Friday, November 9, 2007

Research news: Regenerx / TB4

Not quite "new" news - Regenerx were granted a US patent back in September, but honestly this is the first time it's come onto my radar screen. Everybody and his uncle seems to be in dry eye drug research these days.

Here's a November 5 newsblurb about it.

Reversing LASIK dry eye... now that's a pretty ambitious claim. But, I wish them every success. Sigh.

Late last week, Regenerx Pharmaceuticals (RGN) was awarded a patent in China for its Thymosin beta 4 (TB4) investigational products for the indications of reversing or inhibiting eye degeneration associated with dry eye syndrome. This includes dry eye that is caused by surgical eye procedures such as LASIK and PRK.

TB4 is a synthetic copy of a naturally occurring molecule that is identical across all species. It is a key regulator of actin, which is responsible for cell movement (for example, into a wound). Researchers from the Department of Biology, Shangdong University and the Peking Union Medical College in Beijing are verifying the therapeutic importance of TB4. To move the compound toward commercialization, Regenerx is conducting clinical trials of TB4 for dermal, ophthalmic and internal indications, but none of the trials is being carried out in China. The U.S. granted a patent for TB4 in September.

New drug news: Alcon / Lantibio / HLA

I blogged about this last month as there was a tidbit in Alcon's investor call mentioning they had a deal with Lantibio to market the HLA drop in the US. I still don't see an actual press release on Alcon's, Lantibio's or TRB Chemedica's sites but since it's on PRNewswire, it's presumably not a secret.

If I'm not mistaken... this is the same VisMed product that has been sold OTC in Europe for awhile and it's headed for the US Rx market in... probably not too long. I would think it can't be too hard to get this approved.

Full news report on

CHAPEL HILL, N.C., and VALAIS, Switzerland, Nov. 5 /PRNewswire/ -- Lantibio, Inc. and TRB Chemedica announced today the signing of a licensing agreement with a subsidiary of Alcon, Inc. for the US development, marketing, and manufacture of a Dry Eye Syndrome product. The product consists of a TRB patented formulation containing sodium hyaluronate and is currently being studied in the US under an IND by a subsidiary of Lantibio. An ongoing multi-center Phase III pivotal study is being conducted under the FDA's Special Protocol Assessment program. Lantibio expects to file an NDA in 2008 for the product as a treatment for Dry Eye Syndrome.

Study: Cytotoxicity of castor oil

In a fit of Friday afternoon good humor, I will forbear to editorialize on the implications for the notorious Restasis tolerance problems. Y'all probably know what I would say anyway. :) But... no wonder so few people like Endura.

Benefits and Side Effects of Different Vegetable Oil Vectors on Apoptosis, Oxidative Stress, and P2X7 Cell Death Receptor Activation.

Said T, Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5000-6.

PURPOSE: Ocular side effects in patients using eye drops may be due to intolerance to the vector used in eye drops. Castor oil is the commonly used lipophilic vector but has been shown to be cytotoxic. Effects on cells of four oils (olive, camelina, Aleurites moluccana, maize) were compared with those of castor oil in human conjunctival cells.

METHODS: Human conjunctival cells were incubated with the oils for 15 minutes. After a 24-hour recovery period, cells were tested for viability, proliferation, apoptosis (P2X7 cell death receptor and caspase 3 activation), intracellular redox potential, and reactive oxygen species production. Fatty acid incorporation in cell membranes was also analyzed. In vivo ocular irritation was assessed using the Draize test.

RESULTS: Compared to the four other oils, castor oil was shown to induce significant necrosis and P2X7 cell death receptor and caspase 3 activation and to enhance intracellular reactive oxygen species production. Aleurites moluccana and camelina oils were not cytotoxic and increased cell membrane omega-3 fatty acid content. None of the five tested oils showed any in vivo ocular irritation.

CONCLUSIONS: The results demonstrated that castor oil exerts cytotoxic effects on conjunctival cells. This cytotoxicity could explain the side effects observed in some patients using eye drops containing castor oil as a vehicle. The lack of cytotoxic effects observed with the four other oils, Aleurites, camelina, maize, and olive, suggest that they could be chosen to replace castor oil in ophthalmic formulations.

Study: Self-closing puncta in GVHD...

Well, those who have struggled for years with plug discomfort, dropout, and above all cost might wish their puncta would occlude themselves... though on balance I'm sure they would not want to switch places with any of the patients described in this study.

Spontaneous Lacrimal Punctal Occlusion Associated with Ocular Chronic Graft-versus-Host Disease.

Kamoi M, Curr Eye Res. 2007 Oct;32(10):837-42.

