DRY EYE TREATMENTS
Potential Treatments for Dry Eye, Part III
This final article of a three-part series examines U.S. patents for treating dye eye with pharmaco-logical agents and acupuncture.
By Donald L.
MacKeen, MS, PhD
This is the final article of a three-part series covering dry eye research and topical treatments patented in the past decade. This part discusses topical agents that reportedly stimulate secretion of mucin, lacrimal fluid and acupuncture.
Mucin production stimulant. Yanni's  patent states that certain HETE (hydroxyeicosatetraenoic acid) derivatives stimulate mucin production in human conjunctival epithelium. Production on the epithelial surface in mucin deficient eyes should provide the necessary interface between epithelium and the pre-ocular tear film. The inventor noted that antioxidants would be necessary for stability during storage.
Hamano (1998) advocated instilling gefarnate solutions to stimulate goblet cell density in the conjunctiva. Tests showed that a 1% solution nearly doubled the goblet cell concentration in normal healthy rabbits.
Parasympathetic nerves appear to control conjunctival goblet cell secretion. Rios et al (1999) reported that muscarinic cholinergic agonists have greater stimulating effects than VIP (vasoactive intestinal peptide).
Lacrimators. Lacrimators should be useful in cases of inadequate tear aqueous when there is adequate reactive tissue. Previously, agents reported to increase tear flow like bromhexine (by mouth) or topical eledoisin (from octopus salivary glands) have gotten mixed reviews. According to Goebbels et al (1994), eledoisin required hourly instillations and bromhexin showed no increase in tears over a three-week investigation of systemic treatment.
Gilbard et al  described a phosphodiestererase inhibitor and/or cyclic nucleotide analogues that increase aqueous flow by increasing cyclic nucleotide levels in lacrimal gland tissue. The major effect of topical instillation is presumably limited to the accessory lacrimal glands. The author opined that some agonists could stimulate the production of water and electrolytes, others could stimulate the exocytosis of cell membrane proteins. Dartt et al (1984) report that it was intended to be instilled in an aqueous solution.
Gilbard et al (1991) used topical 3 isobutyl 1 methyl xanthine (IBMX) to increase tear volume. A decrease in tonicity estimated the efficacy. They also reported decreased rose bengal staining (p= 0.02) that was dose dependent and not blocked by proparacaine. Sullivan  expressed concerns that the treatment was subject to tachyphylaxis (decreasing response on re-use) and limitations on the amount and responsiveness of existing lacrimal gland tissue.
Schoenwald et al  patented N, N, dimethyl trans 2 phenylcyclopropylamine as a stimulator of lacrimal gland proteins. Its use increased tear protein and water volume in rabbits. Unlike previous similar compounds, this did not cause stinging. The increases were greater after ten minutes than after 60, possibly due to depleted accessory lacrimal glands.
Mano  used a ligand of serotonin receptor (sarpogrelate HCl) to stimulate the production of water. The patent formulation included water, oils, propylene or polyethylene glycols and cellulose ethers. He noted no irritation in rabbits used to compare active agent vs. vehicle. It is possible that non-lacrimal gland conjunctival tissue produced some of the liquid.
Yerxa et al  stated that UTP (uridine triphosphates) as well as CTP and ATP (cytosine and adenosine triphosphates, respectively) and certain analogues are effective agonists of P2Y purinergic receptors that produce water and chloride ions. Selected purines, analogues and derivatives effectively treated tear deficient dry eye. The authors suggested topical treatment through drops, gels and sprays with a maximum topical concentration of 0.1 Mole/L. The patent also indicates systemic usage. It describes several different methods of in vivo testing but does not list findings.
Muscarinic agents. Agents that stimulate muscarinic receptors are known to stimulate aqueous secretions. Quinuclidines are a class of compounds that stimulate muscarinic receptors and reportedly increase lacrimation with lessened side effects. Iga et al (1998) reported that cevimeline caused increased salivation and lacrimation in rodents. The FDA approved the oral use of this compound for treating dry mouth in January 2000.
