serum eyedrops study

[dianat]

Here's an interesting link on serum drops. I was unable to find more on the actual study. It can be found in the American Journal of Opthalmology Feb 2005.


http://story.news.yahoo.com/news?tmp...drops_serum_dc

[Erik]

Here is the whole article, Diana (and others), spread out over two replies, since we are limited to 10000 characters per reply.

If you want the PDF, PM me with your e-mail address.

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The effect of autologous serum eyedrops in the treatment of severe dry eye disease: A prospective randomized case-control study

Presented at the 28th Japan Cornea Congress, February 19–21, 2003, Yonago, Japan, and at the 2004 ARVO Meeting, Fort Lauderdale, Florida, April 26, 2004.

Purpose
To evaluate the effectiveness of the autologous serum eyedrops in the treatment of severe dry eye patients.

Design
Prospective randomized case-control study.

Methods
Thirty-seven eyes of twenty severe dry eye patients without punctal occlusion were enrolled in this study. After 2 weeks of washout, they were randomly assigned to two groups. Group A patients used only preservative-free artificial tears, and group S patients used only autologous serum eyedrops. We evaluated the results of Schirmer test, fluorescein and rose bengal staining scores, tear film breakup time (BUT), and subjective symptom scores before and 2 weeks after treatment.

Results
Mean BUT and fluorescein and rose bengal staining scores, as well as subjective symptom scores, showed significant improvement in the patients assigned to autologous serum eyedrops compared with subjects assigned to preservative-free artificial tears after 2 weeks of treatment.

Conclusions
Autologous serum eyedrops were found effective in the treatment of severe dry eye disease, as evidenced by improvement of tear stability and ocular surface vital staining scores.


Article Outline
Methods
Patient characteristics
Visual analog pain symptom score
Tear function tests
Ocular surface vital staining
Preparation and application of autologous serum
Statistical analyses
Results
Patients characteristics
Schirmer test
Tear film BUT
Ocular surface vital staining scores
Visual analog ocular pain symptom scores
Discussion
References


Conventional treatment of dry eyes consists mainly of the use of preservative-free artificial eyedrops and punctal occlusion.1 None of the commercially available artificial tear preparations include essential tear components such as epidermal growth factor, hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A, all of which have been shown to play an important role in the maintenance of ocular surface epithelial milieu. We previously reported that autologous serum eyedrops contain these essential factors and that autologous serum eyedrops were beneficial in the treatment of ocular surface diseases such as persistent epithelial defects, superior limbic keratoconjunctivitis (SLK), keratoconjunctivitis sicca, and neurotrophic keratopathy.2, 3, 4, 5, 6 and 7 Comparative controlled studies evaluating the effect of autologous serum treatment on tear function and ocular surface status are still scarce. Studies on autologous serum eyedrops available in the literature do not assess the effects of solitary autologous serum treatment on the ocular surface because of the nature of study designs and presence of punctum plug occlusion in the patients. In this randomized case-control prospective study, we evaluated the solitary effects of autologous serum treatment on the ocular surface health and clinical outcome after a washout period by performing the Schirmer test, BUT, and fluorescein and rose bengal staining scores and comparing the results with those subjects assigned to instillations of preservative-free artificial tear solutions.

Methods
Patient characteristics
Thirty-seven eyes of 20 SS (Sjögren’s syndrome) and non-SS patients who matched the following dry eye criteria were enrolled in this study. All patients met the diagnostic criteria of the Japanese Dry Eye Research group8 and 9 and had no history of punctal occlusion. Washout was carried out in all subjects with preservative-free saline eyedrops instilled six times a day for 2 weeks. After washout, all patients were randomly assigned to two groups: patients in group A used only preservative-free artificial tears, and patients in group S used only autologous serum drops six times a day for 2 weeks. Ten patients were assigned to each group. There were no statistically significant age and sex differences between the control subjects and patients in this study. The examiner who carried out the tear function and ocular surface evaluations was masked to the type of the eyedrops prescribed to the patients in this study. The research followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all the subjects after explanation of the nature and possible consequences of the study.

Visual analog pain symptom score
Absence of any pain constituted a score of 0 points on the visual analog pain scales, and intense, unbearable pain was considered a full pain score of 100 points. Briefly, the visual analog pain symptom scales were prepared as 10-cm lines and the patients were asked to check a point on the line corresponding to their degree of pain.

