IV.
Comparative Studies
These are crucial to understand the
consequences of preservatives and sometimes the differences in the
mechanism of action of each preservative. However, one should exercise
caution when studying the comparative studies made on the behalf of some
laboratories considering that these are usually slightly biased.
As a rule, they usually present their preservative as being safe because
it is safer than the one used by the competition. Nevertheless, such a
conclusion is inaccurate: a preservative may be safer than another, may
still be unsafe regardless of the comparison. In that configuration,
benzalkonium is usually presented as the main culprit and probably the
worst for the eye's surface (rightfully we may add). However, do not
conclude that the other preserved substance has no impact whatsoever or
even negligible consequences. Some studies have made the effort to
compare the different substances to a similar non-preserved solution, or
even to non-treated eyes (this last option is somewhat incoherent!). To
sum up and simplify, a honest study will likely include the comparison
of the preserved solution to the same product without the preservative
and a control or neutral solution (sometimes a physiological saline
solution).
On
the left, a comparative study made on the behalf of Allergan on dry eye
treatments. Some of Allergan's products using Purite®
were compared to some other dry eye drops from the competition using
detergent preservatives (such as Polyquad®
et le Benzalkonium) and to
the absence of treatment (it would have been more logical to compare it
to the non-preserved version of the same.
The study was made
over a period of 7 days with a four-times daily dose, when dry eyes
require longer treatments (usually life-time or very long-term
treatments of several years). Click on the image to display a set of
photographs showing epithelial cells presenting a rather normal
appearance when no treatment was applied, slightly modified cells when
using Purite®,
altered cells when using Polyquad®
and very severely altered (some voided from their
content) when using benzalkonium. This study in a brochure on dry eye
treatments for New Zealand dry eye sufferers.
These studies enabled us to reach the
following conclusions:
1. The absence of preservative is
always preferable and non-preserved options are always less damaging.
2. Detergent preservatives such as
quaternary ammoniums (such as BAK) are always more damaging than
oxidative preservatives. Benzalkonium is usually presented as the worst
solution to preserved drops despite being one of the most commonly used.
3. Oxidative preservatives have less
negative consequences and a closer to control or non-preserved
solutions. But let's not forget that minimal short-term consequences on
healthy eyes do not imply long-term safety for fragile corneas
(especially considering that many pathologies require long-term or life
treatments and certainly frequent dosing).
Comparative Charts
|
Preservative |
Preservative free solution/Control |
Study |
|
Benzalkonium |
Polyquaternium |
Thiomersal |
| caused a 9.24 to 99.28 fold
increase in CF uptake (more corneal staining)
|
caused a 0
to 4 fold increase in CF uptake (less corneal
staining than BAK) |
caused
0 to 4 fold increase in CF uptake (less
corneal staining than BAK) |
No increase in CF
uptake (Corneal Staining similar to control) |
1 |
| compared to
control: dramatically altered the corneoconjunctival surface;
decreased tear production. |
significantly decreased goblet
cell density compared. Some abnormalities
were observed with in vivo confocal microscopy.
No decreased tear production compared
to control. |
** |
No significant
changes (compared to preserved) |
2 |
** = No data
|
Benzalkonium |
Control |
Study |
| [glaucoma drug with
BAK] induced
significantly higher inflammatory levels in the conjunctival
epithelium ; significant decrease in
MUC5AC-positive cells;impairment of goblet
cell density and mucin production |
[glaucoma drug
preservative-free] no significant expression of the
inflammatory marker compared with normal untreated eyes |
3 |
| [glaucoma drug with
BAK] symptoms were
more prevalent with preserved than
with PF drops: discomfort upon instillation (43% versus
17%), & symptoms between instillations such
as burning-stinging (40% vs 22%), foreign body sensation
(31% vs 14%), dry eye sensation (23% vs 14%), tearing
(21% vs 14%), and eyelid itching (18% vs 10%).
|
[glaucoma drug
preservative-free]A reduction in the symptoms
and signs was observed when patients changed from P to PF eye
drops |
4 |
|
Benzalkonium |
Polyquaternium |
Purite
oxychloro complex |
Sodium Perborate |
Cetrimide |
phenylmercury borate |
Study |
|
BAK (0.01%): 5% +/- 1% retention of neutral red
and 58% +/- 2% for a European drop +
disruption of the epithelial membrane;
BAK (0.01%): 5% +/- 1% retention of neutral red |
minimal membrane disruption |
no membrane disruption |
58% +/- 2%
neutral red retention |
34% +/- 1% retention |
27% +/- 2% retention |
5 |
|
BAK showed the highest
cytotoxicity, with a 95%, 69%, and 56% neutral red
release at 100, 100, and 50 ppm,
respectively |
13% neutral red release |
--- |
20% neutral red relase |
66% neutral red release |
73% neutral red release |
|
extensive
superficial erosion of the epithelium and a lack of protruding microvilli |
extensive
superficial erosion of the epithelium and a lack of protruding microvilli
(less extent than BAK) |
no defect or superficial erosion
|
no defect or superficial erosion
|
|
|
|
cytotoxic
effects, either in vivo or in vitro |
cytotoxic
effects, either in vivo or in vitro |
no adverse effect on epithelial cells in vitro or
on in vivo; less disruptive to cellular integrity
than other preservatives currently used
|
cytotoxic
effects, either in vivo or in vitro |
cytotoxic
effects, either in vivo or in vitro |
cytotoxic
effects, either in vivo or in vitro |
|
In general, the cytotoxicity observed for each preservative, from least to most, is as follows: the oxychloro complex; polyquaternium-1;
sodium perborate; BAK 0.005%; cetrimide, phenylmercury borate; and BAK 0.01%.
|
Studies (some studies' abstracts may be available at
Pubmed) used for this article
1.
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]
2..
Quantitative evaluation of the corneal epithelial
barrier: effect of artificial tears and preservatives,
Lopez
Bernal D, Ubels JL.
Department of Ophthalmology, Medical
College of Wisconsin, Milwaukee 53226,
Curr Eye Res.
1991 Jul;10(7):645-56.
PMID:
1914501 [PubMed - indexed for MEDLINE]
3.
Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci 2004; 45:1360-1368.
4.
Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002; 86:418-423.
5.
Purite May be Gentler Preservative for Lubrication Solutions,
Robert J. Noecker, MD,
Ophthalmology Times,
November 1, 2001.
