From: The CenterWatch Directory of Drugs in Clinical Trials, by the Editors.

Boston: CenterWatch Publications, 2000

 

Introduction to chapter entitled: Dermatology, Ophthalmology, and Otolaryngology


According to the National Institutes for Health, 50 million people are suffering from illnesses that fall within the dermatology, ophthalmology and otolaryngology category.  There are approximately 405 drugs being tested in the clinical pipeline treating these diseases. Psoriasis, glaucoma, age-related macular degeneration and rhinitis lead off the pipeline.


An estimated 5.5 million Americans are afflicted with psoriasis, a chronic condition in which the production of skin cells is six or seven times faster than normal, resulting in the appearance of plaques or thick patches of silvery, flaky, irritated skin over joints such as elbows and knees, as well as the scalp, fingers or toenails.  About 15% of sufferers also have psoriartic arthritis, an inflammation of the joints.  Another type of psoriasis produces localized guttate lesions and is caused by bacteria.


The direct cause of psoriasis is still unknown, and it seems to be able to turn itself  “on” and “off”; however, once an outbreak is over, the skin will usually completely recover.  Recent thinking has steered away from the original culprit, the keratinocyte cell that regulates the growth of skin, towards the immune system.  When it was discovered that the anti-immune drug cyclosporin helped psoriasis patients, the focus moved to the cells that control the immune system, eventually stopping at the T-cell.  This lymphocyte is the one that seems to go awry and start the reactions that eventually tell the keratinocytes to produce the extra skin.  However, researchers are unsure what mechanism affects the immune system to make it start attacking its own host.  While some external factors such as stress, infection, and certain antibiotic drugs may trigger outbreaks, the original cause is a mystery.  In addition, scientists are unable to find the reason why psoriasis is inherited by the offspring of one-third of its victims.


In the phase II and III pipeline for psoriasis there are approximately 31 drugs in clinical trials.  The focus of research is split among more effective treatments for the afflicted, discovering the possible genetic links, and finding the original trigger.  Monoclonal antibodies are being studied for their anti-inflammation properties, while research into the short-term therapy of retinoids continues in hopes of providing a less irritating form.  Bexarotene might stimulate the retinoid receptors, and is also being researched.


Other research for psoriasis targets the cytokines or T-cells, which are involved in many of the most common skin disorders including alopecia and cutaneous T-cell lymphoma.  These disorders appear to be caused by miscommunication between different types of skin cells like keratinocytes and the T-cell.  By studying the T-cell lymphoma, a malignancy of the lymphocytes, it is hope that crucial information about the T-cell will be unveiled.


Understanding the way the various cells of the skin communicate with each other and with the rest of the body, so that physicians can ease some channels and inhibit others, is the focus of more research in current trials.  The clinician will find that skin disorders and infections are often manifestations of conditions that do not in fact directly involve the skin, the body’s largest organ. Therefore, trials in everything for anti-cancer drugs to diabetes to pneumonia may have skin disorder components.


The eye area contains very delicate and complex parts that can easily be affected by outside irritants such as pollution and pollen.  The delicate balance of the eye’s structure means that operations or drugs that help one problem might cause another in a different part of the organ.  Also, eye disorders often reoccur and some stimuli, such as pollen, are not always completely avoidable.  The condition attracting the most interest from researchers appears to be glaucoma, with 10 drugs in phase II and III clinical trials.  Glaucoma affects two to three million Americans of age 40 or over and has blinded an estimated 80,000 to 120,000 of them.


Glaucoma is actually a name given to a family of diseases that are associated with an increased pressure within the eye that eventually damages the optic nerve.  The exact cause is unknown; the end result, however, is that the aqueous humor of the eye does not drain properly.  Only a comprehensive eye examination wherein the pupils are dilated can detect it with certainty, and once it has damaged the patient’s vision the loss cannot be regained, only halted or slowed.


Current treatments differ according to the type of glaucoma present, ranging from eye drops, tablets, surgery, or lasers, but most have the goal of either reducing the amount of fluid entering the eye or draining it once it is there, to spare the optic nerve any further pressure.  There are some drawbacks with available treatments including staining of the iris, uncomfortable administration, fluid drainage problems, and side effects of adrenaline and beta blockers.


Current research has a variety of approaches to the goal of reducing aqueous humor pressure.  Brimonidine is being studied for stimulating the alpha-2 receptors and acting as a neuroprotectant for the optic nerve.  Diclofenac and isopropyl unoprostone would work as anti-inflammatories.  An improved version of latanoprost is in Phase III trials; another Phase III drug combines this prostaglandin with a beta blocker.  Memantine, a drug that blocks the cell receptors for an amino acid neurotransmitter called N-methyl-D-aspartate, is being tested for many other indications of nerve damage as well as glaucoma.


Age-related macular degeneration is either “wet”, a leakage of blood vessels around the macula, the point in the aqueous humor where light falls and is assembled into a signal for the brain to interpret, or “dry”, a breakdown in the macula’s function wherein parts of it become less sensitive to light.  It manifests itself usually as a blurring of vision in the center of the field and cannot be cured, only arrested.  The first kind can sometimes be helped with laser surgery that is aimed at the leaky blood vessels.  Diabetic retinopathy, the most common reason for blindness in the United States, is also often treated with such surgery.  The drawback is that the vessels will often start to bleed again.


Research into eye disorders and infections is understandably wide-ranging and has approximately eight drugs in phase II and III clinical trials.  Some drugs, such as ADL-2-2194 and proparacaine, are anesthesias for use after eye surgery.  Amphotcerin would fight histoplasmosis, a fungal infection.  Some drugs like ALT-711 would help fight cardiovascular diseases that could change eye pressure.  A post-operative overgrowth called pterygium might be helped with the MMP-inhibitor batimastat.  Cidofovir fights infections of the eye such as adenovirus and viral keratinoconjunctivitis.  Cysteamine HCl is being studied for the rare disorder of corneal crystine accumulation, the formation of crystals in the cornea as a results of an access of the amino acid cystine.  The even rarer condition called recurrent corneal erosion might someday be treated with Dehyrdrex, which has earned orphan drug status.  INS365 is for the treatment of Dry Eye Disease.  There are also a variety of surgical procedures, or combinations of drugs and technologies, that are under investigation for different conditions.


Rhinitis is essentially an inflammation of the mucous membranes of the nose.  Again, this name covers a variety of conditions and causes.  Rhinitis is a common cause of otitis media, as the eustachian tubes may be inflamed as well as the nose.  Its most common form is allergic rhinitis.  It can also be caused non-allergenically, either hormonally, by nasal polyps, an infection, or (in the case of rhinitis medicamentosa) by overmedication.  It can also aggravate asthma, but will not cause it.


Because rhinitis has so many different causes and affects so many different parts of the head, drugs in trials for it focus on diverse goals.  Currently, there are approximately ten drugs in phase II and III clinical trials for rhinitis.  AG7088, an anti- rhinoviral agent, tries to inhibit the 3C protease that causes infectious rhinitis.  BIRR4 also targets the rhinovirus.  Desloratadine and a Monoclonal antibody called E25 work by inhibiting the histamine-1 receptors in the bloodstream, preventing the release of histamine by inflammatory cells.  Flucatistone proportionate is a kind of corticosteroid inhalant; norastemizole is a non-cardiotoxic formulation of astemizole.


[Listing of drugs by disease category followed]