Patent Application
20210205400
This disclosure generally relates to an extract of Alpinia galanga. The embodiments further include a method for preparing an extract of Alpinia galanga and methods of administering an extract of Alpinia galanga to improve cognitive performance.
Alpinia galanga is a plant related to ginger and is found in various parts of Southeast Asia. It is used in cooking, particularly the rhizome of the plant. There are some folk medicine uses of Alpinia galanga for treating colds. Other uses of Alpinia galanga include treating pain, treating digestive ailments, and treating infections. The extract of Alpinia galanga rhizomes includes phenolic compounds and flavanoids.
Many people use stimulants such as caffeine, or energy drinks, to improve mental function, including improved attention. However, caffeine and energy drinks are known to have side effects such as a “crash,” which results in a less-stimulated state as compared to before their consumption. Despite their side effects, caffeine and energy drinks are widely available and frequently used for their stimulant effect.
Various extraction and isolation processes may be used to substantially alter the characteristics and amounts of the chemical components of the naturally occurring plant. These processes may concentrate or remove various chemicals to form non-naturally occurring compositions. For example, Alpinia galanga extracts may be prepared using alcohol solvents.
In view of the foregoing, it would be desirable to provide a product that improves cognitive performance without side effects.
In light of the present need for a product to improve cognitive performance and an aqueous extract of Alpinia galanga, a brief summary of various embodiments is presented. Some simplifications and omissions may be made in the following summary, which is intended to highlight and introduce some aspects of the various embodiments, but not to limit the scope of the disclosed formulation, extraction process, and use. Detailed descriptions of embodiments adequate to allow those of ordinary skill in the art to make and use the inventive concepts will follow in later sections.
Various embodiments relate to a formulation that includes an effective amount of an extract of Alpinia galanga that is free of methyl eugenol; a method of improving cognitive performance by administering a formulation containing an effective amount of an extract of Aplinia galanga that is free of methyl eugenol; and processes for preparing an extract of Alpinia galanga that is free of methyl eugenol.
The formulation may be in the form of commonly used formulations, including, but not limited to: a tablet, a capsule, a lozenge, a film, a powder, a sustained release formulation, a liquid formulation, a parenteral formulation, an inhaled formulation, a lyophilized formulation, a suppository, and a topical formulation. The formulation may also include commonly used nutraceutical dosage forms, including, but not limited to: functional foods and beverages, energy shots, energy bars, energy drinks, and performance supplements. The formulation may further include an excipient, such as a pharmaceutically acceptable excipient. In some embodiments, the formulation includes an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has a ratio of polyphenols to polysaccharides of about 1:1.6 to about 1:6. In another aspect, the ratio of polyphenols to polysaccharides is about 1:1.6 to about 1:2.2. In another aspect, the ratio of polyphenols to polysaccharides is about 1:5 to about 1:6. In another aspect, the ratio of polyphenols of polysaccharides is about 1:5 to about 1:12. In some embodiments, the formulation includes an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has 1% pyrocatecollic type tannins. In some embodiments, the formulation includes an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has not more than 100 ppm galangin. In some embodiments, the formulation includes 100-900 mg of an extract of Alpinia galanga that is free of methyl eugenol. In other embodiments, the formulation includes 300 mg of an extract of Alpinia galanga that is free of methyl eugenol.
In other embodiments, an effective amount of an extract of Alpinia galanga that is free of methyl eugenol is administered to a mammal to improve cognitive performance. In some embodiments, the effective amount of the extract of Alpinia galanga that is free of methyl eugenol is administered to a human. In some embodiments, administering the effective amount of the extract of Alpinia galanga that is free of methyl eugenol improves mental alertness, increases attention, decreases mean response time, decreases mental fatigue, improves sustained wakefulness, or any combinations of these effects. In one aspect, administering the effective amount of the extract of Alpinia galanga that is free of methyl eugenol in combination with caffeine impedes caffeine crash. Some embodiments include administering an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has a ratio of polyphenols to polysaccharides of about 1:1.6 to about 1:6. In another aspect, the ratio of polyphenols to polysaccharides is about 1:1.6 to about 1:2.2. In another aspect, the ratio of polyphenols to polysaccharides is about 1:5 to about 1:6. In another aspect, the ratio of polyphenols to polysaccharides is about 1:5 to about 1:12. Some embodiments include administering an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has 1% pyrocatecollic type tannins. Some embodiments include administering an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and has not more than 100 ppm galangin. In some embodiments, the effective amount is 100-900 mg of an extract of Alpinia galanga that is free of methyl eugenol. In other embodiments, the effective amount is 300 mg of an extract of Alpinia galanga that is free of methyl eugenol.
Other embodiments include the preparation of an extract of Alpinia galanga that is free of methyl eugenol. In one embodiment, the process includes the steps of:
a) powdering and sieving the dried rhizome of Alpinia galanga to produce a product,
b) extracting the product of Step a with an aqueous solvent to produce a product,
c) concentrating the product of Step b under vacuum to produce a product,
d) drying the product of Step c under vacuum to produce a product,
e) pulverizing the product of Step d.
In some embodiments, the aqueous solution of Step b is added at four times the amount of the dried rhizome of Step a. In some embodiments, Step b further includes the step of soaking the product of Step a in water at 0-25° C. for 8-10 hours and also includes the steps of extracting for a cycle of 5-6 hours in an aqueous solvent at 70-80° C. and a pressure of 1-10 bars. In some embodiments, the process includes repeating the extraction for 5-6 hours at 70-80° C. for two additional cycles. In some embodiments, Step c is performed at 70-80° C., under vacuum. In some embodiments, Step d is performed at 80-90° C. and a vacuum pressure of 650 mm Hg for a period of 6-8 hours. In some embodiments, Step e includes pulverizing the product of Step d with silicon dioxide.
It should be apparent that, in this manner, various embodiments enable formulations containing an extract of Alpinia galanga that is free of methyl eugenol; methods of administering a formulation containing an extract of Alpinia galanga that is free of methyl eugenol to improve cognitive performance; and a process for preparing an extract of Alpinia galanga that is free of methyl eugenol.
