We read with great interest a recent report by Siam et al., “The
amount of intraocular pressure rise during pharmacological pupillary
dilatation is an indicator of the likelihood of future progression of
glaucoma.” These authors report that the likelihood of optic nerve
progression (defined by the disc damage likelihood scale, the glaucoma
staging system 2, or both) in open angle patients is related t...
We read with great interest a recent report by Siam et al., “The
amount of intraocular pressure rise during pharmacological pupillary
dilatation is an indicator of the likelihood of future progression of
glaucoma.” These authors report that the likelihood of optic nerve
progression (defined by the disc damage likelihood scale, the glaucoma
staging system 2, or both) in open angle patients is related to the amount
of intraocular pressure (IOP) elevation following pharmacological
pupillary dilation. We complement the authors on their fine work and
applaud them for highlighting the importance of IOP assessment after
dilation.
The authors included open angle glaucoma patients but did not specify
primary open angle glaucoma (POAG). While they excluded “any condition or
disease that affects pupillary dilatation,” they did not specify whether
exfoliation syndrome patients were excluded. We are interested to know
whether any patients in the study had exfoliation syndrome or pigment
dispersion syndrome, as patients with these conditions can have marked IOP
elevations after dilation.[1-3] Patients with exfoliation syndrome in
particular might be expected to progress more rapidly than patients with
POAG.4
Sincerely yours,
Nathan Radcliffe, MD
Clinical Glaucoma Fellow
New York Eye and Ear Infirmary
drradcliffe@gmail.com
Robert Ritch, MD
Professor, Clinical Ophthalmology
Chief, Glaucoma Service
Surgeon Director
New York Eye and Ear Infirmary
ritchmd@earthlink.net
References
1. Kristensen, P., Mydriasis-induced pigment liberation in the
anterior chamber associated with acute rise in intraocular pressure in
open-angle glaucoma. Acta Ophthalmol 1965;43:714-724.
2. Mapstone R. Pigment release. Br J Ophthalmol 1981;65:258-63.
3. Nanba K, Sobue K, Imai A, et al: Clinical evaluation of
pseudoexfoliation and capsular glaucoma Folia Ophthalmol Jpn 1978;29:1567-
1575.
4. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma
progression and the effect of treatment: the early manifest glaucoma
trial. Arch Ophthalmol 2003;121:48-56.
We read with great interest, the illuminating article by Drs Gomi,
Sawa and Tano. Our limited experience (4 Afro-American patients) with
intravitreal bevacizumab (IVB) for polypoidal vasculopathy (PPV) has been
more positive.
We had reported the first success early this year in terms of lasting
remission [1]. Furthermore, I enclose details on another patient who had
PPV OU, in all likeliho...
We read with great interest, the illuminating article by Drs Gomi,
Sawa and Tano. Our limited experience (4 Afro-American patients) with
intravitreal bevacizumab (IVB) for polypoidal vasculopathy (PPV) has been
more positive.
We had reported the first success early this year in terms of lasting
remission [1]. Furthermore, I enclose details on another patient who had
PPV OU, in all likelihood clinically. ICG confirmation was not possible
due to dye non availability. The details are evident in the legend and the
therapeutic approach was IVB Q 6 weeks OD x 4 and intravitreal
triamcinolone x1.OS was managed with IVB alone X 3. Verteporfin (PDT) was
not a consideration OD and the pigment epithelial detachment OS forced the
use of an anti VEGF agent empirically off label. There are no active
lesions OU for about 3 months.
It is unclear to us if our results were a function of ethnicity or
more limited disease (OS).We respectfully opine that a prospective trial
IVB +/- PDT may be useful, possibly more so in the US population with a
wide ethnic base. We are in the process of finalizing such a study.
Fig 1 A. Visual acuity (VA) OD: Hand motion, with massive subretinal hemorrhage (SRH). VA OS 20/30, superonasal hemorrhagic pigment epithelial detachment (HPED)
Fig 1 B. OD VA 20/200, with significant clearing of the SRH and fibrosis of HPED. OS VA unchanged, HPED resolved entirely with minimal fibrosis
References
1.Ghajarnia M, Kurup S et al: The therapeutic effects of intravitreal
bevacizumab in a patient with recalcitrant idiopathic polypoidal choroidal
vasculopathy.Semin Ophthalmol. 2007 Apr-Jun;22(2):127-31.
PMID: 17564935
According to the Canadian Community Health Survey, approximately 82%
of the population of seniors aged 65 – 80+ (3,000,000 seniors) reported
having vision problems in Canada. [1] Cataracts are the leading cause of
vision impairment among seniors. Between the period of 1994 – 2003,
proportions of seniors with cataracts rose from 14% – 20% with populations
aged 75 and over accounting for higher percentage...