Tear function tests
Tear film BUT was measured three times, and the mean value was calculated.10 The Schirmer test was performed using standard strips (Alcon, Fort Worth, Texas, USA) kept in the lower conjunctival sac for 5 minutes.

Ocular surface vital staining
The ocular surface was examined by the double vital staining method.10 Two milliliters of a preservative-free combination of 1% rose bengal and 1% fluorescein dye was instilled in the conjunctival sac. Rose bengal staining of the ocular surface was scored according to the criteria proposed by van Bijsterveld.10 and 11 The fluorescein staining was scored according to the protocol described by Shimmura and associates12 Briefly, the cornea was divided into three equal areas of upper, middle, and inferior corneal compartments. Each compartment was graded on a scale of 0 (no staining) to 3 points (intense staining). A fluorescein staining score above 1 point was considered as abnormal (maximum: 9 points). The diagnosis of dry eye was based on the diagnostic criteria of the Dry Eye Research Group in Japan.8 and 9 In brief, patients with1 dry-eye-related symptoms,2 positive staining with fluorescein or rose bengal, and3 Schirmer 1 test results of less than 5 mm or tear film BUT values of less than 5 seconds were diagnosed as having dry eyes. Dry eye cases were categorized as non-SS and SS on the basis of the criteria proposed by Fox and associates.13 Briefly, patients who had dry eyes and dry mouth, serum rheumatoid factor, and antinuclear antibody levels 1:160 or greater, positive serology for anti-SS-A or anti-SS-B antibodies and labial salivary gland inflammatory infiltration focus score of 2 or more were diagnosed as SS. The patients did not have any history of ocular surgery including punctal occlusion, ocular or systemic disease, or a history of drug or contact lens use that would alter the ocular surface. According to the study protocol, tear film BUT analysis was performed initially, followed by fluorescein and rose bengal vital staining of the ocular surface. The Schirmer 1 test was then performed. Serum drops were applied six times a day for 2 weeks. Tear film BUT, vital staining of the ocular surface, and visual analog pain symptom scores were compared before and after treatment.

Preparation and application of autologous serum
We prepared autologous serum eyedrops according to a previously reported protocol by Tsubota and associates.2 Briefly, a total of 40 ml of blood was procured by venopuncture and centrifuged for 5 minutes at 1,500 rpm. The serum was carefully separated in a sterile manner and diluted to 20% by saline. The final preparation was aliquoted into 5-ml vials with ultraviolet light protection, because vitamin A is easily degraded by light. Patients were instructed to keep the vials they were using in a refrigerator at 4 C and were instructed to store the other vials in a freezer until required.

Statistical analyses
The nonparametric Mann-Whitney U test was chosen to compare the unpaired noncontinous data at different time points. The Mann-Whitney U test was performed for the comparison of vital staining scores, BUT, and subjective symptom score differences between the two groups. The Chi-square test was applied to test the age and sex differences between group A and S. A P value less than .05 was considered statistically significant. StatView software (SAS Institute, Cary, North Carolina, USA) for Windows 98/2000 was used for statistical analysis.

Results
Patients characteristics
Seventeen patients had SS and 3 patients had non-SS dry eyes in this study. Patient characteristics are summarized in Table 1.

TABLE 1.

Sex, Age, Etiologic Distribution and Baseline Tear Quantities of the Study Population Age (years) Male:Female SS:Non-SS Schirmer Test (mm)
Group A 65.4 ± 9.7 2:8 9:1 3.8 ± 4.5
Group S 62.3 ± 12.5 2:8 8:2 3.5 ± 3.1


Group A = patients assigned to artificial tear drops; group S = patients assigned to autologous serum eyedrops; Non-SS = Non-Sjögren’s syndrome; SS = Sjögren’s syndrome.

[Erik]

Schirmer test
The mean Schirmer test scores did not vary significantly between the two groups before treatment, as shown in Table 1. The final mean Schirmer scores were 3.7 ± 3.1 mm in group A and 3.3 ± 2.6 mm in group S (P > .05), respectively. There were no differences between pre- and posttreatment Schirmer test values in each group, and the mean post-treatment values between the two groups.

