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1 Evaluation of the Efficacy and Safety of PartySmart in the Prevention of Alcoholinduced Hangover: A Prospective, Randomized, Double blind, Comparative, Phase III Clinical Trial Rangamani, MD, Professor and Head Department of Medicine Rajarajeshwari Medical College Bangalore S.A. Kolhapure, MD, Senior Medical Advisor R&D Center The Himalaya Drug Company Bangalore ABBREVIATIONS 5-HIAA : 5-hydroxyindol-3-yl acetic acid 5-HTOL : 5-hydroxytryptophol ADH : Alcohol dehydrogenase ALDH : Aldehyde dehydrogenase BMI : Body mass index CTA : Conditioned taste aversion EEG : Electroencephalogram HPA : Hypothalamic-pituitary-adrenal HS : Highly significant mrna : Messenger ribonucleic acid NADH : Nicotinamide adenine dinucleotide NS : Not significant POMS questionnaire : Profile of mood states questionnaire S : Significant Corresponding author: Dr. S. A. Kolhapure, MD, Senior Medical Advisor R&D Center The Himalaya Drug Company Bangalore, India Phone : Fax : dr.kolhapure@himalayahealthcare.com ABSTRACT Recent studies suggest that alcohol hangover induces cardiovascular and psychomotor morbidity independent of the quantity of alcohol consumed or the frequency of ingestion. PartySmart is a polyherbal formulation, recommended for alcohol-induced hangover. This study was planned to evaluate the comparative efficacy and safety of PartySmart in the prevention of alcohol-induced hangover symptoms, with one of the formulations promoted as a cure for alcohol-induced hangover. The present study was a prospective, randomized, double blind, comparative, phase III clinical trial. The duration of the study was 1 hours, and 1 healthy male volunteers, who were occasional social alcohol drinkers and who were willing to give informed consent were included in the study. A person unconnected with the study did randomization and double-blinding, following which the volunteers were divided into s of 5 in each. The 5

2 PartySmart received Partysmart and the compared drug was given the other drug, which is also being promoted as an effective and safe remedy for alcoholinduced hangover. To induce hangover symptoms, but prevent excessive drinking, all the volunteers were asked to quantify their usual alcohol consumption and also the alcohol consumption that will reliably result in hangover symptoms the next day, based on their previous experience. All the volunteers were assessed at baseline, at hours and 1 hours, after receiving the study drugs, for physical changes, and for blood and urinary alcohol and acetaldehyde levels. All the participants consumed the same brand and type of alcohol and details of the number of alcoholic drinks consumed by each volunteer, Table 1: BMI of the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ±.8349 (N=5) 5.13 ±.11 (N=5) drug Difference between means.364 ± % confidence interval to t=.1671, R =.348, p=.8714; NS BMI PartySmart Figure 1: BMI of the "PartySmart" and "Compared drug" s t=.1671, R =.348, p=.8714; NS Compared drug the time of 'going to bed' and 'rising in the morning' were recorded. The POMS questionnaire was used to evaluate the alcohol-induced hangover the next morning, and the difference in hangover scores was derived from a set of common hangover symptoms. Another questionnaire was used to assess the severity of each symptom on a visual analogue scale. The predefined primary endpoints were the difference in hangover scores, physical parameters and blood and urinary alcohol and acetaldehyde levels. The predefined secondary endpoints were effect on mood reduced, incidence of adverse effects and compliance to the drug. All the adverse events were recorded and relation of adverse events to the study medication was predefined as "Unrelated", "Possible" and "Probable". The data analysis was performed according to intent-to-treat principles. This study observed a significant difference in the mean overall hangover score, which was significantly lower in the PartySmart than in the compared drug. Though there was no blood alcohol levels after hours in both the s, after 1 hours, there was a significant difference in the mean blood alcohol levels. There was a highly significant difference in the mean blood acetaldehyde levels after hours and also after 1 hours, in both the s. There was a urinary alcohol levels after hours, and also after 1 hours, in both s. There was no significant difference in the mean urinary acetaldehyde levels after hours in both s and a significant difference in the mean urinary acetaldehyde levels after 1 hours in both s. These beneficial effects of PartySmart might be due to the synergistic actions of the ingredients of PartySmart. 51