According to the Canadian Community Health Survey, approximately 82%
of the population of seniors aged 65 – 80+ (3,000,000 seniors) reported
having vision problems in Canada. [1] Cataracts are the leading cause of
vision impairment among seniors. Between the period of 1994 – 2003,
proportions of seniors with cataracts rose from 14% – 20% with populations
aged 75 and over accounting for higher percentages. [1]
Cataract surgery is among non-emergency surgical procedures with
highest wait times in Canada. There was a 32% increase in cataract
surgeries over 5 years between 1997/1998 and 2002/2003. In British
Columbia, there were 11,816 patients waiting for surgery and 7897 patients
completed in the 3 months from 31 August 2006 to 31 October 2006. [2] In
addition to being a barometer of accessibility to health care services,
cataract wait times are also a determinant of patient satisfaction which
in turn is correlated with increased health-related quality of life [3]
and possibly decreased injury risk. [4]
Delay of care is a persistent and undesirable feature of current
health care systems. [5] Waits and delays plague health care systems
worldwide, and wait times for most specialists exceed those for primary
care practices. [6] From clinical perspective delay in necessary treatment
due to surgical wait lists is a major concern. [7] Establishing a
clinically appropriate time that patients can safely wait for the
operation is generally perceived as a method to prevent adverse outcomes
of delay. [8]
The cost effectiveness of cataract surgery has been well-established.
[9, 10] In fact, modern techniques used for cataract surgery today result
in rapid visual improvement with 50% of patients experiencing good vision
by 24 hours and 96-99% experiencing good vision by 4 weeks. [11] Evidence
supports cataract surgery among older drivers in producing significant
improvements in driving performance (best predicted by the concomitant
improvement in contrast sensitivity), subsequent crash rates half that of
older drivers with cataracts who opted not to have surgery, and self-reported improved visual function and distance estimation. [4]
References
(1). Millar, W. J. Vision problems among seniors. Health Reports. 2004;
16; 45-49.
(2). BC Ministry of Health (2006). Surgical Wait Times: Cataract
Surgery in BC. [Online]. Available at URL:
http://www.swl.hlth.gov.bc.ca/swl/swl_db/swl.WaitlistPkg.GetHospitalListBySurgSpecNLF?IEvent=27
(3). Conner-Spady, B.L., Sanmugasunderam, S., Courtright, P.,
McGurran, J.J., & Noseworthy, T.W. Determinants of patient
satisfaction with cataract surgery and length of time on the waiting list.
British Journal of Ophthamology. 2004; 88; 1305-1309.
(4). Owsley, C., McGwin, G., Sloane, M., Wells, J., Stalvey, B.T.,
Gauthreaux, S. Impact of cataract surgery on motor vehicle crash
involvement by older adults. JAMA. 2002; 21; 288(7):841-9.
(5). Hodge, W., Horsley, T., Albiani, D., Baryla, J., Belliveau, M.,
Buhrmann, R., O'Connor, M., Blair, J., Lowcock, E. The consequences of
waiting for cataract surgery: a systematic review. CMAJ. 2007 176: 1285 -
1290.
(6). Murray, M.F. Improving access to specialty care. Jt Comm J Qual
Patient Saf. 2007; 33(3):125-35.
(7). Sobolev, B., Mercer, D., Brown, P., FitzGerald, M., Jalink, D.,
Shaw, R. Risk of emergency admission while awaiting elective
cholecystectomy. CMAJ. 2003; 169; 662–665.
(8). MacCormick, A.D., Collecutt, W.G., Parry, B.R. Prioritizing patients
for elective surgery: a systematic review. ANZ J Surg. 2003; 73; 633–642.
doi: 10.1046/j.1445-2197.2003.02605.x.
(9). Laidlaw, D.A.H., Harrad, R.A., Hopper, C.D., Whitaker, A.,
Donovan, J.L., Brookes, S.T., Marsh, G.W., Peters, T.J., & Sparrow, J.
M. Randomised trial of effectiveness of second eye cataract surgery.
Lancet. 1998; 352; 925-929.
(10) Sach, T.H., Foss, A., Gregson, R., Zaman, A., Osborn, F., Masud,
T., Harwood, R.H. Falls and health status in elderly women following first
eye cataract surgery: an economic evaluation conducted alongside a
randomised controlled trial. Br J Ophthalmol. 2007 Jun 21; [Epub ahead of
print]
(11). Harwood, R. H., Foss, A. J. E., Osborn, F., Gregson, R.M.,
Zaman, A., & Masud, T. Falls and health status in elderly women
following first eye cataract surgery: A randomized controlled trial.
British Journal of Ophthamology. 2005; 85; 53-59.
We appreciate the comments of Grzybowski et al. about our article. We
agree that the term "tobacco alcohol amblyopia" is not very accurate and
does not specifically describe the underlying cause of vision loss. It
may also not fit the "historic" description of the condition. However,
the term is still used widely to describe a spectrum characterized by
optic nerve dysfunction and selective involvement of...
We appreciate the comments of Grzybowski et al. about our article. We
agree that the term "tobacco alcohol amblyopia" is not very accurate and
does not specifically describe the underlying cause of vision loss. It
may also not fit the "historic" description of the condition. However,
the term is still used widely to describe a spectrum characterized by
optic nerve dysfunction and selective involvement of the papillomacular
bundle.
This includes toxic optic neuropathies due to medications (e.g.
ethambutol), and nutritional optic neuropathies due to vitamin
deficiency ( B12 and folate). One reason perhaps why the term is still
popular is that cause of vision loss in these patients is often
multifactorial. The evidence of independent toxicity of either alcohol
or tobacco is weak. Many people abuse both substances yet few of them
develop vision problems. We believe that the final step in the
pathophysiology of all these conditions is mitochondrial damage. This is
one reason why the clinical features of this condition is similar to
Leber's heriditary optic neuropathy. Either alcohol or tobacco abuse may
not be enough to cause optic neuropathy especially in patients who
consume amounts within or slightly above the "recommended limit".
