Clinical and Experimental Ophthalmology 2007; 35: 664671

doi: 10.1111/j.1442-9071.2007.01559.x

Perspective
Medical treatment of cataract
TzeYo Toh MBBS(Hons),1 Jim Morton PhD,2 Jim Coxon PhD2 and Mark J Elder FRANZCO1
1

Department of Ophthalmology, Christchurch Hospital, Christchurch, and 2Agriculture and Life Sciences Division, Lincoln University,
Canterbury, New Zealand

ABSTRACT
The incidence of cataract continues to increase with the
ageing of the population. Surgical treatment with phacoemulsification and intraocular lens implantation remains the only
proven treatment. This, however, is associated with significant
cost and is not readily available especially in the developing
countries where the prevalence of cataract is the highest.
Medical treatment of cataract is therefore a highly desired
alternative. Since the last major review of medical treatment of
cataract the search for an anti-cataract agent has advanced on
many fronts. Some anti-cataract drugs, such as carnosine, have
now reached clinical trials and showed encouraging results
that warrant further investigation.The discovery of an effective
medical treatment for cataract is likely to make global impact
on eye health. The aims of this paper are to review the
literature on the drug therapy of cataract and provide updates
of the latest development.
Key words: blindness, cataract, clinical trial, medical
treatment, pathogenesis.

METHODS

OF LITERATURE SEARCH

The authors performed a MEDLINE search with Pubmed for

articles published between 1966 and May 2006. The search
was restricted to publications in English and other-language
publications with English abstract. Initial search strategy was
based on the MESH headings using terms that included
cataract, medical therapy, and clinical trials. Articles obtained from
the reference list were reviewed and included when considered appropriate.

INTRODUCTION
Cataract is a leading cause of blindness. In 1998 it was
estimated that worldwide 19.4 million people were bilaterally

blind from age-related cataract.1 Surgery, with lens extraction

and intraocular lens implantation, is the only currently available treatment. This is associated with considerable cost.
More than 1.3 million cataract operations were performed in
the USA in 1998 at a cost of $US3.5 billion.2 It is impossible
to make cataract surgery readily available in third-world countries where most of the blindness is due to cataract. In India
alone, cataract is responsible for 3.8 million new cases of
blindness each year whereas in Africa 36% of blindness is
caused by cataract.3,4 Even in some developed countries where
cataract surgery is available at taxpayer expense there are
simply not enough surgeons to perform the procedure. Consequently, patients have to wait for years for surgery resulting
in loss of independence and a poor quality of life.
In addition to the immediate cost of cataract surgery it is
not without risk. Pseudophakic patients have been found to
have a fourfold cumulative risk of retinal detachment for up
to 20 years after surgery.5 Even with the modern intraocular
lens the rate of neodynium yttium-aluminium-garnett
capsulotomy for posterior capsular opacification remains
about 10%.6 Yttium-aluminium-garnett capsulotomy is itself
associated with 3.9-fold increase in the risk of retinal
detachment.7 Depending on the surgical technique endophthalmitis rate has been reported to be as high as 0.12%.5
Although death is a negligible risk in cataract surgery and the
percentage risk of complication is low, the large number of
operations currently performed each year means that, even
with the lowest predicted rate of complication, 15 000 individuals in the USA alone in 1998 could have suffered from
irreversible blindness because of surgical complications.
The incidence of cataract increases with ageing with
almost 50% of people suffering cataract by 75 years of age.
This is associated with significant functional impairment
because of reduced visual acuity, contrast sensitivity and
debilitating glare.8 With an ageing population and increasing
longevity, cataract is set to have significant socioeconomic
demand on healthcare resources. There is an urgent need for
a method of cataract prevention or medical treatment that
could slow the progression of cataract.

