Thursday, April 26, 2012

Abstract: Plug complications - part 1, mostly about SmartPlugs

I could have cried when I clicked on the link and found that the abstract of this study ("A review of the complications of lacrimal occlusion with punctal and canalicular plugs", Rabia Bourkiza and Vickie Liee, Orbit, 31(2), 86-93, 2012) was only four sentences. Is there some mysterious medical journal etiquette requiring abstracts from literature review studies to be devoid of actual information? Oh to have free access to all the studies I'd like to read, not just the blurbs that pass as abstracts! Here it is:

Punctal and canalicular plugs are widely used for both temporary and permanent occlusion of the lacrimal puncta in dry eyes. There are many designs and materials available on the market. While their efficacy in improving dry eye symptoms is widely proven, the gamut of complications associated with these devices have never been subject to a general review, although there are numerous case series in the literature associated with one particular device. This review aims to examine the track record of a variety of plugs currently in use, to review the management of complications, and propose strategies for both the prevention of these complications and their treatment.

Knowing that "one particular device" was almost certainly SmartPlugs, this time I gritted my teeth and plunked down the fifty bucks (ouch!) for the 8 page PDF. Good though. It's truly gratifying to see in black and white in a peer-reviewed journal everything I've been yammering about for years, written by those who have actually verified from hands-on experience what I only pick up from scattered conversations. EDIT: The full study is now available as a PDF here.

SO, this post is for all you skeptics who wonder why Rebecca is always getting on this weird anti SmartPlug soapbox, and why she doesn't seem to like durable intracanalicular plugs very much in general, It's not just a personal hangup. The problems are real, and they matter, and doctors, you should be sitting up and paying attention, and patients, you should be too unless you're quite sure your doctor is!

The beginning of the study describes silicone plugs of various types, SmartPlugs, and FormFit hydrogel plugs. Of SmartPlugs it says (my emphasis):

The SmartPlug is an intracanalicular plug which was originally designed to avoid the complications associated with other silicone plugs. It has the advantage of having a standard size, which makes it fit fully within the puncta, reducing the risk of irritating the ocular sur- face, and of extrusion. A study of 31 patients with the SmartPlug showed that 100% of the plugs were removed by irrigation 3 months after plug insertion. Its efficacy compared to silicone plugs was also demonstrated, with the SmartPlug showing a significantly better tear menis- cus height (mean follow-up of 11.2 weeks). However, long-term follow-up has generated a large case series of 28 patients developing canaliculitis, and a large cohort study reported a 7.23% complication rate with 4.34% developing canaliculitis. 

Does anyone reading this consider 7.23% complication rate to be acceptable for a canalicular plug? And incidentally, considering there are risks of complications (some of which can be quite serious as we shall see), do you know how many doctors go through any kind of informed consent process before sticking these things in people? Not many. You wouldn't believe the calls I've had on occasion from people who had plugs put in without their knowledge, let alone consent. Anaesthetic drop... a bit of tugging sensation... done. "Um, what was that, doctor?" "Oh, I just put in some little plugs that will help keep your eyes moist." "Oh."

Moving right along. Next comes a full-page table of 14 studies in which plug complications are reported. The far right column is "Patients requiring surgery". That's our worst-case plug complications scenario, so that's what I'll focus on.

One study didn't say; seven studies (none of which was exclusively SmartPlugs) said none, two were just case reports. That leaves four case series, two of which establish incidence rates and the other two of which were simply collections of complications patients:

  1. Hill et al, 2009, on SmartPlugs: 17 of 235 (7.23%) patients required surgery. The authors of this study thoughtfully pointed out that even after surgery many patients didn't get better, which is one of my biggest concerns about plug complications. (Oh, and when a study's conclusion says, "Ophthalmologists using XXX device/drug... should carefully weigh the risks and benefits..." as this one does, it's polite journalspeak for "Quit using this garbage already!".)
  2. Mazow et al, 2007, on various intracanalicular plug types: 66 of 998 (6.6%) patients required surgery (I'm hoping to pin down how many per type and I will update this post when I get the info). Incidentally, in addition to the intracanalicular group of 998, there were 336 with collared punctal plugs, none of whom had complications requiring surgery.
  3. SmartPlug Study Group, 2006, on SmartPlugs:  22 patients required surgery. This study noted that irrigation might help but might also make things worse.
  4. White et al, 2001, on Herrick plugs: 37 patients requiring surgery, and the authors' conclusion emphasized the permanent nature of the damage incurred. Since the time of this study many more plug types have emerged. 

