Identification of Potential Non-Systemic Therapeutics for Hyperammonemia

Brad Nicklas; Simon Velasquez Morales; Jian Qian; Kyle J. Stephens; David R. Corbin; Mark B. Shiflett; Cory J. Berkland; Alan M. Allgeier

doi:10.3390/ddc2040040

journal article Open Access Sep 30, 2023

Identification of Potential Non-Systemic Therapeutics for Hyperammonemia

Brad Nicklas

Simon Velasquez Morales Jian Qian Kyle J. Stephens

David R. Corbin Mark B. Shiflett

Cory J. Berkland Alan M. Allgeier

Drugs and Drug Candidates Vol. 2 No. 4 pp. 796-809 · MDPI AG

View at Publisher Save 10.3390/ddc2040040

Abstract

A non-absorbable therapeutic candidate for the treatment of hyperammonemia has been identified and characterized. Conventional approaches to reducing ammonia concentration in the blood and colon include acidifying the colon, inhibiting the bacterial production of ammonia, and activation of the urea cycle. Addressing gaps in the literature around therapeutic ammonia adsorption, this study established assays for ammonia uptake from both NH4OH and NH4Cl solutions as well as interference and selectivity for potassium absorption. Performance was characterized for a large number and variety of materials, spanning zeolites, ion-exchange resins, metallopolymers, metal–organic frameworks (MOFs), and polymeric carboxylic acids. The latter class showed low potassium capacity (poly(acrylic acid): 10 mg/g, poly(maleic-co-acrylic acid): 4 mg/g) and a therapeutically relevant depression of pH in buffered simulated intestinal fluid (SIF) (poly(acrylic acid): −2.01 and poly(maleic-co-acrylic acid): −3.23) compared to lactulose (−3.46), an approved therapeutic for hyperammonemia that works by acidifying the colon. In the polymeric organic acids evaluated, pH depression correlated well with pKa and acid site density. Additionally, this class of candidates should avoid the undesirable side effects of lactulose, such as the potential for hyperglycemia in diabetic patients and incompatible use with galactosemic patients.

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Details

Published: Sep 30, 2023
Vol/Issue: 2(4)
Pages: 796-809
License: View

Authors

B

Brad Nicklas

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA

S

Simon Velasquez Morales

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA; Center for Environmentally Beneficial Catalysis, University of Kansas, Lawrence, KS 66045, USA; Institute for Sustainable Engineering, University of Kansas, Lawrence, KS 66045, USA

J

Jian Qian

Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA

K

Kyle J. Stephens

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA; Center for Environmentally Beneficial Catalysis, University of Kansas, Lawrence, KS 66045, USA; Institute for Sustainable Engineering, University of Kansas, Lawrence, KS 66045, USA

D

David R. Corbin

Institute for Sustainable Engineering, University of Kansas, Lawrence, KS 66045, USA

M

Mark B. Shiflett

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA; Institute for Sustainable Engineering, University of Kansas, Lawrence, KS 66045, USA

C

Cory J. Berkland

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA

A

Alan M. Allgeier

Department of Chemical & Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA; Center for Environmentally Beneficial Catalysis, University of Kansas, Lawrence, KS 66045, USA; Institute for Sustainable Engineering, University of Kansas, Lawrence, KS 66045, USA

Funding

Bond Biosciences, Inc.

Cite This Article

Brad Nicklas, Simon Velasquez Morales, Jian Qian, et al. (2023). Identification of Potential Non-Systemic Therapeutics for Hyperammonemia. Drugs and Drug Candidates, 2(4), 796-809. https://doi.org/10.3390/ddc2040040

Identification of Potential Non-Systemic Therapeutics for Hyperammonemia

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