I. Overview of the General
Consequences of Preservatives: Allergies and Cytotoxicity.
The consequences of preservatives in eye
drops have been reported since 1941, however, we must recognize that
little has changed since then. Nevertheless, there is now growing and overwhelming
evidence that preservatives have serious adverse or even very severe
consequences in ocular therapies.
Benzalkonium for instance, is a
quaternary ammonium used a detergent, antiseptic, disinfectant,
fungicide, bactericide, and spermicidal. You can easily imagine that its
use on the ocular surface must have some consequences! However,
Benzalkonium is one of most frequently used preservatives in eyedrops as
well. One of the first obvious consequences of Benzalkonium preserved
eye-drops is the disruption of the lachrymal or the tear film.
The reason why is quite simple since all surfactant detergent are able
to dissolve lipids. Therefore even a healthy tear film containing an
adequate lipid layer will be altered by the presence of such a
detergent. This disruption of the tear film may lead to
dryness by
increasing evaporation and inflammation and ocular surface damage.
But Benzalkonium has other consequences including allergic, cytotoxic
and storage side-effects. Benzalkonium modifies the proteins of the
eye and may provoke two types of immunitary reactions: allergy or
cytotoxicity. Indeed, several studies indicate that Benzalkonium
provokes cell death (apoptosis) of the corneal epithelial cells.
In doing so, Benzalkonium delays corneal wound healing. There is
also evidence that Benzalkonium penetrates the eye and is
stored in
several ocular tissues (notably the conjunctiva, cornea, iris,
retina, the lens, the aqueous humor, choroids coat, etc) [1]. Some
studies even suggest that Benzalkonium may cause cataracts or change the
color of your eyes’ irises by adding brownish spots on the iris.
"Therefore eye drops with benzalkonium
chloride
in concentrations above 0.005% should be abandoned in clinical therapy"
as some authors state [6]. Since most drops use BAK in higher
concentrations and that sterility is unlikely to be achieved with such
minimal concentrations, we may conclude that BAK containing drops should
not be used altogether. Futhermore, one study concludes that after the
withdrawal of BAK, "The improvement was found to be proportional
to the duration of the preceding BAC-containing therapy"[8].
This substance is a hazard to human corneal
biology!
Benzalkonium is only one
the most commonly used preservatives, but most comments above are
applicable to all quaternary ammoniums to some extend.
Quaternary ammoniums are certainly
amongst the most cytotoxic preservatives currently in use, but most
studies reveal that all preservatives to date exert some kind of
toxicity. Some are obviously better than other... or it might be even
more appropriate to say that some are worse than others. Some are not
really used anymore because they have caused too many allergic reactions
(that's the case of thiomersal or thimerosal which is now seldom used).
Some newer preservatives claim to be less aggressive than old ones and
particularly when compared to BAK (that's the case of Purite®, GenAqua® and several types
of polyquarterniums including Polyquad®) [5]. Most studies indicate in fact
that they are less abrasive or toxic than BAK, which isn't obviously the
same as to say they are not toxic or aggressive at all for the human eye.
According to the lastest studies the gentlier
preservatives are in fact oxidative ones such as Purite®
and GenAqua®. There is
still little independent studies to support these claim. It would
seem wise to compare all preservatives between them, and to compare all
of these to a saline solution or the same active substance but without
the preservative. It would also be important to consider
that studies are usually done on healthy eyes whereas drugs are meant
for unhealthy ones. Therefore a preservative that could be considered
safe for normal eyes may not be safe for dry eyes or fragile corneas. "The
elimination of preservatives may be desirable in efforts to protect the
integrity of the corneal surface and its interaction with the tear film"
as one study puts it [7].
So, laboratories and governmental
medical agencies all over the world, independent comparative studies to
confirm or infirm these claims are really welcomed if you are listening!
Some of this products are sold with the warning of being ocular
irritants by their manufacturers from the chemical industry. It's
curious to notice that laboratories assume these may be safe to use
eyedrops for unhealthy eyes.
More generally, according to the AOA [2], “Ophthalmic
preservatives used in artificial tear solutions and their potential
adverse effects are:
-
Thimerosal--hypersensitive reaction in an
estimated 10-25 percent of users
-
Benzalkonium chloride--Preocular tear film
instability, lowered breakup time (BUT), and disrupted
corneal epithelial cell functions when dosed at commercial
concentrations
-
Chlorobutanol--evaporation, corneal
epithelial cell changes
-
Ethylenediaminetetraacetic acid (EDTA)--contact
allergy
-
Chlorhexidine digluconate--storage in the
corneal and conjunctival epithelium”
II. Less Effective
Eyedrops & Decreased Tolerance/Compliance
Another interesting aspect, which has
been addressed by a few studies to date, is that preservatives may
reduce the
effectiveness of treatments particularly when inflammatory processes are
involved (3) or when the abrasive effect of preservative is a serious
contraindication for the eye disease. For instance, antihistaminic
eyedrops are likely to be less effective due to the inflammatory process
maintained by the preservative. Besides that, with less stinging and
adverse reaction to the preservative the patient’s compliance with the
treatment is usually improved (4). So it’s actually in the pharmaceutical
industry interest to address this issue… sooner than
later.