Various embodiments disclosed herein relate to a methof for decreasing stress in a human subject in need thereof, providing increased calmness in the human subject, or reducing physical and mental fatigue in the human subject. The method includes administering a formulation to the human subject, wherein the formulation comprises:
In some embodiments, the formulation may also contain 0-300 mg, 50-275 mg, 100-250 mg, 150-225 mg, or 175-225 mg of caffeine. The formulation may contain no caffeine, but may be administered in conjunction with a separate composition comprising 50-300 mg caffeine. Administration of the formulation causes decreased stress or increased calmness in the human subject. The water extract of Alpinia galanga is soluble in a solvent selected from the group consisting of water, an alcohol, and a combination thereof.
Various embodiments disclosed herein relate to a methof for increasing accuracy and at same time reducing error in a human subject engaged in performing a task, improving an ability of the human subject to perform multiple tasks simultaneously (multitasking), or both. The method includes administering a formulation to the human subject, wherein the formulation comprises:
Administration of the formulation increases accuracy when performing a task, improves ability to perform multiple tasks, or both. The water extract of Alpinia galanga is soluble in a solvent selected from the group consisting of water, an alcohol, and a combination thereof.
Various embodiments disclosed herein relate to a methof for increasing fluid intelligence in a human subject in need thereof. The method includes administering a formulation to the human subject, wherein the formulation comprises:
In some embodiments, the formulation may also contain 0-300 mg, 50-275 mg, 100-250 mg, 150-225 mg, or 175-225 mg of caffeine. The formulation may contain no caffeine, but may be administered in conjunction with a separate composition comprising 50-300 mg caffeine. Administration of the formulation increases fluid intelligence in the human subject. The water extract of Alpinia galanga is soluble in a solvent selected from the group consisting of water, an alcohol, and a combination thereof.
In the various methods disclosed herein, the extract of Alpinia galanga is free of methyl eugenol, and may include at least one of:
In the various methods disclosed herein, the carrier may be selected from the group consisting of microcrystalline cellulose, maltodextrin, and a combination thereof.
The first aspect of the disclosure is a formulation that includes an effective amount of an extract of Alpinia galanga that is free of methyl eugenol and a pharmaceutically acceptable excipient. The formulation may be any type of pharmaceutically acceptable formulation that is used to dose an active agent. Examples of pharmaceutically acceptable formulations include: tablets, capsules, lozenges, films, powders, sustained release formulations, liquid formulations, parenteral formulations, inhaled formulations, lyophilized formulations, suppositories, and topical formulations. In one embodiment, the formulations include oral dosage forms, i.e., tablets, capsules, and sustained release formulations. In another embodiment, the formulation is a capsule. In one aspect, the capsule may include granules of Alpinia galanga that is free of methyl eugenol and a granulating polymer.
The pharmaceutically acceptable excipient may be a binder, a diluent, a filler, a disintegrant, a lubricant, a glidant, a coating, a flavoring, a buffer, or combinations thereof. In one embodiment, the pharmaceutically acceptable excipient is microcrystalline cellulose. In another embodiment, the pharmaceutically acceptable excipient is maltodextrin.
The formulation may also include commonly used nutraceutical dosage forms, including, but not limited to: dietary and nutritional supplements, functional foods and beverages, energy shots, energy bars, energy drinks, performance supplements, and sports products.
In one embodiment, the effective amount of the extract of Alpinia galanga that is free of methyl eugenol is 300 mg. However, the safe and effective amount of the extract of Alpinia galanga that is free of methyl eugenol includes any amount that has the desired effect, i.e., improvement in cognitive performance. In other embodiments, the effective amount may include 100-900 mg of the extract of Alpinia galanga that is free of methyl eugenol.
In other embodiments, the extract of Alpinia galanga that is free of methyl eugenol may include one or more of the following characteristics: having a ratio of polyphenols to polysaccharides of about 1:1.6 to about 1:12; including 1% pyrocatecollic type tannins; including not more than 100 ppm galangin; or combinations of these characteristics.
The Alpinia galanga extract that is free of methyl eugenol includes polyphenolic compound and polysaccharides. In one embodiment, the ratio of polyphenols to polysaccharides is about 1:1.6. In another embodiment, the ratio of polyphenols to polysaccharides is about 1:2.2. In another embodiment, the ratio of polyphenols to polysaccharides is about 1:5. In another embodiment, the ratio of polyphenols to polysaccharides is about 1:6. In another embodiment, the ratio of polyphenols to polysaccharides is about 1:12. As discussed below, the process for extraction of Alpinia galanga that is free of methyl eugenol may be performed with cold water, i.e., water at a temperature of 0-25° C. In other embodiments, the extraction may be performed using hot water (e.g., 70° C. or 80° C.) or using methanol. The amounts of polyphenols and polysaccharides produced by each method are shown in Table 1 below:
As shown by these data, the ratio of polyphenols to polysaccharides is markedly different when cold water is used as the extraction solvent as compared to when hot water is used. In particular, the polyphenol content is relatively low while the polysaccharide content is significantly higher. Therefore, the ratio of about 1:5 is different using cold water as compared to a ratio of 1:1.6 or 1:2.2 using hot water. The use of methanol as an extraction solvent results in a ratio of 1:11.9. Accordingly, using cold water to extract Alpinia galanga results in a ratio of polyphenols to polysaccharides that is distinct from the ratio derived from using other methods.
In another embodiment, the extract of Alpinia galanga is free from methyl eugenol. In one aspect, the extract does not include any detectable amount of methyl eugenol. In another aspect, the extract includes less than 1 ppm of methyl eugenol. Methyl eugenol is a methyl ester of eugenol that may be found in some essential oils. It is also used as a flavoring, a fragrance, and an anesthetic in rodents. However, methyl eugenol has been found to be mutagenic in animals and therefore may be carcinogenic to humans. Accordingly, the Alpinia galanga extract is free of methyl eugenol.
In another embodiment, the extract of Alpinia galanga that is free of methyl eugenol has 1% pyrocatecollic type tannins. In another embodiment, the extract of Alpinia galanga that is free of methyl eugenol has not more than 100 ppm galangin.