Tear film BUT
There were no significant differences between the mean BUT values at the initial visit and after washout between the two groups (P > .05). The mean BUT value was 2.3 ± 2.3 seconds before treatment with autologous serum eyedrops and 4.3 ± 2.6 seconds after treatment. The mean BUT value in the group treated with autologous serum eyedrops was significantly higher at the end of treatment compared with the group assigned to treatment with artificial tears, as shown in Figure 1 (P < .05).

Ocular surface vital staining scores
The mean fluorescein and rose bengal staining scores did not show significant differences at the initial visit or after washout between the two groups, as shown in FIGURE 2 and FIGURE 3 (P > .05). The mean fluorescein staining score was 2.8 ± 1.3 points after treatment with autologous serum and 3.5 ± 2.2 points after artificial tear eyedrops. Mean rose bengal staining score was 2.5 ± 2.0 points after treatment with autologous serum and 4.2 ± 2.5 points after treatment with artificial tear eyedrops. The differences in the mean ocular surface staining scores between the two groups after treatment were statistically significant (P < .05).

Visual analog ocular pain symptom scores
There were no statistically significant differences related to the visual analog ocular pain symptom scores at the initial visit and after washout between the two groups (P > .05). The mean visual analog pain symptom scores were 70 ± 20 points after treatment with autologous serum and 52 ± 24 points after treatment with artificial tear eyedrops. Pain scores were significantly lower in patients assigned to treatment with autologous serum eyedrops compared with patients assigned to artificial tears at the end of 2 weeks (P < .05), as shown in Figure 4.

Discussion
Despite maximal conventional treatment, a cohort of severe dry eye patients exists that has persistent symptoms and signs. Such patients have more serious ocular surface disorder, with significant visual impairment and disability.14 Our previous experience in SLK,4 recurrent corneal erosions,2 neurotrophic keratopathy, Sjögren’s syndrome3 and other reports6 and 15 in uncontrolled trials supported the benefits of autologous serum eyedrops in these disorders, with improvement of ocular health and tear functions. Tananuvat and associates16 reported in a controlled trial comparing autologous serum eyedrops in one eye with the use of artificial tears in the fellow eye as a control that there was a statistically nonsignificant trend toward improvement of vital staining scores and tear stability in both eyes. Most eyes in that study had received punctal occlusion, however, which might have interfered with the evaluation of the solitary effects of autologous serum eyedrops and artificial tear eyedrops; this may have caused a bias toward overevaluation of the effects of solitary artificial tears.

A recent randomized controlled clinical trial by Noble and associates17 assigned severe dry eye patients to either 3 months of autologous serum 50% eyedrops followed by 3 months of conventional treatment with artificial tears or 3 months of conventional treatment followed by 3 months of autologous serum. Use of autologous serum was associated with improvement of impression cytology parameters in that study without any differences found for rose bengal staining, Schirmer test, or tear clearance test. The crossover design of the study confirmed that these improvements were due to serum drops, that the effect was reversed when treatment was reversed, and that the beneficial effects were probably due to the presence of essential tear factors in the serum. Washout was not performed in that study, however, and it included patients who had lacrimal punctal occlusion, which may have resulted in overestimation of the effects of artificial tear drops.

In our study, none of the patients had punctal occlusion, which allowed us to evaluate the solitary effect of the autologous serum drops. We conducted this randomized prospective controlled clinical trial with a 2-week washout and assigned patients into two groups, using only autologous serum or artificial tears. We think this allowed us to evaluate the individual effects of these eyedrops.

We found significant improvements in tear stability, ocular surface vital staining scores, and pain symptom scores in patients treated with autologous serum eyedrops compared with those assigned to nonpreserved artificial tears. Confirmation of our findings with a larger group of patients in additional prospective controlled trials is desirable. Comparative prospective studies on the additive effects of sodium hyaluronate eyedrops and other conventional treatment modalities combined with autologous serum eyedrops would also provide interesting information. Indeed, hyaluroluronate alone has been reported to be effective in improving the corneal epithelial barrier function and in reducing the ocular surface damage in dry eye patients.18 and 19 The viscoelastic properties of hyaluronate might result in a longer exposure of the ocular surface to the essential autologous serum components such as growth factors and retinoids. Serum drops were used for 2 weeks in this study. Studies clarifying the effect and risk of prolonged application or of different concentrations of autologous serum drops to the ocular surface should be the subjects of future investigations.

In summary, we found autologous serum to be superior to conventional treatment with artificial tears for improving ocular surface health and subjective comfort.

