Centrophenoxine
Risk-Benefit Analysis
Forever Healthy Foundation gGmbH
Amalienbadstraße 41
D-76227 Karlsruhe, Germany
Version 1.5 - October 5, 2022
Mario Alvarez-Martinez, PhD
Gabriel Borden, MD
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Preface
This risk-benefit analysis (RBA) is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify new rejuvenation therapies and systematically evaluate them on their risks, benefits, procedures and potential application.
Special thanks are extended to the whole Rejuvenation Now team at Forever Healthy for their friendly contributions.
Section 1: Overview
Motivation
Centrophenoxine (CPH) is a compound consisting of dimethylaminoethanol (DMAE) and para-chlorophenoxyacetic acid (pCPA), joined by a chemical bond. DMAE can be converted by cells into choline, which is a precursor of membrane phospholipids, neurotransmitters, and other important biomolecules. The pCPA component enhances the penetration of CPH across the blood-brain barrier (Miyazaki et al., 1976).
CPH supplementation is hypothesized to increase brain acetylcholine levels, protect neurons from oxidative damage, improve cognitive function, and reduce age-related lipofuscin accumulation.
Key questions
This analysis seeks to answer the following questions:
- Which benefits result from CPH supplementation?
- Which risks are involved in CPH supplementation (general and method-specific)?
- What are the potential risk mitigation strategies?
- Which method or combination of methods is the most effective for CPH supplementation?
- Which of the available methods are safe for use?
- What is the best therapeutic protocol available at the moment?
- What is the best monitoring protocol currently available?
Impatient readers may choose to skip directly to Section 6 for the Presentation of Results and tips on practical application.
Recommended reading/viewing
General introduction
The following site offers information on CPH supplementation at a consumer level and is useful as an introduction to the topic:
- Centrophenoxine: potential uses & side-effects - selfdecode.com
Scientific overview
The following scientific review provides a more detailed overview of the topic of CPH supplementation:
- Centrophenoxine (Meclofenoxate) - alzdiscovery.org
Section 2: Methods
Analytic model
This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012).
Literature search
A literature search was conducted on PubMed, the Cochrane Library, Google Scholar and the China National Knowledge Infrastructure (CNKI) using the search terms shown in Table 1 and included articles available as of September 4, 2022. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.
Inclusion criteria: Any human study that used CPH supplementation was included.
Exclusion criteria: We excluded animal and in vitro studies, as well as trials that used CPH in combination with other molecules if the effect of CPH could not be isolated.
For the assessment of hypothetical risks, selected animal and in vitro studies were also considered.
Table 1: Literature search
Search terms | Database | Number of publications | Number of |
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR brenal OR centrophenoxin OR cerebron OR cerutil OR helfergin OR licidril OR lucidryl | PubMed | 562 | 150 |
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR brenal OR cellative OR centrophenoxin OR cerebron OR cerutil OR closete OR helfergin OR licidril OR lucidryl | Cochrane Library | 62 | |
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR amipolen OR analux OR brenal OR cellative OR centrophenoxin OR cerebron OR cerutil OR closete OR helfergin OR licidril OR lucidryl OR lutiaron OR marucotol OR proserout OR proseryl OR ropoxyl | Google Scholar | 6610 (first 300 results screened) | |
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR lucidryl | CNKI | 782 | |
meclofenoxate OR centrophenoxine OR centrophenoxin OR meclophenoxate OR cerutil OR lucidril OR luciforte OR helfergin | clinicaltrials.gov | 1 | |
Other sources | |||
A manual search of the reference lists of the selected papers | |||
PubChem entries for centrophenoxine, p-chlorophenoxyacetic acid, meclofenoxate, meclofenoxate hydrochloride | |||
Book: Neuro-Psychopharmaka: Ein Therapie Handbuch Band 5 Parkinsonmittel and Nootropika () - available online excerpts only; book in German |
Abbreviation list
Abb | Full text |
ACH | acute cerebral hemorrhage |
ACI | |
ADHD | attention deficit hyperactivity disorder |
ADL | activities of daily living |
AEs | adverse events |
AIM | abnormal involuntary movement |
ALS | amyotrophic lateral sclerosis |