In the second aspect of the disclosure, a formulation containing an effective amount of the extract of Aplinia galanga that is free of methyl eugenol is administered to improve cognitive performance. An improvement in cognitive performance includes, but is not limited to: improved mental alertness, increased attention, decreased mean response time, decreased mental fatigue, impeded caffeine crash, improved sustained wakefulness, and combinations thereof. Therefore, any administration of an effective amount of an extract of Alpinia galanga that is free of methyl eugenol that results in the foregoing effects, or similar effects, is encompassed by the present disclosure.
According to a study described below, in Example 1, the water-soluble extract of Aplinia galanga that is free of methyl eugenol shows increased improvement of cognitive performance as compared to a water-insoluble extract. The data further show the superiority of the water-soluble extract of Alpinia galanga that is free of methyl eugenol as compared to caffeine, placebo, and extracts of other herbs. The mean response time for subjects administered the water-soluble extract of Alpinia galanga that is free of methyl eugenol improved after one hour and after three hours. Further, the water-soluble extract of Alpinia galanga that is free of methyl eugenol improved alertness time after one hour and after three hours.
Without wishing to be bound by any theory, the Applicants believe that the components of the water-soluble extract of Alpinia galanga that is free of methyl eugenol are responsible for the beneficial results. In particular, polyphenols, polysaccharides, and pyrocatecollic type tannins are found in Alpinia galanga. The water-extraction method produced these compounds in ratios and amounts that are distinct from the naturally occurring powder or an alcoholic extraction. Therefore, the superior improvement of cognitive performance may be due to these components.
In another study described below, in Example 2, the effect of an extract of Alpina galanga that is free of methyl eugenol was compared to the effect of caffeine, a composite of an extract of Alpinia galanga that is free of methyl eugenol with caffeine, and placebo. The group administered the extract of Alpinia galanga that is free of methyl eugenol showed improved alertness after one hour, after three hours, and after five hours. The caffeine group showed improvement after one hour but then a reduction as compared to baseline after three hours. This indicates a “caffeine crash.” The composite group showed an improvement after one hour and a return to baseline after three hours, indicating no crash. Therefore, administration of the extract of Alpinia galanga that is free of methyl eugenol in combination with caffeine impedes caffeine crash.
In a third aspect of the disclosure, water is used to extract Alpinia galanga. The extraction process is distinct from extractions using organic solvents. In one embodiment, cold (i.e., 0-25° C.) water is used to extract Alpinia galanga. This embodiment is distinct from extractions using hot water. The extraction process may include the steps of powdering and sieving the dried bark of Alpinia galanga. In one embodiment, the rhizome is used. The powder may then be extracted with an aqueous solution, including water. The extract may then be concentrated under vacuum and dried under a controlled temperature. The dried product is pulverized under a controlled temperature and humidity in order to obtain the extract.
In further embodiments, the aqueous solution is added at four times the amount of the dried rhizome. A first extraction cycle may be performed by soaking the dried rhizome in cold water (i.e., 0-25° C.) for 8 hours. In another embodiment, second, third and fourth extractions are performed for a period of 5-6 hours at temperature of 70-80° C. Without wishing to be bound by any theory, Applicants believe that using four extractions maximizes the recovery of the extracts from the dried rhizome. Additional extraction cycles may be used. The total number of extraction cycles are calculated based on the total dissolved solids in the extract. The collected extract is then distilled at 70-80° C. Distillation stopped after a syrupy material stops bubbling in the distillatory. The product may then be dried under vacuum at 80-90° C. and at a vacuum pressure of 650 mm for 6-8 hours. The dried product may then be pulverized with excipients like silicon dioxide under controlled temperature and humidity conditions, to obtain the desired powder product.
The effect of the Alpinia galanga proprietary extract E-AG-01 (EnXtra®) on focused attention was studied, in comparison with caffeine and placebo in moderate caffeine habitues. Caffeine-habituated healthy young adults (aged 18-40 years) were crossed over in four interventional groups: placebo, E-AG-01, caffeine, and a combination of caffeine and E-AG-01. The results of accuracy parameters in terms of percentage-error rate showed a remarkable difference between E-AG-01 and the other treatment groups, wherein the error rate dropped by 1.63% (1 hour), 1.32% (3 hours), and 0.78% (5 hours) from baseline for the E-AG-01 group. The caffeine group demonstrated a decrease of 0.37% (1 hour) and 0.44% (3 hours), followed by an increase of 0.2% (5 hours), whereas the error rate of subjects in the caffeine +E-AG-01 group decreased by 0.24% (1 hour) and 0.26% (3 hours), followed by an increase of 0.2% at 5 hours. The placebo group exhibited an increase of 0.14% (3 hours) and 0.77% (5 hours). These results show that E-AG-01 selectively enhanced focused attention to a higher extent than caffeine, a combination of E-AG-01 and caffeine, or a placebo.
E-AG-01 improves mental alertness. Enhanced focused attention following E-AG-01 administration may lead to better information-processing speed, possibly due to increased stimulating-neurotransmitter levels and/or enhanced cell signaling by the water-soluble phytoconstituents of A. galanga. EnXtra may help enrich an individual's cognitive functions as well. Administration of E-AG-01 may lead to faster and more focused processing of relevant information, with an improvement in the brain's ability to concentrate for longer periods of time.
Various embodiments disclosed herein relate to a method for decreasing stress in a human subject in need thereof, providing increased calmness in the human subject, or reducing physical and mental fatigue in the human subject. The method includes administering a formulation to the human subject, where the formulation includes 100-900 mg, 125-800 mg, 150-700 mg, 200-600 mg, 225-500 mg, 250-500 mg, 250-450 mg, or 250-350 mg of a water extract of Alpinia galanga that is free of methyl eugenol, and an ingestible carrier. The Alpinia galanga extract may be soluble in a solvent selected from the group consisting ofwater, an alcohol, and a combination thereof. The formulation may also contain 0-300 mg of caffeine. Alternatively, the formulation may be free of caffeine, and may optionally be administered in conjunction with a second composition including up to 300 mg caffeine, e.g., 25-300 mg, 50-275 mg, 100-250 mg, 150-225 mg, or 175-225 mg of caffeine. Alpinia galanga extract and caffeine may be used on a ratio of between 1:3 and 9:1 by weight, between 1:2 and 8:1 by weight, between 1:1 and 4:1 by weight, between 1:2 and 4:1 by weight, between 1:3 and 3:1 by weight, or about 3:2 by weight.