Three out of four of the major studies about surgery resulting from plug complications involved SmartPlugs. What's wrong with this picture?

And now here's what the authors have to say about the accuracy of the complications incidence data as reported in the medical literature at large (my emphasis):

...It is likely that the complications in these studies are underestimated due to the lack of long-term follow-up. Only one study had follow-up of up to 5 years. Hill et al reported that the average time before complications developed with the SmartPlug was 3 years....

Which explains why Medennium (that's the SmartPlug manufacturer) reported NO canaliculitis or dacryocystitis cases in its 120 patient study: the 3 month follow-up period was nowhere near long enough to find out who was going to get it.

...Moreover, often it is difficult to know how many plugs were inserted, especially with the rise in number of patients undergoing laser refractive surgery where plugs are widely used in the early post-operative period. Unless meticulous records are available combined with long-term follow-up, the individual complication rates of each plug design would be impossible to evaluate.

Which brings us to one of my big pet peeves. Many doctors seem to think that if a patient had plugs put in, and some time has gone by and the patient's feeling dry again, there's no reason not to shove a fresh pair in there. But the complications data clearly bring this practice into question, as the oculoplastic surgeons who have to clean up the messes will attest to. You can't necessarily be certain the original plug is gone, and at least with the SmartPlug irrigating isn't always conclusive (or helpful) as Dr. Amy Fowler told Eyeworld a few years ago and the SmartPlug study group also noted that irrigation can actually make things worse. - Then too, if infection ensues and you need to get a plug (or plugs?) out, not knowing for certain how many there are or where won't help.

There's lots more good stuff in this study about different types of complications associated with different types of plugs, and about the truly problematic issues of plug sizing which also plays a significant role, but I'll save those for another day.

At the end of the study, the authors simply make the point I've been making  for years:

Although serious plug complications are not frequent, when they do occur they may necessitate extensive surgical interventions....

To me, that's a compelling reason not to do something. If a complication is rare but "dealable", OK, you think about your risk tolerance and decide whether to go ahead. But if complications are rare but serious, and maybe not even fixable, that's an altogether different kind of assessment.

Now, though, we also have to step back and look at that statement about frequency. If you take serious plug complications as averaged across all plug types including punctal (where, with certain exceptions, for the most part the the problem is that they fall out) complications can perhaps be fairly described as "not frequent". But as we've seen here, with numbers like 7.23% or 6.6%, even the frequency may be far great for some individual plug types than most doctors and patients are aware. Finally, if the incidence is not established at all for a specific plug type - which seems to be the case for several, you may be leaping into the unknown.

Be informed before you get intracanalicular plugs.

Abstract: A BAK vicious cycle

Fascinating stuff, as always from our anti BAK hero Dr. Baudouin. Oh how we need those preservative free Rx options.

Benzalkonium chloride (BAK), the most commonly used preservative in eye drops, is known to induce ocular irritation symptoms and dry eye in long-term treated patients and animal models. As tear film hyperosmolarity is diagnostic of some types of dry eye disease, we determined in vitro on conjunctival epithelial cells the cytoxicity of BAK in hyperosmolar conditions through cell viability, apoptosis, and oxidative stress assays.
The Wong Kilbourne derivative of Chang conjunctival epithelial cells were cultured for 24 h or 48 h either in NaCl-induced hyperosmolar conditions (400-425-500 mOsM), in low concentrations of BAK (10(-4)%, 3.10(-4)%, and 5.10(-4)%), or in combination of both. We investigated cell viability through lysosomal integrity evaluation, cell death (cell membrane permeability and chromatin condensation), and oxidative stress (reactive oxygen species, superoxide anion) using spectrofluorimetry. Immunohistochemistry was performed for cytoskeleton shrinkage (phalloidin staining), mitochondrial permeability transition pore (cytochrome c release), the apoptosis effector active caspase-3, and the caspase-independent apoptosis factor AIF. We also observed early effects induced by the experimental conditions on the conjunctival cell layers using phase contrast imaging of live cells.
As compared to standard culture solutions, hyperosmolar stress potentiated BAK cytotoxicity on conjunctival cells through the induction of oxidative stress; reduction of cell viability; cell membrane permeability increase; cell shrinkage with cell blebbing, as shown in phase contrast imaging of live cells; and chromatin condensation. Like BAK, but to a much lesser extent, hyperosmolarity increased cell death in a concentration-dependent manner through a caspase-dependent apoptosis characterized by a release of cytochrome c in the cytoplasm from mitochondria and the activation of caspase-3. Moreover, the caspase-independent apoptosis factor AIF was found translocated from mitochondria to the nucleus in both conditions.
This study showed increased cytotoxic effects of BAK in hyperosmotic conditions, with characteristic cell death processes, namely caspase-dependent and independent apoptosis and oxidative stress. As BAK is known to disrupt tear film, which could promote evaporative dry eye and tear hyperosmolarity, BAK could promote the conditions enhancing its own cytotoxicity. This in vitro hyperosmolarity model thus highlights the risk of inducing a vicious cycle and the importance of avoiding BAK in patients with dry eye conditions.
Mol Vis. 2012;18:851-63. Epub 2012 Apr 6.

