Recent eLetters

Dear Editor,

In their article Doctors Agrawal and McKibbin evaluate the one-year frequency and the clinical outcome data of Putscher’s retinopathy through the British Ophthalmological Surveillance Unit. [1] All their 15 cases were visually symptomatic. Twelve cases were associated with trauma and 3 cases with acute pancreatitis. The authors conclude that the incidence of Purtsher’s retinopathy is low (0.24 cases per million population) in the United Kingdom, and that in half of the cases visual acuity improves by at least 2 Snellen lines in 6 months. The authors’ data, however, need careful interpretation. We investigated the clinical characteristics, histological features and prognostic significance of retinopathy of pancreatitis (Purtscher’s retinopathy associated with acute pancreatitis) in several studies. [2][3] We found that most of our cases were visually asymptomatic, since the patients were in severe or terminal status in intensive care units. We also found that retinopathy of pancreatitis was an indicator of multi-organ failure and lethal outcome. Our data suggest that pancreatitis associated Purtscher’s retinopathy is more common than reported by Doctors Agrawal and McKibbin, and that the visual outcome may be worse than found by the authors who used data reported by ophthalmologists. One may suppose that the reporting ophthalmologists might have seen only those cases which were associated with less severe systemic damage, and therefore the patients were able to realise their visual symptoms. It is probable that Purtscher’s retinopathy is more frequent than reported by the authors for the United Kingdom, and that the visual outcome is different from that indicated in their article, if all cases are considered.

Correspondence to: Gábor Holló, Department of Ophthalmology, Semmelweis University, Budapest; hg@szem1.sote.hu

The author has no commercial interest in any product mentioned in the article or the comment.

References

1.Agrawal A, McKibbin M. Purtscher’s retinopathy: epidemiology, clinical features and outcome. Br J Ophthalmol 2007;91:1456-1459.
2.Holló G, Bobek I. Clinicopathology of a case with retinopathy of pancreatitis. Acta Ophthalmol (Copenh) 1993;71:422-425.
3.Holló G, Tarjányi M, Varga M, et al. Retinopathy of pancreatitis indicates multiple-organ failure and poor prognosis in severe acute pancreatitis. Acta Ophthalmol (Copenh) 1994;72:114-117.

Dear Editor

We read with great interest the report by Raftery et al on Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness. The authors raise the very pertinent point in respect to a single company owning two competing drugs and the inherent cost to tax payers. The authors conclude their abstract with "Public pressure may be the most potent weapon in persuading Genentech to license bevacizumab for AMD". We would like to suggest what forms this public pressure may take. The pharmaceutical industry claims to educate the medical profession on conditions and its drugs to treat them. Should we be relying on a business to give us unbiased evaluations of products it is selling? Most doctors who accept free lunches and merchandise will claim to be unaffected. However, doctors who have frequent contact with drug representatives are more willing to prescribe new drugs, do not like ending consultations with advice only, and are more likely to agree to prescribe a drug that is not clinically indicated. [1] Doctors are now dependent on drug companies for education and funding for research. Research funded by drug companies has been found to be less likely to be published than research funded by other sources. Studies sponsored by pharmaceutical companies were found to be four times more likely to have outcomes favouring the sponsor than were studies with other sponsors. [2]

We have an unhealthy relationship with the pharmaceutical industry which undermines our ability to make patient centered decisions. To prevent more profit centered drugs coming to market rather than patient centered drugs, we as a profession must take responsibility. When published financial reports indicate pharmaceutical industry spending in marketing is three times that of Research and Development, alarm bells should be ringing.

To reduce this influence we must no longer accept free lunches, merchandise or holidays, look for alternate means of funding research and educational meetings and most of all become educated on the role drug companies play in our decision making. Accepting our need for the pharmaceutical industry should not mean accepting dependence upon them, if we wish to see drugs such as bevacizumab being licensed it is time we make our boundaries clear.

Suggested reading: The Truth About the Drug Companies by Marcia Angell (Former Editor of the New England Journal of Medicine) www.nofreelunch.org

References

1. Watkins C, Moore L, Harvey I, Carthy P, Robinson E, Brawn R. Characteristics of general practitioners who frequently see drug industry representatives: national cross sectional survey. BMJ 2003;326: 1178-9

2. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326: 1167-70

Dear Editor,

We read with great interest the report by Alwitry et al [1] on severe decompression retinopathy after medical treatment of acute angle closure. The authors have speculated that the mechanism of the ‘preretinal’ haemorrhage in this case was similar to the scattered ‘intraretinal’ haemorrhages seen in ocular decompression retinopathy. Although we agree with them that the haemorrhage was caused by sudden lowering of intraocular pressure (IOP), we believe that the exact pathophysiological mechanism, as well the clinical signs, in this case were different from the condition originally described by Fechtner et al [2].