Correspondence: Dr TzeYo Toh, Department of Ophthalmology, Dunedin Hospital, Dunedin, New Zealand. Email: ty_toh@hotmail.com
Received 20 December 2006; accepted 28 June 2007.
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Medical treatment of cataract

AETIOLOGY

OF CATARACT

Many plausible aetiologies for cataract have been suggested

by epidemiological and laboratory studies. Aetiological classification of cataract is the most useful system to understand
the effect of various cataractogenic stressors on the lens and
the identification of target molecules in the lens for which
potential treatment strategies can be developed. Cataract can
be broadly separated into categories such as: age-related,
malnutrition with reduced dietary intake of antioxidant,
radiation (ultraviolet-B [UV-B]) exposure, diabetes, severe
dehydration and side-effect of therapeutic drugs such as
steroids. This is by no means an exhaustive list and many
causes of cataract remain unknown. Public health strategies
to prevent cataract may be possible in developing countries
where it is found to be associated with severe dehydration
resulting from cholera-related diarrhea9,10 or poor nutrition.11
The scope for further prevention in developed countries,
however, is limited because most of the risk factors are
intractable, with the exception of reducing radiation exposure and possibly the stopping of smoking. Anti-cataract
drugs are therefore an alternative option in prevention of
cataract.

AGE-RELATED

665
calcium influx and protect lens proteins against the damaging
effect of sugars.16
Lens membrane contains vitamin E that protects against
lipid peroxidation (LPO). Vitamin C, a powerful reducing
agent, is accumulated in the lens by an active transport
system. It together with glutathione scavenges carboncentred radicals. The lens also has detoxification enzymes
such as catalase and glutathione peroxidase as well as superoxide dismutase that protect against damaging effects of
hydrogen peroxide and superoxide radicals, respectively.
Finally, lens crystallin itself has been shown to form functional aggregates that act as a chaperon-like protein to maintain transparency by sequestering unfolded lens proteins and
inhibiting their subsequent aggregation.12
There is little doubt age-related cataract represents the
cumulative effect of a variety of cataractogenic stressors that
accelerate natural protein degradation coupled with a
reduced efficiency of the lens protective mechanisms. The
concentration of glutathione reduces with age but more
markedly in eyes with cataract.16 The activity of the enzymatic antioxidant systems is also reduced. Therefore replacing the natural antioxidants in the ens may at least in theory
increase the ability of the lens to withstand oxidative stress
thereby preventing the onset of cataract.

CATARACT

The lens crystallins have little biochemical turnover and are

vulnerable to chemical modification from a number of
insults. These post-translational modifications, which cause
the crystallins to unfold and expose reactive groups such as
thiols, have been found to be induced by the Maillard
reaction.12 Maillard reactions are nonenzymatic modification
of amino acids by reaction with sugars, cyanate and steroids.
The unfolded crystallins are susceptible to oxidative damage
characterized by the linkage of polypeptide chains through
disulphide bonds and formation of high molecular weight,
water-insoluble aggregates. The latter accounts for the
increased scattering of light resulting in opacity and a cataractous lens. Absorption of UV radiation and subsequent
chemical reactions give rise to oxidizing agents such as
superoxide, hydroxyl radicals, hydrogen peroxide and
singlet oxygen from photo-ionization of crystallins or bound
chromophore groups. In addition to oxidizing crystallin in
the nucleus of the lens these oxidants also destroy membrane
integrity leading to osmotic imbalance and formation of cortical cataract. The role of oxidizing agents is supported by
experimental findings.13,14
The lens is, however, highly adapted to withstand oxidative stress with natural antioxidants that act as scavenger
molecules in mopping up oxidizing agents. Glutathione is
synthesized in the lens.15 In its reduced state glutathione
protects the thiol groups on lens crystallin thereby preventing the formation of protein aggregates through disulphide
bonding. Glutathione also provides protection at the membrane level by maintaining the reduced state of thiol groups
of important ion transporters such as the Na+K+ ATPase
pump. Moreover, in vitro glutathione was found to control

