BIOSYNTRX™

 

BioTears™

(patent pending - oral gel caps)

Dry eyes, often referred to as Dry Eye Syndrome, is the most frequent patient complaint to eye doctors. According to a report from Jobson Publishing, “Lack of successful treatment for dry eye pain is the primary reason patients change eye doctors”. About 20 million Americans experience varying degrees of dry eye problems. It is a common disorder of the tear film that results from decreased tear production, excessive tear evaporation, or abnormality in mucin or lipid components of the three layers of the tear film that covers the normal ocular surface. Dry eye syndrome is commonly associated with a systemic inflammatory process and like most eye disease, it is often related to health conditions in the rest of the body, including dryness of other mucous membranes such as mouth, vagina, and joints.

Pathology of the three-layer tear film:

The Mucus Layer - the closest layer to the corneal epithelium. It is produced by the conjunctival goblet cells, and is absorbed by the corneal surface glycoproteins, creating a hydrophilic surface. Mucin deficiency, or mucopolysaccharide abnormalities, can lead to poor wetting or glycation of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.

The Aqueous Layer – the layer between the mucous and lipid layers. It is secreted by the lacrimal gland and incorporates all water-soluble components of the tear film. It also comprises 90% of the tear film's thickness. The aqueous layer provides moisture and supplies oxygen and important nutrients to the cornea.

The Lipid Layer - the most superficial layer. It is produced by the Meibomiam glands with contributions from the glands of Zeis and Moll of the eye lids. The secretion is an oily material, which is fluid at body temperature and retards evaporation of the aqueous layer and lowers surface tension, thereby allowing the tear-film to adhere to the eye's surface. Androgen receptors are located in both the lacrimal and meibomian glands. A decrease in circulating androgen hormones can result in loss of the oil layer, exacerbating the evaporative tear loss.

The Blink reflex renews the tear film by delivering aqueous and lipid to the tear film and sweeping away debris. The normal blink interval is about 5 seconds under normal conditions. The tear film is typically stable for about 10 seconds. Tears are normally evaporated or forced out through the nasolacrimal ducts in the inner corner of the eyes on blinking.

Causes of Dry Eye Syndrome:

Many different things cause dry eye syndrome. The normal aging of tear glands, as well as extended use of contact lens, environmental pollutants, prescription drugs, refractive surgery, auto immune diseases, nutrient deficiencies and other disorders can cause disruption in the tear production and retention process.

Symptoms:

The typical symptoms of the dry eye syndrome include dryness, grittiness, irritation, difficulty reading for long periods of time, burning and even the apparent contradiction of excessive tearing or watering. In extreme cases of dry eye, patients may become unusually sensitive to light, experience severe eye pain, and start to notice diminished vision. Successful treatment may be needed to avoid permanent damage.

Blepharitis can often cause dry eye symptoms due to inflammation of the eyelid margins, which is caused by a bacterial infection (Staphylococci). This condition can compromise the quality of the tear film causing tears to evaporate more quickly. The bacteria produce waste material that can cause a mild toxic reaction leading to chronic red, irritated eyes.

Extended Contact Lens Wear can result in dry eye from corneal oxygen and nutrient deficiency. Protein build-up on contact lens can produce a breeding ground for bacterial growth and surface roughness, further contributing to inflammatory changes. Some contact lens solutions contain preservatives that can also cause chemical irritation of the corneal surface and result in dry eye symptoms.

LASIK surgery temporarily disrupts the ocular surface/lacrimal gland unit. Also, during LASIK, roughly 60-70% of the superficial nerve fibers in the cornea are severed, which reduces sensation and affects aqueous tear production and delays wound healing. With compromised sensation, the blink rate can slow to the point that the tear film breaks up before the next blink can reconstitute. Though this condition usually clears up after a few months, it may result in mild to severe dry eye syndrome for several months after surgery.

Diseases that may be associated with dry eyes include Rheumatoid Arthritis, Sjogrens Syndrome, Diabetes, Asthma, Thyroid disease, Lupus, and possibly Glaucoma.

Age - Dry eye syndrome affects 75% of people over age 65. Tear volume decreases from that at age 18 as much as 60% by age 65.

Hormonal changes cause decreased tear production brought on by pregnancy, lactation, menstruation, and menopause. .

Medications that can cause dry eyes are antibiotics, blood pressure medications, antidepressants, diuretics, over-the-counter vasoconstrictors such as Visine, antihistamines, birth control pills, appetite suppressants, and ulcer medications.

Computer Use causes most people to blink less frequently (about 7 times per minute vs. a normal rate of around 22 times/minute). This leads to increased evaporation along with the fatigue and eye-strain associated with staring at a computer monitor. Any task requiring a great deal of concentration can result in decreased blink rate.

