Pathogenics is currently developing N-Chlorotaurine (NCT), a novel, endogenous anti-infective for several topical and body cavity indications. NCT’s efficacy has already been established in several Phase II clinical pilot studies in Europe, including rhinosinusitis, viral conjunctivitis, otitis externa (swimmer’s ear) and crural ulcers. Treatment of rhinosinusitis and ear infections are the most common reason for outpatient antibiotic prescriptions, and conjunctivitis is considered the most common reason for nontraumatic eye complaints. NCT represents a unique and optimal compromise between sufficient microbicidal activity and low toxicity and is therefore ideally suited for the local treatment of infections in humans. When applied in the presence of inflammatory secretions (e.g. human nasal mucus), NCT derivatives cause a stunning increase of microbicidal activity. As a result, even omniresistant Pseudomonas aeruginosa (bacterium resistant against all available antibiotics) is killed in human urine by NCT within minutes.
NCT has an unspecific (non-selective) oxidizing mechanism of action that precludes the development of resistant microorganisms - a characteristic similar to those of antiseptics and disinfectants. This attribute differentiates it significantly from antibiotics, antivirals and antifungals, all of which pathogens eventually develop resistant strains.
Despite its broad-spectrum activity, the cytotoxicity of NCT against human cells is extremely low. Its breakdown products, the amino acid taurine and chloride, are also found in the human body (endogenous) and therefore represent virtually no toxic potential and do not induce allergic reactions. This is a unique and outstanding feature in disinfection practice, and differentiates it significantly from antiseptics and disinfectants.
NCT is also very inexpensive, relatively easy substance to manufacture, and currently stable for more than one year when refrigerated. It is also readily soluble in water, autosterile, needs no preservative and has a neutral pH.
Because of these properties (broad-spectrum microbicidal activity, precludes resistant pathogens, low toxicity, and cost effectiveness, etc.) NCT is ideally suited for the local treatment of infections in humans.
The efficacy of NCT has already been established in several Phase II clinical pilot studies in Europe, including sinusitis, viral conjunctivitis, otitis externa and crural ulcers. There are numerous other additional potential topical and body cavity indications, and preliminary indications that it may be safe and effective enough for internal administration, such as for use as a surgical prophylactic.
Pathogenics currently owns worldwide exclusive rights to N-Chlorotaurine from its inventors, who are currently conducting additional phase II clinical pilot studies in Europe. It plans to undertake a formulation development program to increase the stability of NCT at room temperature, and file an FDA Investigational New Drug (IND) Application.
Rhinosinusitis
Sinusitis is an inflammation of the sinuses caused by an allergy or a viral, bacterial, or fungal infection. Sinusitis may develop in any of the four groups of paranasal sinuses: maxillary, ethmoid, frontal, or sphenoid. In the majority of cases, inflammation of the paranasal sinuses (sinusitis) is accompanied by inflammation of the nasal passages (rhinitis). Sinusitis can be divided into four subtypes: acute (short-lived), recurrent acute, subacute and chronic (long-standing).
Acute sinusitis may be caused by a variety of bacteria and often develops after a viral infection of the upper airways, such as the common cold. The condition may be due to viral, bacterial or fungal growth, or to a self-perpetuating inflammatory process. In a recent study conducted by the Mayo Clinic, a high number of fungal species has been detected in nasal mucos of healthy subjects and of patients suffering from acute sinusitis and chronic sinusitis. The study also showed chronic allergic sinusitis to be associated with the presence of fungi, especially molds, in more than 90% of the cases. In people who have poorly controlled diabetes or an impaired immune system, fungi can cause severe and even fatal sinusitis.
Aspergillosis and cadidiasis are often fatal fungal infections that may develop in the sinuses of people whose immune system is impaired by anticancer treatment or by diseases such as leukemia, lymphoma, multiple myeloma, or AIDS. In aspergillosis, polyps develop in the nose and sinuses. Attempts to control these infections include performing sinus surgery and giving amphotericin B intravenously.