Purpose: To investigate the clinical features of spontaneous lacrimal punctal occlusion (SLPO) after allogeneic hematopoietic stem cell transplantation (HSCT).

Methods: One hundred nineteen recipients after HSCT who visited Keio University between 2001 and 2004 were examined. The condition of the lacrimal punctum, severity of dry eye, meibomian gland secretion, and presence of systemic chronic graft-versus-host disease (cGVHD) were determined with or without SLPO by retrospective chart review.

Results: Among the 119 recipients, SLPO was diagnosed in 8. All the patients with SLPO after HSCT had meibomian gland dysfunction (MGD), dry eye, and systemic cGVHD. The percentage of patients with dry eye, MGD, and systemic cGVHD were significantly higher in recipients with SLPO than non-SLPO recipients (p < 0.0013, p < 0.00015, p < 0.0008, respectively).

Conclusions: SLPO is a clinical presentation of ocular cGVHD and may be an indicator of the severity of dry eye and systemic cGVHD after HSCT.

Study: Dry eye after, yes, CATARACT surgery

I really appreciated this study and hope to see more on the subject. I get calls regularly from people who had a cat surgery anywhere from 3-12 months previously, who are experiencing dry eye for the first time, and who have been told flatly by their doctor that cataract surgery is unrelated to dry eye. According to this study... there is enough risk to warrant finding out more and above all to be sensitive to how much BAK is thrown at the cornea postoperatively including strong attention to patient instruction and compliance monitoring.

Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery.

Li XM, Hu L, Hu J, Wang W. Cornea. 2007 Oct;26(9 Suppl 1):S16-20.

PURPOSE: To study dry eye and analyze pathogenic factors in patients after cataract surgery.

METHODS: A total of 37 patients (50 eyes) were studied by using a 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ25) and Ocular Surface Disease Index (OSDI) 3 days before and 1 week, 1 month, and 3 months after cataract surgery. Slit-lamp microscope examination, cornea and conjunctiva fluorescein staining, tear breakup time (BUT), Schirmer test I (STI), and impression cytology (IC) were carried out at the same time. Cytologic specimens for IC were obtained from the upper lid-covered region, explosive region, and lower lid-covered region of the globe conjunctiva. The average density of goblet cells on these 3 regions was measured, and the pathogenic factors of dry eye after cataract surgery were analyzed.

RESULTS: After cataract surgery, the incidence of dry eye increased dramatically; NEI-VFQ25 and OSDI indicated that most patients developed this symptom after surgery. The lacrimal river line became narrow, and BUT and STI decreased in patients after cataract surgery. IC suggested the presence of serious squamous metaplasia in the epithelial layer of the globe conjunctiva, especially the lower lid region.

CONCLUSIONS: Dry eye can develop or deteriorate after cataract surgery if not treated in time. Misuse of eyedrops is one of the major pathogenic factors that causes dry eye after cataract surgery. Eyedrops should be carefully administered before and after cataract surgery to avoid or reduce the occurrence of dry eye postoperatively.

Thursday, November 8, 2007

Study: Here's one for the Genteal Gel fans

Efficacy, tolerability and comfort of a 0.3% hypromellose gel ophthalmic lubricant in the treatment of patients with moderate to severe dry eye syndrome.

Tauber J. Curr Med Res Opin. 2007 Nov;23(11):2629-36.

OBJECTIVE: To evaluate efficacy, safety and comfort of a 0.3% hypromellose (HM) eye gel (GenTeal Lubricant Eye Gel), with a sodium perborate preservative system and carbomer gelling agent, in patients with dry eye....

CONCLUSIONS: In a small, open-label study, this 0.3% HM eye gel showed statistically significant effects in relieving ocular symptoms and provides a well-tolerated formula that effectively reduced symptoms and improved ocular comfort in patients with dry eye syndrome.

Study: Egg whites, milk, toothpaste... and MGs and dry eye

No, this is not about dietary factors in dry eye... just innovative descriptions for what comes out of the MGs and which type of abnormal crud was most closely associated with dry eye.

Hey, I'm happy when an ophthalmologist deigns to even press on those little MG orifices and watch, let alone come up names for what comes out.

Abnormal property of meibomian secretion and dry eye syndrome

Gao Y et al, Yan Ke Xue Bao. 2007 Jun;23(2):121-5.

PURPOSE: To study the relationship between meibomian secretion and dry eye.

METHODS: To observe 68 outpatients (136 eyes) consecutively. Routine check up included vision, anterior segment and fundus, scoring of tear break up time (BUT), Schirmer I test and rose bengal staining (rb). Recorded the property of meibomian secretion. Defined the dry eye as mild and severe.

