Arginine

證據等級: L5

預測適應症: 1 個

Arginine: From Amino Acid Supplementation to Gastroparesis

One-Sentence Summary

L-Arginine is a semi-essential amino acid with established roles in nitrogen metabolism and nitric oxide biosynthesis, used clinically as a nutritional supplement and in specialist metabolic settings. The TxGNN model predicts it may be effective for Gastroparesis — a condition of delayed gastric emptying — with 1 registered clinical trial and 10 publications providing mechanistic and preclinical context. The supporting evidence is entirely preclinical; no direct human trial evidence for arginine in gastroparesis has been identified.

Quick Overview

Item	Content
Original Indication	No MHRA-licensed indication on record; used as a nutritional/amino acid supplement and in specialist metabolic conditions
Predicted New Indication	Gastroparesis
TxGNN Prediction Score	99.42%
Evidence Level	L4
UK Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

L-Arginine is the obligate substrate for nitric oxide (NO) synthesis, catalysed by nitric oxide synthase (NOS) — in particular neuronal NOS (nNOS) within the enteric nervous system. NO is the principal inhibitory neurotransmitter mediating smooth muscle relaxation throughout the gastrointestinal tract, and coordinated gastric emptying depends on intact nitrergic signalling. When arginine availability is depleted, nNOS activity falls, NO production diminishes, and gastric motility becomes impaired.

Gastroparesis — delayed gastric emptying without mechanical obstruction — is consistently linked to enteric nitrergic dysfunction across multiple aetiologies: diabetic, post-surgical, drug-induced, and Parkinson’s disease-associated forms all share evidence of reduced nNOS expression or activity. The most direct mechanistic demonstration comes from Reichardt et al. (2014; PMID 25057793), who showed that glucocorticoid administration caused gastroparesis in mice specifically through L-arginine depletion, and that restoring arginine reversed the effect. Supporting this, studies in diabetic BB-rats and 6-OHDA Parkinson’s disease models confirm that impaired nitrergic relaxation — dependent on adequate arginine substrate — is a consistent finding in gastroparesis pathophysiology.

The TxGNN model’s 99.42% confidence score reflects this strong mechanistic underpinning. However, demonstrating that the mechanism operates in reverse — that arginine supplementation restores gastric motility to a clinically meaningful degree in patients — requires prospective human evidence, which is currently absent.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT01702051	N/A	Unknown	150	Observational study of autologous pancreatic islet cell transplantation following pancreatectomy for chronic pancreatitis or benign mid-segment tumours; gastroparesis is a recognised sequela in this population, but arginine supplementation is not a study intervention. Included here as the only identified registered trial touching this disease context.

No clinical trials directly evaluating arginine as a treatment for gastroparesis were identified. The single trial above is tangentially relevant through its gastroparesis-prone patient population only.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
25057793	2014	Animal study	Endocrinology	Key mechanistic paper. Glucocorticoids cause gastroparesis in mice through L-arginine depletion; effect was abolished in GR-dim mutant mice. Directly implicates arginine availability in gastric motility control.
35380456	2022	Animal study	Am J Physiol Gastrointest Liver Physiol	Impaired nitrergic (nNOS-dependent) relaxation of the pyloric sphincter in a 6-OHDA Parkinson’s disease rat model underlies gastroparesis; confirms nNOS/arginine pathway relevance across aetiologies.
23639814	2013	Animal study	Am J Physiol Gastrointest Liver Physiol	Tetrahydrobiopterin (BH4) deficiency — a key NOS cofactor — induces gastroparesis in newborn mice, further implicating NO synthesis capacity in gastric emptying.
18312542	2008	Animal study	Neurogastroenterol Motil	Decreased nNOS expression in the jejunum of spontaneously diabetic BB-rats; supports nitrergic dysfunction as a consistent feature of diabetic gastroparesis independent of vagal neuropathy.
21193530	2011	Animal study	Am J Physiol Gastrointest Liver Physiol	Hyperglycaemia inhibits gastric motility through nodose ganglia KATP channels; demonstrates the neural–gastric coupling disrupted in diabetic gastroparesis.
19023028	2009	Animal study	Am J Physiol Gastrointest Liver Physiol	Synchronised gastric electrical stimulation restores impaired gastric accommodation via the nitrergic pathway in vagotomised dogs; reinforces the therapeutic significance of the NO axis.
31984783	2020	Animal study	Am J Physiol Gastrointest Liver Physiol	Sacral nerve stimulation improves impaired gastric accommodation in rats via a spinal afferent / vagal efferent mechanism; adds to the range of interventions targeting gastric nitrergic tone.
33867519	2021	Case report	Am J Case Rep	MELAS patient (m.3243A>G) with gastroparesis as a disease feature; L-arginine is a recognised treatment in MELAS due to its role in restoring NO production in endothelium — provides indirect human-level precedent for arginine’s role in NO-deficit conditions with GI involvement.
18322959	2008	Animal study	World J Gastroenterol	Ghrelin and GHRP-6 improve gastric motor function in diabetic mice with gastroparesis; illustrates the range of prokinetic targets under investigation in this disease space.
8194696	1994	Animal study	Gastroenterology	Antigen challenge in sensitised rats induces delayed gastric emptying via uncharacterised mediators; early demonstration of non-diabetic gastroparesis in animal models.