ALT | alanine aminotransferase |
AS | |
BUN | |
CBF | cerebral blood flow |
CNS | central nervous system |
CO | carbon monoxide |
CPH | centrophenoxine |
CRP | C-reactive protein |
DB | |
DB-RCT | double-blind randomized controlled trial |
DMAE | dimethylaminoethanol |
EEG | electroencephalogram |
G6PD | glucose-6-phosphate dehydrogenase |
GCS | Glasgow Coma Scale |
GI | gastrointestinal |
GSH-Px | glutathione peroxidase |
HRV | heart rate variability |
ICU | intensive care unit |
IL | interleukin |
i.v. | intravenous |
LD50 | median lethal dose |
MCPA | 4-chloro-2-methylphenoxyacetic acid |
MDA | malondialdehyde |
MMSE | Mini-Mental State Examination |
NIHSS | National Institutes of Health Stroke Scale |
NSE | neuron-specific enolase |
pCPA | para-chlorophenoxyacetic acid (4-chlorophenoxyacetic acid) |
RCT | randomized controlled trial |
salvia | |
SGA | small for gestational age |
SOD | superoxide dismutase |
SSEP | somatosensory evoked potential |
TBI | traumatic brain injury |
TCM | traditional Chinese medicine |
TNF-α | tumor necrosis factor alpha |
TSH | thyroid stimulating hormone |
VaD | vascular dementia |
WAIS | |
WMS |
Section 3: Existing Evidence
Summary of results from clinical trials (humans)
Our search terms identified 1707 studies, of which 150 were relevant to this analysis (see Table 2). We also chose to include the clinical studies summarized in chapter 4 () from the book Neuro-Psychopharmaka Ein Therapie-Handbuch (Riederer et al., 1992) in our analysis, despite being unable to access the majority of the original papers (see Table 3).
Some trials from the Chinese literature, mostly comparing CPH to traditional Chinese medicine (TCM), reported only a qualitative superiority of the comparator, at least in the online open-access portion (abstract). These results were not included in our analysis, but are included in Table 2.
The overall quality of the evidence is low. Although most of the selected studies are randomized controlled trials (RCTs) and comparative trials, a large proportion of the available studies are only available as abstracts, many of those from the Chinese literature. In addition, several studies have methodological limitations, such as lack of statistical analysis and generally short-term study periods, or are conducted in elderly populations with high dropout rates due to death and morbidity.
Table 2: Clinical trials
Table 3: Herrschaft summary
Section 4: Risk-Benefit Analysis
Decision model
Risk and benefit criteria
The decision profile is made up of risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and type and are assessed according to magnitude, likelihood, duration and perceived importance. The risk criteria are organized by category and type and are assessed according to severity, frequency of occurrence, and difficulty of detection and mitigation. Each criterion is assigned a numerical value for each assessment category:
1 = low
2 = moderate
3 = high
The numerical values for the criterion are then summarized, serving as the justification for the weighting in the following column.
Weight
The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). The value in the summary column is divided by 4 to result in a weight between 1 → 3.
Score
Each criterion is assessed according to the performance of CPH supplementation against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior), and +1 (superior) to the comparator.
Uncertainty
Uncertainty is determined according to the amount and quality of the evidence, availability of full text articles & supplementary data, number of participants and whether methodological flaws, conflicting studies, or conflicts of interest (i.e. funding) are present. Evidence that is based on RCTs is initially upgraded by 1 point, evidence from open-label trials is considered neutral, and evidence that is based on observational studies is downgraded by 1 point. The uncertainty is then further valued using the above-mentioned criteria to result in an uncertainty score.
Weighted score
The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted according to the uncertainty score. Weighted scores are upgraded where the uncertainty score is low (positive) or downgraded where the uncertainty score is high (negative).
Benefit assessment
We identified a total of 59 benefits associated with CPH. The benefits were mostly observed in aged or diseased populations, were of small magnitude and were not demonstrated to persist after the treatment period.
Table 4: Benefit assessment
For even more detailed information on our analysis, see Supplementary Data.