3 These results suggest that Partysmart may prevent the binding of acetaldehyde to cell proteins, causing a higher initial blood level and subsequent rapid elimination. Lower levels of alcohol and acetaldehyde in the blood at 1 hours were reflected in the decreased symptom scores and the change in the visual analogue score and these observations are indicative of a reduced hangover after PartySmart pretreatment. Further, there were no clinically significant adverse reactions, either observed by investigators or reported by the volunteers in the PartySmart and the overall compliance to PartySmart was found to be excellent. Therefore, it may be concluded that PartySmart is effective and safe than the compared drug, in prevention of alcohol-induced hangover. INTRODUCTION "Hangover!" A hydroid wakes, cells visit cells, hold parties, while you sleep! At the end of the night, you wake wondering, Who kidnapped your body, while you were sleeping! There's a shark rising in your thoughts, Your tongue evolves into some kind of amphibian on the verge of extinction! Pretty in paralytic sleep your dreams are full of reptiles, Spent the night shedding skin, snapping splints out of wishes! Running on the spot for antivenom, your lips are wrinkled fingertips, In the bath too long your eyes are two frightened puffer fish! Pricking in the dark prickling through high kicks, Holding your breath, peering out from under the sheets! 1 Alcohol hangover has been well known since Biblical times: "Woe unto them that rise up early in the morning, that they may follow strong drink". Medical investigation, however, has 5 focused on the acute effects of alcohol ingestion and more than 47 articles have been written about alcohol intoxication since 1965, but only 18 have addressed alcohol hangover. 3-5 Recent studies suggest that alcohol hangover induces cardiovascular and psychomotor morbidity independent of the quantity of alcohol consumed or the frequency of ingestion. 6-7 PartySmart is a polyherbal formulation containing extracts of Phoenix dactylifera, Cichorium intybus, Andrographis paniculata, Vitis vinifera, Phyllanthus amarus and Emblica officinalis. Some studies have shown that PartySmart is useful in preventing alcohol-induced hangover; and PartySmart pre-treatment, before alcohol ingestion was associated with rapid elimination of alcohol and acetaldehyde. 8-1 There are various other formulations, which are being promoted as a cure for alcoholinduced hangover, but the tall claims made by these formulations have not been substantiated by evidence generated in controlled clinical trials, neither the changes in various biochemical parameters and cognitive impairments have been monitored. This study was planned to evaluate the comparative efficacy and safety of PartySmart in the prevention of the alcohol-induced hangover symptoms, Table : Predefined amount of alcohol (ml) required to be consumed to induce hangover in the "PartySmart" and "Compared drug" s Minimum 9 15 Maximum 1 1 Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean t=.63, R =.63, p=.8417; NS Predefined amount of alcohol (ml) required to induce hangover PartySmart t=.63, R =.63, p=.8417; NS Compared drug Figure : Predefined amount of alcohol (ml) required to be consumed to induce hangover in the "PartySmart" and "Compared drug" s

4 with one of the formulations promoted as a cure for alcoholinduced hangover. This formulation with which the activity of PartySmart was compared is recommended in a serving size of caplets, and the amount per serving contains activated calcium carbonate (615 mg) and vegetable carbon (345 mg). Aim of the study This study was planned to evaluate the effect of PartySmart on blood and urinary levels of alcohol and acetaldehyde after alcohol ingestion and to evaluate the comparative efficacy and safety of PartySmart in the prevention of the alcohol-induced hangover symptoms. Study design The present study was a prospective, randomized, double blind, comparative, phase III clinical trial. The duration of the study was 1 hours a night, and the 'Institutional Ethics Committee' approved the study. MATERIAL AND METHODS Inclusion criteria A total of 1 healthy male participants from the pool of volunteers of the R&D Center, The Himalaya Drug Company, Bangalore, India and who were occasional social alcohol Table 3: Mean amount of alcohol consumed (ml) by the "PartySmart" and "Compared drug" s during the study Minimum Maximum 1 1 Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean t=.48, R =.41, p=.6938; NS Mean amount of alcohol (ml) consumed t=.48, R =.41, p=.6938; NS PartySmart Compared drug Figure 3: Mean amount of alcohol consumed (ml) by the "PartySmart" and "Compared drug" s during the study drinkers, aged between 5 to 45 years, in the weight range of 5-7 kg, and who were willing to give informed consent were included in the study, Exclusion criteria Exclusion criteria were volunteers with acid peptic disorder, diabetes mellitus, neurological and psychiatric disorder, chronic alcoholism, history of drug abuse, history of alcohol abuse, score of more than points on the validated brief Michigan Alcoholism Screening Test (MAST). 