The conventional treatment for dry eyes is to treat the symptoms not the cause:

Artificial Tears : Some form of over-the-counter artificial tears is usually recommended. Although they may provide temporary relief, they merely palliate the symptoms. Worse, the preservatives can aggravate the condition, and can even kill corneal cells. Tears that promise to "get the red out" will reduce circulation in the eye, decrease production of the tear film, and worse, eventually make the eyes even drier.

Punctal Occlusion : Punctal occlusion is a procedure used to help dry eye patients by closing the tear drainage canals with silicone plugs, which keep most of the fluid from leaving the surface of the eye. This may provide long-term relief.

The Biosyntrx solution:

The scientists at Biosyntrx have discovered a unique way to treat the underlying causes of dry eye by oral administration of dietary nutritional supplements. These stimulate the natural production of lubricants and supporting elements (oils and mucin), as opposed to the superficial treatment of the symptoms of dry eye by administration of topical lubricants (eye drops). Interestingly, studies have shown that, in addition to restoring normal production of lubricants in the eyes, normal lubrication has been restored in other affected parts of the body, as mucous membranes of the mouth and vagina, and interior body surfaces such as joints and synovial membranes. This further affirms the nutritional basis of the Dry Eye Syndrome.

In developing an antioxidant formula in capsule form for oral administration, Biosyntrx has been able to include all of the elements known to restore function to the oil, tear and mucin glands, treating dry eye syndrome by physiologic rather than pharmacologic means. These ingredients, working synergistically rather than individually, effectively address the inflammatory process responsible for most dry eye syndrome, as well as enhance and restore function to the glands involved in all three layers of the tear film..

Biosyntrx's, ( patent pending) BioTears™ is proving to be effective in approximately 70 percent of the dry eye population. It contains a proprietary blend of omega-3 and omega-6 fatty acids and the nutrient co-factors, Vitamins A, C, B6, and magnesium to successfully produce the GLA downstream anti-inflammatory prostaglandin metabolites PGE1 and PGE3. This anti-inflammatory metabolite cannot be consistently produced with other recommended EFA (Flax Oil) dry eye treatments because the delta six desaturase (D6D) enzyme necessary for the LA to GLA conversion is frequently lost in the aging process.

BioTears also contains Vitamin E, specifically gamma tocopherols, to both prevent oxidation by stabilizing the EFAs, and to better inhibit production of the cyclooxygenase protein enzymes that are necessary to produce the pro-inflammatory prostaglandin PGE2.

Vitamin C, as ascorbic acid and fat-soluble absorbyl palmitate consistently modulates prostaglandin (PGE1) synthesis due to the extended half-life of the fat-soluble vitamin C over water-soluble ascorbic acid. This Vitamin C combination also enhances the production of IgA concentrates in tears when necessary, which is the first line of defense against invading pathogens and allergens that frequently cause dry eye symptoms.

Lactoferrin is included to increase the aqueous level of iron binding proteins to better inhibit viral and bacterial infections and to balance other tear lipocalins (family of proteins that transport small hydrophobic molecules, such as retinol), because they modulate the surface tension of the tear film.

Background: Lactoferrin is also produced by neutrophiles during periods of stress if the immune system is functioning properly.

Curcumin was included to inhibit production of the COX2 enzyme in the aqueous layer, which is an important player in the downstream metabolite of the site-specific pro-inflammatory PGE2. Inflammation of the aqueous producing lacrimal gland can also prevent corneal nerve cells from releasing neurotransmitters necessary for the blink response.

Background: Curcumin is a natural COX2 inhibitor like the ibuprofens Motrin and Advil (NSAIDS). The difference is Curcumin does not inhibit production of the COX1 enzyme that is necessary to protect the stomach lining. NASIDS can cause hemorrhage and have been responsible for a number of deaths. The first sign of an adverse response can be stomach bleeding.

L-carnitine was included to enhance transportation of the EFA nutrients across the mitochondria and to enhance production of ocular neurotransmitters.

Background: Biosyntrx makes every effort to address cellular delivery and nutrient transport issues by including active ingredients proven to deliver specific nutrients across cellular mitochondria and the blood brain eye barriers in a more efficient manner.

BioTears™ Plus (Patent Pending ) for the severely dry eye and surgical patient

BioTears Plus contains all of the ingredients in BioTears, plus additional ingredients proven to address the androgen, auto immune, allergic and surgical dry eye patient.

DHEA, the master hormone and super antioxidant, was included at the 5 mg level because it gently boosts androgen levels of menopausal women and older men. This small amount of DHEA does not negatively affect hormonal levels of younger people.