Various embodiments disclosed herein relate to a method for increasing accuracy in a human subject engaged in performing a task, improving an ability of the human subject to perform multiple tasks simultaneously, or both. The method includes administering a formulation to the human subject, where the formulation includes 100-900 mg, 125-800 mg, 150-700 mg, 200-600 mg, 225-500 mg, 250-500 mg, 250-450 mg, or 250-350 mg of a water extract of Alpinia galanga that is free of methyl eugenol, and an ingestible carrier. The Alpinia galanga extract may be soluble in a solvent selected from the group consisting of water, an alcohol, and a combination thereof.
Various embodiments disclosed herein relate to a method for increasing fluid intelligence in a human subject. “Fluid intelligence” is defined as the ability to use logic and solve problems in new or novel situations without reference to pre-existing knowledge. In contrast, “crystallized intelligence” is the ability to use knowledge that was previously acquired through education and experience. Fluid intelligence frequently declines with age, while crystallized intelligence may be maintained or improved. The present disclosure describes methods which allow a human subject, including a mature human subject, to maintain or improve fluid intelligence, i.e., the ability to apply logic to solve new problems creatively. The methods include administering a formulation to the human subject, where the formulation includes 100-900 mg, 125-800 mg, 150-700 mg, 200-600 mg, 225-500 mg, 250-500 mg, 250-450 mg, or 250-350 mg of a water extract of Alpinia galanga that is free of methyl eugenol, and an ingestible carrier. The Alpinia galanga extract may be soluble in a solvent selected from the group consisting of water, an alcohol, and a combination thereof. The formulation may also contain 0-300 mg of caffeine. Alternatively, the formulation may be free of caffeine, and may optionally be administered in conjunction with a second composition including up to 300 mg caffeine, e.g., 25-300 mg, 50-275 mg, 100-250 mg, 150-225 mg, or 175-225 mg of caffeine.
In the various methods disclosed herein, the extract of Alpinia galanga is free of methyl eugenol, and may include:
a ratio of polyphenols to polysaccharides of about 1:1.6 to about 1:12;
1% pyrocatecollic type tannins; and/or
not more than 100 ppm galangin.
In the various methods disclosed herein, the ingestible carrier carrier may be selected from the group consisting of microcrystalline cellulose, maltodextrin, and a combination thereof.
The following study compared the effects Cymbopogon flexuosus (lemongrass, LG), Alpinia galanga (AG1 and AG2), and Glycyrrhiza glabra (licorice, GG1 and GG2) on improving brain performance, mainly by enhancing attention network-related functioning.
Participants
Seventy subjects (male and female) between 18-40 years of age with a body mass index (BMI) of 18-25 kg/m2, a resting blood pressure <140/90 mmHg, and habituated to—average caffeine consumption were considered eligible for inclusion in the study. Only right-handed subjects were included in the study to avoid spatial bias. Subjects had to refrain from caffeine products and vigorous physical activity 12 h prior to the study. As caffeine abstinence tends to increase sleepiness, consequently reducing the alertness score, the included subjects had to have an Epworth's sleeping scale ≥10 indicating low mental alertness during general situations in day-to-day activities at screening and at all visits. The subjects had to refrain from smoking 24 h before study onset and refrain from alcohol intake throughout the study. Subjects with a history or presence of clinically important cardiac, renal, hepatic, endocrine (including diabetes mellitus), pulmonary, biliary, gastrointestinal, pancreatic, or neurological disorders and uncontrolled hypertension were excluded from the study. For each subject, the study was terminated after data collection on the assessment day.
Interventions
On day 1 of assessment, subjects were randomized in one of the arms to receive either the investigational product (IP), comparator (caffeine: CF), or the placebo. The IPs included Cymbopogon flexuosus (LG), water-soluble and water-insoluble extracts of Alpinia galanga (AG1 and AG2 respectively), and water-soluble and water-insoluble extracts of Glycyrrhiza glabra (GG1 and GG2 respectively). All interventions were administered to subjects in the form of identical capsules that had been packed in duly labeled HDPE bottles. The double-blinded nature of the study was ensured and strictly followed. All IPs were standardized for their activity, and the extracts were prepared by elimination of impurities using modern manufacturing techniques. The manufacture extracts and packaging of the finished product were carried out at a GMP-certified contract manufacturing facility in India. To maintain blinding, all the capsules were averaged to a weight of 500 mg. The composition details of all treatments are:
Test Visit Procedure
On day 1 of the assessment, subjects reported to the clinic during the morning hours, and testing began at an early time of day (8:00-9:00 a.m.) for each visit to avoid influence of daily challenges (related to mental and physical stress) on outcomes. The time of day was matched for all visits to reduce variability due to the diurnal pattern. Subjects reported to the clinic after 24 hours of abstinence from caffeine and caffeine-containing products or any psychostimulants prior to all visits during the study. The subjects were also instructed to get sufficient sleep during the night prior to testing, which was self-reported by the participants in a sleep diary. Upon arrival at the clinic, subjects were asked to rest quietly for 15-20 minutes, after which physical examination was done, caffeine history was recorded, and the subjects were asked to fill out an Epworth's sleep scale questionnaire to rate their sleepiness. A standardized meal of approximately 200 calories was provided to control variations from possible digestion confounds. Baseline data on ANT was collected 30 minutes after breakfast followed by administration of the IP. Each dose consisted of two capsules of the product with a glass of water, which was administered to subject by the trial coordinator at the investigational site. After ingestion of IP, data were collected at 1, 3, and 5 hours and controlled for mean response time, alertness, orientation, and executive attention before and after IP administration. No other food or calorie-containing beverages were provided during the five-hour period. The subjects were allowed to drink water as desired and allowed to relax in an isolated room at a comfortable temperature and were free to use a computer, listen to music, or read magazines during the clinic stay period.