MULTIVITAMINS

SUPPLEMENT

Compared with the plasma level, Vitamin C or ascorbate is

present in a significantly higher concentration in human lens
and aqueous humour. In addition to preventing aggregation
of crystallin by inhibition of disulphide cross-linking, ascorbate also act as a scavenger of reactive oxygen species as well
as sequestering unfolded proteins. The protective role of
ascorbate was demonstrated by in vitro study of rat lenses
incubated in medium generating oxygen radicals.17 Exogenously administered ascorbate was shown to prevent the
lens from oxidative damage. In vivo, diabetic rats whose diet
was supplemented with 1% ascorbate were significantly protected against lens opacification.18
Vitamin E or beta-tocopherol is the lipophilic counterpart
of ascorbate and is thought to prevent oxidation of lens
membrane lipids. In an in vitro study of rat lenses Varma et al.19
showed that vitamin E significantly inhibited production
of lipid peroxides, thereby decreasing photoperoxidative
damage in the lens. In their retrospective case-controlled
study Robertson et al.20 showed that reduced intake of vitamins C and E supplements was correlated with increased
incidence of cataract in 175 patients aged over 55 years. In a
prospective non-controlled population study of more than
17 000 US male physicians aged 4084 years, men who took
multivitamin supplements were found to experience a
decreased risk of cataract over a 5-year follow-up period.21
However, plasma levels of ascorbate and tocopherol were
found to correlate poorly with the development of cataract.22
In addition to a cardiovascular protective effect, moderate
intake of wine has been shown to halve the risk of developing cataract (risk ratio [RR], 0.47; 95% confidence interval,

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666

Toh et al.

0.260.80, P < 0.01) in an Icelandic population cohort, an

effect presumably due to increased intake of antioxidants.23
Dietary supplementation with multivitamins have however,
not been shown to have significant influence on ascorbate
and tocopherol levels in the human lens.24
Three prospective randomized clinical trials that examined the potential benefit of oralantioxidants in prevention of
cataract have been completed. The Age-Related Eye Disease
Study (AREDS) was a multicentre double-masked clinical
trial.25 4629 participants aged between 55 and 80 were randomly assigned to receive daily oral tablets containing either
antioxidants (vitamin C [500 mg], vitamin E [400 IU] and
beta carotene [15 mg]) or no antioxidants over an average of
6.3-year follow up. Main outcomes measured were an
increase from baseline in nuclear, cortical, or posterior subcapsular opacity grades or cataract surgery, and at least moderate visual acuity loss from baseline (15 letters). The study
found no statistically significant effect of the antioxidant
intake on the development or progression of age-related
cataract (odds ratio = 0.97, P = 0.55).
The use of long-term antioxidant supplementation was
concluded to be of limited benefit in otherwise wellnourished older populations. The Roche European American
Cataract Trial was a multicentre, double-masked and
placebo-controlled trial that monitored cataract progression
with serial digital retroillumination imagery over a 4-year
period.26 A total of 297 patients with cataract were randomized to receive a mixture of oral antioxidant micronutrients
(beta-carotene [18 mg/day], vitamin C [750 mg/day], and
vitamin E [600 mg/day]). Overall, it was found that there was
a small positive treatment effect especially in the US patients
with a small deceleration in progression of age-related cataract over 3 years. The trial, however, suffered from a high
drop-out rate with only 53% and 12% of the patients completed the 3- and 4-year follow up, respectively. Furthermore, the treatment effect differed significantly between the
US and UK cohorts.
More recently results of the Vitamin E, Cataract and AgeRelated Maculopathy Trial (VECAT) have been published.27
In VECAT 1193 subjects with or without cataract were randomly assigned to receive either 500 IU of natural vitamin E
in soybean oil encapsulated in gelatin or a placebo with an
identical appearance. The incidence and progression of cataract were assessed annually using a combination of clinical
lens opacity assessment and digitalized Scheimpflug imagery
over a period of 4 years. A total of 87% of the study population completed the 4-year follow up. The results showed
that, during the trial period, a daily intake of 500 IU of
Vitamin E did not prevent the development or delay the
progression of nuclear, cortical, or posterior subcapsular
cataracts.

