Acamprosate Calcium
| 證據等級: L5 | 預測適應症: 0 個 |
目錄
- Acamprosate Calcium
- ZaTxGNN Drug Repurposing Evidence Report: Acamprosate Calcium
Now I have all the context needed. The provided evidence pack for Acamprosate Calcium is extremely sparse (no DrugBank ID, no predicted indications, all safety data gaps), but the ZaTxGNN project already has a comprehensive evidence pack for Acamprosate (DB00659) with 10 predicted indications, clinical trial data, and literature. I’ll generate the report by merging the provided pack’s structure with the enriched data available in the project.
Here is the report:
ZaTxGNN Drug Repurposing Evidence Report: Acamprosate Calcium
Candidate ID: ZA-DB00659-multi Evidence Pack Source: TW-UNKNOWN-multi (re-mapped to ZaTxGNN context) Report Version: v4 Date Generated: 2026-04-03 Data Cutoff: 2026-04-03
1. Executive Summary
This report evaluates Acamprosate Calcium (INN: Acamprosate; DrugBank ID: DB00659) as a drug repurposing candidate based on TxGNN knowledge graph predictions, contextualised for the South African healthcare system.
Acamprosate is a glutamate-modulating agent approved internationally (including US FDA, 2004) for the maintenance of abstinence in alcohol-dependent patients following detoxification. It is not currently registered with SAHPRA and is not listed on the South African Essential Medicines List (EML).
Key Findings:
- The submitted evidence pack contained significant data gaps: no DrugBank ID was resolved, no mechanism of action was populated, no predicted indications were included, and all safety fields (warnings, contraindications, drug-drug interactions) were absent.
- Cross-referencing with the ZaTxGNN acamprosate knowledge base (ZA-DB00659-multi) reveals 10 TxGNN-predicted novel indications, with the strongest candidate being alcohol withdrawal (Evidence Level L1, Decision Stage S3), supported by 7 registered clinical trials (~442 participants) and 19 PubMed publications.
- Secondary research candidates include ADHD in Fragile X syndrome (L3/S1), Tourette syndrome, Trichotillomania, and Wernicke-Korsakoff syndrome (all L4–L5/S0).
- Five additional computational-only predictions (DECR deficiency encephalopathy, alcohol amnestic disorder, glaucoma, absence epilepsy, Aarskog syndrome) are classified as Hold due to weak mechanistic rationale or safety concerns.
SAHPRA Registration Status: Not registered. Access in South Africa would require a Section 21 application (unregistered medicines) to SAHPRA.
Critical Data Gaps: Two blocking/high-severity gaps were identified — (DG001) SAHPRA labelling information (warnings/contraindications) is unavailable; (DG002) formal mechanism of action data was not retrieved.
2. Drug Information
| Parameter | Details |
|---|---|
| INN (Generic Name) | Acamprosate (calcium acetylhomotaurinate) |
| DrugBank ID | DB00659 (resolved via ZaTxGNN drug mapping; not resolved in submitted pack) |
| South African Brand Names | Besobrial (identified in SA Medicine Price Registry mapping); not currently marketed |
| Chemical Class | Synthetic GABA analogue (calcium bis-acetyl-homotaurinate) |
| SAHPRA Registration | Not registered |
| Schedule Classification | Not scheduled (not registered with SAHPRA) |
| Essential Medicines List | Not listed on the South African EML (Adult, Paediatric, or PHC levels) |
| International Approvals | US FDA (2004, as Campral®); EMA; approved in >25 countries for maintenance of abstinence in alcohol dependence |
| Current Approved Indication | Maintenance of abstinence in alcohol-dependent patients who are abstinent at treatment initiation (international labelling) |
| Mechanism of Action | [Data Gap — DG002] Putative mechanism: functional antagonism at NMDA glutamate receptors; modulation of glutamatergic neurotransmission; reduction of neuronal hyperexcitability associated with chronic alcohol exposure. May also involve calcium-mediated effects and modulation of GABA-ergic tone. |
| Dosage Forms (International) | Enteric-coated tablets, 333 mg; typical dose 666 mg TID (1,998 mg/day) |
| Single Exit Price (SEP) | Not applicable — not marketed in South Africa |
Availability Considerations for South Africa
Acamprosate would need to be accessed via Section 21 application (unregistered medicines) to SAHPRA if required for individual patient use. There is currently no generic manufacture in South Africa. The Standard Treatment Guidelines (STGs) for alcohol use disorders in South Africa do not include acamprosate; current first-line pharmacotherapy for alcohol dependence in the public sector relies on benzodiazepines for withdrawal management and psychosocial interventions for relapse prevention.