11 Similarly, volunteers consuming certain concomitant medications like antibiotics (furazolidone, griseofulvin, imidazoles), anticoagulants (warfarin), antidepressants (tricyclic antidepressants), antihistamines, anticonvulsants (phenytoin), cardiovascular medications (nitroglycerin, reserpine, methyldopa, hydralazine and guanethidine), sedatives and hypnotics (benzodiazepines), and those volunteers, who had known hypersensitivity to alcohol, were excluded from the study. Randomization and blinding A person unconnected with the study did randomization in blocks of 4, by using a computer generated random number allocation. Double-blinding was done, and neither the volunteers, nor the investigators were aware of the block size, and therefore were unable to predict the treatment allocation. The codes were kept in sealed envelopes at a secure location to ensure the double blinding of the treatment allocation. Study drugs Randomly allocated volunteers were divided into s namely the "PartySmart " and "Compared drug ". The PartySmart received 1 capsule of Partysmart before alcohol consumption (Batch No. 41//R&D/HDC/4) (Daily dose of 1 capsule of PartySmart has been shown to be safe and effective, therefore was considered adequate for 53

5 this study). The compared drug was given the other drug, which is being promoted as an effective and safe remedy for alcohol-induced hangover. This formulation with which the activity of PartySmart was compared is recommended in a serving size of caplets, and the amount per serving contains, activated calcium carbonate (615 mg) and vegetable carbon (345 mg). The recommended dose is caplets with first drink and more caplets every to 3 hours (or 5 to 6 drinks). The volunteers from the compared drug consumed the other drug as per the recommended dose. Study procedure All the volunteers were instructed to refrain from consuming any alcoholic beverages at least 48 hours before the study. To induce hangover symptoms, but prevent excessive drinking, all the volunteers were asked to quantify their usual alcohol consumption that will reliably result in hangover symptoms the next day, based on their previous personal experience. All the volunteers were assessed at baseline (before taking the study drugs) at and 1 hours after receiving the study drugs for the physical changes, and for blood and urinary alcohol and acetaldehyde levels. The alcohol and acetaldehyde levels were measured by gas chromatography (Michro-91, NETEL Chromatograph), which is a reliable and sensitive method for estimating blood and urinary levels of alcohol and acetaldehyde. All the investigations were performed at the R&D Center, The Himalaya Drug Company, Bangalore, India. The investigators supervised the intake of the PartySmart capsules and the other compared drug caplets, by volunteers. All the participants had their food from the same restaurant, where they had same type of food, on the study day after consuming alcohol. To prevent over drinking, all the participants were reminded to 54 limit their alcohol consumption to the predefined quantity, before alcohol consumption. All the participants consumed same brand and type of alcohol (48w/v, 75% proof whisky); and the details of number of alcoholic drinks consumed by each volunteer, the time of 'going to bed' and 'rising in the morning' were recorded in a structured case record form. Local accommodation and taxi transport were provided to all participants. There are various studies done on psychoactive drugs and also on alcohol-induced hangover by using the POMS questionnaire. 1 Profile of mood states questionnaire is a selfadministered questionnaire and the objective of POMS is to measure the effects on mood of various therapeutic approaches. One limitation of the POMS questionnaire is that the complete POMS has 65 different questions, perhaps a few too many to evaluate and therefore an abbreviated version, which included 1 questions was used for this study. The volunteers were asked these 1 questions in the local language (Kannada) by the investigators next morning, after the blood was withdrawn (before breakfast). The volunteers were asked to tick-mark on a paper, on which checking boxes of 1 cm length were drawn, which was calibrated every cms. One end of the Table 4: Mean overall hangover score in the "PartySmart" and "Compared drug" s Minimum 1 1 Maximum 3 Mean 1..4 Standard deviation Standard error..4 Lower 99% CI of mean Upper 99% CI of mean t=.683, R =.4737, p=.78; S Mean hangover score t=.683, R =.4737, p=.78; S PartySmart Compared drug Figure 4: Severity of the "Mean Hangover Score" in the "PartySmart" and "Compared drug" s

