Interaction Between a Natural Aldehyde Dehydrogenase 2 (ALDH2) Inhibitor and Alcohol

Study Overview
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Brief Summary
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The main objective is to assess whether a natural inhibitor of aldehyde dehydrogenase 2 (ALDH2) contained in a soy extract could interfere on alcohol metabolism and effects in humans.

Detailed Description
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Soybeans contain isoflavones, which are biologically active polyphenols known as antioxidants and phytoestrogens. These isoflavones include daidzin, daidzein, genistin and glycitin, and have been implicated in the beneficial effects of soy consumption. Daidzin and daidzein are isoflavones contained in soybean that can act as natural inhibitors of aldehyde dehydrogenase 2. Animal studies have demonstrated that some soy isoflavones can reduce the auto-administration of cocaine and suggest they might be useful to treat cocaine dependence. Aldehyde dehydrogenase inhibitors, as disulfiram, are currently used in humans to treat alcohol dependence because they interfere with ethanol metabolism (specifically in the transformation of acetaldehyde to acetate. Alcohol intake after disulfiram administration increases concentration of acetaldehyde in the blood (five to 10 times higher than that found during metabolism of the same amount of alcohol alone). The combination produced acute symptoms of a severe hangover (named disulfiram-like reaction), and the patient may experience symptoms as flushing of the skin, tachycardia, shortness of breath, nausea, vomiting, throbbing headache, visual disturbances, mental confusion, and in some cases severe reactions as postural syncope, and circulatory collapse. In addition, disulfiram have demonstrated clinical efficacy in cocaine dependence. The mechanism of action for that effects are related to its ability to decrease dopamine degradation by inhibiting the dopamine-beta-hydroxylase enzyme (metabolizes dopamine to norepinephrine), and increasing its concentrations in some areas of the brain. The aim of the study is to assess whether a soy extract containing isoflavones (daidzin, daidzein and genistein) could interfere on alcohol metabolism and produce adverse effects in humans.

Official Title
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Human Pharmacology Study to Evaluate the Interaction Between a Natural Inhibitor of Aldehyde Dehydrogenase 2 (ALDH2) and Alcohol in Healthy Volunteers. Pilot Clinical Trial

Conditions
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Healthy

Intervention / Treatment
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* Dietary Supplement: Daidzin
* Dietary Supplement: Alcohol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understanding and accepting the study procedures and signing the informed consent Clinical history and physical examination demonstrating no organic or psychiatric disorders The ECG and general blood and urine laboratory tests performed before the study should be within normal ranges. Minor or occasional changes from normal ranges are accepted if, in the investigator's opinion, considering the current state of the art, they are not clinically significant, are not life-threatening for the subjects and do not interfere with the product assessment. These changes and their non-relevance will be justified in writing specifically The body mass index (BMI=weigh/height2) will range from 19 to 27 kg/m2, and the weight from 50 to 100 kg Ethanol consumption of minimum 2 units per week and previous experience with ethanol intoxication Women with regular menstrual cycle (26-32 days) Exclusion Criteria: Not meeting the inclusion criteria History or clinical evidence of alcoholism, psychiatric disorders, drug abuse or dependence, or regular use of psychoactive drugs Having suffered any organic disease or major surgery in the three months prior to the study start Smokers Consumption of more than five coffees, teas, colas, other stimulant or xanthine beverages daily in the three months prior to the beginning of the study Taking more than 20 g of alcohol per day in women and 40 g of alcohol per day in men Regular use of any drug in the month prior to the study sessions.The treatment with single or limited doses of symptomatic medicinal products in the week prior to the study sessions will not be a reason for exclusion if it is calculated that it has been cleared completely the day of the experimental session Blood donation 8 weeks before or participation in other clinical trials with drugs in the previous 12 weeks Subjects with allergy, intolerance or adverse reactions to alcohol, soya and lactose. History or clinical evidence of gastrointestinal, liver, renal or other disorders which may lead to suspecting a disorder in drug absorption, distribution, metabolism or excretion, or that suggest gastrointestinal irritation due to drugs Subjects unable to understand the nature, consequences of the study and the procedures requested to be followed Subjects with positive serology to Hepatitis B, C or HIV Pregnant or breastfeeding women. Women not using effective contraceptive methods History or presence of breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daidzin and alcohol<br>Daidzin 80 mg, single dose, oral administration (4 capsules of Super-Absorbable Soy Isoflavones®). Alcohol 0.5 g/kg (vodka diluted in lemon-flavoured water), single dose, oral administration. Solution of 150 ml. | Dietary Supplement: Daidzin<br>* Super-Absorbable Soy Isoflavones, LifeExtension, USA. Single oral dose of 4 capsules (containing 80 mg of daidzin-daidzein).<br>Dietary Supplement: Alcohol<br>* Alcohol single oral dose<br>|
| Active Comparator: Alcohol<br>Alcohol 0.5 g/kg (vodka diluted in lemon-flavoured water), single dose, oral administration. Solution of 150 ml. | Dietary Supplement: Alcohol<br>* Alcohol single oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time curve (AUC 2-10h) | Calculation of AUC for blood alcohol concentrations | From 2h to 10h after the first administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in signs and symptoms of disulfiram-like reaction | Vital signs (heart rate, blood pressure, respiration rate, oral and facial temperature) and adverse effects measured by visual analogue scales (nausea, vomiting, vertigo, dizziness, headache, breathing difficulty, facial flushing) | From baseline to 10h after the first administration | 
| Change in drunkenness and euphoria effects | Drunkenness and euphoria will be measured by a visual analogue scale (VAS). | From baseline to 10h after the first administration | 
| Area Under the Concentration-Time curve (AUC 0-10h) | Calculation of AUC of plasmatic concentrations of daidzein, genistein and equol | From baseline to 24h after the first administration | 
| Number of participants with Serious and non-serious adverse events | Collection of adverse events spontaneously reported by the participants and/or observed by the investigators. | 3 days after each condition | 
| Change in other subjective effects | Subjective effects will be measured with the Addiction Research Center Inventory (ARCI) | From baseline to 10h after the first administration | 
| Elimination half-life | Calculation of elimination half-life from blood ethanol concentrations | From 2h to 10h after the first administration | 
| Elimination half-life | Calculation of elimination half-life of plasmatic concentrations of daidzein, genistein and equol | From baseline to 24h after the first administration | 
| Cumulative amount of drug excreted into urine up to collection time | Urine will be collected in the following periods:0-2h,2-8h,8-14h,14-24 h after administration. Concentrations of daidzein, genistein and equol will be measured | From baseline to 24h after the first administration |