Abstract: Keratograph 4 and capturing better MG data

PURPOSE.: To examine the ability of a novel non-contact device (Keratograph 4) to image the meibomian gland (MG) structures and their morphological changes in the upper and lower eyelids.
METHODS.: Thirty-seven participants (mean age 57.8 ± 8.5 years; 3 males and 34 females) completed the Ocular Surface Disease Index questionnaire to assess dryness symptoms. Meibum secretion quality score, number of blocked gland orifices, and meibum expressibility scores were assessed. The lower lid (LL) and upper lid (UL) of all subjects were everted and images of the MGs were taken using the Keratograph 4 (OCULUS). A MG dropout score (MGDS) due to complete or partial gland loss of both lids was obtained using a subjective 4-grade scoring system, and digital analysis of the images using ImageJ was performed. Presence of tortuosity and visible acinar changes of the MGs were also noted.
RESULTS.: MGDS for both lids was significantly positively correlated with the Ocular Surface Disease Index score (r = 0.51; p < 0.05). The MGDS determined using the digital grading was also significantly positively correlated (UL: r = 0.68, p < 0.05; LL: r = 0.42, p < 0.05). The sum of the MGDS for both lids using the subjective grading scale was significantly different between the non-MGD and MGD group (1.3 ± 1.0 vs. 3.1 ± 1.1; p = 0.0004). MGDS assessment using the digital grading was significantly different between non-MGD (UL = 6%, LL = 8%) and MGD group (UL = 32%, LL = 42%; p = 0.001). Tortuous MG was observed only on the UL in 6% of the participants. Visible acinar changes were noted in 40% of the study participants.
CONCLUSIONS.: Infrared meibography is now possible in a clinical setting using commercially available devices, and meibography can help determine differences in MG structure in subjects symptomatic of dry eye.

Optom Vis Sci. 2012 Apr 19. [Epub ahead of print]
Centre for Contact Lens Research, School of Optometry, University of Waterloo, Waterloo, Ontario, Canada.

Abstract: CP-690,550

Somehow outperforming Restasis sounds rather inevitable than impressive in this context, but nonetheless the drug sounds promising.