From days 2 to 6, participants were advised to take two capsules daily until day 6. On the day 7 visit, subjects followed the exact same schedule as that of day 1: after ingestion of two capsules, the subjects were allowed to rest for 30 minutes and last time point data were collected by ANT. To ensure treatment compliance, product accountability was monitored by a clinical research coordinator on the following visit.
Outcome Measures
The Attention Network Test (ANT) examines the effects of cues and targets within a single reaction time task in order to explore the efficiency of the alerting, orienting, and executive control networks of attention and mean response time with respect to different psychological and physiological states. It also provides an opportunity to examine the brain activity of these three networks as they operate in a single integrated task.
An adaptation of ANT, Centre for Research on Safe Driving Attention Network Task (CRSD-ANT), was used to evaluate the effect of IP on outcome measures.
Primary Efficacy Variables
CRSD-ANT was utilized to assess the effect of IPs on the mean response time (MRT) in milliseconds. Data were used to capture superiority within groups from baseline to each time point on the same day and intergroup comparisons.
Secondary Efficacy Variables
Effects of IPs on different aspects of the attention network, such as alertness, orientation, and executive control, were also assessed by ANT. These parameters are collectively responsible for achieving and maintaining vigilance and alertness while performing a continuous task.
Statistical Analysis
The sample size was calculated using PS: Power and Sample Size Calculation version 3.1.2 (2014). Continuous response variables were analyzed from matched pairs of subjects. In absence of prior data, an assumption was made that the difference in the response of matched pairs is normally distributed with a standard deviation of 2. Considering the mean response of matched pairs is two, at least eight subjects per arm were targeted to reject the null hypothesis that this response difference is zero with a probability (power) of 0.8. The Type I error probability associated with the test of this null hypothesis was 0.1.
All values are presented as means±standard deviation (SD). Statistical analyses were carried out on the data characterized by 95% confidence interval. Variables were tested for normality followed by student's paired t test for intergroup comparisons at different time points. p values of ≤0.05 were considered statistically significant.
Results:
70 subjects were recruited, of which 64 completed the study and 6 were withdrawn due to non-compliance. Analysis was performed on the intention to treat (ITT) population, which included subjects who were administered at least a single dose and for whom at least a single post-baseline assessment was available.
None of the treatment groups showed any significant reduction in response time at 1 h after IP administration. However, subjects in the LG group showed a significant increase in the MRT at 1 h (p=0.01), indicating delayed response. The caffeine group showed an improvement in the MRT at 3 h after IP administration (p=0.06), followed by a reversed trend in response time. The change in the response time in various groups is presented in
Alertness
Among all the treatment groups, only the AG1 group showed a consistent improvement in the alertness time at 1 h (p=0.07) and 3 h (p=0.07) and achieved statistical significance at 5 h (p=0.007), which can be attributed to the reduction in the alertness score in placebo group at 5 h. However, the GG1 group exhibited a significant increase in alertness at 3 h, which slightly dropped at 5 h. Changes in the other groups were not as appreciable.
Orientation
None of the investigated IPs and the comparator demonstrated any significant effect on orientation compared to the baseline. At day 7 after administration of IP, none of the products demonstrated a better effect than placebo.
Executive Attention
None of the interventional groups showed any significant improvement in executive attention compared to placebo at 1, 3, and 5 hours after administration. At day 7, none of the groups showed significant effect on executive attention.
Discussion and Conclusion:
The above data were used to evaluate the efficacy and safety of natural product extracts in subjects with caffeine dependence. Several extracts were screened to elucidate the psychostimulant potential of the selected natural sources. Unlike studies which report findings on the basis of subjective feelings, these data were used to compare the effects of the IPs on different aspects of the attention network using the ANT, which is the only tool to independently analyze the different aspects of the attention network.
Although, change in caffeine group at 3 h did not reach statistical significance, it indicates caffeine's efficacy in reducing the mean response time, thus ascertaining its literature reported effect. This finding also validated the reliability of the ANT as an assessment tool for attention-related studies.
Among the extracts (LG, AG1, AG2, GG1, and GG2), AG1 showed a consistent improvement in alertness at 1, 3, and 5 h as compared to baseline and placebo. This can be attributed to the water-soluble compounds such as polyphenols, pyrocatecollic type tannins, and polysaccharides, abundantly present in A. galanga, which were skillfully extracted in the water-soluble extract.
The neurocognitive effect responsible for improving alertness (observed in the AG1 group) cannot be solely attributed to purine-like alkaloids such as caffeine or theacrine, as AG1 has a rich phytochemical profile in addition to alkaloids. Moreover, the polyphenols and flavonoids of AG1 may be helpful in combating the caffeine-like “crash.”
Data were collected to assess the stimulant effect of A. galanga that is free of methyl eugenol in healthy young volunteers on specific parameters related to attention network and sleep architecture using standardized tests and questionnaires.
The efficacy of the extract of Alpinia galanga that is free of methyl eugenol was analyzed with a principal objective of developing a safe alternative to caffeine for increasing mental alertness and decreasing mental fatigue. The data were used to assess the extract of Alpinia galanga that is free of methyl eugenol as a psycho-stimulant in healthy young volunteers using specific parameters related to important aspects of attention networks and using standardized tests and questionnaires.
Subjects and Methods
Subjects
Subjects were derived through multiple sources including a healthy volunteer's database and a consumer group's survey agency. The subjects were then screened. Subjects were 18-40 years old, male and female, healthy, did not consume alcohol, did not smoke, and had minimal computer literacy. All subjects were predominantly right handed with a history of moderate caffeine consumption (2-4 cups of caffeinated beverages per day). The caffeine history was taken to ensure that the participants were acquainted with caffeine's stimulant effect and were not caffeine-sensitive. The subjects with body mass index (BMI) between 18.50 and 25.00 kg/m2and a resting blood pressure ≤140/90 mm Hg were considered eligible. To avoid subjects with psychotic disorders such as anxiety, depression, ADD or ADHD, subjects with Generalized Anxiety Disorder Screening (GAD-7) score ≥7 & Patient Health Questionnaire-9 (PHQ-9) score ≥14 were excluded from the study. Subjects with alertness score (Jin Fan's Attention Network Test, version 1.3.0) of 50±20 milliseconds at screening visit were considered eligible. Concomitant therapy was strictly prohibited in order to exclude any significant effect on the results. All the subjects were instructed thoroughly on the investigation procedures.