Beta-1, 3-D glucan is included to address the autoimmune (Sjogrens), surgical and allergic dry eye patient. Beta Glucan keeps the immune system in homeostasis by turning on glucan receptors sites present on the surface of phagocytes (macrophages) and natural killer cells. Those cells will perform their normal function at a higher state of sensitivity that causes them to either properly signal the T4 cells to selectively stimulate the Th1 cell mediated immunity (CMI, cytokine cascade) when necessary, or the Th2 cell (humorol response, which regulates all B cell activity and antibody production) when appropriate.

Immune modulation is beneficial to the LASIK dry eye patient. Corneal surface surgical wound healing, as all wound healing, is dependent on the proper signaling of the Th1 (CMI) cytokine cascade of specific fibroblasts and lymphocytes. This particular macrophage mediated cytokine cascade is necessary to destroy and remove the dead epithelial cells and debris created by the surgical procedure. When Th1 mediated cytokines bind to the receptor sites of damaged corneal cells (debris) they activate the Fas-ligand, which stimulates Fas protein production, causing timely cell death by apoptosis of the surgically damaged cells, thus allowing a cleaner site for reepithelialization and neuronal healing.

Background: Beta glucan is a complex carbohydrate. Beta-1, 3-D glucan is the sole active ingredient in Beta Glucan. It is derived from the cell walls of baker's yeast, making it the precise substance for which the actual glucan macrophage receptor has been identified. Beta-1, 3-D glucan is technically referred to as a polybranched polyglucose. It is so complex some refer to it as fiber.

Wound Healing Background: A properly mediated macrophage cytokine cascade response is central to the wound repair process. The response is primitive but essentially an innate one aimed at restoring tissue integrity. Whether microbes, foreign materials or surgical trauma initiates the injury, a shared pattern of overlapping events ensues, including inflammation, granulation, epithelialization, matrix generation and tissue remodeling. As a highly regulated cascade of events, wound healing is mediated by interacting molecular signals, which orchestrate complex cellular activities as the repair process re-establishes tissue homeostasis. This macrophage response is a remarkably pleiotropic cytokine cascade that has multiple functions, which control both up-regulation and down-regulation of healing and other processes. The vast effector roles that the macrophage plays make it a central player in this and many other obvious immune system roles that relate to dry eyes. This is why we employ Beta Glucan in BioTears Plus .

Biosyntrx suggests that BioTears Plus be recommended to all LASIK patients at least one week pre-op with continued use for at least 3 months post-op to help prevent surgically induced dry eyes.

Biosyntrx also addressed the cellular delivery system in the severe and surgically induced dry eye patient by specifically including acetyl-l-carnitine and lipoic acid in the BioTears Plus formulation. Recent studies prove this active ingredient combination facilitates the transport of nutrients across the mitochondria, which enhances production of cellular ATP, which faster stimulates the neuronal production of acetylcholine, the neurotransmitter responsible for the blink response. The extra energy these two active ingredients provide seems to give most patients a sense of well-being, according to the most published antioxidant researcher in the world, Bruce Ames, PhD, from UC Berkeley.

Documentation:

Jiang Q, Elson-Schwab, Courtemanche C, Ames BN – Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells: Proc Natl Acad Sci U S A. 2000 Oct 10; 97(21):11494-9.

Ben J. Glasgow, Gary Marshall, Oktay K. Gasymov, Adil R. Abduragimov, Taleh N. Yusifov and Charles M. Knobler - Tear Lipocalins. Potential Lipid Scavengers for the Corneal Surface: Pathology,Ophthalmology, the Jules Stein Eye Institute, and the Department of Chemistry and Biochemistry, University of California, Los Angeles, School of Medicine.

Tei M, Spun-Michaid SJ, et al. - Vitamin A deficiency alters the expression of mucin genes by the rat ocular surface epithelium : Invest Ophthalmol Vis Sci. 2000 Jan;41(1):82-8.

Kunert KS, Tisdale AS, Gipson IK. - Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine: Arch Ophthalmol 2002 Mar;120(3):330-7

Abraham Solomon, Dilek Dursun, Zuguo Liu, Yuhuan Xie, Angelo Macri and Stephen C. Pflugfelde - Pro- and Anti-inflammatory Forms of Interleukin-1 in the Tear Fluid and Conjunctiva of Patients with Dry-Eye Disease : Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Florida; and the Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Sciences, Guangzhou, China.

