Pharmacokinetics of intranasal amiloride in healthy volunteers

Abstract

Anxiety and panic disorders are the most common mental illnesses in the United States and lack effective treatment options. Acid‐sending ion channels (ASICs) in the brain were shown to be associated with fear conditioning and anxiety responses and therefore are potential targets for treating panic disorder. Amiloride is an inhibitor of the ASICs in the brain and was shown to reduce panic symptoms in preclinical animal models. An intranasal formulation of amiloride will be highly beneficial to treat acute panic attacks due to advantages such as the rapid onset of action and patient compliance. The aim of this single‐center, open‐label trial was to evaluate the basic pharmacokinetics (PKs) and safety of amiloride after intranasal administration in healthy human volunteers at three doses (0.2, 0.4, and 0.6 mg). Amiloride was detected in plasma within 10 min of intranasal administration and showed a biphasic PK profile with an initial peak within 10 min of administration followed by a second peak between 4 and 8 h of administration. The biphasic PKs indicate an initial rapid absorption via the nasal pathway and later slower absorption by non‐nasal pathways. Intranasal amiloride exhibited a dose‐proportional increase in the area under the curve and did not exhibit any systemic toxicity. These data indicate that intranasal amiloride is rapidly absorbed and safe at the doses evaluated and can be further considered for clinical development as a portable, rapid, noninvasive, and nonaddictive anxiolytic agent to treat acute panic attacks.

Enhanced harm detection following maternal separation: Transgenerational transmission and reversibility by inhaled amiloride

“…In conclusion, our data point at the enhancement of ASICs as a molecular basis for responses to ELA in mammals, which could be extended to man; this mechanism has an explanatory value for both adaptive and maladaptive responses, depending on an individual’s biological setup, developmental history, and their environmental niche. In this context, our findings, together with the safety and distribution properties of amiloride nasal spray in humans ( 80 – 82 ), support this formulation as a viable individualized therapeutic avenue for panic disorder and related conditions, as well as for some pain states, in the foreseeable future.…”

Quantification of Budesonide Retained in the Sinonasal Cavity After High-Volume Saline Irrigation in Post-Operative Chronic Rhinosinusitis

“…33 The results of this study raise concerns about higher retained doses compared to previous estimates, supporting the need for formal clinical PK investigations and PKPD modeling studies to determine the actual sinonasal delivered dose and systemic absorption associated with budesonide HVSI. 34–36 These data further support the consideration of using corticosteroids with lower bioavailability, such as mometasone furoate, to treat CRS.…”