Ischemic heart disease, also known as coronary artery disease, occurs when the heart muscle doesn’t receive enough blood flow and oxygen, often due to plaque buildup in the arteries. This can lead to chest pain (angina) and, if a blockage is severe, a heart attack. The cornerstone of therapy for ischemic heart disease is a class of drugs known as organic nitrates, with isosorbide dinitrate being the most widely used therapy. These drugs are metabolized into nitric oxide which then dilate the coronary arteries relieving symptoms of angina. Although they are effective acute treatment, patients tend to develop tolerance to these drugs over time. In fact, in some cases, patients can develop a 50% less response to the same dose after the very first dose. Furthermore, long term outcome studies reveal that patients on chronic organic nitrate therapy have poorer outcomes.
There is a need for safe and effective new therapy for ischemic heart disease that utilizes nitric oxide based therapy that does not cause tolerance. BTI’s lead drug candidate, Nitricardia, is an orally disintegrating tablet that releases nitric oxide gas and restores the NOS enzyme in the endothelium, offering a tolerance-free alternative to traditional organic nitrates.
Since this technology is not dependent upon cellular metabolism and activation by mitochondrial enzymes, no tolerance is expected, addressing the major limitation of current nitrate therapies that can lose 50% effectiveness after the first dose. Nor has tolerance been observed in human studies. There are more than 23 millions Americans living with ischemic heart disease and more than 250 million people worldwide with diagnosed ischemic heart disease. BTI’s nitric oxide drug therapy will revolutionize the treatment and management of patients with ischemic heart disease. Drug trials are expected to begin later this year.
Alzheimer’s disease is the most common form of dementia, a progressive neurologic disease that slowly destroys memory and thinking skills and eventually the ability to carry out activity of daily living. Currently there is no therapy that has been satisfactorily shown to slow or stop the progression of Alzheimer’s disease. Using computational methodology reported that in a review of a large database (7 million patients) that sildenafil was associated with a 69% reduction in the incidence of Alzheimer’s disease. Sildenafil is an inhibitor of phosphodiesterase 5 (PDE5) an enzyme that prevents the breakdown of cGMP. By increasing cGMP sildenafil has profound effects on vascular physiology, causing vasodilation. Nitric oxide signals through the activation of sGC and increase in production of cGMP resulting in smooth muscle relaxation and vasodilation. The increase in cerebral perfusion improves the elimination of protein degradation products.
Vascular abnormalities often precede Alzheimer’s dementia. MRI and SPECT scans often reveal hypoperfusion in patients with dementia and Alzheimer’s. Nitrite increases cGMP production, cytochrome P450 activity and heat shock protein 70. Heat shock protein may play a protective role in Alzheimers’. Additionally, heat shock protein 70 plays a crucial role in preventing protein misfolding and in inhibiting protein aggregation involving a class of proteins potentially involved in Alzheimer’s disease pathogenesis. Another potential mechanism for NO being beneficial in Alzheimer’s is the augmentation of neural excitability by modulation of voltage – gated potassium channel activity (KV7 & KV2).
The decreases in ß amyloid and the increase in activity of genes involved in antioxidant defense, detoxification, autophagy and cytoprotection combine to suggest a salutary benefit in increasing cGMP. While sildenafil is a drug that can increase cGMP indirectly, a far more effective way to target cGMP is through the messenger nitric oxide (NO). The therapeutic effects of PD5i therapy is dependent upon NO production and activation of sGC. NO activates soluble guanylyl cyclase which activates protein kinase G(PKG) that acts as the intermediate messenger for neuroprotective pathways. NO can be increased in the body utilizing a nitrite formulation that generates NO by way of an orally disintegrating lozenge administration twice daily. Given the possible benefit of an increase in cGMP by NO releasing lozenges and the safety record in man, BTI is developing a safe and effective dose of a nitric oxide releasing lozenge in patients with early onset Alzheimer’s disease to determine if disease progression can be modified or even reversed.
BTI has proposed a novel therapeutic to facilitate wound healing (Nitrican). The field of wound care has seen little advance in many years. Wounds due to pressure injury, vascular ulcer, diabetes ulcers, trauma or secondary to surgical procedures affect between 3 to 6 million people in the U.S. Wounds can cause significant disability, pain and be a nidus for infection. The longer the healing process the greater the likelihood of infection and the greater the patient burden. Chronic diabetes and/or ischemic ulcers are a very considerable source of disability as well as a source of infection, often leading to hospitalization and at times death. There is indeed a high societal cost of these conditions. Improvement in wound healing would decrease the societal cost, patient suffering and potential for infection.
One may ask why wounds are so difficult to heal and a festering source for infection. Wounds most often occur in areas with insufficient blood supply. Blood supply resulting in adequate oxygenation is critical for effective and rapid wound healing. But patients with diabetes, ischemic ulcers, trauma, or wounds resulting from surgical procedures have poor vascularization of the surrounding areas decreasing the likelihood of healing. The wound is often open permitting bacterial colonization. The bacterial presence along with poor blood supply, compromises the effectiveness of the body’s immune system to gain access to the wound. These problems all combined to make wound healing difficult and thus favors the development of progressively more serious infections. Without an adequate circulation, covering the wound may facilitate the development of anerobic infections and thus potential sepsis. Just keeping the wound clean and awaiting the body’s natural healing capacity for healing often proves inadequate for complete wound healing, especially with infected wounds.
We believe that improving the vascularization of the wound while decreasing the infectious milieux will increase the rate of healing, as well as the completeness of the healing process. To improve circulation and to make the wound area less prone to infection, Bryan Therapeutics, Inc. has developed Nitrican, a dual chamber formulation that generates Nitric Oxide (NO gas) which dilates blood vessels increasing blood flow to the wound creating an environment facilitating vascularization. High O2 tissue content with vascularization promotes growth factors being delivered to the wound area that further facilitates healing. Nitrican also contains collagen which forms the basis of the matrix that is requisite for new vascularization and tissue regeneration. Nitric oxide has also been found to possess potent anti¬microbial activity against pathogens as virulent as pseudomonas. This has been shown with mycobacterium infected ulcers, and with methicillin – resistant staphylococcus aureus (MRSA).
The container serves as a pump and releases 200uL in volume from chamber one and 200uL in volume from chamber two for a total of 400uL being administered into the wound. The material spreads around the wound bed and wound perimeter and is applied 2 times daily. The application is continued till the wound is completely healed. BTI proposes a multi-center, randomized controlled, observer blinded study of nitrican in diabetic ulcers in patients with diabetes. The study will compare nitrican application to a placebo application, both applied twice per day to patients with chronic (present for 2 weeks) full thickness ulcers with a cross section between 28 to 2,500 mm2. Patients with infected ulcers will not be excluded. The duration of therapy will be for 12 weeks. During the course of therapy and at 12 weeks the ulcer will be evaluated using a Global Assessment Scale. The primary outcome of the study will be a comparison of the treatment group to the placebo group at 12 weeks as to the extent of wound healing, as well as the rate of wound healing 12 as well as the rate of wound healing to 12 weeks. The presence, absence, or recurrence of infection at the wound site will be a secondary endpoint for comparison between the treated groups. We plan to have twice the number of patients in the treatment group as the control group.