RESULTS: Meibomian secretion was sorted as egg-white-like secretion (n=28), milk-yellowish secretion (n=26), granular secretion (n=30) and toothpaste-like secretion (n=52). The result declared that BUT and rb scoring stepped up consecutively in the above secretions, that was higher in toothpaste-like secretion than in other groups (all P < 0.01). Schirmer I scoring was below 1 in all groups, and there was no difference in the groups. Fifty-four eyes (40%) met the criteria of dry eye syndrome. The incidence of dry eye stepped up in groups as egg-white-like secretion (2/28) 7.1%, milk-yellowish secretion (4/26) 15%, granular secretion (8/30) 27% and toothpaste-like secretion (40/52) 77%. The incidence was higher in granular secretion than in egg-white-like secretion (P < 0.05), while the incidence was higher in toothpaste-like secretion than in any of other 3 groups (P < 0.01). There was no severe dry eye in egg-white-like secretion and milk-yellowish secretion, while dry eye was found in 2 out of 8 in granular secretion, and in 19 out of 40 in toothpaste-like secretion. Incidence of severe dry eye was found higher in toothpaste-like secretion than in non toothpaste-like secretion (P < 0.05).

CONCLUSION: Abnormal meibomian secretion affects the stability of ocular surface. The patients with toothpaste-like secretion are prone to dry eye and tend to have a worse dry eye than other secretion groups.

Study: (yawn) Another Restasis cocktail

Evaluation of an isotonic tear in combination with topical cyclosporine for the treatment of ocular surface disease.

Hardten DR et al, Current medical research and opinion, 2007 Sep;23(9):2083-91

PURPOSE: To determine whether a new category of artificial tear product, carboxymethylcellulose 0.5% with compatible solutes (CMC-solutes) (Optive, Allergan, Inc., Irvine, California) improves clinical outcomes when used adjunctively with topical cyclosporine 0.05% (Restasis, Allergan, Inc., Irvine, California) for the treatment of ocular surface disease. METHODS: Nineteen patients with ocular surface disease treated with cyclosporine 0.05% for at least 3 months and who had previously used other artificial tears adjunctively were enrolled. Patients discontinued their previous artificial tear and used CMC-solutes, concomitant with topical cyclosporine 0.05%. Corneal evaluation and tear production parameters were evaluated before and during combined CMC-solutes/cyclosporine treatment. Patients also completed a questionnaire before and during treatment with combined CMC-solutes/cyclosporine. Follow-up was at 1 and 3 months. RESULTS: Most objective measures of ocular surface health were unchanged, but an improvement in conjunctival lissamine green staining and tear break-up time was found. Conjunctival lissamine green staining scores improved from 3.4 +/- 2.5 to 1.9 +/- 2.5 by Month 3 (p = 0.004). Tear break-up time improved from 4.6 +/- 3.9 s pre-treatment to 5.3 +/- 3.8 s post-treatment (p = 0.049). Ocular Surface Disease Index (OSDI) scores improved from 16.2 +/- 9.4 at baseline to 11.5 +/- 8.9 at month 3 (p = 0.007). Subjectively, patients graded their ocular discomfort as 2.7 at baseline and as 2.3 at Month 3 (p = 0.049). At Month 3, 89.5% of patients said they liked CMC-solutes as well or better than previous drops they had used. All patients said CMC-solutes provided similar or improved relief of symptoms of dry eye than previous eye drops. There were no tear-related adverse events reported. CONCLUSIONS: In this study, CMC-solutes, when used in conjunction with cyclosporine 0.05%, provided patients with an improvement in objective signs and subjective symptoms of ocular surface disease compared to their previous artificial tears. Further studies are warranted.

My translation: (Forgive me, or put it down to PMS...)

PURPOSE: To keep as many patients on Restasis as possible by finding yet another drop which if taken with Restasis might make them feel better. Oh, and to sell yet another Allergan product.

METHODS: Hand 19 random Restasis users (hm, wonder how long they had been on Restasis and whether they were at the magic 3 month point - or is the the magic 7 month point - or is it the magic 12 month point now?) yet another artificial tear (hm, wonder what they used to use and which ones the discontinuation of which is most likely to lead to improved comfort?) to try. Most of those tears have a honeymoon period before they join the drawerful of rejects in the bathroom, so there's always a chance they might like it better for long enough to capture some useful data.

RESULTS: No need to translate this part, I'll just quote: "Most objective measures of ocular surface health were unchanged". Ah, but OSDI improved. Go figger.

CONCLUSIONS: Start prescribing Optive with Restasis to patients who aren't yet showing any benefit from Restasis until somebody publishes a study with better results than this.