[jcorbett]

question

Sorry - I have a hard time understanding all this. When people use this serum, are the results long lasting? Or does the eye revert to the dry state after discontinuation of the serum?

[dianat]

I'm quite sure the serum is something one would use regularly if it helped in the first place. My eyes are too rotten this week to take in that whole article. But in my experience, a patient would use a load dose in the first couple weeks (4 times a day maybe) and then taper off to maybe just morning and night. I wouldn't expect it to be a permanent fix, though perhaps stranger things have happened.

Thanks for posting it, Erik. I had a particular interest in it because it was serum drops, and because it was the first of any blood serum study I've read that included LASIK patients.

[Erik]

Sorry - I have a hard time understanding all this. When people use this serum, are the results long lasting? Or does the eye revert to the dry state after discontinuation of the serum?

Looks like they did not test longevity here. The bottom line of this article is that the serum did improve symptoms, TBUT, and ocular surface staining scores after two weeks of using the autologous serum drops. This goes along with the idea that there is something in the tears ("essential tear factors") that keeps the cornea healthy (i.e., something that has not been discovered or named yet) and that these "essential tear factors" are also present in the serum.

I think the results of this study are very good news. Interesting that at the end they mention use of a hyaluronate derivative along with the serum drops as a future area of study. I believe that Dr. Frank Holly (inventor of Dakrina, Dwelle, etc) has tested a similar drop this under the name Heluran (sp?) with positive initial results. (Maybe Rebecca knows something about this?)

[dianat]

That part about Dr. Holly's Heluran is very, very interesting. I tried to get my hands on that last year and had no luck. He suggested I try it because it had analgesic properties. It was not understood why it worked, but that it did - at least at times.

Heluran is given by Rx only, which is why I couldn't get it. None of my eye care practitioners knew of Dr. Holly's work, so none would give me the Rx. It's too bad. But, I'm very happy to know it was mentioned in the article and that you recognized it. I wouldn't have made the connection.

[Rebecca Petris]

I first got interested in autologous serum quite some time ago after reading a case study published by Sandra Brown, a pediatric ophthalmologist (the one who at my request tried to arrange for a clinical trial for LASIK patients at Texas Tech as discussed over on D'Eyealogues). In that study an infant was treated for a very severe condition and recovered so well that further treatment ultimately was not needed.

I believe that Dr. Frank Holly (inventor of Dakrina, Dwelle, etc) has tested a similar drop this under the name Heluran (sp?) with positive initial results. (Maybe Rebecca knows something about this?)

Yes, there were many reports of some excellent results with Heluran from patients in quite bad condition. However unfortunately I don't anticipate it becoming readily available anytime soon. The other four - Dwelle, Dakrina, Freshkote and NutraTear - are over-the-counter products (that is, compliant with the FDA's monograph for ophthalmic demulcents) but to the best of my understanding Heluran is clearly not and therefore getting it would probably require either a cooperative prescribing doctor who is familiar with and sympathetic to the specific research, or some very expensive clinical trials to get it approved as a drug. I certainly hope the latter can ultimately be done - and we'll sure help if/when we can - but I don't expect it to happen anytime soon.

[kdc66]

There are actually two products currently on the market: Aquify and Blink that contain sodium hyaluronate. Blink has the higher concentraction. I believe they market sodium hyaluronic as a contact lens rewetting drop because if they tried to market as a dry eye treatment drop they would have to get FDA approval. I've been trying the blink drops. I think they maybe helping some although I probably need to give it a month. It's worth a try and they are available at most drugstores. You might want to try the blink drops first since it has a higher concentration and I believe a less irritating preservative. However, the Blink drops are alot more expensive.

From review of Optometry:
• Hyaluronic acid. This chemical, which occurs naturally in the human body, is a useful structural tool. Though long-term studies have yet to be done, treatment with sodium hyaluronate appears to accelerate recovery of the damaged cornea.19 Specifically, sodium hyaluronate eye drops increase precorneal tear film stability and corneal wettability, reduce the tear evaporation rate, and the healing time of corneal epithelium.20 Sodium hyaluronate can be found in AQuify contact lens comfort drops (CIBA Vision).—B.C.