Incidence: Sinusitis is one of the most common infections in the United States. Millions of cases occur each year, affecting all age groups and all segments of the population. Sinusitis has a self-reported incidence of 135 per 1,000 of the population per year and was the principle reason for almost 12 million physician office visits (1% of total) in 1995. Sinusitis significantly impacts quality of life measures and with decrements in general health perception, vitality and social functioning comparable with that observed in patients who have angina or chronic obstructive pulmonary disease. Approximately 25% of the population will have a sinusitis episode at some time.
Sinusitis is one of the main reasons for which an antibiotic is prescribed and for lost productivity in the work force (e.g., the Medical Outcomes Study SF-36). In 1992 Americans spent $200 million on prescription medications for rhinosinusitis and more than $2 billion for over-the-counter medications. Figures suggest the total annual direct cost of treatment, including drugs, doctors’ office visits and surgery, and indirect costs, including restricted activity days, is in excess of US $6 billion.
Current Treatments: Despite the common nature of rhinosinusitis, its management is controversial. Treatment of acute sinusitis is aimed at improving sinus drainage and curing the infection. Therapies are usually directed to alleviating or reducing symptoms, eradicating the underlying cause, or both. Drugs that cause blood vessels to constrict, such as phenylphrine, can be used as nasal sprays but only for a limited time. Similar drugs, such as pseudoephedrine, taken by the mouth aren’t as effective. A major question is whether an antibiotic should be used. Because bacterial infection of the sinuses is potentially serious, antimicrobials are prescribed to prevent complications.
For both acute and chronic sinusitis, antibiotics such as amoxicillian are given for at least 10-14 days, but people who have the persistent symptoms of chronic sinusitis take antibiotics for 28 days. A change of antibiotics is recommended if the patient shows no improvement after 3 days. Beta-lactamase resistance in acute cases is <30%, but rises to between 40-50% in chronic cases. When antibiotics aren’t effective, surgery may be performed to improve sinus drainage and remove infected material.
NCT Treatment: Phase 2a Human Safety & Tolerability Trial. An open label study with no control group was conducted in 12 patients suffering from rhinosinusitis including polyposis nasi. 10-20ml of NCT aqueous solution via a special nose catheter (YAMIK) was applied to the nasal and paranasal cavities 3 lavages a week for 4 weeks. Auris Nasus Larynx 2005; 32: 359-364.
Conjunctivitis (Pink Eye)
Conjunctivitis is inflammation of the thin membrane (conjunctiva) covering the white of the eye (sclera) and the inner surface of the eyelid. The conjunctiva produces mucus to coat and lubricate the surface of the eye. The term describes any inflammatory process that involves the conjunctiva; however, to most patients, conjunctivitis (often called pink eye) is a diagnosis in its own right.
A normal conjunctiva has fine blood vessels within it, which can be seen on close inspection. When the conjunctiva becomes irritated or inflamed, the blood vessels which supply it enlarge and become much more prominent (bloodshot), the eye turns red or pink, and a discharge often appears in the eye. In bacterial conjunctivitis, the discharge may be thick and white or creamy. In viral conjunctivitis the discharge is usually clear. The eyelid may also swell and itch intensely.
Conjunctivitis is usually caused by viruses, bacteria, or an allergy. Infective conjunctivitis (Epidemic Keratoconjunctivitis) is highly contagious form of viral conjunctivitis. Summer outbreaks are the most common, and the virus continues to be shed for 14 days.
Sometimes, conjunctivitis can last for months or years. This type of conjunctivitis may be caused by conditions in which an eyelid is turned outward (ectropion) or inward (entropion), problems with the tear ducts, sensitivity to chemicals, exposure to irritants, and infection by a particular bacteria – typically chlamydia.