It can be hypothesised that a pupillary block caused the volume of aqueous humor in the posterior chamber to increase markedly. The vitreous gel was therefore pushed toward the posterior pole. Following medical therapy the pupillary block was reversed and the aqueous humor moved rapidly through the pupil from the posterior chamber to the anterior chamber. This coupled with decreased aqueous production due to administration of aqueous suppressants allowed the vitreous body to move forward rapidly. This induced a rapid posterior vitreous detachment (PVD), disrupting small vessels on the retinal surface or optic disc, and resulted in the subhyaloid haemorrhage. In the present case the very short duration of raised IOP makes significant impairment of autoregulation of retinal vasculature unlikely and the absence of multiple intraretinal haemorrhages rules out a general compromise of mechanical stability of retinal capillaries. Obana et al [3] were the first to demonstrate a subhyaloid haemorrhage caused by PVD induced after laser iridectomy for primary angle-closure glaucoma and it should be distinguished from ocular decompression retinopathy.

This leads to an interesting conclusion that a sudden lowering of IOP may cause posterior segment bleeding by three different mechanisms. Ocular decompression retinopathy is caused by overwhelming of capacitance of retinal capillaries and results in multiple intraretinal haemorrhages. The second mechanism and clinical picture is similar to a central retinal vein occlusion [4,5]. A sudden change in hydrostatic equation between the posterior and anterior chambers, induces a rapid PVD and may result in subhyaloid haemorrhage, as in this case.

Figure 1 Three different mechanisms of posterior segment bleeding after sudden lowering of intraocular pressure

References

1. Alwitry A, Khan K, Rotchford A et al. Severe decompression retinopathy after medical treatment of acute primary angle closure. Br J Ophthalmol 2007;91:121

2. Fechtner RD, Minckler D, Weinreb RN et al. Complications of glaucoma surgery. Ocular decompression retinopathy. Arch Ophthalmol 1992;110:965-8

3. Obana A, Gohto Y, Ueda N, Miki T, Cho A, Suzuki Y. Retinal and subhyaloid hemorrhage as a complication of laser iridectomy for primary angle-closure glaucoma. Arch Ophthalmol. 2000 Oct;118:1449-51

4. Suzuki R, Nakayama M, Satoh N. Three types of retinal bleeding as a complication of hypotony after trabeculectomy. Ophthalmologica. 1999;213:135-8

5. Dev S, Herndon L, Shields MB. Retinal vein occlusion after trabeculectomy with mitomycin C. Am J Ophthalmol. 1996 Oct;122:574-5

Dear Editor

We read with interest the article by Aisenbrey et al [1] who have described the results of surgical treatment of peripapillary choroidal neovascularisation in eight patients.

As reported, peripapillary choroidal neovascularisation is a relatively uncommon entity that can be a variant of macular choroidal neovascularisation in elderly patients. Accordingly to the MPSG[2], early small peripapillary choroidal neovascularisation should be first treated with red thermal laser photocoagulation. If applied by an experienced specialist the risk of burning the interpapillomacular bundle is limited. However, the therapeutical approach is more delicate for laser resistant, extended and/or very exsudative peripapillary choroidal neovascularisation.

In their study, Aisenbrey et al report good clinical outcome after surgical treatment. Nevertheless, as published by Rosenblatt et al [3], photodynamic therapy with Verteporfin can also be a good option because of its efficacy and very limited risk. This is also our clinical experience.

Figure 1 shows the left eye of a male patient in his early seventies with very exsudative peripapillary choroidal neovascularisation before and one year after one photodynamic therapy with Verteporfin. The current parameters for choroidal neovascularisation and a spot of 4200 µ covering a great part of the optic nerve were used. This case looks very similar to the illustrated case of Aisenbrey et al, except the fact that we first unsuccessfully tried to treat the lesion with thermal laser.

Figure 1: left eye of a male patient in his early seventies with very exsudative peripapillary choroidal neovascularisation before (a) and one year after one photodynamic therapy with Verteporfin (b).

Figure 1a

Figure 1b

In our experience with Verteporfin we have never noted any clinical damage to the optic nerve after partial exposition and it has been shown by Schmidt-Erfurth et al [4] that optic nerve can be exposed to a light dose twice as high as conventionally used without showing histopathological alterations.

Regarding the potential major risks of the surgical approach of peripapillary choroidal neovascularisation we suggest that PDT could be the first therapeutical choice in these cases.

References

1. Aisenbrey S, Gelisken F, Szurman P, et al. Surgical treatment of peripapillary choroidal neovascularisation. Br J Ophthalmol 2007;91:1027- 1030.