Like I said, I'm a cynical old thing, especially of a Wednesday morning without caffeine. Down in the depths of my heart...somewhere... I do sincerely appreciate all the efforts to make Restasis more tolerable.

Study: The search for hormonal links goes on...

This one found no differences in testosterone levels amongst women with and without dry eye.

Total testosterone level in postmenopausal women with dry eye

Duarte MC et at, Arg Bras Oftalmol. 2007 May-Jun;70(3):465-9

PURPOSE: The purpose of this study was to compare total testosterone blood level among three groups of postmenopausal women: control, mild to moderate dry eye and severe dry eye.
METHODS: Twenty-nine postmenopausal women were selected. The exclusion criteria were: hormone replacement therapy in the last 8 weeks, mechanical palpebral abnormalities, pterygium, lacrimal obstructions, intraocular inflammation or contact lens use. A blood sample was collected for total testosterone level determination, and the patients were submitted to an ophthalmologic examination (emphasizing on dry eye detection) and answered the OSDI (Ocular Surface Disease Index) questionnaire. Five patients were excluded. Postmenopausal women were divided into three groups according to OSDI score and the ophthalmic examination.
RESULTS: Five patients were classified in the no dry eye group (control), fifteen in the mild to moderate dry eye group and four in the severe dry eye group. There were no statistically significant differences regarding mean age (p=0.3915); instruction level (p=0.9333); number of comorbidities (p=0.2551); medication taken (p=0.2844) and total testosterone level among those groups (p=0.1275).
CONCLUSION: Further research with a greater bigger sample is necessary to establish the relation of androgen levels in dry eye patients.

Study: Bleph underdiagnosed, undertreated

Well golly, I'd kinda noticed that - based on the number of people visiting Dry Eye Talk or calling who had never heard of it but from whose description of their symptoms almost certainly have it. Seems like sometimes it only gets diagnosed if the patient's got horribly crusty lid margins.

Chronic blepharitis. Pathogenesis, clinical features, and therapy

Auw-Haedrich C, Reinhard T, Ophthalmologe, 2007 Sep;104(9):817-26; quiz 827-8

Chronic blepharitis is one of the most common diseases of the eyelids, but surprisingly, it is not often recognized. Frequently, a skin disease such as seborrheic dermatitis, atopic dermatitis, or acne rosacea is the underlying cause of chronic blepharitis. Bacterial pathological lipase, cholesterylesterase production, and bacterial lipopolysaccharides are pathogenetically relevant. Only rarely do genuine bacterial infections play a role. Collarettes occur at the base of the eye lashes, and the Meibomian glands show either abundant fluid secretion or inspissated secretion with obstruction of the orifices. Chronic blepharitis can include sequelae including dry eye and corneal and lid contour changes. The basic treatment comprises attendance of the underlying dermatological disease and lid hygiene. In addition, preservative-free tear film substitutes, antibiotics, immunomodulatory agents, or even surgical intervention may become necessary.

Study: OCI an alternative to OSDI?

The "Ocular Comfort Index"

Measurement of ocular surface irritation on a linear interval scale with the ocular comfort index.
Johnson ME, Murphy PJ, IOVS, 2007 Oct;48(10):4451-8.Click here to read

PURPOSE: To examine the psychometric properties of the Ocular Comfort Index (OCI), a new instrument that measures ocular surface irritation designed with Rasch analysis to produce estimates on a linear interval scale.

....CONCLUSIONS: The OCI was shown to have favorable psychometric properties that make it suitable for assessing the impact of ocular surface disease on patient well-being and changes in severity brought about by disease progression or therapeutic strategies.

With more scientifically validated instruments emerging to measure how people with ocular surface disease feel... there is even less excuse for failing to employ them.

It's not hard. Your tech hands the patient a sheet of paper where they answer 12 simple questions. Slip it into their medical record. Repeat in six months. Not too painful now was it?

Some suggested times for doing it... And no, this is NOT a multiple-choice test.

1) Every time a dry eye patient comes in for a checkup.
2) Every 6 months for your glaucoma patients who are on BAK-preserved drops.
3) Every LASIK pre-operative exam.
4) The 1-, 3-, 6- and 12-month LASIK follow-up exams - and not just for the patients who are actually complaining about discomfort. If you don't measure them all, you won't know. I'm generously assuming you might like to.

Dry eye PATIENTS - you can self-administer these tests. For those of you who are compulsively trying new therapies, consider undergoing the discipline of actually finding out whether they're working by limiting yourself to one at a time, and using one of these questionnaires before you start and 3 months later. Oh, and keep your copies, and ask the technician at your eye doctor's office to place it in your medical records.