Dr. Joseph Sirven interviews Dr. James Cloyd on Seizure Emergency Treatment, focusing on Benzodiazepine Prodrug/Enzyme Combinations for Intranasal Rescue Therapies.
Recently, I interviewed Dr. James Cloyd for Hallway Conversations regarding a new treatment for seizure emergencies. You can find a recording of the interview in the sidebar on this page. Below is a brief summary of the project as reported by Dr. Cloyd and his colleagues working on the project. - Dr. Joseph Sirven, editor-in-chief of epilepsy.com
Seizure emergencies require quick intervention. Our aim is to develop methods for rapid, well-tolerated intranasal (IN) delivery of benzodiazepines (BDs) that avoid the significant delays associated with intravenous (IV) administration and offer an alternative to the rectal route. A barrier to development of the IN route is the low aqueous solubility of BDs.
Intranasal formulations currently under development contain organic solvents that improve solubility, but these additives often cause irritation. An alternative approach is to use water-soluble BD prodrugs. We envision a spray system in which a prodrug and a converting enzyme are mixed at the point of administration producing a supersaturated solution in the nasal cavity, followed by rapid conversion to the active BD and absorption across the nasal mucosa. This system, if successful, could quickly abort or even prevent seizure emergencies.
We have synthesized avizafone (AVF), a water-soluble lysine prodrug of diazepam (DZP), which has been used by European military as an intramuscular battlefield anticonvulsant to treat nerve agent-induced seizures. AVF is converted to DZP by one or more enzymes in the blood. After screening a panel of proteases, peptidases, and esterases for hydrolytic activity, we found that Aspergillus Orizae Protease possesses the desired function, and the kinetics of conversion of AVF to DZP by this enzyme were characterized. We were also able to show that supersaturated levels of DZP could be produced in this manner. Next, transport of supersaturated DZP across Maden Darby Canine Kidney Cell II-wild type cell monolayers, an accepted preclinical model for nasal mucosa, was measured. We found that the rate of DZP diffusion was proportional to the degree of supersaturation obtained by enzymatic conversion of AVF. Virtually none of the prodrug crossed the membrane, and the membrane remained viable after treatment by the prodrug and enzyme. No crystallization of the water -insoluble drug occurred before it crossed the membrane.
These results suggest that enzymatic production of normally insoluble BDs in situ can lead to rapid nasal absorption. As a next step, toxicological assessment of the prodrugs, the enzyme, and their combination will be carried out in rodents. If adverse reactions are absent, pharmacokinetic-pharmacodynamic studies will be carried out in dogs with naturally occurring epilepsy who have implanted intracranial EEG systems. A series of BD and converting enzymes will be tested as described above and those showing the most potential will be then be subjected to Phase I studies in healthy human volunteers.
Supported by grants from the University of Minnesota Academic Health Center, the American Epilepsy Society, and the Epilepsy Foundation.