UK Market Information

L-Arginine currently holds no MHRA marketing authorisation as a medicinal product in the United Kingdom. It is available as a food supplement under general food law (Regulation (EC) No 1925/2006 as retained in UK law), but any therapeutic indication for gastroparesis would require a formal medicinal product licence under the Human Medicines Regulations 2012.

There are no current NICE technology appraisals, NICE guidelines, or BNF entries for arginine in gastroparesis. The BNF does not list arginine as a prokinetic agent. MHRA Pre-Submission Scientific Advice would be required to determine the regulatory pathway before any clinical development programme targeting this indication.

Safety Considerations

No MHRA SmPC or BNF safety data are available, as no UK marketing authorisation exists. Please refer to published pharmacological literature and consult the Yellow Card Scheme for adverse reaction reporting. Based on the known pharmacology of L-arginine, the following considerations apply:

Cardiovascular/haemodynamic: As a direct NO precursor, high-dose arginine supplementation can cause systemic vasodilation and clinically significant hypotension. This warrants careful monitoring in patients with cardiovascular disease or those taking antihypertensive agents.
Renal caution: Arginine metabolism is integral to the urea cycle; excessive supplementation may increase renal nitrogen burden. Dose adjustment or avoidance may be required in renal impairment.
Potential drug interactions: Additive hypotensive effects are plausible with phosphodiesterase-5 inhibitors (e.g., sildenafil), organic nitrates, and antihypertensive drugs. No formal DDI data were identified in this evidence pack.
Electrolyte and metabolic monitoring: Arginine infusions have been associated with hyperkalaemia, particularly in renal or hepatic impairment; monitoring of serum potassium and acid-base status is advisable.

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic case for L-arginine in gastroparesis is scientifically credible and well-grounded in preclinical evidence — L-arginine depletion is a demonstrated cause of gastroparesis in animal models, and the nitrergic pathway is consistently implicated across multiple gastroparesis aetiologies. However, all current evidence is preclinical (L4); no human clinical trial has directly evaluated arginine supplementation as a treatment for gastroparesis, and L-arginine has no MHRA marketing authorisation in the United Kingdom. The prediction cannot be advanced to clinical consideration without human proof-of-concept data.

To proceed, the following is needed:

A Phase 2 proof-of-concept clinical trial evaluating oral or intravenous L-arginine supplementation in patients with confirmed gastroparesis — glucocorticoid-induced or idiopathic subtypes offer the strongest mechanistic rationale as a starting population
Pharmacokinetic/pharmacodynamic studies establishing the plasma arginine concentration required to meaningfully restore gastric nNOS activity in humans
MHRA Pre-Submission Scientific Advice to clarify whether a food-supplement-to-medicine reclassification pathway is viable, and what evidence package would be required
A comprehensive safety assessment covering haemodynamic monitoring, renal function, and electrolyte balance specifically in a gastroparesis-eligible patient population
Dose-ranging studies in healthy volunteers to establish a safe therapeutic window prior to patient trials

⚠️ This report is for research purposes only and does not constitute medical advice. Drug repurposing candidates require clinical validation before therapeutic application. Healthcare professionals should refer to the MHRA, BNF, and relevant SmPCs for prescribing decisions. Suspected adverse reactions should be reported via the Yellow Card Scheme (https://yellowcard.mhra.gov.uk/).

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.