6 row was marked as one and the other end was marked as 5. The volunteer's were asked to tick-mark on that predefined scale in the particular box, rating each question in the following manner: 1 = strongly disagree; = disagree; 3 = neutral; 4 = agree; 5 = strongly agree. The POMS questionnaire, which was used to evaluate the alcoholinduced hangover state in this study included the following 1 questions to evaluate the concerned parameter: (a) "Tension" - Do you feel emotionally stretched out or as being under some kind of unusual nervous strain or pressure? (b) "Anxiety" - Do you have a feeling of being generalized and vague, uneasy or apprehensive? (c) "Depression" - Do you have a feeling Table 5: Mean blood alcohol levels (mg/dl) after hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± (N=5) 31. ± 4.49 (N=5) drug Difference between means ± % confidence interval to 5.7 t=.7179, R =.65, p=.4933; NS Mean blood alcohol levels (mg/dl) PartySmart t=.7179, R =.65, p=.4933; NS Compared drug Figure 5: Mean blood alcohol levels after hours in the "PartySmart" and "Compared drug" s of sadness or helplessness? (d) "Dejection" - Are you feeling somewhat hopeless with low spirits? (e) "Anger" - Do you have a feeling of generalized displeasure or irritation or hostility about things happening around you? (f) "Hostility" - Do you have a feeling of nonspecific or generalized aggressiveness? (g) "Activity" - Are you feeling energetic and lively enough, as you feel usually? (h) "Vigor" - Do you have enough strength of the body and mind for your routine activities? (i) "Fatigue" - Do you feel physically and mentally tired due to exertion? (j) "Inertia" - Do you feel like lacking enough inclination and willingness, for your routine daily activities? (k) "Confusion" - Do you feel strange or impaired regarding time, place or people around you? (l) "Bewilderment" - Are you feeling too disturbed due to inability to understand or comprehend these questions? 13 Each volunteer also indicated the severity of each symptom experienced during the alcohol-induced hangover, on a predefined symptom score scale, and another visual analogue score scale. 14 The physical parameters for the evaluation of hangover included (1) headache, () facial and dermal flushing, (3) nausea, (4) burning sensation in the stomach, (5) tachycardia, (6) body ache, (7) burning sensation in the eyes, (8) drowsiness and (9) overall feelings (euphoric / dysphoric and fresh / lousy). The volunteer's were asked to tick-mark on these predefined score scales in the rating each symptom in the following manner: 1=nil; =negligible; 3=mild; 4=moderate; 5=severe. The final hangover scores was derived after averaging the scores of POMS, symptom score scale, and visual analogue score scale. Primary and secondary endpoints The predefined primary endpoints were the difference in hangover scores, physical parameters and blood and urinary alcohol and acetaldehyde 55

7 levels. The primary outcome measures were assessed after and 1 hours after alcohol exposure, on the next day. The predefined secondary endpoints were mood (as measured by the POMS questionnaire), reduced incidence of adverse effects and overall compliance to the drug under investigation. Intercurrent illness and concomitant medication The investigators recorded any information about intercurrent illness, therapeutic interventions and concomitant medication. Antacid or any other drug given for symptomatic relief from acute alcohol-induced gastritis was allowed concomitantly with the study medication. Adverse events All the adverse events reported by the subjects or observed by the investigators were recorded with information about severity, date of onset, duration and action taken regarding study drugs. Relation of adverse events to study medication was predefined as "Unrelated" (A reaction that does not follow a reasonable temporal sequence from the administration of the drug), "Possible" (follows a known response pattern to the suspected drug; but could have been produced by the subject's clinical state or other modes of therapy administered to the subject) and "Probable" (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the subject's clinical state). Analysis of data The data analyst was blind to the treatment allocation and the analysis was performed according to intent-totreat principles. The "independent sample's unpaired 't' test" was used to compare both the s for baseline parameters, predefined amount of alcohol to induce hangover, actual 56 alcohol consumption and changes in various biochemical parameters. A two-sided p value of less than.5 was considered significant and a power of 8% was considered for this trial. RESULTS There were 5 volunteers in the PartySmart and compared drug. There was no significant difference in the age and BMI in both the s (t=.1671, R =.348, p=.8714; NS) (Table 1 and Figure 1). Similarly, there was no significant difference in the mean predefined amount of alcohol consumption to experience the hangover (t=.63, R =.63, p=.8417; NS) (Table and Figure ), and also in the mean amount of alcohol actually consumed by the volunteers during the study Table 6: Mean blood alcohol levels (mg/dl) after 1 hours in the "PartySmart" and "Compared drug" s Minimum.57.4 Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ±.145 (N=5) ± (N=5) drug Difference between means ± % confidence interval to t=3.94, R =.5756, p=.11; S Mean blood alcohol levels (mg/dl) t=3.94, R =.5756, p=.11; S PartySmart Compared drug Figure 6: Mean blood alcohol levels after 1 hours in the "PartySmart" and "Compared drug" s

