Comparative Toxicity of Preservatives in Ophthalmic Solutions

[Blinks]

Hi All,
Does anyone know of (or use) a Pataday equivalent without the cell damaging BAK preservative?
Not sure if it's equivalent but I've read about Catacrom preservative free single use vials by Moorfields but it doesn't appear to be available in the US. Thanks for any suggestions.
Blinks

[clairvoyant]

I signed the petition. Sucks pataday has BAK and those other drops.

[Z351]

But I am pretty sure I am not to that point yet.

The questions remain: where does that point start?
wouldn't non preserved drops be better for everyone (including you)?
Most doctors supporting our petition are DE experts as well.

Keep you eyes open!

[clairvoyant]

I've had dry eyes for like 4 years now. I was first put on alrex right when it started. Used a couple of bottles of that way back then. Then less than a year ago I started using pataday and azasite. And I probably used some lotemax peroidically. Used durazol for no reason though =o- that one I regret. That didn't have BAK though.

Then just recently 2 bottles of omni pred and some azasite/pataday. Oh and some xibrom. Think I am ok with the bak though cause it was used with steroids for the most part so it probably didn't have a chance to do any damage.

Maybe some are real sensitive to this but consider this- I fully trust both doctors who indicated to me that the BAK is fine. They are both experts in dry eye. I don't know about either of your situation's but maybe you are limiting your treatment because of this preservative?

If you have an ulcer from it though, you probably have to stay away from it but who knows. If you know you can't use it cause you have a really good doctor then you know. But I am pretty sure I am not to that point yet.

[Z351]

At concentrations and dosing used clinically, however, BAK doesn’t appear to have significant adverse effects unless its frequency of use exceeds four to six times daily.4 This becomes a concern when patients use other drops on top of chronic medications, such as glaucoma drops. It’s important to recall that preservatives themselves are bactericidal.

Additionally, patients with soft contact lenses must remove their lenses for 5 minutes to prevent the absorption of the medication into the lens.5

Clearly, BAK is a wonderful, safe preservative, since it’s been used for years. It’s important to note, however, that we need to be careful with its use in patients who are using several medications, are overdosing or have a history of severe corneal damage.

Just a small excerpts from your study:

"Reports have shown that BAK can accumulate in ocular tissue, however, and can cause different types of cell death with frequent dosing.

It’s thought that patients at greatest risk for BAK-induced adverse effects are those suffering from dry-eye syndrome. Because of the lack of natural tears in these patients, the BAK in each eye drop is not as diluted as it would be in a patient with normal tear formation. This may damage the corneal epithelium, contributing to ocular surface disease. These patients may also overdose (use more than six drops per day), which increases the likelihood of BAK-induced adverse effects.

Another French study, this one from 1999, investigated the action of BAK on epithelial conjunctival cells in vitro. Cell exposure to 0.1% and 0.05% BAK induced cell lysis immediately after treatment. All cells treated with 0.01% BAK died within 24 hours. The study’s results suggest that BAK induces cell growth arrest and death at a concentration as low as 0.0001 percent.3

Reports have shown that BAK can accumulate in ocular tissue, however, and can cause different types of cell death with frequent dosing.

It’s thought that patients at greatest risk for BAK-induced adverse effects are those suffering from dry-eye syndrome. Because of the lack of natural tears in these patients, the BAK in each eye drop is not as diluted as it would be in a patient with normal tear formation. This may damage the corneal epithelium, contributing to ocular surface disease. These patients may also overdose (use more than six drops per day), which increases the likelihood of BAK-induced adverse effects.

Another French study, this one from 1999, investigated the action of BAK on epithelial conjunctival cells in vitro. Cell exposure to 0.1% and 0.05% BAK induced cell lysis immediately after treatment. All cells treated with 0.01% BAK died within 24 hours. The study’s results suggest that BAK induces cell growth arrest and death at a concentration as low as 0.0001 percent.3"

your wonderful preservatives has caused me to have dry eyes and some central visual loss due to that ulcer that wouldn't heal (3 months, it eventually heal but nothing's the same after that, it's still fragile).

May i insist on:
"The study’s results suggest that BAK induces cell growth arrest and death at a concentration as low as 0.0001 percent."
So your cornea may be fine but this might not me the case for ever nor for everyone. We're not equal in terms of corneal healing/health.
It is a concern for DE and allergy sufferers (my case at the beginning, now both thanks to BAK).
Preservatives are bactericidal, sure, but the best way to avoid bacteria is still single use vials or specific containers that cannot be contaminated. So I hope you understand that I want those options for me, for you and all of us!