3. Predicted New Indications
The submitted evidence pack contained no predicted indications. However, cross-referencing with the ZaTxGNN acamprosate knowledge base (ZA-DB00659-multi) reveals the following TxGNN knowledge graph predictions:
Summary Table
| Rank | Predicted Indication | TxGNN Score | Evidence Level | Decision Stage | Recommendation |
|---|---|---|---|---|---|
| 1 | Progressive encephalopathy with leukodystrophy (DECR deficiency) | 0.985 | L5 | S0 | Hold |
| 2 | Trichotillomania | 0.981 | L5 | S0 | Research Question |
| 3 | Wernicke-Korsakoff syndrome | 0.981 | L4 | S0 | Research Question |
| 4 | Alcohol amnestic disorder | 0.957 | L5 | S0 | Hold |
| 5 | Glaucoma | 0.943 | L5 | S0 | Hold |
| 6 | Tourette syndrome | 0.926 | L5 | S0 | Research Question |
| 7 | Attention deficit-hyperactivity disorder | 0.919 | L3 | S1 | Research Question |
| 8 | Absence epilepsy | 0.913 | L5 | S0 | Hold |
| 9 | Alcohol withdrawal | 0.906 | L1 | S3 | Proceed with Guardrails |
| 10 | Faciodigitogenital syndrome (Aarskog syndrome) | 0.904 | L5 | S0 | Hold |
Note on TxGNN Scores: Higher scores indicate stronger graph-based prediction confidence but do not equate to clinical validity. The highest-scoring indication (DECR deficiency, 0.985) has zero clinical evidence, while the indication with the richest evidence base (alcohol withdrawal, 0.906) ranks 9th. This underscores the critical importance of evidence triangulation.
3.1 Lead Candidate: Alcohol Withdrawal (Rank 9) ⭐
Biological Rationale: The mechanistic link is strong. Alcohol withdrawal syndrome results from chronic ethanol-induced upregulation of NMDA receptors and downregulation of GABA-A receptors, leading to glutamatergic hyperexcitability upon cessation. Acamprosate’s functional NMDA antagonism directly addresses this pathophysiology by:
- Reducing glutamatergic hyperexcitability
- Restoring excitatory/inhibitory neurotransmitter balance
- Attenuating withdrawal-associated neurotoxicity
This represents a direct mechanistic extension of the drug’s approved indication.
3.2 ADHD in Fragile X Syndrome (Rank 7)
Biological Rationale: Moderate-to-strong within the Fragile X subgroup. Fragile X syndrome involves excessive mGluR5 activation, and acamprosate may modulate mGluR5 signalling. This mechanism is not generalisable to primary/idiopathic ADHD.
3.3 Tourette Syndrome, Trichotillomania, Wernicke-Korsakoff Syndrome (Ranks 6, 2, 3)
Biological Rationale: Moderate. All involve glutamatergic signalling abnormalities to varying degrees. For trichotillomania, the analogy with N-acetylcysteine (another glutamate modulator with RCT evidence) is noteworthy. For Wernicke-Korsakoff syndrome, acamprosate cannot replace thiamine supplementation, which remains the definitive treatment.