A French prospective
study to evaluate the occurrence of ocular adverse effects
observed after administration of anti-allergic eye drops with
(usually benzalkonium) and without a preservative
in patients with allergic conjunctivitis included a
total of 3090 patients with allergic conjunctivitis and treated with
anti-allergic eye drops by 507 general practitioners located throughout
France. The proportion of patients experiencing
at least one adverse drug reaction was 24% for eye drops with no
preservative and 89% for eye drops with a preservative.
The study concluded by saying " Compliance was significantly
higher for anti-allergic eye drops without preservative than for those
with a preservative"[9].
Read the
consequences
Per Preservative
Studies (some studies' abstracts may be available at
Pubmed)
1: Les Conservateurs en
Ophtalmologie, Docteur Patrice Vo Tan, Docteur Yves Lachkar, Librairie
Médicale Théa, 64 pages.
2: American
Optometric Association. Care of the patient with ocular surface
disorders. St. Louis (MO): American Optometric Association.
3:
Comparative study of topical anti-allergic eye drops on human
conjunctiva-derived cells: responses to histamine and IFN
gamma and toxicological profiles
Pauly A,
Brignole-Baudouin
F,
Guenoun JM,
Riancho L,
Rat P,
Warnet JM,
Baudouin C.
U598, INSERM, Cordeliers Biomedical Institute, 15 rue de l'ecole de
medecine, 75006, Paris, France. CONCLUSIONS: The
ability of topical ocular anti-H(1) drugs to significantly reduce the
production of IL-6 and IL-8 argues that they may help treat the
inflammatory processes occurring in allergic ocular surface disorders.
Nevertheless, preserved ophthalmic formulations may enhance epithelial
conjunctival expression of ICAM-1 in the presence of a low inflammatory
stimulus, such as IFNgamma, and displayed toxic as well as pro-oxidative
effects on these cells. Therefore, BAC used as preservative might in
part interfere with the potential anti-inflammatory properties of the
active compound by modulating the immuno-inflammatory response of
epithelial conjunctival cells. To
display study click here
4: A
comparative study of the ocular tolerance after administration of
anti-allergic eye drops with or without a preservative. [Article in
French] ,
Beden C, Helleboid L, Marmouz F, Liard F. Societe Naxis, Lyon, France.
CONCLUSION: The prescription of eye drops with no preservative allows a
significant decrease in ocular adverse drug reactions and a greater
acceptance by the patient regarding his/her anti-allergic treatment.
5: Comparison of
toxicological profiles of benzalkonium chloride and polyquaternium-1: an
experimental study. Labbe A, Pauly A, Liang H,
Brignole-Baudouin F, Martin C, Warnet JM,
Baudouin C. Department of Ophthalmology III, Quinze-Vingts National
Ophthalmology Hospital, and INSERM U598, Cordeliers Biomedical
Institute, University of Paris 5, Paris, France.
PMID: 16910868,
J Ocul Pharmacol Ther. 2006 Aug;22(4):267-78
[PubMed - indexed for MEDLINE]
6:
How the most common preservative affects the
Meibomian lipid layer, Kaercher T.; Hönig D.; Barth
W., Orbit, Volume 18, Number 2, June 1999, pp.
89-97(9), Taylor & Francis Ltd.
7.
Comparison
of the short-term effects on the human corneal surface of topical
timolol maleate with and without benzalkonium chloride.
Ishibashi T, Yokoi N, Kinoshita S, Department of Ophthalmology,
Kyoto Prefectural University of medicine, Kyoto, Japan,
J Glaucoma,
2003 Dec;12(6):486-90.
PMID: 14646684 [PubMed - indexed for MEDLINE]
8.
Topical timolol
with and without benzalkonium chloride: epithelial permeability and
autofluorescence of the cornea in glaucoma. de Jong C,
Stolwijk, Kuppens, de Keizer R, van Best J, Department of
Ophthalmology, Leiden University Hospital, The Netherlands.
PMID: 8034210 [PubMed - indexed for
MEDLINE].
9.
Etude comparative de la survenue d’effets indésirables suite à l’administration
de collyres anti-allergiques sans ou avec conservateur: A Comparative
Study of the Ocular Tolerance After Administration of Anti-Allergic Eye
Drops With or Without a Preservative, Beden, Cecile; Helleboid,
Laurent; Marmouz, Farid; Liard, Francois, Société Naxis, Lyon, Service
d’Ophtalmologie, Hôpital Tenon, Paris, Cabinet
d’Immuno-Allergologie, Pontoise, France Cabinet de Médecine Générale,
Saint-Epain, France, Therapie, Volume 59, Number 2, 2004 , pp.
259-264(6)