Interventions
Subjects were randomized and allocated to interventional products in each visit, divided in four treatment arms based on randomization chart [SPSS version 10.0, IBM] and similar trend was followed for subsequent visits. The interventional products (IP) include: the Alpinia galanga extract that is free of methyl eugenol (E-AG-01), caffeine, a combination of the Alpinia galanga extract that is free of methyl eugenol with caffeine (Composite) and a placebo. All these treatments were administered to subjects in the form of capsules which were identical in appearance and packed in duly labeled HDPE bottles. The blinding codes were secured at the site in tamper-evident sealed envelopes with no access to the investigators. Thus, the double blind nature of the data were ensured and strictly followed. As subjects in one arm received a combination of caffeine and A. galanga, the subjects receiving solely A. galanga or caffeine or placebo were co-assigned to additional placebo capsule to achieve double dummy design. Composition details of all these IPs are:
Test Visit Procedure
Subjects reported to the clinic during the morning hours and testing began at early time of day (8:00-9:00 a.m.) for each visit to avoid influence of daily challenges (related to mental and physical stress) on outcomes and the time of day was matched for all three visits to reduce variability in response due to diurnal pattern. Subjects reported to the clinic following a 24 hours abstinence from caffeine and caffeine-containing products or any psycho-stimulants prior to all visits to the site. Subjects were also instructed to obtain sufficient sleep during the night prior to testing which was confirmed using sleep diary. Upon arrival at clinic, subjects were asked to rest quietly for 15-20 minutes after which vital parameters were measured and a standardized meal of approximately 200 calories was provided to control variations from possible digestion confounds. Baseline data were collected 30 minutes post breakfast followed by administration of IP, wherein one dose of the product was administered to subject by trial coordinator at investigational site.
Post ingestion of IP, data were collected at 1, 3, and 5 hours. No other food or calorie-containing beverages were provided. Subjects were allowed to drink water as desired. Subjects were allowed to relax in an isolated room at a comfortable temperature and free to use the computer, listen to music or read magazines during the clinic stay period. To analyze the effect on IP on sleep architecture, a second dose was supplied in a labeled bottle to be taken before dinner in the night of the same day and subjects were asked to record all the details pertaining to sleep quality and duration in sleep diary. To ensure treatment compliance, product accountability was monitored by clinical research coordinator on the following visit.
Outcome Measures
The data were used to elucidate investigational product's effect on various psychoactive measures in habitual caffeine consumers. Also, the likelihood of desired synergistic effect to reduce caffeine crash was explored by consuming the Alpinia galanga extract that is free of methyl eugenol and caffeine.
The primary efficacy variable was mental alertness. Alertness is defined as achieving and maintaining a state of high sensitivity to incoming stimuli. The Attention network test (ANT) was implemented for this purpose as it provides a behavioral measure of the efficiency of the different components of attention networks separately within a single task. The downloaded JAVA version of ANT 1.3.0 (Fan et al., 2002, 2005) was used to conduct the trial. The subject was seated in a silent and secluded room. All external distractions were avoided and subjects were asked to give complete attention to the task at hand. Mental alertness in ANT was calculated in terms of difference score quantified in milliseconds and calculated by subtracting average double-cue RTs from the no-cue RTs. Higher score indicates more efficient functioning of the alerting system.
The secondary efficacy variables, namely sustained attention [assessed by Psychomotor Vigilance Task (PVT)], mental fatigue [assessed by Karolinska Sleepiness Scale (KSS) Score], sustained wakefulness (assessed by sleep duration), and sleep pattern [assessed by Groningen's Sleep Quality Scale (SQS) and sleep diary], were also assessed.
The data were used to assess the effect of IP on mean response time using psychomotor vigilance test. A 10-minute computer-based PVT was performed. Subjects were asked to respond by clicking the mouse on first appearance of red colored digit on screen for the duration of 10 minutes. The mean MRT was calculated in milliseconds, which is the time a subject took to press the response button as soon as each stimulus appeared. Lower MRT thus indicates more efficient sustained attention.
Mental fatigue is an indicator of individual's mental or physical performance capability and can impair an individual's alertness and ability to perform a continuous task. The subjects were asked to complete a standardized Karolinska sleepiness scale (KSS) questionnaire for assessment of mental fatigue at first visit to site and then prior to all sessions of ANT and PVT. The questionnaire is a self-defined 10 grade KSS score scale where lower score implies low mental fatigue and higher alertness.
Wakefulness in terms of sleep quality was assessed by Groningen's sleep quality score questionnaire and sleep diary in which sleep quality was graded in the form of a score (SQS) on the scale of 0-14 score. Lower score on this scale indicates higher subjective quality of sleep and vice versa. Subject was asked to fill SQS at all visit to site. They were provided with a sleep diary to fill in the morning immediately on waking up and SQS on the day after IP administration at night. The effect of IP on wakefulness was also assessed by recording the duration of sleep between two assessment sessions. Subject were asked to start the stop watch before taking a nap and to stop it once they are awake or when they are woken up by the investigator for assessment. The stop watch was lapped and re-started if the subject wanted to nap again.
Power Calculation
The trial was designed to demonstrate efficacy of E-AG-01 over placebo. Internal unpublished data show at least 12±3% increase in alertness score in the active arm compared to placebo arm with a type I error (α) of 5%. A sample size of 60 subjects was used to achieve 90% study power, accounting for dropouts &withdrawals (˜20%) as well as non-evaluable subjects for the primary efficacy outcome (˜25%).