To evaluate safety and efficacy of topical ophthalmic tofacitinib (CP-690,550), a novel Janus kinase inhibitor, in treating dry eye disease (DED).
A phase 1/2 prospective, randomized, double-masked, multicenter, vehicle- and comparator-controlled trial (NCT00784719).
Patients (n = 327) 18 years of age and older with a DED diagnosis for 6 months or more.
Tofacitinib (0.0003% twice daily, n = 46; 0.001% in both eyes twice daily, n = 47; 0.003% twice daily, n = 48; 0.005% twice daily, n = 48; 0.005% once daily, n = 44) results were compared with those of groups receiving active treatment cyclosporine ophthalmic emulsion 0.05% twice daily (n = 47) and vehicle twice daily (n = 47). Safety and efficacy evaluations were performed at baseline and throughout the 8-week study.
Schirmer wetting, corneal staining, tear film break-up time, conjunctival staining, Ocular Comfort Index (OCI), and Ocular Surface Disease Index (OSDI).
All tofacitinib doses were well tolerated, exhibiting better patient-reported ocular tolerability than cyclosporine. For the proportion of patients achieving 10 mm or more Schirmer wetting (without anesthesia) at week 8 (primary end point), greater response rates were observed in the tofacitinib 0.001% twice daily (27.3%), 0.005% twice daily (25.5%), and 0.005% once daily (26.1%) groups versus vehicle (20.0%); however, the differences were not statistically significant. Mean increase in Schirmer wetting (without anesthesia) from baseline was statistically significant (P<0.2, 2-sided) for all tofacitinib doses (1.7-3.1 mm), cyclosporine (3.9 mm), and vehicle (1.4 mm). For corneal staining (total score), significant improvement (reduction) from baseline was observed for all tofacitinib doses (-0.9 to -1.9) and vehicle (-2.0), but not for cyclosporine. The proportion of patients with complete corneal clearing (CCC; 100%) at week 8 was greatest with tofacitinib 0.005% once daily (15.9%) versus vehicle (6.7%). Symptom scores (OCI, OSDI) at week 8 showed significant improvements from baseline for all tofacitinib groups, and tofacitinib demonstrated greater improvements than cyclosporine. The tofacitinib 0.005% once daily group showed significant improvements in both a sign (Schirmer wetting without anesthesia) and symptom (OSDI environmental triggers subscale) versus vehicle and also demonstrated the highest response rate for CCC (16.7%) at week 8.
This phase 1/2 study of tofacitinib demonstrated a trend for improving both signs and symptoms of dry eye. All doses of tofacitinib exhibited a reasonable safety profile and were well tolerated by patients with DED.

Ophthalmology. 2012 Apr 21. [Epub ahead of print]
Liew SHNichols KKKlamerus KJLi JZZhang MFoulks GN.
Pfizer, Inc, Collegeville, Pennsylvania.

Abstract: Symptoms & signs, line by line

Aaaah. About time. I like to see somebody actually caring about the possible significance of actual symptoms rather than just lumping them together in some kind of aggregate severity measure.

Purpose: The present study aimed at analyzing the relationship between several particular symptoms, risk factors or global questionnaire scores and some tear clinical signs in early dry eye patients.
Material and methods: A total of 77 volunteers were enrolled in the study without any prior classification, although patients with severe dry eye were excluded. Two questionnaires were used to assess ocular symptoms and risk factors, and clinical tear signs were evaluated with four tests (osmolarity, ferning, break-up time and the phenol red thread test). Multiple linear regression analysis was performed to determine the relative predictive value of each particular ocular symptom and risk factor, for each clinical sign. This analysis was repeated using symptoms and risk factors global scores.
Results: The symptom "eyes stuck shut in the morning" was the only predictor variable for the sign "ferning crystallization" (R = 0.228, p < 0.05) and "dryness" for "break-up time" (R = -0.315, p < 0.01). "Burning sensation" and "computer use for more than 3 h" were predictor variables for "tear osmolarity" (R = 0.342, p < 0.01), while "itching" and "female gender" were found to predict the outcomes of the "phenol red thread test" (R = -0.462, p < 0.05). Global questionnaire scores were not found to predict any tear clinical sign.
Conclusions: The present findings support the informative value of exploring the associations between clinical signs, ocular symptoms and risk factors by following an item by item strategy rather than opting for global questionnaire scores.

Curr Eye Res. 2012 May;37(5):357-64.
Ocular Surface Research Group, Optics and Optometry Department, Universitat Politècnica de Catalunya , Terrassa , Spain.

Abstract: 0.03% Tacrolimus

To report the clinical outcome of the treatment of dry eyes using 0.03% tacrolimus eye drops.

Sixteen eyes of 8 patients with Sjögren syndrome dry eyes (age, 51.13 ± 9.45 years) were enrolled in this study (prospective noncontrolled interventional case series). Patients were instructed to use topical 0.03% tacrolimus eye drops twice a day (every 12 hours) in the lower conjunctival sac. Schirmer I test, break-up time, corneal fluorescein, and rose bengal staining score were performed in all patients 1 day before, and 14, 28, and 90 days after treatment with 0.03% tacrolimus eye drops.