8 period (t=.48, R =.41, p=.6938; NS) (Table 3 and Figure 3) from the both s. There was a significant difference in the mean overall hangover score, which was significantly higher in the compared drug, as compared to the PartySmart (t=.683, R =.4737, p=.78; S) (Table 4 and Figure 4). There was no significant difference in both the s, in the mean blood alcohol levels after hours (t=.7179, R =.65, p=.4933; NS) (Table 5 and Figure 5); but there was a blood alcohol levels after 1 hours (t=3.94, R =.5756, p=.11, S) (Table Table 7: Mean blood acetaldehyde levels (µg/dl) after hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± (N=5) ± (N=5) drug Difference between means ± % confidence interval -8.6 to t=4.786, R =.741, p=.14; HS Mean blood acetaldehyde levels (µg/dl) PartySmart t=4.786, R =.741, p=.14; HS Compared drug Figure 7: Mean blood acetaldehyde levels after hours in the "PartySmart" and "Compared drug" s 6 and Figure 6). There was a highly significant difference in both the s, in the mean blood acetaldehyde levels after hours (t=4.786, R =.741, p=.14; HS) (Table 7 and Figure 7) and after 1 hours (t=3.147, R =.5531, p<.1; HS) (Table 8 and Figure 8). There was a significant difference in both the s, in the mean urinary alcohol levels after hours (t=.349, R =.483, p=.467, S) (Table 9 and Figure 9) and there was a urinary alcohol levels after 1 hours (t=3.987, R =.665, p=.1; S) (Table 1 and Figure 1). There was no significant difference in both the s, in the mean urinary acetaldehyde levels after hours (t=1.467, R =.119, p=.187; NS) (Table 11 and Figure 11) and there was a significant difference in the same after 1 hours (t=3.331, R =.5811, p<.14; S) (Table 1 and Figure 1). There were no clinically significant adverse reactions, either observed by the investigators or reported by the volunteers, in the both s and overall compliance was good. DISCUSSION The ADH and ALDH enzymes influence alcohol metabolism. Alcohol dehydrogenase is located almost exclusively in cell cytoplasm, and its exhibited as different molecular forms (isoenzymes), and the highest ADH concentration is in the liver (8-9%). Alcohol dehydrogenase isoenzymes in non-hepatic tissues have lower affinity for alcohol and their contribution to overall alcohol metabolism is minimal. The alcohol not acted upon by hepatic ADH, enters systemic circulation and the "blood alcohol cycle" (hepatic arteryliver-hepatic vein-inferior vena cavaheart) is continued until all alcohol is metabolized, by an oxidationreduction reaction (Figure 13). All people do not experience 57

9 hangovers and one population that might provide some insight into the hangover, is that of individuals of Asian heritage. Certain Asians have lower rates of alcohol use and alcoholism, which is associated with a mutation in the ALDH gene. Asians with ALDH alleles drink less and are less likely to be alcoholic than those Asians without this mutation. Following alcohol ingestion, they exhibit more intense reactions to alcohol and generate higher levels of acetaldehyde. 18 Cyanamide is a potent inhibitor of ALDH and is used for the treatment of chronic alcoholism. In the presence of alcohol, cyanamide causes an accumulation of acetaldehyde, with unpleasant side effects, and a similar accumulation is seen in some oriental people with low ALDH activity. Kinoshita et al. investigated the effects of alcohol and cyanamide coadministration, on the activation of the HPA axis (using in-situ hybridization histochemistry and radioimmunoassay). Alcohol and cyanamide coadministration resulted in a significant increase in corticotrophin-releasing factor and arginine vasopressin mrna in the paraventricular nucleus, and proopiomelanocortin mrna in the anterior pituitary, while the levels of pro-opiomelanocortin mrna in the anterior pituitary decreased. Plasma corticosterone concentrations were also significantly elevated and the blood concentration of acetaldehyde in the ethanol and cyanamide increased significantly. These results suggest that acetaldehyde, induced by blocking ethanol metabolism, is able to activate the HPA axis operating through a central mechanism. 