2. The Macular Photocoagulation Study Group. Laser photocoagulation for neovascular lesions nasal to the fovea. Results from clinical trials for lesions secondary to ocular histoplasmosis or idiopathic causes. Macular Photocoagulation Study Group. Arch. Ophthalmol. 1995; 113:56-61.

3. Rosenblatt BJ, Shah GK, Blinder K. Photodynamic therapy with verteporfin for peripapillary choroidal neovascularisation. Retina. 2005; 25:33-37.

4. Schmidt-Erfurth U, Laqua H, Schlotzer-Schrehard U, et al. Histopathological changes following photodynamic therapy in human eyes. Arch. Ophthalmol. 2002 Jun; 120(6):835-44.

Dear Editor,

We thank Dr. Camras for his interest in our report on levels of bimatoprost and its free acid in the aqueous humour of cataract patients after a single topical dose of bimatoprost [1] and welcome the opportunity to respond to his comments. We are in agreement with Dr. Camras that the results of our study [1] and those of his previously reported study [2] are similar, showing low nanomolar concentrations of 17-phenyl PGF2alpha (bimatoprost acid) in the aqueous humour. There is no question that bimatoprost acid is a metabolite of bimatoprost. The issue is whether bimatoprost acid levels account for the IOP-lowering activity of bimatoprost. The evidence suggests that they are insufficient to do so. As Dr. Camras stated in his correspondence: “bimatoprost yields peak free acid concentrations in the aqueous 3 to 6 times lower than latanoprost acid”. It is accepted that the biological effects of latanoprost are exerted by latanoprost acid: the relatively high concentration of latanoprost acid achieved after latanoprost dosing [1-3] is sufficient to activate a substantial proportion of the prostaglandin FP receptors present in the target tissues and account for the IOP-lowering effect of latanoprost. It is difficult to understand, however, how the much lower levels of bimatoprost acid achieved could be believed to account for the IOP-lowering effect of bimatoprost, particularly since bimatoprost has reduced IOP more effectively than latanoprost in some clinical studies [4,5] and is effective in patients who fail to respond to latanoprost [6,7].

Dr. Camras contends that there is overwhelming evidence that bimatoprost acid is more potent than latanoprost acid at prostaglandin FP receptors, but the 10 references he cites to support this statement [8-17] include 3 studies in which bimatoprost acid and latanoprost acid were not compared [8-10], 3 reviews from a single laboratory that reported greater functional potency of bimatoprost acid compared with latanoprost acid in the cat iris sphincter preparation [11-13], and a study that found 3-fold lower functional potency of bimatoprost acid compared with latanoprost acid in human trabecular meshwork cells (EC50 of 112 nM vs 34.7 nM) [14]. Dr. Camras fails to note that the study showing very high functional potency of bimatoprost acid in human HEK-293 cells [15] used transfected cells with overexpression of the FP receptor. Bimatoprost acid was reported to be very potent in stimulating phosphoinositide hydrolysis in nontransfected mouse 3T3 and rat A7r5 cells [16]. However, in other studies by the same laboratory, bimatoprost acid was 10-fold less potent in mobilizing intracellular Ca++ in these cell lines [9,18]. Reported potency values in human ciliary muscle cells were 3.8 nM and 3.6 nM for bimatoprost acid and 124 nM and 198 nM for latanoprost acid [16,17], but bimatoprost acid was less effective than latanoprost acid in stimulating MAP kinase at 100 nM [17]. In summary, review of the literature does not reveal compelling evidence that bimatoprost acid is more potent than latanoprost acid. In fact, in human trabecular meshwork cells as well as human fibroblasts expressing endogenous, nontransfected prostaglandin FP receptors, bimatoprost acid and latanoprost acid have shown similar functional potency [1,14,16]. The results with trabecular meshwork cells are more clinically relevant because one pathway by which bimatoprost is believed to reduce IOP is through effects on the trabecular meshwork [19]. Wan et al [20] have shown that bimatoprost produces a decrease in outflow facility, which is blocked by a prostamide antagonist, in a human anterior segment organ culture model.