The average fluorescein staining and rose bengal staining scores improved statistically significantly after 14 days of treatment and improved even more after 28 and 90 days. The average Schirmer I test did not improve statistically significantly after 28 days of treatment, although we did observe a significant improvement after 90 days of treatment with 0.03% tacrolimus eye drops. The average break-up time did not improve statistically after 14 days of treatment, although we observed a significant improvement after 28 and 90 days of treatment with 0.03% tacrolimus eye drops.

Topical 0.03% tacrolimus eye drops successfully improved tear stability and ocular surface status in patients with dry eyes.

Cornea. 2012 Apr 16. [Epub ahead of print]
*Department of Ophthalmology, School of Medicine, University of São Paulo (Hospital das Clínicas of da Universidade de São Paulo), São Paulo, Brazil †Department of Ophthalmology, Santa Casa de São Paulo, São Paulo, Brazil ‡Department of Ophthalmology, Tokyo Dental College, Chiba, Japan.

Newsflash: Twinkies... er, coffee... er, caffeine... cures dry eyes?

In a study, participants twice took capsules containing caffeine or placebo. Some experienced increased tear production (nothing whatever is said about the tear quality or whether their symptoms improved), depending in part apparently on genetic factors.

Those few measly caffeine capsules and what they did have been extrapolated all over the press to headlines like these:

Caffeine use may offer relief for millions of dry eye sufferers!

Caffeine intake: Give tears to your dry eye without a cry!

Put down those carrots! Coffee is what's good for your eyes!

Researchers discover simple dry eye treatment!

Drinking coffee may offer relief to dry eye sufferers, study says!

I'm not even going to bother quoting from any of these articles because I think the headlines are sufficiently indicative of the calibre of reporting. What the popular press distills from medical studies cracks me up. Reminds me of the stuff Hawkeye and Trapper used to filter through their dirty army socks.

Abstract: Novasorb

Topical ophthalmic delivery of active ingredients can be achieved using cationic nanoemulsions. In the last decade, Novagali Pharma has successfully developed and marketed Novasorb, an advanced pharmaceutical technology for the treatment of ophthalmic diseases. This paper describes the main steps in the development of cationic nanoemulsions from formulation to evaluation in clinical trials. A major challenge of the formulation work was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time. Then, toxicity and pharmacokinetic studies were performed showing that the cationic emulsions were safe and well tolerated. Even in the absence of an active ingredient, cationic emulsions were observed in preclinical studies to have an inherent benefit on the ocular surface. Moreover, clinical trials demonstrated the efficacy and safety of cationic emulsions loaded with cyclosporine A in patients with dry eye disease. Ongoing studies evaluating latanoprost emulsion in patients with ocular surface disease and glaucoma suggest that the beneficial effects on reducing ocular surface damage may also extend to this patient population. The culmination of these efforts has been the marketing of Cationorm, a preservative-free cationic emulsion indicated for the symptomatic treatment of dry eye.

J Drug Deliv. 2012;2012:604204. Epub 2012 Feb 27.
Research and Development Department, Novagali Pharma SA, 1 rue Pierre Fontaine, 91058 Evry Cedex, France.

Abstract: Addressing PED after PK

Always nice to see the 'extra' issues being addressed - especially eyelid issues like blinking & lagophthalmos. 

Ocular Surface Deficits Contributing to Persistent Epithelial Defect After Penetrating Keratoplasty.

PURPOSE: To determine the ocular surface deficits contributing to persistent epithelial defect (PED) after penetrating keratoplasty (PKP).

METHODS: Four ocular surface deficits that contribute to PED and their corrective measures were reviewed in 11 eyes of 11 patients with PED after PKP.

RESULTS: Among these 11 eyes, PED developed early in 8 eyes and late in 3 eyes after PKP. They all had more than 2 ocular surface deficits, with infrequent blinking (11 eyes) and lagophthalmos (9 eyes) being more common. Proper corrective measures resulted in rapid epithelialization in 1 week (1 eye), 2 weeks (9 eyes), and 3 weeks (1 eye) via insertion of a bandage contact lens to maintain tear film for treating infrequent blinking (4 eyes), tarsorrhaphy to correct nocturnal lagophthalmos (2 eyes), and fornix reconstruction to eliminate pathogenic symblepharon (4 eyes). During the follow-up of 22.1 ± 7.6 months after healing of PED, 8 eyes retained a stable and clear graft, whereas 3 eyes with more ocular surface deficits had recurrent PED and graft failure develop. Two of the latter were corrected by a repeat PKP combined with oral mucosal graft to correct the remaining cicatricial eyelids.

