PROJECT AMMONEX-HE | Ammonia Modulators for Hepatic Encephalopathy

SCF Ethnobioprospecting Workflow Initiated

Program Focus: Ammonia Modulators for Hepatic Encephalopathy

Program Codename: PROJECT AMMONEX-HE

Therapeutic Aim: Gut–liver–brain ammonia modulation for hepatic encephalopathy.

Regulatory Scope: Research → Discovery → Preclinical → Pre-IND → IND/FIH readiness.

Clinical comparator logic: current HE standards reduce ammonia burden through lactulose and rifaximin-based gut ammonia control; rifaximin is FDA-indicated to reduce overt HE recurrence in adults.

1. SCF Disease Target Definition

Target Layer	HE-Ammonia Fault Node	SCF Therapeutic Objective
Gut microbiome	Urease-producing bacteria, dysbiosis	Reduce ammonia generation
Intestinal barrier	Endotoxemia, inflammatory permeability	Restore mucosal containment
Liver	impaired urea-cycle clearance	Support nitrogen handling
Blood-brain axis	astrocyte glutamine/osmotic stress	Reduce neurotoxic ammonia signaling
Systemic inflammation	TNF-α, IL-6, oxidative stress	Lower neuroinflammatory amplification

2. SCF Ethnobioprospecting Search Parameters

Search Domain	Priority Source Systems	Candidate Logic
Hepatoprotective ethnomedicine	Ayurveda, TCM, Amazonian, MENA, African systems	liver detoxification, bile flow, anti-inflammatory use
Gut ammonia modulation	bitter tonics, antimicrobial botanicals, prebiotic botanicals	microbiome ammonia reduction
Neuroprotection	adaptogens, flavonoids, polyphenols	astrocyte and neuroimmune stabilization
Safety harmonization	mucosal protectants, antioxidants	cirrhosis-compatible tolerability

This follows SCF botanical selection, authentication, extraction, MoA/MeA profiling, PK/metabolic profiling, and role assignment logic.

3. Initial Candidate Classes

SCF Role	Candidate Bioactive Class	Rationale
Target Modulator	urease-inhibitory polyphenols / tannins	reduce gut ammonia production
Metabolic Regulator	lignans, saponins, AMPK/SIRT-modulating compounds	support hepatic metabolic resilience
Safety Harmonizer	mucilage, β-glucans, hepatoprotective flavonoids	protect gut barrier and reduce inflammation
Absorption Enhancer	lipid carriers, phospholipid complexes	improve exposure while limiting systemic toxicity
Resistance Prevention	multi-compound antimicrobial–anti-inflammatory stack	avoid single-target microbiome pressure

4. Priority Ethnobioprospecting Leads

Candidate Source	Bioactive Focus	SCF Development Rationale
Phyllanthus niruri	lignans, flavonoids	hepatoprotective and liver-metabolic candidate
Silybum marianum	silymarin flavonolignans	hepatic antioxidant/safety harmonizer
Curcuma longa	curcuminoids	NF-κB / inflammatory tone modulation
Cichorium intybus	inulin, bitter sesquiterpenes	prebiotic gut ammonia-axis modulation
Terminalia chebula	tannins/polyphenols	possible urease/gut microbial modulation
Ganoderma spp.	β-glucans, triterpenes	immune and gut-barrier harmonization
Genipa americana	iridoids	Amazonian hepatoprotective lead from available SCF database.

5. Proposed SCF Fibonacci Ammonia-Modulator Stack

Stack Position	Role	Development Candidate Type
F1	Primary ammonia modulator	urease-inhibitory polyphenol fraction
F1	Safety harmonizer	hepatoprotective flavonolignan
F2	Metabolic stabilizers	AMPK/SIRT and antioxidant compounds
F3	Gut-axis optimizers	prebiotic fiber, mucosal protectant, microbiome modulator
F5	Supportive agents	anti-inflammatory, bile-flow, redox, neuroprotective, barrier-support agents

6. Discovery Assay Plan

Assay Module	Endpoint
Urease inhibition	IC50 against bacterial urease
Ammonia production model	ammonia reduction in gut fermentation model
Hepatocyte protection	oxidative stress, mitochondrial function, urea-cycle gene expression
Gut barrier model	TEER, tight-junction proteins, LPS translocation
Neurotoxicity model	astrocyte swelling, glutamine accumulation, inflammatory markers
Microbiome safety	dysbiosis risk and antimicrobial spectrum

7. SCF Synergy Metrics

Metric	Use
TSSM	potency × precision × persistence
HSV-F²	metabolic efficiency and signal coherence
SV-EQ	target specificity versus diffuse activity
MGIS	ligand–target and PK geometry
SPCI	translational compatibility and phenotype fit

These align with the SCF Synergistic Evaluation Framework.

8. FDA-Aligned Preclinical Pathway

Stage	Required Output
Discovery	lead fractions, molecular fingerprints, MoA/MeA
Lead optimization	standardized extract or purified/semi-synthetic API
IND-enabling	pharmacology, ADME, GLP toxicology, safety pharmacology
CMC	identity, potency assay, stability, contaminants, batch reproducibility
Pre-IND	FDA meeting package
IND	nonclinical, CMC, and FIH protocol package

FDA IND submissions require adequate preclinical data, CMC, investigator information, and clinical protocols; botanical candidates should also follow FDA botanical drug development expectations when applicable.

Immediate GPT Trigger Commands

Trigger	GPT Action
Disease Map	Build HE ammonia fault architecture
Source Scan	Identify ethnomedical ammonia-modulator candidates
Lead Rank	Rank candidates by SCF potency and safety
Assay Plan	Generate in vitro and ex vivo screening matrix
Stack Build	Design SCF Fibonacci ammonia-modulator stack
IND Map	Build FDA preclinical-to-IND roadmap

Next Command

Use “Lead Rank” to generate the first ranked candidate table for PROJECT AMMONEX-HE.

INDEX

SCF-ETHBIO-HE-AMM-0001 — Ethnobioprospecting Initiation

SCF-AMMONEX-HE-0001 — Ammonia Modulator Program

SCF-SEF-HE-0001 — Synergy Evaluation Pathway

SCF-IND-HE-0001 — Preclinical-to-IND Alignment