3.4 “Hold” Indications (Ranks 1, 4, 5, 8, 10)
| Indication | Key Concern |
|---|---|
| DECR deficiency encephalopathy | Mitochondrial defect unrelated to NMDA modulation; likely statistical artefact |
| Alcohol amnestic disorder | Overlaps with WKS; no direct evidence |
| Glaucoma | Memantine (similar NMDA antagonist) failed Phase 3; poor ocular bioavailability expected |
| Absence epilepsy | Safety concern — glutamatergic modulators may worsen absence seizures |
| Aarskog syndrome | FGD1 gene/Rho GTPase pathway unrelated to NMDA; likely false positive |
4. Evidence Summary
4.1 Clinical Trial Evidence (ClinicalTrials.gov)
Alcohol Withdrawal — 7 registered trials (~442 total participants):
| NCT ID | Phase | Status | N | Design | Relevance |
|---|---|---|---|---|---|
| NCT03634917 | 3 | ✅ Completed | 82 | Double-blind, placebo-controlled, 3-arm RCT (Acamprosate vs Calcium vs Placebo) | Grade A |
| NCT00004552 | 2 | ✅ Completed | 120 | Pre-treatment with acamprosate prior to abstinence vs placebo | Grade A |
| NCT00330174 | 4 | ✅ Completed | 90 | Double-blind RCT in alcohol dependence with comorbid mood/anxiety | Grade A |
| NCT00106106 | 2 | ✅ Completed | 56 | Acamprosate for CNS hyperexcitability in alcohol withdrawal | Grade A |
| NCT00466661 | 4 | ✅ Completed | 33 | Double-blind RCT in alcohol dependence + bipolar disorder | Grade A |
| NCT00855699 | 4 | ✅ Completed | 36 | Feasibility study of alcohol detoxification in primary care | Grade B |
| NCT02771925 | 4 | Terminated | 25 | Gabapentin trial (possible acamprosate comparator arm) | Grade B |
ADHD — 1 trial:
| NCT ID | Phase | Status | N | Design |
|---|---|---|---|---|
| NCT01300923 | 2 | ✅ Completed | 14 | Pilot study in Fragile X youth; open-label |
Tourette Syndrome — 1 trial:
| NCT ID | Phase | Status | N | Design |
|---|---|---|---|---|
| NCT02217007 | 2a | ❌ Withdrawn | 0 | SNC-102 (acamprosate calcium SR) in adult Tourette; zero enrolment |
4.2 Published Literature (PubMed)
23 total publications identified across indications. Key publications for the lead candidate (alcohol withdrawal):
| PMID | Year | Type | Key Finding |
|---|---|---|---|
| 38747203 | 2024 | Clinical Guideline (GRACE-4) | SAEM guideline on ED management of alcohol withdrawal; references acamprosate in AUD management |
| 24825644 | 2014 | Systematic Review/Meta-analysis (JAMA) | Pharmacotherapy for alcohol use disorders — comprehensive evaluation |
| 32696076 | 2021 | Review (Der Nervenarzt) | Update on pharmacotherapy of alcohol withdrawal |
| 11524307 | 2001 | RCT (Alcohol and Alcoholism) | n=296 multicentre double-blind RCT; acamprosate from start of withdrawal |
| 38741835 | 2024 | Prospective study (Cureus) | 12-week comparison of acamprosate vs baclofen as anti-craving agents |
| 33567423 | 2021 | RCT | Calcium carbonate vs acamprosate; supports calcium component hypothesis |
4.3 South African Studies
No South African-specific clinical studies were identified. The South African National Clinical Trials Register (SANCTR) and Pan African Clinical Trials Registry (PACTR) were not queried in this evidence pack and should be consulted in subsequent updates.
4.4 African Context Considerations
Alcohol use disorders represent a significant burden of disease in South Africa. The 2016 South African Demographic and Health Survey estimated harmful alcohol use prevalence at approximately 31% among male drinkers. Alcohol withdrawal syndrome is frequently managed in public sector emergency departments. Introduction of acamprosate could provide a non-controlled substance option, particularly relevant given concerns about benzodiazepine diversion and dependence in the public sector.
5. Safety Considerations
⚠️ Data Gap (DG001 — Blocking): SAHPRA labelling information is not available as acamprosate is not registered in South Africa. The following is based on international regulatory data (US FDA, EMA).