Genetic suceptibility caused by either by compromised mitochondrial
function or deficiency of vitamins necessary to detoxify cyanide, formic
acid and oxygen radicals, plays an important role in the pathogenesis of
this condition. We agree that case 2 had mitochondrial optic
neuroapthy, which probably manifested because of heavy smoking.
We did not test these patients with pattern ERG as we believe that mfERG
is a very good tool in differentiating between optic neuropathy and
retinopathy. We did not intend to imply that those patients had only
maculopathy. Rather we believe that the electrophysiological dysfunction
was not limited to the optic nerve as has been demonstrated in
experimental animal models. We did publish a series of patients with
presumed ethambutol-induced optic neuropathy, who also had mfERG
abnormalities [1]. In patients with poor central vision we do enlarge
the fixation target and our technician does monitor fixation during
testing. Therefore, fixation errors are unlikely to be the cause of the
abnormalities.
References
(1) Behbehani R, Affel E, Savino PJ. Multifocal ERG abnormalities
in ethambutol associated vision loss. Br J Ophthalmol. 2005;89:976-82.
We read with interest the paper by Keenan [ref 1] and colleagues.
We recently studied the 2005/06 Hospital Episode Statistics (HES)
data for cataract and have reached similar conclusions. We agree with the
authors’ observations that as NHS cataract surgery rates (CSRs) in England
have increased significantly in recent years, several questions are now
raised. What is the appropriate CSR in a d...
We read with interest the paper by Keenan [ref 1] and colleagues.
We recently studied the 2005/06 Hospital Episode Statistics (HES)
data for cataract and have reached similar conclusions. We agree with the
authors’ observations that as NHS cataract surgery rates (CSRs) in England
have increased significantly in recent years, several questions are now
raised. What is the appropriate CSR in a developed market economy? Is
the observed geographical variation in CSR in England a marker of
increased incidence and requirement for surgery in some ‘high activity’
regions or a marker for overprovision?
Conversely, in relation to lower activity regions, are there data set
issues from the use of an administrative database such as the HES, or are
there genuine clinical differences or variations in the organisational
provision of cataract care? Private CSR rates are not considered as HES
returns are restricted to NHS care.
In our consideration of the most up to date HES returns there are some
data problems -due to coding issues- at some hospital Trusts (details on
request). Observational studies of cataract surgical practice and
population studies of regional prevalence of cataract are now needed.
An electronic clinical database -a cataract national dataset- is the most
pragmatic method of capturing such data in a timely fashion. Such an e-tool would track changing thresholds for referral for cataract surgery and
importantly, consider outcomes for patients at a national level. Such an
initiative is technically possible, is strongly supported by the Royal
College of Ophthalmologists and now requires government support. With the
UK Government’s commitment to developing an electronic patient care
record, the deployment of a national electronic cataract dataset would
greatly assist in our better understanding of these questions.
Care of NHS cataract patients has improved as a result of better
technology and improved access to care, much of which followed the Action
on Cataract (AoC) initiative. [2] A recent quality improvement report in
relation to NHS cataract care in Scotland has been compelling. [3]
However ophthalmologists and commissioners of ophthalmic care should not
become complacent. Pressures on eye care services for the future are
likely to be significant; as a result of the aging population, lower
clinical thresholds for safe treatment for cataract, the introduction of
new treatments for patients with age-related maculopathy and other
conditions.
Cataract surgery is a highly effective procedure which provides rapid
improvement in vision related, as well as non-vision related, outcomes as
well as being very cost effective. [4] Benefits to patients are
lifelong. The principal causal factor of adult cataract is ageing and
demand for services for cataract and other diseases of the aging eye are
expected to increase as the UK population ages. The indications for
surgery as recommended in the consensus guidelines from the College,
simply stated, are: failing vision attributable to lens opacity despite
optimal optical correction or ocular co-morbidity and patient willingness
and fitness to undergo cataract surgery. The last issue is not problematic
as surgery is almost always carried out under day care and local
anaesthesia. There is no evidence, that we are aware of, to suggest that
patients are having ‘inappropriate’ cataract surgery in the UK
We are aware some Primary Care Trusts (PCTs) are attempting to
‘demand manage’ cataract surgery to certain thresholds of patient visual
impairment. Such decisions, if simply based on Snellen visual acuity
levels, are likely to disadvantage elderly patients. [5] Attempts to
include chronological age as a factor in healthcare policy are likely to
be insensitive. [6] Some have suggested that access to surgery could
be determined by an assessment of a range of a patient’s visual symptoms
and disability, rather than a simple measurement of monocular visual
acuity. [7] We support the concept that decision to operate for
cataract remains a matter of balanced clinical judgment and consensus
reaching with the individual patient.
The World Health Organization recommended 3,000 cataract operations per
million residents as the minimum to eliminate blindness from cataract and
recommended 3,500 per million for established market economics for the
year 2000. [8] This latter target is being attained across the
English NHS.