I had no history of corneal damage before I had the damage so how are you planning to prevent that problem? (I just don't mean that just for you but for anyone using BAK). Don't you think this might be a problem?

Look at those pictures they tell a lot

Remember that there are alternatives - single use vials or specific containers - for BAK and that's what we want.

When did your BAK escalade start, because it sounds like you're using a lot of drops a day?

[clairvoyant]

Just as I said, 4-6 per day.

[clairvoyant]

At concentrations and dosing used clinically, however, BAK doesn’t appear to have significant adverse effects unless its frequency of use exceeds four to six times daily.4 This becomes a concern when patients use other drops on top of chronic medications, such as glaucoma drops. It’s important to recall that preservatives themselves are bactericidal.

Additionally, patients with soft contact lenses must remove their lenses for 5 minutes to prevent the absorption of the medication into the lens.5

Clearly, BAK is a wonderful, safe preservative, since it’s been used for years. It’s important to note, however, that we need to be careful with its use in patients who are using several medications, are overdosing or have a history of severe corneal damage.

[Scout]

MGD: I read your article, written in 2002. Even this article makes the point clear that those of us with dry eye syndrome are much more sensitive to the effects of BAK and anyone who is on more than one medication containing BAK is more sensitive to the toxic effects.

• Benzalkonium chloride. BAK is a quaternary ammonium compound that’s often used in conjunction with disodium EDTA. It’s a chemical detergent preservative that’s chemically stable, doesn’t degrade easily, even at high temperatures, and is very effective and fast-acting against many microorganisms. BAK acts upon microorganisms by altering cell membrane permeability and lysing cytoplasmic contents. It’s also been shown to increase the corneal penetration of some drugs by causing a separation of the epithelium.

BAK has been the gold standard of preservatives for years, and is the most common antimicrobial preservative currently used in topical multiuse ophthalmic solutions. Reports have shown that BAK can accumulate in ocular tissue, however, and can cause different types of cell death with frequent dosing.

It’s thought that patients at greatest risk for BAK-induced adverse effects are those suffering from dry-eye syndrome. Because of the lack of natural tears in these patients, the BAK in each eye drop is not as diluted as it would be in a patient with normal tear formation. This may damage the corneal epithelium, contributing to ocular surface disease. These patients may also overdose (use more than six drops per day), which increases the likelihood of BAK-induced adverse effects.

In my case, the effects of long-term use of an allergy drop with BAK did eventually improve. But it took close to a year (I had used the allergy drop with BAK for over two years).

[clairvoyant]

Yea, I'm backing off the BAK for a while cause I used a lot of that OmniPred over the last month. Then all the other drops too... cause like I'll totally douse my eye with the omni pred like 2 or 3 drops each eye then wait a few mins and drop some more lol. So I was probably doing like 12 drops a day some days and probably upward of 6 as I tapered down. I haven't done this blind though, I was in the doctors office a month ago and a week ago. They said cornea looked great a week ago but admitedly that foreign body I just expierenced yesterday has me a lil worried!

My eyes feel fine today since I didn't use any BAK drops before bed last night. Just gonna use azasite and restasis till I see my doctor again.

Here is the article I promised. Also did you notice in that CME article that they said the damage reveresed after stopping the BAK?

http://www.revophth.com/index.asp?page=1_97.htm

Is your ulcer chronic or did it go away?

[Z351]

Also read some other crap that it can cause scar tissue in your eye, not sure I'm buying that one. Ah, jk im sure anything is possible.

http://cme.medscape.com/viewarticle/574777

Tha's not crap, I know that for a fact after a BAK induced ulcer!!!
And were at least two within Keratos to have this experience (since you don't trust studies).
I did use BAK for a long long time (10 years maybe, but small doses, maybe 2 months a year, do not exactly). In Portugal, there are very few or none preservative free drops whereas in France you do have more choice. Thanks to the people of Keratos I've been "travelling" to get better treatment.

It sounds like you are using a lot of BAK, anyway, wouldn't cyclosporin make sense to control part of the inflammation?
would'nt a non preserved steroid be better?
Isn't there preservative free cortisone in the US?

My advice: Don't drop the medications but do discuss this with your doc or another one and check for unpreserved options. So no on the spot paranoia but look ahead for alternatives.

[clairvoyant]

yea I use that crummy drop restasis 2 to 4 times per day

[Z351]

I'm not sure people can access that article I linked, might need a subscription.