Feldman M, McMahon AT. - Do natural cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs,with less gastrointestinal toxicity? Ann Intern Med 2000;132(2):134-43.

de Felippe Junior J, da Rocha e Silva Junior M, Maciel FM, et al., Infection prevention in patients with severe multiple trauma with the immunomodulator beta 1-3 polyglucose (glucan): Surg Gynecol Obstet. 1993 Oct; 177(4): 383-8.

[1]

Williams DL, Ha T, Li C, et al., - Inhibiting early activation of tissue nuclear factor-kappa B and nuclear factor interleukin 6 with (1-->3)-beta-D-glucan increases long-term survival in polymicrobial sepsis: Surgery. 1999 Jul; 126(1): 54-65.

Bonecchi R, Bianchi G, Bordignon PP, et al. - Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s: J Exp Med. 1998;187:129-134.

Li DQ, Lokeshwar BL, Solomon A, Monroy D, Ji Z, Pflugfelder SC: -Regulation of MMP-9 production by human corneal epithelial cells : Exp Eye Res 2001 Oct;73(4):449-59

Nagyova B, Tiffany JM. - Components responsible for the surface tension of human tears: N uffield Laboratory of Ophthalmology, University of Oxford, UK.

Okon A, Jurowski P, Gos R. - The influence of the hormonal replacement therapy on the amount and stability of the tear film among peri- and postmenopausal women: Klin Oczna 2001; 103(4-6^:177-81

Valtysdottir ST, Wide L, Hallgren R. - Low serum dehydroepiandrosterone sulfate (DHEA) in women with primary Sjogren's syndrome as an isolated sign of impaired HPA axis function: J Rheumatol 2001 Jun;28(6):1259-65

Peluso G, Petillo O, Barbarisi A, Melone MA, Reda E, Nicolai R, Calvani M. - Carnitine protects the molecular chaperone activity of lens alpha-crystallin and decreases the post-translational protein modifications induced by oxidative stress: FASEB J. 2002 July, 15 (9) 1604-6

Pettorossi VE, Draicchio F, Fernandez E, Pallini R. - The influence of L-acetylcarnitine on reinnervation of the oculomotor nerve.: Int J Clin Pharmacol Res 1993;13(3):193-9

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN. - Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid: Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA.

Horrobin DF, Campbell A. - Sjogren's syndrome and the sicca syndrome: the role of prostaglandin E1 deficiency. Treatment with essential fatty acids and vitamin C: Med Hypotheses 1980 Mar;6(3):225-32

Guex-Crosier Y. - Non-steroidal anti-inflammatory drugs and ocular inflammation: Klin Monatsbl Augenheilkd 2001 May;218(5):305-8

Solomon A, Rosenblatt M, Monroy D, Ji Z, Pflugfelder SC, Tseng SC. -Suppression of interleukin 1alpha and interleukin 1beta in human limbal epithelial cells cultured on the amniotic membrane stromal matrix: Br J Ophthalmol 2001 Apr;85(4):444-9

Ilpo Tuominen, Minna Vesaluoma, Anna-Maija Teppo, Carola Grönhagen-Riska, Timo Tervo , - Soluble Fas and Fas ligand in human tear fluid after photorefractive keratectomy Br J Ophthalmol 1999;83:1360-1363 ( December )

Bacman S, - Muscarinic Acetylcholine Receptor Antibodies as a New market of Dry Eye Sjogren Syndrome : Invest Ophthalmol Vis Sci 2001 Feb; 42 (2); 321-327

Dursun D, Wang M, Monroy D, Li DQ, Lokeshwar BL, Stern ME, Pflugfelder SC. - A mouse model of keratoconjunctivitis sicca. : Invest Ophthalmol Vis Sci 2002 Mar;43(3):632-8

Dursun D, Piniella AM, Pflugfelder SC. - Pseudokeratoconus caused by rosacea.
Cornea 2001 Aug;20(6):668-9

Dry Eye Epidemiology :

Caffery BE, - The Canadian Dry Eye Epidemiology Study: Adv Exp Med Biol 1998; 438:805-6

Lemp MA; Epidemiology and Classification of Dry Eye : Adv Exp Med Biol 1998; 438: 791-803

LASIK and Dry Eye:

Pisella PJ, Godon C, Auzerie O, Baudouin C. - Influence of corneal refractive surgery on the lacrymal film: J Fr Ophtalmol 2002 Apr;25(4):416-22

Breil P, Frisch L, Dick HB. - Diagnosis and therapy of LASIK-induced neurotrophic epitheliopathy: Ophthalmologe 2002 Jan;99(1):53-7

Ang RT, Dartt DA, Tsubota K. - Dry eye after refractive surgery: Curr Opin Ophthalmol 2001 Aug;12(4):318-22

Biosyntrx Inc . 415-860-9874 Copyright 2002. All rights reserved