References
1. Keenan T, Rosen P, Yeates D, Goldacre M. Time trends and
geographical variation in cataract surgery rates in England: study of
surgical workload Br J Ophthalmol 2007; EP. doi: 10.1136/bjo.2006.108977
2. Department of Health. Action on cataracts – Good Practice
Guidance. NHS Executive. Feb 2000
http://www.dh.gov.uk/assetRoot/04/01/45/14/04014514.pdf
3. Tey A, Grant B, Harbison D, Sutherland S, Kearns P, Sanders R.
Redesign and Modernisation of an NHS cataract service (Fife 1997-2004):
multifaceted approach. BMJ. 2007; 334: 148-152
4. Walker JG, Anstey KJ, Hennessy MP, Lord SR, von Sanden C. The
impact of cataract surgery on visual functioning, vision-related
disability and psychological distress: a randomized controlled trial. Clin
Experiment Ophthalmol. 34, 734-42 (2006)
5. Westcott, M C, Tuft, S J, Minassian, D C Effect of age on visual
outcome following cataract extraction Br J Ophthalmol 2000 84: 1380-1382
6. Beare N, Dandona L. Cataract surgery in very elderly patients BMJ
2001;323:455.
7. Crabtree HL, Hildreth AJ, O'Connell JE, et al. Measuring visual
symptoms in British cataract patients: the Cataract Symptom Scale. Br J
Ophthalmol 1999;83:519-523
8. World Health Organisation Global Initiative for the Elimination
of Avoidable Blindness. Geneva, Switzerland: World Health Organization;
2000. WHO/PBL/97.61 Rev 2.
We have read Manzano et al’s insightful paper[1] with interest and appreciated the comments concerning the inhibitory effects of bevacizumab on corneal neovascularisation (NV). However, the manuscript had some important aspects that need to be clarified. Cumulative data from numerous basic and clinical studies strongly implicates the central role of VEGF in ocular and corneal angiogenesis. Binding all free-ci...
We have read Manzano et al’s insightful paper[1] with interest and appreciated the comments concerning the inhibitory effects of bevacizumab on corneal neovascularisation (NV). However, the manuscript had some important aspects that need to be clarified. Cumulative data from numerous basic and clinical studies strongly implicates the central role of VEGF in ocular and corneal angiogenesis. Binding all free-circulating VEGF by specific antibodies inhibits VEGF-mediated receptor stimulation which normally leads to an abnormal angiogenesis in pathological conditions.[2,3] Bevacizumab (Avastin) is a humanised version of a monoclonal parent antibody originally produced in mice specifically against human VEGF. Since the parent antibody of avastin is a murine protein likely to provoke an immune response and thus unsuitable for use in humans, it has been humanised by genetic engineering to overcome these disadvantages. The humanisation process turns the parent antibody into commercially available avastin molecule, 93% human and 7% murine. However, the specificity of avastin molecule is exactly similar to that of the parent antibody, which binds to human VEGF with a high affinity, but has “no effect on host VEGF” (i.e., that produced by the mouse).[4] This is why preclinical anti-tumor studies of both avastin and its parent antibody have been conducted on human xenografts model in animals, and complete inhibition of tumor growth was not seen (and would not be expected) due to the interfering effects of host VEGF, which is not inhibited by the anti-human VEGF antibody, avastin.[5] Our previous case report [6] demonstrated that bevacizumab, a humanized anti-VEGF antibody, may actually have a therapeutic option for corneal NV in human beings. However, bevacizumab should not reasonably be considered to serve as an antiangiogenic agent in rat corneal tissue for the inherited characteristics of this molecule explained in detail above. Furthermore, we have previously tested this hypothesis in a similar (unpublished) pilot study of silver nitrate induced corneal NV in rats, but on the contrary found no improvement on the degree of corneal NV after intraperitoneal injection of bevacizumab 5 mg/kg, equivalent to its effective intravenous dose applied for the treatment of human colorectal cancers. Therefore, it is problematic to select such a monoclonal anti-human VEGF antibody, as an anti-rat VEGF agent in any experimental study conducted in rats. So, we unfortunately consider that this is a major methodological error in this experimental study.
The possible explanation for the difference encountered in the extent of corneal NV after topically applied avastin in rat eyes could be an unexpected cross-reaction of bevacizumab molecule with rat VEGF. We think that cross-reactivity of human specific monoclonal recombinant antibodies (if such exists), particularly bevacizumab, with other murine subspecies is another interesting topic of extensive researches. Another, but a minor concern in this paper is about the dose of topically applied avastin, yet not explained by the authors how to determine 2 drops of avastin 4mg/ml (i.e, approximately corresponding to 0.4 mg/day) solution daily would be sufficient for inhibiting corneal NV, since its minimal intravitreal dose is 1.25 mg in clinical practice, and also bioavailability of topically applied avastin drops in the cauterized corneal tissue has not been established. Finally, we obviously support the suggestion of using anti-human VEGF agents for prevention and management of corneal NV in the clinical practice [6], yet consider this experimental research has a major methodological error.
References
1. Manzano RP, Peyman GA, Khan P, et al. Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol. 2007;91:804-7.
3. Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci 2000;41: 2514–22.
4. Presta LG, Chen H, O’Connor SJ, et al. Humanization of an anti-VEGF monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593–9.
5. Gerber H, Kowalski J, Sherman D, et al. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 2000;60:6253-8.
6. Erdurmus M, Totan Y. Subconjunctival bevacizumab for corneal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2007 Apr 26; [Epub ahead of print]
We read with interest the letter by Decock et al regarding the rare
congenital ocular malformation (orbital cyst and bilateral colobomatous
microphthalmos). [1]
The female child reported was the product of a mother with documented
vitamin A deficiency (VAD) during the second trimester of pregnancy after
previous gastric bypass surgery for morbid obesity. The authors do not
report the sympto...