Creating a Healthy, Moist Environment
Find out how viscoelastic material in eye drops benefits contact lens wearers.
By Louise A. Sclafani, OD, FAAO

Contact lens wearers often turn to lubricant eye drops to ease discomfort from dry eye symptoms. In fact, a 1998 survey showed that 65% of contact lens patients used eye drops to relieve discomfort.

Many eye drops are commercially available to relieve dry eye, but only a few are designed specifically for contact lens wearers. We now have a new drop -- Blink Contacts with sodium hyaluronate (HA) -- that's answering a need among many patients. In this article, I'll describe how this product can help contact lens wearers stay more comfortable longer.



OCULAR APPLICATIONS OF HA

Sodium hyaluronate is a natural viscoelastic material found throughout the body, including the vitreous and aqueous humor, joints and organs. It functions as a lubricant thanks to its viscosity, and a shock absorber owing to its elasticity. It helps maintain hydration and the integrity of the intercellular matrix.

A water-retaining polymer, HA has been used in ocular surgery since 1979. It helps maintain the shape of the anterior chamber and protects the corneal endothelium during phacoemulsification and intraocular lens implantation. When used in eye drops, HA supports tear film stability, maintains corneal lubrication, decreases tear film evaporation and shortens healing time for the corneal epithelium.

STUDIES CONFIRM HA BENEFITS

Rewetting or lubricant eye drops are a popular option for treating the symptoms of dryness, foreign body sensation and stinging. HA has been shown to help relieve discomfort and dryness in patients with Sjögren's syndrome. What's more, it reduced the itching, burning and foreign body sensation in 26 of 28 dry eye patients treated with hyaluronate 0.1% solution four times daily for 2 months. Fifteen patients in this study had longer tear breakup times (TBUTs) and eight had reduced mucus strands.

In another study, 40 patients with Sjögren's syndrome used the 0.4% concentration six times daily for 90 days. Their symptoms improved significantly by day 15; and TBUT and epithelium protection improved over the course of the study.

UNDERSTANDING THE HA MOLECULE

Some high-viscosity agents help bind water to the eye. However, they may leave a crusty residue, may not spread evenly over the ocular surface, and can decrease lubrication by increasing friction and drag.

Hyaluronate is a long molecule that retains large amounts of water and is highly viscous under low shear force -- when the eye is open, for example -- because the molecules are random and tangled. This helps slow TBUT and resist moisture evaporation. When the eye blinks, HA is under high shear force. The molecules become untangled and aligned, so fluid flows freely around them and spreads over the ocular surface. After the blink, the molecules return to their random and tangled state, water binds to the surface, and the eye stays moist.

HA BENEFITS CONTACT LENS WEARERS

Blink Contacts contains 0.15% HA and a gentle peroxide-free, non-sensitizing oxychloro complex preservative that breaks down into sodium chloride and water when exposed to light.

Most contact lens wearers use a rewetting product to add moisture to their eyes. The new generation of lubricant eye drops, such as Blink Contacts, is now available to bring the benefits of a dry eye product to contact lens users.

References
1. Ky W, Scherick K, Stenson S. Clinical survey of lens care in contact lens patients. CLAO J. 1998;24:216-219.
2. DeLuise VP, Peterson WS. The use of topical Healon tears in the management of refractory dry-eye syndrome. Ann Ophthalmol. 1984;16:823-824.
3. Aragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjgren's syndrome patients. Br J Ophthalmol. 2002;86:879-884.
4. Goa KL, Benfield P. Hyaluronic acid: a review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing. Drugs. 1994;47:536-566.
5. Bernatchez SF, Camber O, Tabatabay C, Gurny R. Use of hyaluronic acid in ocular therapy. In: Edman P, ed. Biopharmaceutics of Ocular Drug Delivery. Boca Raton, Fla: CRC Press; 1993:106-120.


Dr. Sclafani is is an associate professor of ophthalmology and director of optometric services at the University of Chicago. Her main interests include contact lenses, corneal disease and refractive surgery.



Lubricants and Preservatives in Contact Lens Wetting Solutions

Product Hyaluronate Preservative Essential Electrolytes
Blink Contacts 0.15% OcuPure Sodium, potassium, calcium, magnesium chloride
AQuify 0.10% Sodium perborate with phosphoric acid Sodium chloride, sodium phosphate
Refresh Contacts 0.00% (CMC 0.5%) Purite Sodium, potassium, calcium, magnesium chloride