Neostigmine and Glycopyrrolate by Iontophoresis to Induce Bowel Evacuation

Subjects will progress to receive the standard dose previously reported and employed for these agents [NEO (0.07 mg/kg) + GLY (0.014 mg/kg)] by transdermal administration by use of a wired ION system. NEO and GLY can be delivered into the systemic circulation by transcutaneous route by ION to induce a safe and predictable bowel evacuation in persons with SCI. If digital rectal stimulation was utilized in the screening session, this method will be utilized for the remaining sessions as needed at the discretion of the primary investigator. In the anesthesiology literature, a ratio of NEO to GLY of about 5 to 1 has been employed in clinical situations. Participants will be requested not to have bowel care for at least 1 day prior to the study. The subject will assume normal bowel evacuation position until a bowel movement occurs. Privacy draping and privacy will be provided at the time of bowel evacuation. The subjects will be monitored for 120 minutes. A minimum of two research personnel will be present during the study visit to record all of data and perform the tasks required.

From recent work, it is extrapolated that 85 to 90% of participants will have a bowel evacuation to transdermal administration of NEO by ION. The pharmacokinetics of only those who have a bowel evacuation to NEO will be used in the calculation to determine the peak plasma concentration (PPC) and area under the curve (AUC) of NEO and GLY. The PPC and AUC for the non-responders to NEO will be analyzed separately; it is speculated that the PPC of NEO for the non-responders will be blunted-that is, at least below the mean value of the PPC for NEO administration.

The absorption of study agents is, to a certain extent, subject-specific because of differential absorption through the skin. As such, each participant is expected to display differing responses: shorter or longer times to bowel evacuation (or the absence of bowel evacuation), as well as the absence or presence of cholinergic (increased bowel activity, bradycardia, bronchoconstriction) or anti-cholinergic activity, as previously described in the text above. The pharmacokinetic data will, to a large extent, reflect this variability in transdermal drug absorption. The data collected will include the presence or absence of bowel evacuation, time to bowel evacuation, consistency (Bristol stool scale), and quantity (by weight). The presence/number of cholinergic and anti-cholinergic side-effects on a standardized point scale will be determined, as well as their severity (e.g., mild, moderate, or severe). Heart rate, blood pressure, oxygen saturation, and pulmonary mechanics (airway patency by impulse oscillation system) will be recorded at baseline and sequentially at intervals the initiation of ION (at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes).

To quantitate the amount of these agents absorbed into the systemic circulation, pharmacokinetic studies will be performed for 2 hours after the start of transdermal drug delivery. Venous blood (2 ml) will be collected into an EDTA tube for both agents at the following time points: baseline (time zero), 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, and 480 minutes. Upon drawing, the blood will be placed in an ice bath and spun using a centrifuge within 5 minutes of collection. Upon completion of 5 minutes of centrifugation, the plasma will be aliquoted into two separate vials, with equal volumes and labeled with date and time of draw, study information, NEO or GLY testing destination, and the subject's unique identifier. The transfer vials will be inserted into dry ice for at least 10 minutes, after which they will be placed into the -80 degrees Celsius freezer. Plasma levels of NEO and of GLY will be batched and measured at a later date. A file designating the tubes with random numbers associated with the draw times will be created for each subject to conceal the sequence of draw and to attempt the removal of possible bias during the measurement and recording of the concentrations of NEO and GLY. NEO and GLY will be measured by mass spectroscopy.

To determine the reproducibility of the transdermal absorption of NEO and GLY, as well as the potential side-effects, subjects will again receive NEO (0.07 mg/kg) + GLY (0.014 mg/kg) by transdermal administration by use of a wired ION system. Additionally, digital rectal stimulation will be utilized as needed at the discretion of the primary investigator. Pharmacokinetic data and all other measurements and questionnaires that were previously obtained will be acquired once again and compared to Trial 1.