Camras et al proposed that the 22 nM aqueous humour concentration of bimatoprost acid is sufficient to lower IOP based on its agonist potency. Following his line of reasoning, the 100 nM aqueous humour concentration reported for latanoprost acid should not be sufficient to account for the IOP lowering, based on EC50 potency values of 124 nM and 198 nM in ciliary muscle cells. In fact, the data suggest that aqueous humour concentrations of bimatoprost acid are not sufficient to activate the FP receptor for effective diurnal IOP lowering, particularly taking into account the aqueous humour concentration of latanoprost acid and respective agonist potencies. The most plausible explanation for the greater efficacy of bimatoprost, despite lower levels of bimatoprost acid in the aqueous humor, is that bimatoprost reduces IOP through a mechanism other than or in addition to production of bimatoprost acid. There is excellent evidence from animal studies that the intact bimatoprost molecule has biological activity distinct from the activity of prostaglandin FP agonists [21]. For example, in a dissociated cat iris preparation, a specific population of cells responds to bimatoprost with an increase in calcium levels, and a separate and distinct population of cells responds to bimatoprost acid with an increase in calcium levels [22]. The selective stimulation of different cells in the same preparation by bimatoprost and prostaglandin FP agonists suggests the involvement of receptors for bimatoprost distinct from prostaglandin FP receptors. The recent identification of an antagonist that blocks the effects of bimatoprost, but not bimatoprost acid or latanoprost acid, in the cat iris preparation has provided additional evidence for biological activity of bimatoprost mediated through novel receptors [23]. Although studies in prostaglandin FP receptor knockout mice have shown that the intact FP receptor gene is needed for the IOP response to bimatoprost in the mouse eye [24,25], the IOP response does not appear to be mediated by interaction of bimatoprost acid with prostaglandin FP receptors, because there is minimal hydrolysis of bimatoprost in the mouse eye [25]. Instead, intact bimatoprost may interact with an alternatively spliced prostaglandin FP receptor pharmacologically distinct from the well-characterized FP receptor [26].

The mechanism of action of bimatoprost is of considerable interest because bimatoprost appears to be the most effective medication now available for reducing IOP [4,27]. Further drug discovery may well aim to develop drugs that take advantage of a similar mechanism of action. For this reason it is important to consider the data from both clinical and laboratory studies and to be open-minded in reaching reasonable conclusions. To assume that the mechanism of action of bimatoprost is the same as that of latanoprost and ignore or misinterpret evidence inconsistent with that assumption is neither good science nor helpful to clinical advancements in lowering IOP.

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 2004;111:2193-8.

3. Sjöquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 2002;47(Suppl 1):S6-12.

4. Denis P, Lafuma A, Khoshnood B, et al. A meta-analysis of topical prostaglandin analogues intra-ocular pressure lowering in glaucoma therapy. Curr Med Res Opin 2007;23:601-8.

5. Dirks MS, Noecker RJ, Earl M, et al. A 3-month clinical trial comparing the IOP-lowering efficacy of bimatoprost and latanoprost in patients with normal-tension glaucoma. Adv Ther 2006;23:385-94.

6. Gandolfi SA, Cimino L. Effect of bimatoprost on patients with primary open-angle glaucoma or ocular hypertension who are nonresponders to latanoprost. Ophthalmology 2003;110:609-14.

7. Williams RD. Efficacy of bimatoprost in glaucoma and ocular hypertension unresponsive to latanoprost. Adv Ther 2002;19:275-81.

8. Sharif NA, Kelly CR, Williams GW. Bimatoprost (Lumigan®) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracellular Ca2+ mobilization studies. Prostaglandins Leukot Essent Fatty Acids 2003;68:27-33.

9. Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol 2001;432:211-3.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. Brubaker RF. Mechanism of action of bimatoprost (Lumigan). Surv Ophthalmol 2001;45(Suppl 4):S347-51.

20. Wan Z, Woodward DF, Stamer WD. Bimatoprost effects on conventional drainage tissues. Invest Ophthalmol Vis Sci 2007;48:E- Abstract 3919. Full manuscript in press.

21. Chen J, Senior J, Marshall K, et al. Studies using isolated uterine and other preparations show bimatoprost and prostanoid FP agonists have different activity profiles. Br J Pharmacol 2005;144:493-501.

22. Spada CS, Krauss AH, Woodward DF, et al. Bimatoprost and prostaglandin F(2 alpha) selectively stimulate intracellular calcium signaling in different cat iris sphincter cells. Exp Eye Res 2005;80:135- 45.

23. Woodward DF, Krauss AH, Wang JW, et al. Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris. Br J Pharmacol 2007;150:342-52.

24. 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.

25. 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.

26. Liang Y, Li C, Guzman VM, Woodward DF. Identification of alternatively spliced variants of human prostaglandin FP receptor mRNA [Abstract 639.4]. Presented at: Experimental Biology 2005 and XXXV International Congress of Physiological Sciences, March 31-April 6, 2005; San Diego, CA.

27. Cantor LB, Hoop J, Morgan L, et al. Intraocular pressure-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in patients with glaucoma or ocular hypertension. Br J Ophthalmol 2006;90:1370-3.