5.1 Known Adverse Effects
Common (≥5%):
- Diarrhoea (most frequent; dose-related)
- Nausea, flatulence, abdominal pain
- Headache, dizziness
- Insomnia, anxiety
- Pruritus, asthenia
Serious but Rare:
- Suicidal ideation (post-marketing reports; causal relationship not established)
- Hypersensitivity reactions
- Renal impairment exacerbation
5.2 Contraindications
| Contraindication | Detail |
|---|---|
| [Data Gap — DG001] | Full SAHPRA contraindication data unavailable |
| Severe renal impairment | CrCl ≤30 mL/min (international labelling) |
| Hypersensitivity | To acamprosate calcium or excipients |
| Pregnancy/Lactation | Category C (US); avoid unless benefits outweigh risks |
5.3 Drug Interactions Relevant to South African Prescribing
| Interaction | Clinical Significance |
|---|---|
| Naltrexone | Often co-prescribed in AUD; combined use increases acamprosate Cmax by ~25% but is generally considered safe |
| Disulfiram | No significant pharmacokinetic interaction; may be used concomitantly |
| Benzodiazepines | No documented interaction; relevant given SA STG benzodiazepine-based withdrawal protocols |
| Antiretrovirals (ARVs) | No documented interactions with efavirenz, dolutegravir, or tenofovir-based regimens — important given high HIV/ART prevalence in South Africa |
| TB medications | No documented interactions with rifampicin or isoniazid, though formal studies are lacking |
Note: Drug-drug interaction data returned as “not_found” in the evidence pack (query_status: not_found, total_count: 0). The above is based on international pharmacological references.
5.4 Adverse Drug Reaction Reporting
Healthcare professionals in South Africa should report suspected adverse drug reactions to:
- SAHPRA Pharmacovigilance Centre
- National Adverse Drug Event Monitoring Centre (NADEMC), University of Cape Town
- Reporting form available on the SAHPRA website
- ADR reporting is especially important for unregistered medicines accessed via Section 21
6. Data Gaps and Limitations
| Gap ID | Category | Item | Severity | Impact | Remediation |
|---|---|---|---|---|---|
| DG001 | Drug Level | SAHPRA label warnings/contraindications | Blocking | Cannot proceed to S1 safety assessment | Query SAHPRA database; obtain package insert via Section 21 application |
| DG002 | Drug Level | Full mechanism of action | High | Limits mechanistic linkage analysis | Query DrugBank API for complete MOA data (DB00659) |
| — | Evidence Pack | DrugBank ID not resolved in submitted pack | High | Cannot link to knowledge graph | Resolved via ZaTxGNN mapping: DB00659 |
| — | Evidence Pack | No predicted indications in submitted pack | High | Report requires cross-reference to ZA-DB00659 | Data available in ZaTxGNN knowledge base |
| — | Regulatory | SAHPRA registration pathway assessment | Medium | No local regulatory pathway analysed | Submit regulatory intelligence query to SAHPRA |
| — | Evidence | South African clinical studies | Medium | No local population data | Search SANCTR and Pan African CTR |
| — | Pharmacoeconomic | Cost-effectiveness in SA context | Medium | Cannot assess SEP or budget impact | Health economic modelling required |
7. Recommendations
7.1 Evidence Strength Assessment
| Tier | Indications | Action |
|---|---|---|
| Tier 1 — Actionable | Alcohol withdrawal | Proceed with regulatory pathway assessment; consider SAHPRA Section 21 access; identify SA trial sites |
| Tier 2 — Investigational | ADHD (Fragile X subgroup), Tourette syndrome, Trichotillomania, Wernicke-Korsakoff syndrome | Formulate as research questions; seek preclinical/early clinical data |
| Tier 3 — Archive | DECR deficiency, Alcohol amnestic disorder, Glaucoma, Absence epilepsy, Aarskog syndrome | Insufficient evidence and/or safety concerns; no further action |
7.2 Suggested Next Steps
Immediate (Data Gap Resolution):
- Resolve DG001: Obtain full SAHPRA-equivalent labelling data (contraindications, warnings) from international regulatory authorities (US FDA, EMA) to enable safety assessment
- Resolve DG002: Query DrugBank API with DB00659 for complete mechanism of action data
For Alcohol Withdrawal (Lead Candidate):
- Regulatory Intelligence: Determine whether any pharmaceutical company has submitted or plans to submit a SAHPRA registration application for acamprosate
- Section 21 Access: Establish a Section 21 unregistered medicine access pathway for clinical use at SA academic centres
- Local Clinical Trial: Design a pragmatic RCT comparing acamprosate-augmented vs standard benzodiazepine-only detoxification in SA public hospital settings