CONCLUSIONS: Besides the neurotrophic state and aqueous tear deficiency dry eye common in this cohort, infrequent blinking, lagophthalmos, and pathogenic symblepharon also contribute to PED after PKP. Proper corrective measures and vigilant follow-up are crucial for maintaining PKP graft survival in these severe cicatricial ocular surface diseases.

Cornea. 2012 Apr 10. [Epub ahead of print]
Fu YLiu JTseng SC.

*Department of Ophthalmology, Ninth People's Hospital, Medical School of Shanghai Jiaotong University, Shanghai, China †Department of Ophthalmology, Eye Hospital, Wenzhou Medical College, Wenzhou, China ‡Ocular Surface Center and Ocular Surface Research & Education Foundation, Miami, FL.

Abstract: Pranoprofen & dry eye (mouse study)

Pranoprofen = an NSAID (non-steroidal anti-inflammatory). They're comparing sodium hyaluronate drops vs. SH plus this NSAID vs. SH plus FML (corticosteroid).

I sometimes find it interesting (sad too but won't dwell on that right now) what they use to cause corneal disease or dry eye in animal dry eye studies. They used to use PRK to induce limbal stem cell deficiency... now BAK (BAC, benzalkonium chloride) to induce dry eye. Of course this BAK percentage is exponentially higher than what they'd ever put in an eyedrop as a preservative but still, it tells you something when the most common eyedrop preservative is used to cause dry eye for study purposes.

[Therapeutic effects of Pranoprofen on the mouse dry eye induced by topical medication of Benzalkonium Chloride].

Randomized controlled experimental study to investigate the therapeutic effect and the possible mechanism of Pranoprofen on the recovery of dry eye induced by topical medication of Benzalkonium Chloride (BAC) in mouse.

It was an experimental study. Seventy BALB/c mice were treated with topical administration of 0.25% BAC to establish the dry eye condition. Based on the consistency of break-up time of tear-film (BUT), corneal fluorescein staining scores and inflammation index, the eyes were re-selected and randomly divided into four groups on day (D) 21 after the BAC treatment. Group A was set up as blank control, while group B, C and D were treated respectively with 0.1% sodium hyaluronate eye drops, 0.1% fluorometholone eye drops plus 0.1% sodium hyaluronate eye drops, 0.1% pranoprofen eye drops plus 0.1% sodium hyaluronate eye drops. BUTs, tear volumes, corneal fluorescein staining scores and inflammation index were evaluated in each group on D0, 1, 3 and 5 after the therapeutic treatment. Global specimens were collected on D6. Sections were stained with hematoxylin and eosin (HE) or by periodic acid-schiff (PAS) assay, and labeled with cytokeratin 10 (K10) antibody. The expression of tumor necrosis factor-α (TNF-α) in the cornea and conjunctiva was quantified by western blot.

72 eyes were included in the sequential experiment, 18 eyes for each group. On D0, 1 and 3, no clinical differences were observed among the groups. On D5, the BUT was (2.933 ± 0.320), (2.900 ± 0.280), (3.464 ± 0.498) and (3.643 ± 0.413) s in group A, B, C and D respectively; the BUTs in group C and D were significant longer than those of group A and B (F = 13.774, P = 0.000). The corneal fluorescein staining score was (11.640 ± 1.008), (11.790 ± 1.188), (10.330 ± 1.371) and (10.270 ± 1.104)s in group A, B, C and D respectively; the scores in group C and D were significant lower than those of group A and B (F = 6.145, P = 0.001). The corneal inflammatory index was (0.232 ± 0.059), (0.229 ± 0.078), (0.151 ± 0.055) and (0.154 ± 0.056) in group A, B, C and D respectively; the index in group C and D were significant lower than those of group A and B (F = 6.703, P = 0.001). No significant difference was found in tear volume among groups. No significant difference was found between Pranoprofen and Fluorometholone treatment in BUT, corneal fluorescein score or inflammatory index. Corneal morphology showed the feature of thicker corneal epithelial layer in group A and uniformity in group C and D. PAS assay revealed similar goblet cell numbers in group C and D, but less goblet cells in group A and B. Cytokeratin 10 was almost negatively expressed in Pranoprofen or Fluorometholone treated groups, and remained positive in the corneal epithelium with other treatments. The level of TNF-αin the cornea was down-regulated in Pranoprofen or Fluorometholone treated groups.

