Satiety Solutions, is developing a novel histamine agonist, betahistine, as a treatment for attention-deficit, hyperactivity disorder (ADHD). Betahistine is a histamine activator which has been found to improve vigilance in normal volunteers. Conventionally, betahistine has been used world-wide at low dose to treat Meniere's Syndrome (vertigo) for over thirty-five years. Exploratory dose-ranging in normal volunteers suggests that higher doses of betahistine are required to enhance vigilance. The immediate goal of this Phase I SBIR is to determine safety, tolerability, and pharmacokinetics of betahistine single-doses >48 mg and to determine a dose-response for improving attention and impulsivity in young adults with ADHD.
Specific Aim 1 : Evaluate the safety and tolerability of betahistine hydrochloride in a single-blind, placebo- controlled, across-subjects, single-dose escalation design at doses up to 192 mg in adult ADHD subjects. Of 16 subjects at each dose level, twelve will be randomly assigned to receive betahistine (48, 96, 192 mg) and four to placebo. Safety measures, including vital signs, electrocardiogram, peak respiratory flow, and clinical laboratory tests will be performed during the trial and clinical adverse events will be recorded. Safety data from each dose will be evaluated before progression to the next dose level. Prediction: Betahistine at all doses will be well tolerated with a frequency of adverse events not different from placebo.
Specific Aim 2 : Determine the single-dose pharmacokinetics and relative dose proportionality of betahistine hydrochloride administered at doses of 48, 96, and 192 mg. Using sampling times determined from preliminary testing at 16 mg single oral dose, we will evalulate a 24 hour sampling period after study drug administration. Betahistine and it's predominant metabolite (2-pyridylacetic acid) concentrations will be determined and AUC, Cmax, Tmax, and half-life will be calculated. AUC and Cmax will be examined statistically for proportionality with rising dose. Prediction: Betahistine will show linear increases in AUC and Cmax with increasing doses while Tmax and half-life will remain relatively constant.
Specific Aim 3 : Examine feasibility of betahistine to improve attention and reduce impulsivity by evaluating cognitive performance in adult ADHD subjects following betahistine at doses up to 192 mg relative to placebo. Subjects will be assessed at baseline and at 2 and 4 hours after a single betahistine dose for attention using a Continuous Performance Test and Stroop task, and assessed for impulsivity using the stop-signal reaction time (SSRT). The results of cognitive assessments will be compared statistically as a function of time and betahistine dose. Prediction: Betahistine will demonstrate dose-dependent increases in attention and faster stop-signal reaction times (SSRT) relative to placebo, indicating improved attention and greater capacity to inhibit response.Project Narrative: Attention-deficit, hyperactivity disorder (ADHD) is the most prevalent behavioral disorder of childhood (5-10%), which persists into adult life, causing significant morbidity in terms of academic and vocational outcomes as well as psychosocial impact on families. The financial cost of illness is estimated at $12-17K per annum with a total cost to the health care system of $42 billion. First-line treatment with psychostimulants, while effective, exhibit significant side-effects, abuse potential, and can aggravate movement disorder (i.e. Tourette Syndrome). A novel approach to the treatment of ADHD through selective cortical histamine activation is now feasible using betahistine. Betahistine at low dose has been used to treat Meniere's Syndrome (vertigo) for over thirty-five years, but only recently has it been demonstrated that higher doses can improve vigilance in normal volunteers. This Phase 1 SBIR proposal will determine the safety, tolerability, and pharmacokinetics of higher doses of betahistine and characterize dose-response for improving attention and impulsivity in young adults with ADHD.