LIPID

PEROXIDATION AND CARNOSINE

Although lipid is only a minor component of the lens structure compared with proteins (2% vs. 35% lens wet weight),
the role of LPO as an endogenous source of injury has been

established.28 LPO leads to formation of reactive oxygen

radicals and formation of high molecular weight protein
aggregates of low solubility secondary to disintegration of
lens fibre plasma membrane. LPO products were found in the
lens cytoplasmic protein aggregates using phosphorous registration and gas chromatography technique with an
electoron-capture detector.29 In vivo study of oxidized liposomes injected into the vitreous of rabbit eyes was shown to
induce posterior subcapsular cataract whereas injection of
saturated phospholipids resistant to preoxidation in the same
concentration did not induce any lens opacification.30 Moreover, concentration of LPO products were found to correlate
with other known cataractogenic markers such as reduced
level of glutathione.
A potential treatment strategy is to prevent activation of
LPO and accumulation of damaging LPO products by exogenously administered antioxidants with a strong affinity to
LPO. Carnosine is a natural-occurring, histidine containing
compound found in several tissues, especially in muscles. It
was originally thought to act as a cytosolic pH buffering
agent with favourable effect on contractile activity.31 Studies
have since found carnosine to be a most potent lipid peroxidase mimetic with a powerful antioxidant property. It prevents peroxidation of model membranes, making carnosine
the water-soluble counterpart to lipid-soluble antioxidant
such as tocopherol in protecting cell membranes from oxidative damage.32
An ophthalmic pro-drug of carnosine N-acetylcarnosine
(NAC) has recently been developed for clinical use.33 NAC
is more soluble than its parent compound. In rabbit eyes
NAC was found to have a dose-dependent hydrolysis while
passing through the cornea before releasing carnosine in
the anterior chamber 1530 min after topical installation.34
Exogenous carnosine is mainly excreted by the renal system
or destroyed by carnosinase, a dipeptidase that presents in
the plasma and kidney but not in the lens.35 Once in the
aqueous humour it was able to maintain at an effective concentration of 515 mmol/L before entering the lens tissues
with a prolonged therapeutic effect.36
Babizhayev et al.28 performed a placebo-controlled study in
which NAC was administered as topical eyedrops (CanCTM, Innovative Vision Products, Inc., DE, USA) twice daily
in 50 canine eyes with cataract compared with 40 controls.
After 6 months of treatment, 96% of the treated eyes showed
improvement of lens clarity based on slit image and retroillumination photographs. The most striking result was that
NAC was found to be able to reverse lens opacities in the
canines and a melting snow phenomenon has been described.
A randomized, double-blind, placebo-controlled clinical
trial of NAC has been conducted.33 Seventy-six eyes, with
mild to advanced cataracts, of 49 elderly patients (mean age
65 years) were randomized to receive two NAC eyedrops
twice daily or placebo eyedrops. Measured outcomes
included best corrected visual acuity (BCVA), glare sensitivity testing with the halometer,37 and objective monitoring of
lens opacities based on stereocinematographic slit images
and retro-illumination photography. The first set of results

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Medical treatment of cataract

were reported 6 months into the trial as follow: 90% of the
treated eyes had a BCVA improvement of 7100%; glare
sensitivity test improved in 89% of the treated eyes by
27100%; 42% of the treated eyes had improved lens trasmisivity of 1250%.
Similar margins of improvement were reported at the
completion of the trial (24 months). In comparison, 89% of
the untreated eyes were found to have deterioration in BCVA
by 1780% after 24 months. The results were reported to be
statistically significant with P < 0.001. The results appeared to
be impressive but several limitations have been noted. The
study has very small number of participants with 41 treated
eyes and 35 eyes as controls. The study had low power as
reflected by the extremely wide 95% confidence intervals that
actually overlapped between the treated and control eyes.
The study was reported as two separate trials (at 6 and
24 months) because of high dropout rate with 45% of patients
lost to follow up at 24 months. At 6 months follow up, BCVA
was unchanged in 65% of the control eyes. There was therefore too little progression to show convincing worsening of
untreated cataract with insufficient baseline measurement to
compare the effect of NAC. Although 90% of the treated eye
reported improvement in BCVA, this did not correspond with
objective assessment of the lens opacity where majority of the
treated eyes showed no improvement. The reported data were
also incomplete especially the outcome of the glare tests in the
control eyes. A separate larger trial is needed to justify the
benefit of long-term NAC therapy.