Statistical Analysis
Statistical analysis was carried out using SPSS 15.0 for Windows (Chicago, Ill., USA). Variables were tested for normality using the Shapiro-Wilk test. The chi-square test and the student's unpaired t test were applied while comparing different groups of responders for different independent variables. The student's paired t-test was used for the inter-group comparisons at different time points. Multivariate analysis of variance (MANOVA) was used to evaluate the amongst group statistical significance. Further, a repeated two-way ANOVA was performed to investigate the difference in alertness score due to a time treatment interaction. The p value <0.05 was considered as statistically significant at 95% confidence level. The subjects who met all inclusion-exclusion criteria and received at least one dose of each investigational product were considered as “intent to treat” (ITT) population. However, as the neurobehavioral functioning is heavily masked by homeostatic drive for sleep and metabolism, the alertness score is expected to have interpersonal variability. Hence, final analysis was conducted on the per protocol (PP) population, wherein included subjects had baseline alertness score of 50±20 ms at each individual study visit and completed the study visit successfully. The data were segregated based on the four interventional groups before subjecting it to the statistical analyses and represented in a similar manner in the results section.
Continuous variables (age, height, weight and BMI) were summarized by the treatment group using a summary statistics (number of observations, mean and standard deviation). ANOVA was applied to prove the insignificance in demographic characteristics across the four groups. Data pertaining to PHQ-9 and GAD-7 parameters were also evaluated statistically by ANOVA for assessment of within group significance level.
The effect size was calculated by the “Cohen's d” method to determine a clinical relevance of the observed effects in case of statistically significant outcomes.
Results
Study Population
59 subjects met the protocol-defined inclusion-exclusion criteria and were enrolled. Six subjects out of 59 were dropped out, primarily due to consent withdrawal (4/6) or were lost to follow-up (2/6). Two of the withdrawals were attributed to safety concerns.
Further statistical analyses were performed on the data collected from Per Protocol (PP) and Intended to Treat (ITT) populations. PP group represents the subjects whose baseline alertness score matched with protocol specified screening criteria on each baseline alertness score and completed the study successfully. ITT group included the subjects who met all inclusion/exclusion criteria and received at least one dose of each investigational product. Only the results pertaining to PP group are presented and considered to obtain clinically significant outcomes.
Varying number of subjects for some efficacy parameters in PP group is accountable to discarded data for the subjects for whom baseline did not match to protocol specified inclusion-exclusion criteria. Hence, the corresponding data were excluded from the statistical analysis, which did not affect the minimum study power (90%).
All subjects were screened for demographic parameters (age, gender, height, weight and BMI) at screening visit to confirm compliance with the protocol. Analysis of demographic characteristics of all subjects confirmed that there was no significant standard deviation (p>0.05) among the treatment groups. Analysis of baseline characteristics of all subjects analyzed by PHQ-9 and GAD-7 questionnaires confirmed that none of the groups had PHQ-9 and GAD-7 scores beyond the specified range, assuring that none of the subjects was suffering from any mental disorders such as anxiety and depression. The groups did not differ statistically from each other (p>0.05) at screening.
Effect on Primary Outcome Measures
Mental alertness was considered as primary outcome measure based on its importance in the assessment of cognitive performance. Data obtained for alerting network are expressed as alertness score in the following table and in
#Decreased significantly as compared to baseline;
##Statically significant difference in score across the groups;
##Significant change in score as compared to placebo,
In the placebo group, there was a statistically insignificant increase in alertness score of 5.05±19.71, 2.61±20.66, and 9.79±20.07 ms from baseline at one, three and five hours, respectively.
In the E-AG-01 group, there was a significant increase in alertness score of 11.65±23.94 (95% CI: −3.67-16.86, p=0.008),12.50±19.73 (95% CI: 0.37-19.42, p=0.001), and 12.62±24.71 (95% CI: −7.69-13.35, p=0.005) ms from baseline at one, three and five hours, respectively.
In the caffeine group, alertness score as compared to baseline increased significantly by 8.97±18.20 ms (95% CI: −4.96-12.80, p=0.006) at one hour; however, the score decreased by 1.23±18.60 ms (95% CI: −13.04-5.37, p=0.698) from the baseline at three hours, indicating a caffeine crash. Also, in composite group, the score significantly increased by 10.27±20.34 ms(95% CI: −4.96-12.80, p=0.004) from baseline at one hour followed by the return approximately to the baseline score with decrease of 0.68±21.87 (95% CI: −13.01 to 6.43, p=0.074) at three hours.
As the changes across the groups were significant at three hours (p=0.03), theywere individually compared to the placebo using a student's paired t-test, wherein the E-AG-01 group demonstrated a statistically significant improvement in the alertness score (p=0.04).
At five hours, all groups demonstrated an increase in the alertness score, owing to the logistic factors of the study and asymptomatic performance improvement due to the diurnal pattern of the alertness, however the increase in the alertness score was maximum in the E-AG-01 group (12.62±0.68 ms from baseline).
As the result was statistically significant for E-AG-01, the effect size was calculated in terms of a Cohen's d value in comparison with placebo. The derived value of d=0.59 for the EAG-01 group as against d=0.08 for the caffeine group confirmed a significant medium effect size in alertness score in E-AG-01 group compared to a remarkably small effect size in caffeine group.
Effect on Secondary Outcome Measures
The data were used to assess the effect of IP on the sustained attention by using the PVT and the results were expressed as MRT in msecs. As evident from the results, the E-AG-01 group did not demonstrate any significant improvement in the MRT whereas the results from the caffeine group suggested a declining trend in the MRT till 3 hours after which it showed an increase which may be attributed to the crash effect. The composite group exhibited a trend similar to the caffeine group but achieved a within-group statistical significance at 5 hours interval as compared to baseline (p=0.02). In addition, the intergroup analysis for the composite group revealed a significant decrease in MRT compared to the placebo at 1 hour (p=0.01), 3 hours (p=0.04) and 5 hours (p=0.01).The mean response time as computed by PVT is expressed in the following table and in
#Decreased significantly as compared to baseline;
###Significant change in score as compared to placebo,
After the statistical evaluation and interpretation of the data obtained for the mental fatigue, it was found that none of the groups showed significant reduction in mental fatigue as assessed by KSS. Intergroup analysis also confirmed the statistically insignificant results in this outcome parameter. We also assessed the effect of IP on wakefulness and sleep quality and the results obtained for all four groups imply no statistically significant change in these outcome measures as well.