Pranoprofen or Fluorometholone combined with sodium hyaluronate treatment presented similar therapeutic effects on BAC-induced mouse dry eye, with the more stable tear film, the better regularity of epithelium recovery, the down-regulation of inflammatory TNF-α, the increased number of goblet cells, and the elimination of squamous metaplasia, when compared with the treatment of sodium hyaluronate eye drops only. Our results showed the great potentialities of Pranoprofen in the clinical treatment of ocular surface inflammation in the mild and severity dry eye.
[Article in Chinese]

He HLiu ZGLin ZRLiu XCHe HXiao QG.
Zhonghua Yan Ke Za Zhi. 2012 Jan;48(1):33-40.
Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen 361005, China; Department of Ophthalmology, the Second Affiliated Hospital of Nanhua University, Hengyang 421001, China.

Tuesday, April 24, 2012

Abstract: VisMed (SH) vs carbomer

Efficacy of 0.18% hypotonic sodium hyaluronate ophthalmic solution in the treatment of signs and symptoms of dry eye disease.
BACKGROUND/AIMS: To compare the safety and efficacy of hypotonic 0.18% sodium hyaluronate solution (0.18% SH) versus saline and versus 0.3% carbomer for the treatment of signs and symptoms of moderate dry eye syndrome. 

METHODS: A total of 304patients were randomized (1:1:1) in this parallel-group, multi-center, phase III trial. They were instructed to instill one drop of the allocated product in each eye two to four times per day over 84 days. The primary efficacy criterion was the change from baseline at Day 28 in symptom frequency score. The superiority of 0.18% SH (Vismed(®)) over saline and its non-inferiority versus carbomer were statistically tested. 

RESULTS: At Day 28, there was a statistically significant superiority of 0.18% SH over saline in change from baseline for subjective symptom frequency score (P=0.0376, primary endpoint) and objective fluorescein staining score (P=0.0074, secondary endpoint). 0.18% SH had an excellent safety profile over 84days. A strong trend was observed in favour of 0.18% SH to cause less blurred vision than carbomer throughout the trial (P=0.0798 at Day 28). 

CONCLUSION: 0.18% SH caused a statistically significant improvement in both a subjective endpoint (symptom frequency score) and an objective endpoint (fluorescein staining score). 0.18% SH was well tolerated and resulted in low incidence of adverse events.
J Fr Ophtalmol. 2012 Apr 5. [Epub ahead of print] Baeyens V, Bron A, Baudouin C; the Vismed/Hylovis Study Group. Source TRB Chemedica International SA, 12, rue Michel-Servet, P.O. Box 352 1211, Geneva 12, Switzerland.

Abstract: PRO instrument standards

Appraisal of patient-reported outcome instruments available for randomized clinical trials in dry eye: revisiting the standards.
Clinical signs in dry eye (DE) often underestimate the severity of the condition, correlating poorly with symptoms and the impact on patients' health-related quality of life (HRQL). Patient-reported outcome (PRO) questionnaires are therefore essential to accurately evaluate the health status of DE patients and the severity of their condition. A comprehensive evaluation of HRQL in addition to clinical signs and visual function is necessary to fully characterize the impact of DE on patients' health. Growing interest in PRO measures and their implementation in clinical trials has resulted in more formal guidance on the design and properties of these instruments. To be scientifically sound and accepted by regulatory authorities, an instrument's development process and its appropriateness for use in the target population, its psychometric properties and responsiveness must be described. To address the recent health authority guidance, this review discusses the design, development methodology, and performance of currently available PRO instruments for DE.
Ocul Surf. 2012 Apr;10(2):84-99. Epub 2012 Jan 28. Guillemin I, Begley C, Chalmers R, Baudouin C, Arnould B. Source Mapi Consultancy, Lyon, France.