We read with interest the letter by Decock et al regarding the rare
congenital ocular malformation (orbital cyst and bilateral colobomatous
microphthalmos). [1]
The female child reported was the product of a mother with documented
vitamin A deficiency (VAD) during the second trimester of pregnancy after
previous gastric bypass surgery for morbid obesity. The authors do not
report the symptoms or biochemical evidence of VAD in this particular
mother nor the treatment she received but presumably it is likely that she
had subclinical VAD during the first trimester when the foetal fissure may
be disturbed causing coloboma.
This has striking parallels with a cases series of children with
ocular coloboma from South India reported previously by our group. In
that study maternal night blindess presumable from VAD was reported in 16%
of mothers of children with coloboma compared with 5% rate for the normal
local population of mothers. Studies by the Indian Institute of Nutrition
of the same population showed that 50% of mothers have biochemical
evidence of VAD during pregnancy mostly asymptomatic and subclinical. [2]
We have previously reported epidemiological and laboratory evidence
to support a hypothesis that there may be a genetic (recessive)
predisposition to the teratogenic effect of mild to moderate maternal
vitamin A deficiency in pregnancy. This may explain the higher prevalence
of colobomatous malformations in certain Asian countries where maternal
vitamin A deficiency is common and consanguineous marriages popular, the
low risk to siblings, and birth-order effect with increased frequency of
colobomas in higher birth-orders. Mutations in a gene involved in
cellular access to vitamin A that normally protects the mother or the
embryo from natural variation in dietary vitamin A intake could render
that individual intolerant of conditions of vitamin A deficiency. [3]
If such a gene-environment interaction is shown to be true there are
public health implications for the prevention of blindness from anomalies
akin to the research showing benefits of folic acid supplementation in
prevention of neural tube defects. However, this form of intervention
would be much more difficult with vitamin A which is itself a powerful
teratogen if present in excess.
References
1. Decock, C. E., Breusegem, C. M., Van Aken, E. H, and Leroy, B. P.
High beta-trace protein concentration in the fluid of an orbital cyst
associated with bilateral colobomatous microphthalmos. Br.J Ophthalmol.
91(6), 836-837. 2007.
2. Hornby SJ, Ward SJ, Gilbert CE, Dandona L, Foster A, Jones RB.
Environmental risk factors in the aetiology of congenital malformations of
the eye in children in South India. Arch.Trop.Paed. 2002;22:67-77.
3. Hornby, S. J., Gilbert, C. E., and Ward, S. J. Eye birth defects
in humans may be caused by a recessively-inherited genetic predisposition
to the effects of maternal vitamin A deficiency during pregnancy. Med Sci
Monit 9(11), HY23-26. 2003.
Further to the article of Behbehani R, Sergott RC and Savino PJ
Tobacco-alcohol amblyopia: a maculopathy? [1], we question whether either
patient had tobacco-alcohol amblyopia (TAA).
“TAA” occurs in patients with high alcohol and tobacco
intake, but is perhaps a misnomer with “nutritional optic
neuropathy” being more appropriate. Many such patients are
nutritionally deficient consequent u...
Further to the article of Behbehani R, Sergott RC and Savino PJ
Tobacco-alcohol amblyopia: a maculopathy? [1], we question whether either
patient had tobacco-alcohol amblyopia (TAA).
“TAA” occurs in patients with high alcohol and tobacco
intake, but is perhaps a misnomer with “nutritional optic
neuropathy” being more appropriate. Many such patients are
nutritionally deficient consequent upon a poor diet [2] and even with
continuation of smoking, improvement in vision can occur following dietary
supplementation.[3] Pure “tobacco amblyopia” has been
described [4] and is usually associated with pipe and cigar smoking rather
than cigarettes.[2] One of us (GH) has seen only two cases of presumed
“tobacco optic neuropathy”, and both patients smoked large
amounts of pipe tobacco, inhaling the smoke. However, despite the
explosion of cigarette smoking during the 20th Century, the number of
reported cases significantly decreased, leading to the suggestion that the
disorder may not exist as a single nosological entity.[5] In addition, it
has been suggested that mitochondrial function may be implicated in, for
example, the “epidemic” optic neuropathies in Tanzania, Cuba
or Nigeria,[6] and that some cases of “tobacco-alcohol
amblyopia” were in fact Leber hereditary optic neuropathy (LHON).[7]
The authors present two cases. In both the level of alcohol and
tobacco consumption is considerably less than our experience dictates
would be required to consider a tobacco-alcohol related aetiology. Case 1
smoked only one pack of cigarettes per week, and consumed two to three
beers daily, only slightly more than the UK recommended limit for women;
less than that for men. Case 2 consumed even less alcohol (5-8 drinks per
week), yet the authors state that both patients had a “high alcohol
intake”. Further, the second patient was shown by mutational
analysis to be suffering from LHON, previously shown by the same group to
be a disorder that can be mistaken for tobacco-alcohol amblyopia.[7]
Electrophysiology may be valuable in such cases, but only mfERGs are
presented. Delayed VEPs may occur in maculopathy, but as delayed VEPs
usually occur in toxic optic neuropathy, a normal latency would have been
re-assuring evidence of the lack of optic nerve involvement.[8,9] The
pattern ERG, because of its ability both to separate optic nerve and
macular dysfunction and directly to assess the retinal ganglion cells with
the N95 component [10], may have provided confirmatory evidence of macular
dysfunction, particularly in the patient with LHON; it has been reported
that fixation errors in a poorly sighted patient may give artefactual
central mfERG abnormality.[11]
ACKNOWLEDGEMENT:
The authors do not declare any financial support or relationships that
may pose a conflict of interest.
