Comparative Toxicity of Preservatives in Ophthalmic Solutions

[Scout]

I use to think bak was bad too.

I was just as paranoid as you but truthfully it is not that bad as advertised. Those other preservatives are bad too but as long as you limit your use to say 3 a day you should be fine.

MGD:

Could you please cite your references or cite a link to a professional study or opinion to support this? I don't mean to be picky here, but I am concerned that someone could interpret this as medical advice.

Scout

[mary kenny badami]

I'm adding some comments especially for Stella -- as well as other users of "Dr. Holly's drops":

Yes, I did sign the anti-preservatives petition, as well as making several posts here urging others to consider doing likewise.
Well, I subsequently received private correspondence from someone following these matters who supports the petition initiative,
but wonders why I continue to acknowledge that I use Dakrina and NutraTear daily. Below I reproduce an edited version of my replies.

============================
As for my opinion on preservatives: 
simply as a non-doc, as a layperson/ patient, I am convinced that preservatives are trouble for healthy eyes, and potential poison for damaged eyes.

BIG EXCEPTION: I exclude the materials in "Dr. Holly's Drops" from that statement. 
Dr. Holly is, was, and I expect always will be my hero.

To answer your question about why I make exceptions for "Dr. Holly's drops":
for me, as a non-scientist, I struggle through the scientific and medical citations, 
but at some point I'm simply going on faith in Dr. Holly, as well as my own trial-and-error.
Dakrina and NutraTear were the only, only, drops ever to bring relief to my post-Lasik (also post-menopausal, and having been previously diagnosed) dry eyes. 
And believe me, I was one of the most skeptical of skeptics when he started posting over on SurgicalEyes.
It was only after my trusted online buddy Tron/Ethel posted regularly in her "Dwelle Diary" about the relief she'd getting, that I reluctantly gave them a try.

============================
Let me add that I think that "indrep's" comment earlier on this thread is brilliant:

A presentation at ARVO stated similar findings. The excuse docs give for not being more forceful with patients is: "patient wants the cheapest eye drop." I think patients deserve to know what's bad for their eyes. then if they choose they can continue to use a product that doesn't help. But the doctor should inform the patient.

Amen to that, indrep, amen! . . . In which case, I CHOOSE "Dr. Holly's Drops." < insert smiley-face here >

[stella]

Well said Mary ---

Dr Holly's drops are my lifeline and as you rightly say it comes down to a matter of trust.
The fact is that there are quite a lot of us on this site who have found Dr Holly's drops to be the only ones which make a significant difference and i suppose the last thing we want to hear is that the preservatives he uses will harm our eyes
Dr Holly obviously thinks otherwise ---
So you either believe him or not

[clairvoyant]

Think about it, if you use BAK in a potent steroid you don't think that steroid will more than heal the damage caused by the BAK?

[clairvoyant]

MGD:

Could you please cite your references or cite a link to a professional study or opinion to support this? I don't mean to be picky here, but I am concerned that someone could interpret this as medical advice.

Scout

No, not at all. I completely understand. There are so many abstracts and things on this site that say BAK is a no no.

Truthfully I do not know as much as an expert in the subject would but I do know it is not as bad as people on this site are makeing it out be.

What that means is that I am not sure if the more you use it, the more you will become sensitive to it. That is the only part I am not sure about.

As far as proof well I could search pub med for hours and find that article but I already looked for like 30 mins and could not find it. I do know though that I have read an article that said as long you use less than 4 drops a day you are ok. They might have gave a concentration too but I don't remember that, I just remember coming away from that article knowing not to go over 4 drops a day.

The other proof I have, that I can't prove, is that I have been to a number of good doctors, including leading authorities on dry eye and 2 of them seem to feel BAK in these situations are OK.

At the same time they have also said preservitive free stuff is better. So I think it is a matter of if you can get the drop perservitive free than that is probably preffered but if you can't it probably doesn't matter in the grand scheme of things. And if a knowledgable doctor gives you such a drop he probably has you on other things to negate the damage. Now an unknowledgable doctor is a different story..

Hope that helps

[Z351]

Think about it, if you use BAK in a potent steroid you don't think that steroid will more than heal the damage caused by the BAK?