Incidence: Conjunctivitis is one of the most common nontraumatic eye complaints resulting in presentation to the emergency department. Conjunctivitis is considered extremely common in the US. 3% of all emergency department visits are ocular related, and conjunctivitis is responsible for approximately 30% of all eye complaints. Japanese sales of anti-infective eye-drops including Levofloxin (Cravit) and Ofloxacin (Taravid) were $232 million in 2001, and Japanese sales generally represent roughly 25% of the worldwide pharmaceuticals market.
Current Treatments: Treatment for conjunctivitis depends on the cause. If the cause is a bacterial infection, antibiotic eye drops or ointment may be prescribed. Bacterial conjunctivitis usually resolves itself in two weeks without treatment, and may clear up in 48 – 72 hours with treatment. Antibiotics don’t help allergic or viral conjunctivitis, and there is no approved treatment for viral conjunctivitis.
Antihistamines taken orally may relieve the itching and irritation. If not, corticosteroid eyedrops can help. Corticosteroid eyedrops aren’t used with antibiotics and should never be used by someone who might have a herpes infection because corticosteroids tend to make herpes worse.
NCT Treatment: Phase 2a Human Safety and Tolerability Trial. Open pilot study in 10 patients with infectious conjunctivitis (7 bacterial, 3 viral). Application of 1 % NCT 5 times a day. NCT proved to be excellently tolerated and showed no adverse effects. All seven subjects with bacterial conjunctivitis were cured within 3 - 5 days. Two subjects with epidemic keratoconjunctivitis were treated for 7-10 days and 1 subject with herpes simplex blepharitis for 3 days with no rapid improvement but probable mitigation of inflammation. Ophthalmologica 2000; 214: 111-114.
Phase 2bTrial. Efficacy and tolerability in 60 patients suffering from viral conjunctivitis (preferentially adenoviral = epidemic keratoconjunctivitis). Double blind, randomised. Control group: gentamycin eye drops. J Ocular Pharmacol Ther 2005; 21: 157-65.
Otitis Externa(Swimmer's Ear)
External otitis (otitis externa) is an infection of the ear canal. The infection may affect the entire ear canal, as in generalized external otitis, or just one small area, as a boil (furnuncle). External otitis, often called swimmer’s ear, is most common during the summer swimming season.
A variety of bacteria (90%), or rarely, fungi (10%), can cause generalized external otitis; the bacterium Staphyloccoccus usually causes boils. Certain people, including those who have allergies, psoriasis, eczema, or scalp dermatitis, are particularly prone to external otitis. Injuring the ear canal while cleaning it or getting water or irritants such as hair spray or hair dye in the canal often leads to external otitis.
Symptoms of generalized external otitis are itching, pain, and a malodorous discharge. If the ear canal swells or fills with pus and debris, hearing is impaired. Usually, the canal is tender and hurts if the external ear (pinna) is pulled or if pressure is placed on the fold of the skin in front of the ear canal. Boils cause severe pain. When they rupture, a small amount of blood and pus may leak from the ear.
Current Treatments: To treat generalized external otitis, a doctor first removes the infected debris from the canal with suction or dry cotton wipes. After the ear canal is cleared, hearing frequently returns to normal. For bacterial external otitis, a person is usually given antibiotic eardrops to instill in the ear several times a day for up to a week. The generally established therapy with instillation of a local antibiotic in the outer ear is not always sufficient, particularly when resistant strains of bacteria are causing infection.
NCT Treatment: Phase 2b Human Efficacy Trial. Open label, controlled and randomised clinical study in 50 patients with otitis externa. Application of 1% NCT via a strip (or by direct rinsing in special cases with abscesses) into the external ear canal verses the topical antibiotic Otosporin for 5 days. This study was completed in January 2003. NCT proved to be excellently tolerated and highly active. NCT proved significantly (P<.001) more rapid healing than Otosporin. In patients with abscesses including one with a fungal abscess NCT was clearly superior to common treatment. Laryngoscope 2004; 113: 76-81.