ASPIRIN,

IBUPROFEN AND PARACETAMOL

The potential protective role of aspirin-like analgesics

against cataract is problematic. It was first noted from an
epidemiological study of diabetic patients suffering from
rheumatoid arthritis.38 Reduced frequency of cataract was
noted in patients treated with aspirin for their rheumatoid
arthritis. The results suggested that aspirin could delay the
onset of cataract or progression of cataract to a stage where
surgery is necessary by 43%, even though the exact mechanism of action was unknown.
Subsequent investigations found evidence that supported
the protective effect of aspirin-like analgesics against
cataract. In vitro study of incubated rat lens found that lens
proteins were protected by aspirin against cyanate-induced
opacification.39 Aspirin, ibuprofen and paracetamol delay
diabetic cataract in rats and other experimental cataracts in
vivo.40 Aspirin, an acetylating agent, is thought to prevent
various mechanisms of lens protein denaturation by acetylating the proteins to protect them from attack by cyanate,
sugars and steroids. It may also have an indirect effect by
maintaining glutathione levels in the lens.41
Three case-controlled studies had shown that aspirin-like
analgesics could prevent cataract. In their study of 300 cataract patients and 609 controls in England, van Heyningen
et al.42 found that the use of aspirin-like analgesics was associated with 50% reduction in the risk of cataract. Two other
case-controlled studies in different continents had found

667
similar benefit of aspirin in prevention of cataract.43,44 Casecontrolled studies are subject to selection bias and cannot
establish a causal relationship. The results from prospective
population-based studies had not been favourable. A crosssectional study of 835 fishermen aged over 30 years in USA
did not identify a protective effect of aspirin against visually
impairing cataract.45 Similarly, Paganini-Hill et al. monitored
61% of 22 781 residents in California over a period of 6 years
and found aspirin to have no significant protective effect
against cataract.46

IRRADIATION

CATARACT

The cataractogenic effect of sunlight is well established.4749

The precise mechanism by which ultraviolet radiation results
in lens opacity remains unknown. The lens absorbs much of
the light between 300 and 400 nm. This relatively long-wave
light is thought to induce formation of oxygen radicals that
are damaging to lens proteins and destroy the integrity of
lens fibre membrane. Absorption of light by the lens also
results in biochemical changes associated with formation of
various fluorophores and pigments that contribute to the
development of brunescent cataract.

BENDAZAC
Bendazac, an oxyacetic acid with a chemical structure similar
to indomethacin, was originally developed as an antiinflammatory, antinecrotic and antilipidaemic agent. In 1983,
Silverstrini et al.50 demonstrated its protective effect against
lens protein denaturation both in vitro and in vivo. Pandoflo
et al.51 found that bendazac was especially effective in protection against X-ray-induced cataract in the rabbit lens with
preservation of the lens enzymatic antioxidant system. The
exact mechanism by which this effect is produced is
unknown, but it was proposed that bendazac inhibited
binding of cataractogenic stressors on the reactive lens proteins side chains thereby preventing lens proteins denaturation, aggregation and precipitation. Bendazacs main
metabolite, 5-hydroxybendazac, was found to be an effective
hydroxy radical scavenger.52 Most recently, bendazac was
shown to inhibit adhesion of lens epithelial cells to PMMA
intraocular lenses in vitro which suggested that bendazac
might have potential benefit in preventing secondary cataract development.53
Many clinical trials, including double-blind, placebocontrolled trials, have been conducted in the 1980s. These
were summarized in Blafour & Clissolds major review.54 The
majority of the studies investigated the effect of 500 mg of
bendazac-lysine (better absorbed compared with its parent
compound) administered orally 3 times daily. Bendazaclysine
can also be administered as 0.5% solution eyedrops with
reported comparable results. Essentially all the trials suffered
from small number of participants and short duration of
follow up. There was no uniform methodology making combined analysis impossible. Many clinical trials were criticized
for drawing conclusions based on subjective criteria. One

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Toh et al.

objectively monitored double-masked, placebo-controlled

trial with photography-based light scattering assessment of
cataractous lens had a high dropout rate.55 Although a
number of studies demonstrated the efficacy of bendazac in
stabilizing and delaying progression of cataract, overall the
results were concluded to be equivocal because of the limitations discussed.