19 In an experimental study, Quintanilla et al. had found the existence of a relation between the activity of the brain mitochondrial ALDH and consumption of ethanol in rats of the low-alcohol-drinking and the high-alcohol-drinking strains. The 58 aim of the present study was to determine whether the low-alcoholdrinking and the high-alcoholdrinking rats also differed in sensitivity to the aversive effects of acetaldehyde. Aversion to acetaldehyde was studied by using a CTA paradigm. A strong dosedependent CTA to acetaldehyde was found in the low-alcohol-drinking rats, whereas the high-alcoholdrinking rats did not show a CTA to any dose of acetaldehyde. At equal doses of acetaldehyde, cerebral venous blood acetaldehyde levels in the low-alcohol-drinking rats were consistently higher than in the highalcohol-drinking rats, a finding that may reflect the previously observed differences in the activity of ALDH between these strains. These results support the suggestion that, Table 8: Mean blood acetaldehyde levels (µg/dl) after 1 hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ±.6 N=5 3.5 ± N=5 drug Difference between means 18.4 ± % confidence interval to 38.5 t=3.147, R =.5531, p<.1; HS Mean blood acetaldehyde levels (µg/dl) t=3.147, R =.5531, p<.1;hs PartySmart Compared drug Figure 8: Mean blood acetaldehyde levels after 1 hours in the "PartySmart" and "Compared drug" s

10 differences in central or systemic effects of acetaldehyde play a major role in determining the aversion to acetaldehyde in drinker and nondrinkers. There is some recent evidence that acute/chronic alcohol toxicity is mediated primarily via the generation of free radicals in various tissues, and by spectroscopic analysis, these studies have demonstrated that alcohol-induced free radicals increase the levels of indirect markers of oxidative damage in tissues (e.g. lipid peroxides and protein carbonyl), alongwith endogenous tissue antioxidants, by a complex interactive process. The classical pathway for ethanol metabolism, catalysed by ADH to form acetaldehyde results in the formation of free radicals (resulting from concomitant changes Table 9: Mean urinary alcohol levels (mg/dl) after hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± 1.69 (N=5) ± 11.3 (N=5) drug Difference between means 6.19 ± % confidence interval to t=.349, R =.483, p=.467; S Mean urinary alcohol levels (mg/dl) t=.349, R =.483, p=.467; S PartySmart Compared drug Figure 9: Mean urinary alcohol levels after hours in the "PartySmart" and "Compared drug" s in NADH levels and NADH/NAD+ redox ratios, which in turn modulate the activity of the free radical generating enzyme (xanthine oxidase)). The induction of cytochrome P45 E1 in the microsomes results in the generation of hydroxyethyl radicals (HER), another major route by which ethanol induces free radical formation. In addition to the above, ethanol also induces free radical formation via the reaction of aldehyde oxidase with acetaldehyde, or NADH (to generate oxyradicals via disturbance in the metabolism of the pro-oxidant iron), or via increased efflux from mitochondria following altered mitochondrial oxidative metabolism 1 (Figure 14). There are various studies in which different methodologies have been used to evaluate the phenomenon of alcohol-induced hangover. In a study done by Bendtsen et al., healthy social drinkers drank 5-8 gms of ethanol in the evening over hours, with a meal. At the end of drinking, at bedtime, in the following morning after waking-up, during the morning and at early afternoon, breath-alcohol tests were performed and samples of urine were collected for analysis of ethanol, methanol, and 5-HTOL to 5- HIAA ratio. The participants were also asked to quantify the intensity of hangover symptoms on a scale from (no symptoms) to 5 (severe symptoms). The first morning urine void, which was collected 6-11 hours after bedtime contained measurable amounts of ethanol and the corresponding breath-alcohol concentrations were (except for three individuals who registered.1-.9g/l). Ethanol was not measurable in urine samples collected later in the morning and early afternoon. The peak urinary methanol occurred in the first morning void, when the mean concentration after 8 g ethanol was approximately 6-fold higher than predrinking values. This compares with 59

11 an approximately 5-fold increase for the 5-HTOL/5-HIAA ratio in the first morning void. Both methanol and the 5-HTOL/5-HIAA ratios remained elevated above pre-drinking baseline values in the nd and even the 3rd morning voids. Most subjects experienced only mild hangover symptoms after drinking 5 g ethanol, but the scores were significantly higher after drinking 8 g. A highly significant correlation was found between the presence of hangover symptoms and the urinary methanol concentration in the morning voids, whereas 5-HTOL/5-HIAA correlated with hangover symptoms. These results support that methanol is an important factor in the etiology of hangover. Nagy et al. compared the effects of alcoholic drinks rich in fusel oil with the effects of diluted pure alcohol of the same quantity on 19 clinically healthy university students. The investigations utilized EEG and physiopsychic testing methods. The clinical symptoms were observed both under the effect of drinks and during hangover. It was found that alcoholic drinks rich in fusel oil can produce a more deviating EEG curve, an increased worsening of physiopsychic performance and hangover symptoms. 