Funding/support: none.
Financial disclosures: none.
References:
1. Behbehani R, Sergott RC, Savino PJ. Tobacco-alcohol amblyopia: a
maculopathy? Brit J Ophthalmol 2005; 89:1543-4.
2. Heaton JM, McCormick AJA, Freeman AG. Tobacco amblyopia: A clinical
manifestation of vitamin B12 deficiency. Lancet 1958;2:286-290.
3. Victor M. Tobacco-alcohol amblyopia. A critique of current concepts of
this disorder, with the special reference to the role of nutritional
deficiency in its causation. Arch Ophthalmol 1963;70:313-318.
4. Dunphy EB. Alcohol and tobacco amblyopia: a historical survey. Am J
Ophthalmol 1969;68:569-578.
5. Grzybowski A. Rozwój badañ wp³ywu tytoniu na narz±d wzroku w ostatnich
200 latach (The development of research on the effect of tobacco
consumption on the visual organ over the last 200 years). Przegląd Lekarski (Medical Review) 2005; 62:1167-1170.
6. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and
mitochondrial dysfunction: genetic and acquired optic neuropathies.
Neurochem Int 2002;40:573-584.
7. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber’s
hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia.
Arch Ophthalmol 1993;111: 1482-1485.
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmat...
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmatory data, Cantor et al1 appear to reach conclusions that are not supported by their own data. Whereas the 2 previous studies(2,3) conclude that BP is a prodrug that is hydrolyzed to its free acid to account for its ocular hypotensive effect by activation of known FP prostanoid receptors, the current publication1 surprisingly concludes that BP is not a prodrug and acts directly as an amide to reduce intraocular pressure (IOP).
The clinical studies cited above(1-3) are not the only ones that have demonstrated the hydrolysis of BP in ocular tissues. Previous studies have demonstrated its hydrolysis in vitro in rabbit, bovine, and human ocular tissues(4-7) and after topical application in vivo in rabbit and monkey ocular tissues.(8) The hydrolysis of BP to produce sufficient concentrations of its very potent free acid, a well-described FP receptor agonist, provides clear evidence of its prodrug properties. Studies in FP receptor knockout mice have clearly demonstrated the importance of FP receptors for effective IOP reduction after topical application of FP receptor agonists, including BP.(9-12)
The 3 clinical studies1-3 provide very consistent data. Each demonstrates equal or higher levels of the free acid than the intact amide of BP in aqueous humor. Each demonstrates peak levels occurring within the first few hours after topical application of BP, with lower levels afterwards. Peak concentrations of the free acid were 35 nM,3 22 nM,2 and 7 nM1 in each of the 3 studies. After topical application of latanoprost (LP), Cantor et al1 demonstrated a free acid concentration in aqueous of 41 nM at 3 hours, which is less that half of the 100 nM concentration found in a previous study.13 Therefore, when assessing the 4 clinical studies1-3,(13) which evaluated the hydrolysis of LP and/or BP, the lowest concentrations (2 to 5-fold less than the other studies) of the free acids of either LP or BP were consistently demonstrated by Cantor et al.1 Cantor et al1 suggest that the lower levels might be partially explained by single dose administration of BP or LP in their study, compared with multiple dosing in other studies. However, another clinical study also involved single dose administration and yet found approximately 2-fold higher concentrations of LP acid.(13)
The key and unambiguous observation that we believe is critical is that, no matter what values were obtained in each and every study, all of the concentrations, including the lower concentrations of the free acid of either LP or BP found by Cantor et al,1 are sufficiently high enough to account for their activity at FP prostanoid receptors. At 24 hours after LP, the aqueous humor concentration of the free acid was found to be well less than 1 nM,13 demonstrating that very low aqueous concentrations are found during periods of substantial IOP reduction. Therefore, the lower limits of quantitation of 1.3 nM for BP acid and 2.6 nM for LP acid in the current study1 apparently are not sensitive enough to detect substantial, clinically significant aqueous concentrations of the free acids of these prodrugs.
Although lower than the free acid concentrations, the relatively high concentrations of the amide of BP in the aqueous1-3 compared with nondetectable levels of the LP ester is hardly an adequate criterion to support the hypothesis that BP is not a prodrug. These data instead demonstrate that BP amide is an inefficient prodrug compared with LP ester simply because the ester bond is more labile than the amide bond. BP is topically applied at 6 times the concentration of LP, but, unlike LP, is not completely hydrolyzed. 1-3,13 Despite its 6-fold higher concentration, BP yields peak free acid concentrations in the aqueous 3 to 6 times lower than LP acid, 1-3,13 clearly demonstrating the inefficiency of hydrolysis of the amide compared with ester prodrug. Despite these lower concentrations of the BP free acid, they appear to be sufficient to fully account for the effect of BP. Studies have repeatedly demonstrated that the free acid of BP is 3 to 10 times more potent at the FP receptor than the free acid of LP.(14-23) Therefore, the 3 to 6-fold lower concentrations of BP, compared with LP, acid in aqueous still can account for similar activation of FP receptors when their differences in potency are considered.