DIABETIC

CATARACT

Diabetes, which affects 250 million people worldwide, is

associated with 1012% of all cataracts extracted.56 Hers first
described the role of NADPH-dependent aldose reductase
(AR) enzyme in converting glucose to the sugar alcohol
sorbitol.57 The lens derives 80% of its metabolic energy from
anaerobic glycolysis with the remaining 15% and 5% from
hexose monophosphate shunt and Krebs cycle, respectively.
It was hypothesized that increased intracellular glucose may
overflow the glycolysis pathway resulting in activation of AR
and accumulation of membrane-impermeable sorbitol. The
latter increases cellular osmotic pressure with influx of water
that lead to lens swelling and opacification.58 Sorbitol had
been shown to accumulate in rat lens incubated in high
glucose media as well as in the lenses of diabetic rats.59 In
addition, diabetes is associated with increased oxidative
stress with the formation of hydroxyl radicals that may accelerate damage to the cell membranes resulting from sorbitol
accumulation.60

ALDOSE

REDUCTASE INHIBITORS

Aldose reductase, which is the key enzyme of the polyol

pathway, has been the prime target for possible prevention of
diabetic cataract. There are literally hundreds of AR inhibitors (ARIs) reported in the literature. They can be divided
into two main classes (i) acetic acids such as epalrestat and
imirestats; and (ii) spirohydantoins such as sorbinil. Sorbinil
reduced polyol production in experimental diabetic cataract
of rat lenses in vitro.
By inhibiting AR, sorbinil also prevents oxidation of
NADPH which is essential for keeping glutathione in the
reduced state. Sorbinil had shown promising protective effect
in preventing and slowing progression of experimental cataracts. In vivo, it reduced the progression of cataract in the
diabetic rats.61,62 In clinical trials, however, sorbinil had failed
to show beneficial effect against cataract61 and in some trials it
had to be withdrawn because of unacceptable side-effects.63
The rationale behind the use of ARI has weakened over the
years and many problems have been identified with the AR
hypothesis.64 These include the fact that AR has never been
shown to convert glucose stoichiometrically to sorbital. ARIs
have also been found to have poor efficiency and selectivity.
Recent effort have discovered a novel series of ARIs led by the
compound lidorestat 9 which was found to be more
efficient,65 although more work is still needed before its role as
anti-cataract agent can be established.

THE

CALPAIN MODEL

Elevated intracellular calcium levels have been associated

with deleterious effect on lens metabolism that lead to a
cascade of cataractogenic events with eventual loss of lens
transparency.66,67 Calcium levels in human cataract had been
found to be pathologically elevated.68 In vitro, this has been
shown to be associated with the development of cortical lens
opacity secondary to calcium-induced proteolysis of lens
crystallin.69,70
The effects of unregulated intracellular calcium levels
include depression of glycolysis, inhibition of protein synthesis, formation of lens protein aggregates and activation of
proteases such as calpain.66 There is increasing evidence to
suggest that calpain could play a role in some forms of
cataract. This has been the subject of a recent major review
article which summarized the structures of calpain isomers
and their potential role in cataractogenesis.71 Among the
many calpain isomers, calpain 2 has been found to be the
major calpain in the epithelial cells of human lenses showing
age-related cortical cataract.72 It is hypothesized that
calcium-mediated activation of calpain 2 can lead to denaturation of lens proteins and the development of cataract.
Calpain is thus the prime target for prevention of calciumrelated cataract.

CALPAIN

INHIBITORS

Recent studies of calpain 2 structures have led to the synthesis of mercaptoacrylate derivatives as the new generation of
calpain inhibitors.71 The leading candidate compound,
SJA6017, has shown promising protective effect against cataract both in vitro and in vivo. In cultured rodent lens SJA6017
was found to prevent calcium-induced cortical cataract.73
Similar findings were observed in porcine lenses.71 In both
studies the effect of SJA6017 appeared to correlate with its
ability to inhibit calpain 2. The compound is undergoing
further modification with the latest version shown to have a
high corneal permeability when administered as eyedrops in
rabbits.73 Many of these calpain inhibitors are awaiting clinical trial.