Anyway they also focus a lot, at the end of the article, on cytokines and inflammation. So I think it basically boils down to inflammation.

How was the ulcer treated/healed... steroids? and how much freaking bak did you use?

I had access to the article. Here it is but read at the end educational grand from ALCON !!!!



Introduction

More than 6000 abstracts, almost 1000 of which were related directly or indirectly to glaucoma, were presented at the 2008 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), held in Fort Lauderdale, Florida, April 27-May 1, 2008. Covering a wide range of sections from antibody profiles and biomechanics through refractive surgery and vascular disease, the 2008 meeting offered a diverse assortment of the ongoing research on glaucoma.

Glaucoma is a common eye disease and leading cause of blindness.[1] Prescription eye drops to lower intraocular pressure (IOP) are the most widely used treatment, and many such pharmaceutical preparations exist.[2,3] A recent "hot" area of research has dealt with the potential toxicity of, and proinflammatory cytokine profiles induced by, these preparations. Toxicity from pharmaceutical agents can result in decreased visual acuity, which can adversely affect patient comfort, leading to decreased compliance. A number of presentations at ARVO focused on this area of research.
Ocular Surface Disease

Most eye drops contain preservatives to provide a level of antimicrobial activity in the bottle, limiting secondary bacterial, mycotic, and amoebal ocular infections caused by contaminated solutions and prolonging the half life of the drug by preventing biodegradation and maintaining drug potency.[4] The pharmaceutical preparations for the treatment of glaucoma are no different; most contain preservative. Such preservatives, added for their microbicidal/microbistatic actions against single-celled microorganisms, have the potential for evoking at least some cellular toxicity.[4] Certainly any chemical infused into the eye, whether it be active agent, preservative, or "inactive" ingredient, has such a potential.[4] Although the toxicity of topical ocular agents to any part of the eye is of concern, ocular surface disease (OSD) directly involving alteration of the conjunctival and/or corneal epithelial cells is of significant importance.

Godfrey and colleagues[5] reported at ARVO an increased prevalence of OSD symptoms in glaucoma patients using IOP-lowering medications. In this multi-center, survey-based study of 630 glaucoma patients currently on one or more IOP-lowering medications, OSD symptoms were evaluated based on patient answers to a questionnaire. Almost half of the patients, 305 (48.4%), had an Ocular Surface Disease Index (OSDI) score reflecting at least some symptomatology. The number of medications a patient took was found to correlate directly with OSDI score.

The findings of Peace and colleagues[6] lent credence to the notion that it is not just the number of medications, but also the presence of the preservative benzalkonium chloride (BAK) in the medications that may contribute to OSD. In this study, which examined tolerability and ocular surface changes with travoprost without BAK, a total of 691 patients were evaluated by the validated OSDI and baseline IOP and hyperemia readings collected. The patients were switched from latanoprost (N = 471) or travoprost (N = 215) to travoprost without BAK once per day and re-evaluated 3 months later. OSDI scores of approximately 70% of the patients studied improved after changing medications. At the same time, there was no significant difference in efficacy (IOP control).
Cytotoxicity

Alexander and colleagues[7] reported on the results of a study designed to assess the effects of the prostaglandin analogs on corneal epithelial cells. Commercial preparations of bimatoprost (containing BAK 0.005%), latanoprost (BAK 0.02%), travoprost (BAK 0.015%), travoprost BAK-free, media (control), and methanol (toxic control) were tested utilizing an in vitro cytotoxicity assay on immortalized human corneal epithelial cells as well as an ex vivo assay on whole globe porcine eyes. The in vitro study used ethidium bromide to evaluate the effects of a 25-minute exposure to the above pharmaceuticals, whereas the ex vivo study used Richardson's staining solution globes 48 hours after a 10-minute exposure to the test solutions. In the ex vivo study, the globes first received a standardized 5 mm corneoepithelial wound 24 hours before exposure to the test solution. The cytotoxicity assay showed bimatoprost, travoprost, and BAK-free travoprost test solutions evoked less cellular toxicity than latanoprost or toxic controls. In the wound healing assay, bimatoprost and BAK-free travoprost did not impede wound closure to a significant degree; travoprost and latanoprost impeded wound closure approximately 15%.