All steroids reduce healing (just like antibiotics) increasing BAK nocivity. Did you mean inflammation? vascularisation?

Anyway, potent steroids have side-effect too so If you use potent steroid to control BAK side-effects that's not going to be very effective. Single use vials would be better serve you

[Z351]

Truthfully I do not know as much as an expert in the subject would but I do know it is not as bad as people on this site are makeing it out be.

What that means is that I am not sure if the more you use it, the more you will become sensitive to it. That is the only part I am not sure about.

As far as proof well I could search pub med for hours and find that article but I already looked for like 30 mins and could not find it. I do know though that I have read an article that said as long you use less than 4 drops a day you are ok. They might have gave a concentration too but I don't remember that, I just remember coming away from that article knowing not to go over 4 drops a day.

The other proof I have, that I can't prove, is that I have been to a number of good doctors, including leading authorities on dry eye and 2 of them seem to feel BAK in these situations are OK.

At the same time they have also said preservitive free stuff is better. So I think it is a matter of if you can get the drop perservitive free than that is probably preffered but if you can't it probably doesn't matter in the grand scheme of things. And if a knowledgable doctor gives you such a drop he probably has you on other things to negate the damage. Now an unknowledgable doctor is a different story..

Hope that helps

Many impressions. Nothing supported.
Even the DEWS report recognizes this as a major problem...
Even Allergan and Alcon have recognised the problem...check their letters
Make your own opinion by reading relevant research on this matter:
http://preservative.free.fr/

If you find such an independent study indicating 3 drops a day is fine, please let us know

[Toril]

Hello, everyone!

Just wanted to share my experience with BAK. I have very dry eyes due to autoimmune disease, and I've also got allergies to pollen, dust, etc. When I started my treatment with a dry eye specialist, he started me on 1 drop a day with Vexol (steroid with BAK....the doctor would have prescribed me Vexol without preservatives if it was available, as he's agaist the use of preservatives).

He wanted me to try steroids to see if my eye inflammation got reduced by it, and yes, it did. The first 2 days my eyes felt better than in a long time. Then gradually...after 2 weeks or so, my eyes got more and more irritated, they were again as inflamed as before, and in addition to it, they got so sensitive I was hardly able to keep them open.

After 1 month I had no choice but quit the Vexol, and and after 1 week or so, my eyes were back to "normal bad." The healing effect that I experienced the first days were "beaten" by the effects of BAK. BAK affects the lipids in the tearfilm, and for me, as I have a very low TBUT, it made my eyes more sensitive and painful than before I started the treatment.

So...how you react to BAK, and how fast you react, well, that's very individual.


Toril

[stella]

We have to ask why the large "watch dogs" of the ophthalmic /medical world ,like the BMA in GB and AMA in USA have not banned BAK ?

There must not be enough evidence of damage for them to have let it remain on the market

They have been known to take harmful drugs off the market -- for example some NSAIDS such as Vioxx have been boycotted 'cos of harm to the heart i believe

Is there any watchdog in Europe or the USA that have concerns about BAK and if not why not ?

[clairvoyant]

All steroids reduce healing (just like antibiotics) increasing BAK nocivity. Did you mean inflammation? vascularisation?

Anyway, potent steroids have side-effect too so If you use potent steroid to control BAK side-effects that's not going to be very effective. Single use vials would be better serve you

But of course, what do you think BAK does? It would cause inflammation. Steroids would more than negate the BAK, even the dilute lotemax. Steroids do not reduce healing though lol they are the best medicine for inflammatory problems most of the time but like you said they carry side effects so doctors tend to use them spariningly. Sometimes stuff can come back stronger after steroids but this can happen with ANY medicine. So if you have chronic inflammation you will need some type of suppression. And if you would rather your site regress to a worse prescription caused by the dry eye then go right ahead.

On the same accord the side effects from steroids very from person to person and are probably not as bad as people make them out to be. You gotta think a lot of people with these different diseases are required to take high amounts of oral steroids for life.

I will look for that article per your post.

Have you ever had a conversation with a dry eye expert about this?

[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!!!

[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

[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?

[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]

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