Despite the overwhelming evidence for greater potency of the acid of BP compared with LP, (14-23) Cantor et al1 claim that the acids are equally potent and cite a single published study(19) using trabecular meshwork cells from a limited number of donor eyes to support their claim. Cantor et al fail to acknowledge that BP acid exhibits a potency (EC50) of 2.8 to 3.8 nM in numerous cell-types derived from several different species (e.g. human ciliary muscle cells, mouse fibroblast, and rat smooth muscle cells)(18) such that even the amount of BP acid they detected (7 nM) would be sufficient to occupy and stimulate many of the FP receptors in the target tissues. In more comprehensive studies using trabecular meshwork cells derived from numerous donor eyes,(18) BP acid still exhibits a relatively high potency (EC50 = 26 ± 10 nM) at the FP receptor that could help account for the observations of Cantor et al.(1) By citing and concentrating on only a single reference as opposed to the many other published studies, Cantor et al1 appear to bias their interpretation of their data.
We fully agree that drugs might reach target tissues via routes independent of aqueous humor. However, in the case of prostaglandin analogs, including both LP and BP, drug concentrations measured in the aqueous will leave the eye via trabecular or uveoscleral outflow pathways, thereby providing active drug to these tissues. These drugs also might enter these outflow tissues by other routes, and also might be hydrolyzed to their active free acids either along these alternative routes or after they arrive at their target tissue. Therefore, the possibility of alternative routes of delivery of these drugs to target tissues does not negate their action as prodrugs.
While the manufacturer of BP has repeatedly tried to present data to support the hypothesis that BP’s mechanism of action does not rely on FP receptor agonism of the free acid but rather is due to intrinsic receptor occupancy of the amide, their arguments fail to be convincing for several reasons. First, as previously reported, the presence of FP receptors are essential for BP’s hypotensive action as demonstrated by experiments in FP knockout mice.(10,11) More importantly, there has not been, to the best of our knowledge, any putative receptor that has been adequately identified that can explain the actions of BP at a unique non-FP receptor. The elusive, mystery receptor in question has never been cloned or characterized by receptor binding kinetics. In short, BP’s hypotensive action appears to require FP receptor agonism that occurs following the hydrolysis of the prodrug that liberates the free acid that then activates the classic FP receptors in the target tissues. The shared characteristics of BP with other prostaglandin analogs, including the side effects of iris color darkening and eyelash changes, also would argue that BP exerts its biological actions by activating the FP receptor. Even if “prostamide” receptors were demonstrated to exist in the anterior uvea, the IOP effect of BP still can be more reasonably explained by its ability to activate FP prostanoid receptors following its demonstrated hydrolysis to its potent free acid.
In conclusion, we agree with the data presented by Cantor et al1 finding substantial, albeit somewhat lower,(2,3,13) concentrations of the free acid of BP or LP in aqueous after topical application in humans. However, we strongly disagree with their conclusions. Cantor et al,(1) like others,(2,3,13) have confirmed that BP is an inefficient prodrug that is hydrolyzed to its free acid to activate well-described FP prostanoid receptors resulting in IOP reduction. Postulation of the existence of enigmatic “prostamide” or yet to be identified unknown receptors is not necessary or warranted.
Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
Najam A. Sharif, Ph.D., Molecular Pharmacology Unit, Alcon Research, Ltd. Fort Worth, TX
Martin B. Wax, M.D., Research and Development, Ophthalmology Discovery Research, Alcon Laboratories, Fort Worth, TX; Department of Ophthalmology and Visual Sciences, University of Texas Southwestern Medical School, Dallas, TX
Johan Stjernschantz, M.D., Ph.D., Department of Neuroscience, Uppsala University Biomedical Center, Uppsala, Sweden
Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.
Dr. Camras was a consultant to Pfizer Ophthalmics. Drs. Sharif and Wax are employees of Alcon Laboratories. Dr. Stjernschantz was an employee of Pharmacia Ophthalmics.
Correspondence to: Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, 985540 Nebraska Medical Center, Omaha, NE 68198-5540
References:
1 Cantor LB, Hoop J, WuDunn D, et al. Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract. Br J Ophthalmol 2007;91:629-32.
2 Camras CB, Toris CB, Sjoquist B, et al. Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery. Ophthalmology Same 2004;111:2193-8.
3 Dahlin DC, Craven ER, Moster M, et al. Human aqueous humor concentrations of bimatoprost and bimatoprost free acid following topical ocular dosing of Lumigan (bimatoprost (17-phenyl-trinor-PGF2a) 0.03% ophthalmic solution) [abstract]. Invest Ophthalmol Vis Sci 2004;45:ARVO E-Abstract 2096.
4 Maxey KM, Johnson JL, LaBrecque J. The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist. Surv Ophthalmol 2002;47(Suppl 1):S34-S40.
5 Davies SS, Ju WK, Neufeld AH, et al. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther 2003;19:45-54.
6 Hellberg MR, Ke TL, Haggard K, et al. The hydrolysis of the prostaglandin analog prodrug bimatoprost to 17-phenyl-trinor PGF2a by human and rabbit ocular tissue . J Ocul Pharmacol Ther 2003;19:97-103.
7 Kriatchko A, Zhan G, Cheruvu N, et al. In vitro transport and hydrolysis of bimatoprost in bovine cornea [abstract]. ARVO 2003;B81.