Cormier and colleagues[8] used a standardized MTT assay to evaluate the in vitro cytotoxicity of 8 of the currently available beta-blockers (propranolol, alprenolol, atenolol, labetalol, metoprolol, pindolol, timolol, and bisoprolol) on both primary and immortalized human corneal epithelial (HCEpiC and HCE) and retinal pigment epithelial (HRPEpiC and ARPE-19) cell lines, as well as primary human skin keratinocytes and fibroblasts. The authors found large differences (about 60-fold) between the observed cytotoxicity of the different studied beta-blockers on the same cell line, while only finding relatively small differences in cytotoxicity between the different cell lines. These findings indicate that neither the cell line utilized, nor the choice of primary vs immortalized cells, plays a major role in in vitro toxicity readings via the MTT assay.

Baudouin and colleagues[9] and Uusitalo and Huhtala[10] both studied the cytotoxic effects of the BAK-free prostaglandin analog tafluprost. Baudouin studied it in rabbits in comparison with the commercial prostaglandin analog preparation latanoprost (0.02% BAK), BAK (0.02%) alone, and a saline solution. Uusitalo and Huhtala studied tafluprost in vitro (on HCE and conjunctival [IOBA-NHC] epithelial cells), in comparison with commercial preparations of the BAK-containing commercial preparations latanoprost (BAK 0.02%), travoprost (BAK 0.015%), and bimatoprost (BAK 0.005%), as well as the corresponding concentrations of BAK alone. They used the WST-1 colorimetric assay of cellular growth and viability and the lactate dehydrogenase test of cell membrane integrity. Through clinical observation using slit-lamp and confocal microscopy, Baudouin found that BAK alone and latanoprost had the highest toxicity, while preservative-free tafluprost had similar results as the saline solution. They also found that BAK alone and latanoprost had higher expression of CD45+ inflammatory cells and TUNEL+ apoptotic cells. Meanwhile, Uusitalo and Huhtala found the cytotoxic effects of latanoprost, travoprost, and bimatoprost to be directly dependent on, and correlate with, the BAK concentration in the formulation of the commercial pharmaceutical preparation. They also found that preservative-free tafluprost was the least toxic of the pharmaceuticals tested. Finally, they found the in vitro toxicity of BAK itself to be highly concentration-dependent and to be observable at the concentrations above those corresponding to 0.001% of BAK in ophthalmic medications.
Pro-inflammatory Biomarkers

Preservatives such as BAK can be classified into 4 main categories: detergents, oxidants, chelating agents, and metabolic inhibitors (subdivided into pentavalent antimonials [SbV], quartenary ammoniums, and organomercurials).[4,11,12] The most common of the topical ophthalmic medication preservatives is BAK. As previously mentioned, any chemical infused into the eye, whether it be active agent, preservative, or even "inactive" ingredient, has the potential of harming the eye,[4] and several authors who presented at ARVO added to this aspect of the discussion.

Epstein and colleagues,[13] who also presented at the 2007 ARVO on the toxicity of the prostaglandin analogs,[14] analyzed the inflammatory response evoked by exposure of immortalized HCE and conjunctival (Wong-Kilbourne derivative of conjunctiva, clone 1-5c-4) cells to the commercial formulations of the prostaglandin analogs travoprost BAK-free (preserved with SofZia), travoprost (BAK 0.015%), and latanoprost 0.005% (BAK 0.02%), as well as the corresponding concentrations of the preservative BAK (0.015%, 0.02%), by quantifying via enzyme-linked immunosorbent assay the pro-inflammatory biomarkers (C-reative protein [CRP], interleukin [IL]-1, IL-10, IL12, TNF) after a 1-hour exposure. All prostaglandin analogs were reported as evoking an increase of all inflammatory biomarkers to some degree, and the addition of BAK was reported to increase this response. Travoprost BAK-free was reported as having elicited the lowest inflammatory response and latanoprost 0.005% (BAK 0.02%) the greatest. The authors found that, of the components studied, the preservatives appeared to induce the majority (approximately 70%) of the response.

Studies further demonstrating the cytokine profile of pro-inflammatory biomarkers were presented by Vallabhajosyula and colleagues and Zhivov and colleagues.[15,16] Vallabhajosyula evaluated the cytoprofile of pro-inflammatory biomarkers (CRP, IL-1, IL-10, IL12, TNF) evoked by exposure of immortalized ocular surface epithelial cells (HCE and Wong-Kilbourne derivative of conjunctiva, clone 1-5c-4) to various concentrations of BAK (0.10%-0.0001%) for 1 hour (quantifying again via ELISA). One-hour exposure to BAK was reported as inducing increased quantities of all inflammatory biomarkers in both of the cell lines. Increases occurred in a dose-dependent fashion, and IL-1 and TNF were the most significantly increased. Zhivov evaluated the influence of BAK on Langerhans cells in corneal epithelium by studying the distribution and density of Langerhans cells in the central and peripheral corneal epithelium of 20 healthy human volunteers via in vivo confocal laser scanning microscopy. The authors instilled 0.01% BAK solution into one eye and a placebo into the contralateral one. They reported a significant increase of Langerhans cells density in the central cornea of the BAK-instilled eye after 6 weeks and in both the central and peripheral corneas after 12 weeks. Langerhans cells density reportedly decreased after the termination of the therapy.