Category | Benefit type | Magnitude | Likelihood | Duration | Importance to patient | Summary | Weight | Score | Uncertainty | Weighted score | |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | Dementia & cognitive decline | ↑ clinical improvement/stabilization in dementia & cognitive decline | 1 | 2 | 1 | 2 | 6 | 1.5 | +1 | 0.75 | |
2 | Dementia & cognitive decline | ↑ ADL in dementia & cognitive decline | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 0 | |
3 | Dementia & cognitive decline | ↑ clinical improvement in corpus callosum degeneration | 1 | 2 | 1 | 3 | 7 | 1.75 | +1 | 2 Open-label: Dai & Li, 2012 | 0.5 |
4 | Dementia & cognitive decline | ↓ neurological deficit in VaD | 1 | 2 | 1 | 3 | 7 | 1.75 | +1 | 1.25 | |
5 | Dementia & cognitive decline | ↑ clinical improvement in VaD | 1 | 2 | 1 | 3 | 7 | 1.75 | +1 | 1.25 | |
6 | General | ↑ CBF | 1 | 3 | 1 | 2 | 7 | 1.75 | +1 | 2 Comparative/Open-label: | 1 |
7 | General | ↑ clinical improvement in chronic cerebrovascular disease | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 0 | |
8 | Metabolism & biochemistry | ↓ age-related intracellular water loss | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 1 RCT: Fülöp et al., 1990 | 0.75 |
9 | Metabolism & biochemistry | ↑ blood oxygen saturation & consumption | 1 | 1 | 1 | 1 | 4 | 1 | +1 | ; | 0 |
10 | Metabolism & biochemistry | ↓ fasting glucose levels | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Open-label: | 0 |
11 | Metabolism & biochemistry | ↑ normalization of blood glucose dynamics | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Comparative: Stoica et al., 1974 | 0 |
12 | ↑ oxidative stress mitigation | 2 | 1 | 1 | 1 | 5 | 1.25 | +1 | 1 RCT: Zheng et al., 2011 2 Comparative: Tang & Dong, 2018 | 1.25 | |
13 | Metabolism & biochemistry | ↑ energy | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Open-label: | 0 |
14 | Metabolism & biochemistry | ↑ biomarkers in cerebrovascular disease | 2 | 1 | 1 | 2 | 6 | 1.5 | +1 | 1.5 | |
15 | Movement disorders | ↑ reflexes in cerebral palsy | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 2 Open-label: Bradna, 1967 | 0 |
16 | Movement disorders | ↓ involuntary movements in tardive dyskinesia | 2 | 2 | 2 | 2 | 8 | 2 | +1 | 2 Open-label: | 0 |
17 | Movement disorders | ↓ ALS symptoms | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 2 Comparative: Sercl & Kovarik, 1963 | 0 |
18 | Musculoskeletal | ↑ bone mineral density | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Comparative: Li et al., 2019 | 0 |
19 | Musculoskeletal | ↓ shoulder stiffness | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Open-label: Herrschaft, 1992 Conflict: | 0 |
20 | Neurological symptoms | ↓ ischemia-induced orthostatic hypotension & abnormal catecholamine response | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 2 Open-label: Stoica & Enulescu, 1991 | 0 |
21 | Neurological symptoms | ↓ dizziness | 1 | 2 | 1 | 2 | 6 | 1.5 | +1 | 1 RCT: | 1.5 |
22 | Neurological symptoms | ↓ headache | 1 | 2 | 1 | 2 | 6 | 1.5 | +1 | 2 Open-label: Lin, 2001; Conflict: | 0 |
23 | Neurological symptoms | ↑ HRV in ACI | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 0 | |
24 | Neurological symptoms | ↓ vertigo | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 0 | |
25 | Neurological symptoms | ↓ visually-triggered gaze saccade latency in post-traumatic cervical syndrome | 2 | 2 | 1 | 1 | 6 | 1.5 | +1 | 0 | |
26 | Neurological symptoms | ↑ clinical improvement in cortical blindness | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 0 | |
27 | Perinatal & pediatric | ↑ long-term memory & learning in children | 1 | 1 | 1 | 2 | 5 | 1.25 | +1 | 0 | |
28 | Perinatal & pediatric | ↑ general cognition & mental performance in children | 1 | 2 | 1 | 2 | 6 | 1.5 | +1 | 0 | |
29 | Perinatal & pediatric | ↑ behavior & mood in children | 1 | 1 | 1 | 1 | 4 | 1 | +1 | 0 | |
30 | Perinatal & pediatric | ↑ clinical improvement in | 1 | 2 | 2 | 3 | 8 | 2 | +1 | 1 RCT: Guo, 2013; Pu & Liu, 2008; Xiang & Wang, 2005; Wang, 2011; Fang et al., 2010; Hui & Zhang, 2022 2 Comparative: | 1.5 |
31 | Perinatal & pediatric | ↑ condition of the newborn in SGA fetuses | 2 | 2 | 2 |