going, for those who want to try out this night protection system at a lower price than the usual $49 or $65 kits.

New 7Eye BALI
Excellent new frame from 7Eye... very nice fit and styling.

New Wiley-X Products
Wiley-X has two new sunglasses frames in their Climate-Control foam-lined series, the Airborne and the Jake. I like the Airborne especially, in the rootbeer color... very nice. Like the others, the baseline lens is $80, light-adjusting is $135 and polarized is $130.
Also, we now have the spare eyecups available for all 7 Wiley-X models, for $15.

Scleral contact lens cases ($12.50)
Specially designed for Boston Foundation for Sight. Suitable for all scleral lenses.

Scleral contact lens case/kit ($19.34)
A scleral lens case, an inserter, a remover, and a padded soft carrying case that fits all these plus your lubricating drops. 15% discount off the price of these items purchased separately.

7Eye SPF100 Brochure
Wiley-X Climate Control Brochure
If you want to learn more about foam-lined eyewear, with some great pix, add brochures to your next DryEyeShop order.

Live chat!

If you are browsing the shop and have a question... check the livechat window (bottom right, under the shopping cart) in case we're online. If not use that same screen to send an email - you never know, we may respond even if it's after hours.