This activity is supported by an independent educational grant from Alcon.

maybe we shoud deleted this since it under subscription ...
My purpuse it not to make everyone paranoid but just be aware that the are risks and that preservative-free solutions would better serve you.
Have you tried cyclosporin?

[clairvoyant]

I'm not sure people can access that article I linked, might need a subscription.

Anyway they also focus a lot, at the end of the article, on cytokines and inflammation. So I think it basically boils down to inflammation.

How was the ulcer treated/healed... steroids? and how much freaking bak did you use?

[clairvoyant]

Tried to find that article.. Haven't found it yet. Anyway I did find an article confirming the cumulitive effect thing.

At the same time the damage observed always reverses after discontinuation of the BAK, well with these specific cells anyway and I think with all of them(not sure though, being honest).

Finally, if you notice, most of these abstracts are talking about glaucoma containing medications. And the reason for that may lie in the concentration I know one of them from this CME article said the concentration was like .02 where as azasite is .003. The article did say though that they started to notice effects starting at .001... so azasite just made it

Also read some other crap that it can cause scar tissue in your eye, not sure I'm buying that one. Ah, jk im sure anything is possible.

Anyway you guys have me a lil paranoid now cause I've had to go through 2 bottles of omni pred from my epi-lasik. Just finished my 2nd bottle today and started to get foreign body in the left eye. Been using azasite twice a day and just started pataday back. Oh yea and used some lotemax..

Hmm I'll see my doctor in a week. I'm a lil more concerned with how much I'm using but I think if you use OSD(ocular surface disease) meds <4/day you will be fine. I will keep trying to find that article though. I am positive it exists

http://cme.medscape.com/viewarticle/574777

[Z351]

denying everything strange method

That's common medical knowledge cortisone (steroids) reduces healing. They control inflammation which is in turn may help to better heal (vascularisation).
I did some medecine some years ago but hey if you want to deny it suit yourself. "BAK is fine", etc I must admit that you say surprising thins. Again show me a study pointing out that cortisone does not reduce cell mitosis... If you're able to do that then you'll probably get an award in medecine along with your go ahead use BAK 3 times a day and you'll be fine
The evidence of BAK deleterious effects is overwhelming. You always deny but do not refer yourself to studies...

Unfortunately and fortunately, I have met many experts or have had to regarding corneal healing (due to one BAK caused ulcer).

on healing:
http://bjo.bmj.com/cgi/pdf_extract/35/11/708

Steroids cause glaucoma et cataracts to begin with, maybe that's not that bad either by your standards. Of course in some cases you have to use it, but that does not deny the side-effects, does it?

Why not suppress inflammation with cyclosporin... it's better on the long term (and does not reduce as much healing, sometimes the oil excipient is slightly toxic).

http://preservative.free.fr/English/indexen.htm

Do you really think that a BAK containing steroid drops is better than the same drop without it? (Actually in France and the UK they have one) Wouldn't it be better to have preservative free steroid drop? aren't preservative free drops always better? .
That's basically the question on this thread...
Anyway, we'll never agree.

As for Stella questions: I believe that the is one big difference with the Vioxx (and like) scandals: people died. Then, you'll see a lot of watchdogs, but (you know I don't often defend BAK) BAK never killed anyone (directly, indirectly I don't know).
But there are smaller watchdogs like Keratos, Gêniris and Amalyste and researchers like Baudouin and al, Noecker et al and recently Pr Douailly joined us (interesting letter from her on the website).

German watchdogs have forced the industry to put warning on their inserts everytime BAK is used in nasal spray (stating it destroy nasal mucosa). So why nasal spray?
The only obvious answer is: it involves more people than drops.
Anyway another German group is trying to do the same thing for the eyes (so another small watchdog there). But it's a matter of leverage and public opinion.

The evidence of BAK deleterious effects is overwhelming and when you actually met someone suffering from pseudo-pemphigoid medicamentosa (due to BAK the eye structures basically fall apart; of course this is a rare side-effect) you really wonder, if BAK does not kill it can ruin lives!!!