- Pharmacoeconomic Analysis: Model cost-effectiveness relative to current STG management
- EML Consideration: If clinical evidence supports efficacy, prepare a dossier for National Essential Medicines List Committee (NEMLC) review
For Research Questions:
- Engage the Division of Human Genetics at NHLS and UCT Department of Psychiatry regarding a South African Fragile X treatment study
- Monitor international literature for new Tourette/trichotillomania trials; liaise with SASOP Neuropsychiatry Special Interest Group
7.3 Relevant South African Research Institutions
| Institution | Relevance |
|---|---|
| South African Medical Research Council (SAMRC) | Alcohol and substance abuse research programme |
| University of Cape Town — Dept of Psychiatry & Mental Health | Addiction research; clinical trials infrastructure |
| University of Stellenbosch — Dept of Psychiatry | Neuropsychiatric genetics; Tourette/OCD research |
| University of the Witwatersrand — Perinatal HIV Research Unit | Trial execution capacity; pharmacovigilance |
| SAHPRA Clinical Trials Committee | Regulatory approval for local trials |
| National Health Laboratory Service (NHLS) | Genetic testing for rare disease indications |
7.4 Public Health Implications
South Africa bears one of the highest burdens of alcohol-related harm globally. The Western Cape, Gauteng, and KwaZulu-Natal provinces have particularly high rates of alcohol use disorders. Access to evidence-based pharmacotherapy for alcohol withdrawal and relapse prevention is limited in the public sector.
Introduction of acamprosate into the South African therapeutic armamentarium could:
- Provide a non-controlled substance option for alcohol relapse prevention
- Reduce benzodiazepine prescribing burden and associated diversion risks
- Align with WHO mhGAP intervention guidelines for alcohol use disorders
- Address a significant gap in the current Essential Medicines List
Key barriers include:
- Absence of SAHPRA registration (requires pharmaceutical applicant or government initiative)
- Cost considerations for public sector procurement (no SEP established)
- Limited specialist addiction medicine capacity at primary care level
- Need for local clinical data in South African populations
8. Evidence Level and Decision Stage Definitions
| Level | Definition |
|---|---|
| L1 | Systematic review/meta-analysis or clinical guideline with direct evidence |
| L2 | Randomised controlled trial(s) |
| L3 | Non-randomised studies, small pilot trials, or case series |
| L4 | Case reports or narrative reviews with indirect evidence |
| L5 | Computational prediction only; no clinical evidence |
| Stage | Definition |
|---|---|
| S0 | Computational prediction — not yet assessed for safety |
| S1 | Safety screening initiated |
| S2 | Preclinical/early clinical evaluation |
| S3 | Clinical evidence sufficient for risk-benefit assessment |
9. Query Log
| # | Source | Query Date | Query Parameters | Status | Results | Notes |
|---|---|---|---|---|---|---|
| 1 | DrugBank | 2026-03-26 | drug: ACAMPROSATE CALCIUM | ✅ Success | 1 | Vocab match only; MOA not retrieved |
Note: The submitted evidence pack contained only 1 query log entry. The comprehensive ZaTxGNN evidence pack (ZA-DB00659) additionally queried ClinicalTrials.gov (10 queries, 10 trials), ICTRP (10 queries, 0 results), and PubMed (10 queries, 23 publications). SANCTR and Pan African CTR were not queried and should be included in subsequent evidence collection cycles.
Disclaimer
Research Use Only: This report is generated for research purposes only and does not constitute medical advice. Drug repurposing predictions require clinical validation before therapeutic application. This is not a SAHPRA-approved assessment. Always refer to current Standard Treatment Guidelines and the Essential Medicines List. Healthcare professionals should exercise independent clinical judgement. Any use of acamprosate in South Africa for indications described in this report would require appropriate SAHPRA authorisation (including Section 21 access for unregistered medicines). Adverse events should be reported to SAHPRA’s pharmacovigilance programme.
Generated by ZaTxGNN — South Africa Drug Repurposing Predictions Report ID: ZA-DB00659-multi-v4 | Source Pack: TW-UNKNOWN-multi (re-mapped) Model: TxGNN Knowledge Graph + Evidence Triangulation Data sources: DrugBank, ClinicalTrials.gov, PubMed, ICTRP
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.