Author: van Kuijk, Sander M J ; Wu, Michael ; Gutzki, Frank ; Schmidt, Harald H H W ; Thol, Jens ; Wingler, Kirstin ; Tongers, Jörn ; Bauersachs, Johann ; Kleikers, Pamela ; Seifert, Roland ; Mucke, Hermann ; Schmidt, Beate M L ; Martin, Catherine ; Bavendiek, Udo ; Macchiusi, Cecilia ; Nogales, Cristian ; van der Arend, Inés ; Sonnenschein, Kristina ; Schmidt, Tim M ; Casas, Ana I ; McGrath, Barry ; Bähre, Heike ; Chen, Suzi ; Krahn, Thomas ; Hahn, Andreas ; Sedding, Daniel ; Thao-Vi Dao, Vu ; Elbatreek, Mahmoud H

BACKGROUNDPeripheral artery disease (PAD) is a major public health concern due to its high prevalence, severe impact on individuals' health and quality of life, and substantial economic burden. Pharmacological interventions are still limited with numbers needed-to-treat ranging from 6 (cilostazol) to 50 (aspirin, statins, and vorapaxar).OBJECTIVESThis randomized, placebo-controlled, double-blinded crossover interventional trial aims to measure the effect of L-citrulline and tetrahydrobiopterin (H₄Bip) on walking distance in patients with PAD, stratified by plasma levels of asymmetric dimethyl L-arginine (ADMA), the endogenous inhibitor of endothelial nitric oxide (NO) synthase.METHODSWe measured preinterventional ADMA levels in 51 patients with PAD in Australia and Germany with mean changes in absolute claudication distance (dACD) as the primary outcome upon orally supplementing the L-arginine precursor, L-citrulline (3 g) twice daily for 12 weeks, and, in one arm, additionally H₄Bip (0.45 g) once per day for a further 2 weeks.RESULTSPreinterventional ADMA levels were pathological (>0.4 μM) in 34 patients. Supplementation with L-citrulline significantly increased the mean plasma levels of both L-citrulline and L-arginine, from 41.8 ± 2.7 μmol/l to 246.3 ± 67.3 μmol/l (P = 0.004) and from 75.2 ± 4.2 μmol/l to 119.2 ± 6.9 μmol/l (P < 0.0001) respectively, when compared with placebo. dACD in % of control was significantly improved by L-citrulline vs placebo (20.11% ± 4.50% vs 5.73% ± 2.74%, respectively; P = 0.011). Further addition of H₄Bip increased the mean percentage dACD to 28.15% ± 6.84% (P = 0.021), but only in patients with preinterventional pathological ADMA levels.CONCLUSIONSL-citrulline and, when ADMA levels are pathological, H₄Bip are effective nutritional interventions in patients with PAD warranting further confirmatory trials.

01 Jan 2025·ASSAY and Drug Development Technologies

Drug Repurposing Patent Applications July–September 2024

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Author: Mucke, Hermann A.M.

01 Oct 2024·ASSAY and Drug Development Technologies

Drug Repurposing Patent Applications: April–June 2024

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Author: Mucke, Hermann A.M.

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