3 The impairing effects on memory functioning after alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. Verster et al. did a single blind study, amongst 48 healthy volunteers in which an evening (baseline) session of alcohol drinking (ethanol 1.4 g/kg or placebo). Memory was tested with a "word-learning test" (immediate and delayed recall, and recognition). Further, a 45-min "Mackworth clock test" for measuring vigilance was included (parameters: number of hits 6 and false alarms). The subjective alertness was assessed, to infer whether "word-learning test" findings reflect specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol, as compared to the placebo ; and in contrast, immediate recall and recognition were unimpaired in the alcohol. In the morning session, subjective alertness was significantly reduced in the alcohol. However, in the "Mackworth clock test", the alcohol and placebo did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. 4 Kauhanen et al. studied the Table 1: Mean urinary alcohol levels (mg/dl) after 1 hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± 1.33 (N=5) 37.5 ± 7.9 (N=5) drug Difference between means 8.77 ± % confidence interval 4.56 to 5.98 t=3.987, R =.665, p=.1; S Mean urinary alcohol levels (mg/dl) t=3.987, R =.665, p=.1;s PartySmart Compared drug Figure 1: Mean urinary alcohol levels after 1 hours in the "PartySmart" and "Compared drug" s

12 relation between frequent hangovers and cardiovascular mortality in a representative population sample of middle-aged Finnish men who participated in the "Kuopio Ischemic Heart Disease Risk Factor Study". Complete data on alcohol consumption, hangover frequency, prior cardiovascular diseases, and risk factors were obtained for,16 nonabstinent men. Frequent hangovers were rare in the 3 lowest alcohol consumption quartiles, but in the highest quartile, a total of 39 men (43.6%) reported having a hangover at least monthly. During an average follow-up time of 6.7 years, these men had a.36 fold risk of cardiovascular death compared with men with fewer hangovers, with adjustment for age and total alcohol consumption. Systolic blood pressure, BMI, resting Table 11: Mean urinary acetaldehyde levels (µg/dl) after hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± (N=5) 3.91 ± 4.38 (N=5) drug Difference between means ± % confidence interval to 15.1 t=1.467, R =.119, p=.187; NS Mean urinary acetaldehyde levels (µg/dl) PartySmart t=1.467, R =.119, p=.187; NS Compared drug Figure 11: Mean urinary acetaldehyde levels after hours in "PartySmart" and "Compared drug" s heart rate, or serum lipids had no appreciable role in the relation, but plasma fibrinogen concentration appeared as one possible pathway to increased risk of cardiovascular death in men who frequently experience hangovers. The findings underline the importance of preventive actions regarding not only the amount but also the way people consume alcohol. 6 Previous work suggests that sons of alcoholics report greater hangover symptoms than do sons of nonalcoholics. In a study done by Span et al., examination of the relation between personality risk for alcoholism and hangover was done. Twenty sons of alcoholics and sons nonalcoholics completed the "MacAndrew scale" as an index of personality risk for alcoholism. They also completed the "McCaul et al." 5-8 and "Newlin and Pretorious" 9 assessments of hangover after consuming a placebo in one session and alcohol (.5 g/kg) in subsequent consecutive sessions. Data revealed that main effects for familial risk for both hangover questionnaires and sons of alcoholics reported significantly greater hangover symptoms than did sons of nonalcoholics. Individuals at elevated familial risk for alcoholism reportedly experienced more acute withdrawal and hangover, which might contribute to the development of problem drinking. 3 This study used the POMS questionnaire, which was developed in 1971, for people undergoing counseling or psychotherapy; and it quickly gained popularity. The objective of POMS is to measure the effects of various therapeutic approaches on mood. The POMS questionnaire is used extensively in athletics to evaluate the impact of training and to control overtraining. Increases in training load are associated with a decrease in vigor and increase in fatigue, and these two states exhibit the largest and fastest 61