PROSPECT

OF MEDICAL TREATMENT
OF CATARACT

The financial burden of cataract surgery places it beyond the

reach of many parts of the world. An alternative non-surgical
approach to the treatment of cataract is urgently needed.
This is a challenging mission because cataract is a multifactorial disease. The physiology of lens transparency has many
interdependent elements. In order to develop an effective
treatment, a precise understanding of the underlying mechanism in different types of cataract (cortical, nuclear and posterior subcapsular cataracts) is needed. This will identify
potential target for treatment strategy. Once developed, the
latter needs to be subjected to critical experimental and
clinical examinations.

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669

Table 1. Summary of potential medical therapy of cataract

Potential anti-cataract agents

Proposed mechanisms of action

Level of evidence

Prospect

Multivitamins supplement
(Vitamins C & E)
N-acetylcarnosine

Anti-oxidation

Randomised clinical trials

Not promising

Anti-lipid peroxidation

Aspirin, ibuprofen and

paracetamol
Aldose reductase inhibitors
Calpain inhibitors

Acetylating agent protects against

protein denaturation
Inhibition of aldose reductase
Inhibition of protease calpain

One small randomised clinical

trial by the developer
Population-based
case-controlled studies
Old clinical trials
In vitro and in vivo studies

Promising results that need further

independent investigation
Equivocal results

The problems of cataract drug trials are well summarized

by Bron et al.74 Cataract is a slowly progressive disease over
several years. Clinical trial of any drug treatment effect will
therefore have to be a long-term, well-designed study in
order to have sufficient data for comparison of baseline findings in the untreated patients. Moreover, in order to detect
significant treatment effect and offset high dropout rate, a
large number of participants are required. A multicentre,
randomized, double-masked, placebo-controlled trial is still
the gold standard. Robust and uniform selection criteria as
well as consistent approaches to data collection and interpretation are essential. Preferably the outcome measures
should be an objective assessment in addition to BCVA, as
the latter has too many potential confounders. Objective
methods of determining cataract progression, such as the
Cataract Image Analysis system, are now widely available but
such a trial would be costly.75
Unfortunately, the reality is that the substantial costs
involved in developing a new anti-cataract drug may make it
unaffordable to be widely used in developing countries
where it is most needed. There is also a lack of financial
support from the pharmaceutical companies for studies of
drugs out of patent, such as the aspirin-like analgesics. On
the other hand, cataract surgery of not only the first eye, but
also the second eye, has been shown to be an extremely
cost-effective procedure compared with other interventions
across medical specialties in terms of quality-adjusted lifeyears gain.76,77 Cost-utility study has also shown that cataract
surgery is affordable in many developing countries.78
However, until a proper trial of a successful anti-cataract
drug is being conducted its actual impact compared with
surgery is unknown. At the moment, in developing countries,
the most effective strategies are still prevention of identifiable risk factors such as dehydration illness, nutritional
improvement, smoking and sun exposure.
Nonetheless, successful prevention or delay of cataract
formation is still a highly desirable alternative to surgical
treatment. Among the anti-cataracts agents, multivitamins
supplement is an attractive solution because it is relatively
cheap and safe as well as widely available, although results
from several clinical trails have been less than promising.
N-acetylcarnosine eyedrops is also now widely available. It is
marketed as a popular health supplement by Food and Drug
Administration-approved online pharmacy. No prescription

Not promising
In developmental phase

is needed and it costs around USD$30.00 for 75 days of

treatment. The development of N-acetylcarnosine as an anticataract drug is supported by interesting basic physiology
and the clinical trial has shown the most promising results.
An independent study that investigates its effectiveness is
required to validate its claim. The interest in other anticataract agents has waned. Calpain inhibitors are still in the
development phase. Table 1 summarizes these potential
medical therapy of cataract.

CONCLUSIONS
The quest for medical treatment of cataract has widened our
knowledge of cataractogenesis with identification of new risk
factors and the development of new disease models. Such
effort has led to the discovery of potential treatments. At this
stage drugs are available but all are without adequate proof of
efficacy. Studies are intensifying with the aim to identifying
a therapy that will prevent lens opacity development. It is
likely that different drugs will be specifically designed for
each of the many pathways that give rise to cataract. In the
meantime surgical treatment of cataract remains the only
proven strategy with the accompanying cost implications for
health budgets.

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