Urea. Charlton et al  noted the beneficial effects of urea on skin including softening keratin, increasing hydration, promoting epithelialization, decreasing fibroblast action and having mucolytic properties. They believe urea treatment of dry eyes would benefit loss of epithelial cells, keratinization and scarring and subjective irritation. They feel that their formulation (0.01% to about 30% urea) is superior because it will not degenerate into ammonia. There were no in vivo reports. Grant (1974) used urea in debridement and noted transient damage to the eye results only with high concentrations. The odor of a urea solution may be problematic.
Anti-blepharitic. On the premise that blepharitis causes many dry eye states, Martin et al  patented a nitroimidazole compound intended for instillation (0.1 to 2.0% aqueous or ointment vehicle) or as an eyelash wash to treat blepharitis. One purpose is to replace the use of systemic tetracycline. They noted that nitroimidazole had been used for the treatment of dermal not ocular rosacea, a condition associated with blepharitis. No experimental or clinical ocular data were provided.
Figure 1. Effects of two different inhibitor-antibodies on the adhesion between lymphocytes and glandular cells.
Anti-inflammatories. Inflammation associated with dry eyes elevates corneal temperature. Recent studies reported by MacKeen and Roth (2000 and in press) have shown that closed lid temperature is elevated two or more degrees in dry eye patients. We reported that supracutaneous application (via the lower lid skin) of calcium carbonate ointment (DEO) reportedly reduced dry eye-associated inflammation based on decreased post-treatment closed lid temperatures. Topical steroids can reduce the inflammation associated with dry eyes. However, most have undesirable side effects on protracted use.
Cyclosporin. Cyclosporin A (CsA) has been reportedly beneficial in certain dry eyes its topical administration decreases the down-modulating and subsequent destructive effects of lymphocytic infiltration on accessory lacrimal glands. Laibovitz et al (1993), Gunduz et al (1994) used a 2% solution in olive oil to assess its immunological effects on secondary Sjögren's syndrome. They noted that CsA seemed to modulate goblet cell function and helped maintain the structural integrity of the epithelium. Some patients reported burning and stinging. Sall et al (2000) reported some improvement with 0.05% and 0.1% CsA formulation over the vehicle.
Inhibitors of Lymphocyte Adherence in Sjögren's Syndrome (SS)
Tsubota and Takeuchi  patented a treatment for SS that decreases the destructive effects of activated T cell lymphocytes on lacrimal and salivary acinar cells. In auto-immune diseases such as SS, activated T cell lymphocytes adhere to acinar cells and secrete cytotoxic substances that cause destruction of the secretory lacrimal and salivary glands. The treatment uses monoclonal or polyclonal antibodies to adhere to the sites necessary for this unwanted attachment (antibodies to E cadherin on the acinar cell surfaces and integrin *E ß7 ). The authors presented ex vivo data showing a marked difference in SS vs non-SS adhesion from lymphocytes (Figure 1). Topical administration is assumedly limited to accessory lacrimal glands.
Nepp et al (1998, 1999) reported on the efficacy of acupuncture in the treatment of keratoconjunctivitis sicca. In 1998 they compared needling with laser stimulation. There were multiple locations where the needles were inserted; an unidentified number of sites were periocular. The found equal improvement in tear break-up time, Schirmer and frequency when compared with artificial tears. In the 1999 paper, the patients were needled once weekly for 10 weeks at half-hour sessions. Again they reported improvement in Schirmer values and TBUT.
The ultimate dry eye treatment would return patients' tear-making capability. This goal will be achieved when new treatments prevent or reverse the problems that impair production of a stable pre-ocular tear film. Eyedrops are the primary treatments currently available. To be maximally effective, topically-delivered agents should be patient friendly (such as supracutaneously applied medication), especially when considering handling problems of older patients.
Increased knowledge of the causes of dry eye, a better method of administering topical drugs, more specific drug delivery of agonists or antagonists and the products of bio-engineering will hopefully result in an enormous leap in the prevention and treatment of dry eye in the next decade.
To receive references via fax, call (800) 239-4684 and request document #70. (Have a fax number ready.)
Dr. MacKeen is CEO of MacKeen Consultants, Ltd, Bethesda, MD. MCL assists in obtaining FDA approval, especially for ophthalmic devices and drugs. He is on the faculty of Georgetown University Medical Center Center for Sight and has been involved in dry eye research for the past 30 years.
*Note: Dates of patents are in brackets [ ] and dates of scientific papers are in parentheses ( ).