8 Dahlin DC, Bergamini MVW, Curtis MA, et al. Bimatoprost hydrolysis to 17-phenyl PGF2a by rabbit and monkey ocular tissues, in vivo [abstract]. Invest Ophthalmol Vis Sci 2002;43:ARVO E-Abstract 4109.
9 Ota T, Aihara M, Saeki T, et al. The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice. Br J Ophthalmol 2007;91:673-6.
10 Crowston JG, Lindsey JD, Morris CA, et al. Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol Vis Sci 2005;46:4571-7.
11 Ota T, Aihara M, Narumiya S, et al. The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci 2005;46:4159-63.
12 Crowston JG, Lindsey JD, Aihara M, et al. Effect of latanoprost on intraocular pressure in mice lacking the prostaglandin FP receptor. Invest Ophthalmol Vis Sci 2004;45:3555-9.
13 Sjöquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 2002;47(Suppl 1):S6-S12.
14 Resul B, Stjernschantz J, Selén G, et al. Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids. Surv Ophthalmol 1997;41(Suppl 2):S47-S52.
15 Stjernschantz JW. From PGF2a-isopropyl ester to latanoprost: a review of the development of Xalatan: the Proctor Lecture. Invest Ophthalmol Vis Sci 2001;42:1134-45.
16 Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol 2001;432:211-3.
17 Sharif NA, Kelly CR, Crider JY, et al. Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells. J Ocul Pharmacol Ther 2003;19:501-15.
18 Sharif NA, Crider JY, Husain S, et al. Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation. J Ocul Pharmacol Ther 2003;19:437-55.
19 Sharif NA, Kelly CR, Crider JY. Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues. Invest Ophthalmol Vis Sci 2003;44:715-21.
20 Sharif NA, Kelly CR, Williams GW. Bimatoprost (Lumigan®) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracelluar Ca2+ mobilization studies . Prostaglandins Leukot Essent Fatty Acids 2003;68:27-33.
21 Sharif NA, Kelly CR, Crider JY. Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor. J Ocul Pharmacol Ther 2002;18:313-24.
22 Kelly CR, Williams GW, Sharif NA. Real-time intracellular Ca2+ mobilization by travoprost acid, bimatoprost, unoprostone, and other analogs via endogenous mouse, rat, and cloned human FP prostaglandin receptors. J Pharmacol Exp Ther 2003;304:238-45.
23 Stjernschantz J, Albert D, Hu D, et al. Mechanism and clinical significance of prostaglandin-induced iris pigmentation. Surv Ophthalmol 2002;47 (suppl 1):S162-S175.
We read with interest the recently published paper by Manzano et al.
titled ‘Inhibition of experimental corneal neovascularisation by
bevacizumab (Avastin)’. The authors used topical eyedrop application of
either saline or bevacizumab in a rat model of corneal neovascularization,
with apparent moderate success. Furthermore, in their discussion, they
mention that there was incomplete inhibition of th...
We read with interest the recently published paper by Manzano et al.
titled ‘Inhibition of experimental corneal neovascularisation by
bevacizumab (Avastin)’. The authors used topical eyedrop application of
either saline or bevacizumab in a rat model of corneal neovascularization,
with apparent moderate success. Furthermore, in their discussion, they
mention that there was incomplete inhibition of the neovascularization and
speculate several other cytokines or growth factors may be responsible.
However, bevacizumab has previously been reported to be incapable of
binding rodent VEGF [2]. The findings in this study suggest that either
there is in fact a low affinity interaction with bevacizumab and rat VEGF,
or the effects observed are due to other non-VEGF mediated interactions of
bevacizumab. If the latter is the case, then the question arises as to
whether this interaction is specific to bevacizumab or can be replicated
with other type specific normal IgG. Recently Gerber et al. reported the
generation of transgenic mice producing humanized VEGF-A [1], which
produce a VEGF protein that, in contrast to wild type mouse protein, does
bind bevacizumab. This mouse would be suitable for evaluating human
specific anti-VEGF therapies in vivo. We anticipate Lucentis will be
evaluated in this new model and await the results eagerly.
References
1. Gerber, H.P., Wu, X., Yu, L., Wiesmann, C., Liang, X.H., Lee,
C.V., Fuh, G., Olsson, C., Damico, L., Xie, D., Meng, Y.G., Gutierrez, J.,
Corpuz, R., Li, B., Hall, L., Rangell, L., Ferrando, R., Lowman, H.,
Peale, F., and Ferrara, N., Mice expressing a humanized form of VEGF-A may
provide insights into the safety and efficacy of anti-VEGF antibodies.
Proc Natl Acad Sci U S A, 2007. 104(9): p. 3478-83.
2. Lin, Y.S., Nguyen, C., Mendoza, J.L., Escandon, E., Fei, D., Meng,
Y.G., and Modi, N.B., Preclinical pharmacokinetics, interspecies scaling,
and tissue distribution of a humanized monoclonal antibody against
vascular endothelial growth factor. J Pharmacol Exp Ther, 1999. 288(1): p.
371-8.
Dear Editor
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Dear Editors
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Dear Editor,
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmat...
Dear Editor,
We read with interest the recently published paper by Manzano et al. titled ‘Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin)’. The authors used topical eyedrop application of either saline or bevacizumab in a rat model of corneal neovascularization, with apparent moderate success. Furthermore, in their discussion, they mention that there was incomplete inhibition of th...
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