13 change in response to staleness. Additionally, mood disturbance increases with decreased performance and increased muscle soreness. This study observed a significant difference in the mean overall hangover score, which was significantly lower in the PartySmart than in the compared drug. Though there was no blood alcohol and acetaldehyde levels after hours in both the s, after 1 hours, there was a significant difference in the mean blood alcohol levels and a highly significant difference in the mean blood acetaldehyde levels. There was a urinary alcohol levels after hours, and also after 1 hours, in both s. There was no significant difference in the mean urinary acetaldehyde levels after hours in both s and a significant difference in the mean urinary acetaldehyde levels after 1 hours in both s. These beneficial effects of PartySmart might be due to the synergistic actions of the ingredients of PartySmart. The administration of PartySmart caused higher blood alcohol levels after hours, (possibly by inhibiting the presystemic metabolism of alcohol), and the blood acetaldehyde levels were also found to be higher. The rapid lowering of acetaldehyde concentration in the blood is reflected in significantly in the higher excretion of acetaldehyde in the urine over a 1- hour period. 31 These results suggest that PartySmart may prevent the binding of acetaldehyde to cell proteins, causing a higher initial blood level and a subsequent rapid elimination. Lower levels of alcohol and acetaldehyde in the blood at 1 hours were reflected in the decreased symptom scores and the change in the visual analogue score. These observations are indicative of a 6 reduced hangover after PartySmart pretreatment. In the other drug, increase in POMS scores for mood states indicated that the alcohol challenge had the anticipated effect. In previous studies with PartySmart, lower alcohol and higher acetaldehyde concentrations were reported in chronic alcohol users, and one study confirmed that regular users of alcohol had lower blood alcohol concentrations. This was interpreted to signify the inhibition of the presystemic metabolism of alcohol, as chronic ingestion of alcohol causes induction of enzymes involved in alcohol metabolism. The same study evaluated cognitive functions after a standard drinking session before and after treatment for weeks with a similar herbal formulation, and cognitive functions showed less Table 1: Mean urinary acetaldehyde levels (µg/dl) after 1 hours in the "PartySmart" and "Compared drug" s Minimum Maximum Mean Standard deviation Standard error Lower 99% CI of mean Upper 99% CI of mean ± (N=5) 5.77 ± 6.57 (N=5) drug Difference between means ± % confidence interval to.69 t=3.331, R =.5811, p<.14; S Mean urinary acetaldehyde levels (µg/dl) PartySmart t=3.331, R =.5811, p<.14; S Compared drug Figure 1: Mean urinary acetaldehyde levels after 1 hours in "PartySmart" and "Compared drug" s

14 NAD + NADH + H + NAD + NADH + H + CH3CHOH (Ethanol) ADH CH3CHO CH3COOH (ACA) (Acetate) ALDH 4-MP Cyanamide Cytosol Mitochondrial matrix Figure 13: ADH/ALDH pathway Figure 14: Acetaldehyde interactions impairment after drug pretreatment. These findings suggest that the rapid elimination of acetaldehyde might be responsible for this effect. 3,33 There were no clinically significant adverse reactions, either observed by investigators or reported by the volunteers in the PartySmart and the overall compliance to PartySmart was found to be excellent. CONCLUSION Recent studies suggest that the alcohol hangover induces cardiovascular and psychomotor morbidity independent of the quantity of alcohol consumed or the frequency of ingestion. PartySmart Acetaldehyde Menadione Aldehyde oxidase Xanthine oxidase Allopurinol Increase in reactive oxygen species is a polyherbal formulation and some studies have shown that PartySmart is useful in preventing alcohol-induced hangover and PartySmart pretreatment, before alcohol ingestion was associated with rapid elimination of alcohol and acetaldehyde. This study was planned to evaluate the comparative efficacy and safety of PartySmart in the prevention of the alcohol-induced hangover symptoms, with one of the formulations promoted as a cure for alcoholinduced hangover. This study observed a significant difference in the mean overall hangover score, which was significantly lower in the PartySmart than in the compared drug. Though there was no blood alcohol and acetaldehyde levels after hours in both the s, after 1 hours, there was a significant difference in the mean blood alcohol levels and a highly significant difference in the mean blood acetaldehyde levels. There was a urinary alcohol levels after hours, and also after 1 hours, in both s. There was no significant difference in the mean urinary acetaldehyde levels after hours in both s and a significant difference in the mean urinary acetaldehyde levels after 1 hours in both s. These beneficial effects of PartySmart might be due to the synergistic actions of the ingredients of PartySmart. These results suggest that PartySmart may prevent the binding of acetaldehyde to cell proteins, causing a higher initial blood level and subsequent rapid elimination. Lower levels of alcohol and acetaldehyde in the blood at 1 hours were reflected in the decreased symptom scores and the change in the 63

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