The data show the effect of an extrac of Alpinia galanga that is free of methyl eugenol in comparison with the caffeine (comparator) and the placebo (control) on various aspects of attention network. Consistent with caffeine's well known effect on the alerting network, alertness score increased till one hour followed by a reduction, probably due to a caffeine crash at three hours. At the same time, the extracts of Alpinia galanga that is free of methyl eugenol showed an improvement in alertness score until five hours interval. In the composite group, alertness score increased significantly at one hour followed by a reduction, indicating a caffeine crash, which was less than that observed in the caffeine group. Hence, it can be hypothesized that the extract of Alpinia galanga that is free of methyl eugenol is able to impede the caffeine crash as evident from three hour and five hour alertness score.
The alerting network recruits a distributed network of brain regions, primarily the thalamus and bilateral frontal and parietal brain regions. Given the dense dopaminergic innervation of the human thalamus and prefrontal cortex and that the caffeine is generally thought to up regulate the dopaminergic availability, the present results are consistent with the theorized effects of caffeine on the CNS function. Based on these facts, it can be postulated that the extract of Alpinia galanga that is free of methyl eugenol also improves alertness in a similar way as that of caffeine by enhancing the dopaminergic activity.
The effect size for this efficacy parameter was calculated in terms of standardized mean effect, (denoted as Cohen's d) which expresses the mean difference between two groups in the standard deviation units. The results suggest that in terms of probability of superiority of treatments, there is a 66% chance that a randomly selected subject from the E-AG-01 group will exhibit a definite improvement in the mental alertness than a randomly selected subject from the placebo group.
Alternatively, it can be stated that the effect size represented as Cohen's d value indicates that 73 subjects from the E-AG-01 group (d=0.599) would exhibit higher alertness than the subjects in the placebo group as compared to the caffeine group wherein only 47% subjects would have a better alertness.
The sustained attention was assessed by the PVT, which generally reflects the arousal and attention state of an individual. Caffeine appears to exhibit dose-dependent performance improvement in a variety of basic psychomotor tasks as a direct result of altered CNS activity and is well reported by a number of studies. Some studies also suggest that the extended vigilance is generally improved following a caffeine consumption at a dose of ˜400 mg and performance diminishes with very high dose of caffeine (e.g. 600 mg). In agreement with these reported findings, the data show that neither caffeine at 200 mg nor the extract of Alpinia galanga that is free of methyl eugenol at 300 mg independently exhibited significant reduction in the MRT. However, the combination of these ingredients at the same dose was found to be effective in improving the sustained attention as indicated by statistically significant data obtained for the composite group. It has been reported that the relationship between the sustained attention and the task performance follows an inverted U-curve, i.e. poor performance can occur due to both under- and over-arousal. This can be one of the reasons for wide-spread range of observations in MRT, leading to the bigger SDs and insignificant p values. However, derived p values showed a positive trend in the reduction of MRT in the caffeine and composite groups. Hence, an attempt was made to analyze the treatment groups individually in comparison with placebo by student's t-test which showed that the improvement in sustained attention was statistically significant in comparison with placebo, implying the superiority of the composite group in enhancing the sustained attention and arousal state. Thus, co-administration of the extract of Alpinia galanga that is free of methyl eugenol with caffeine may modulate the neural activity in the cerebral regions related to the sustained attention.
Within and between group analyses provided the statistically significant results, which serve as a constructive evidence for the beneficial effect of the extract of Alpinia galanga that is free of methyl eugenol on enhancement of mental alertness and sustained attention.
Study volunteers were recruited through multiple sources that included in-house healthy volunteers' database and also a consumer group's survey agency. Potential participants having a history of moderate caffeine ingestion aged between 18-60 years with BMI in the range of 18-25 kg/ m2 were included in the present study. Participants were screened for anxiety and depression using ‘Generalized anxiety disorder (GAD)’ and ‘Patient health questionnaire (PHQ)’. Potential participants with history or presence of cardiac, vascular, endocrine, gastrointestinal, pancreatic or neurological disorders were excluded. Furthermore, a urine pregnancy test was performed in females of childbearing potential at assessment visits and those pregnant, planning pregnancy, or breastfeeding were not included. Abstinence from caffeine and alcohol or related products prior to scheduled visits was mandatory.
The study interventions included
Study products were manufactured in the form of size 0 capsules and packed in duly labeled high-density polyethylene bottles. For preserving the study blinding, identical placebo capsules were manufactured and matched for size, shape, color, texture, and packaging. The participants receiving EnXtra® or placebo were co-assigned to an additional placebo capsule for achieving the double-dummy design similar to EnXtra® with caffeine regime. Two capsules twice daily were to be consumed by the recruited participants for the study duration.
This was a 12-week double-blind, randomized, placebo-controlled, parallel-group study in adults with moderate caffeine usage. Participants were randomized in blocks of 6 using Stats Direct software (version 3.1.17) to either receive EnXtra® , EnXtra® plus caffeine, or placebo. The blinding codes were secured in tamper-evident, sealed envelopes and access was limited to authorized personnel as per Vedic Lifesciences standard operating procedures.
Participants were assessed for safety and efficacy on day 28, 56, and 84 (±2 days). An additional visit was scheduled at day 90 after 6 days of investigational product (IP) abstinence for evaluating if increased calmess was sustained. The IP was administered for a total of 84 days.
A total of 87 participants were screened out of which 70 were found to be eligible for the study. The number of screening failures was 12 and 5 participants could not be randomized as they were lost for further follow-ups. One participant dropped out during the course of the study and final population consisted of 23 participants each in EnXtra® , EnXtra® plus caffeine, and placebo groups. The participant disposition has been provided in
The Bond and Lader visual analogue scale (B&L-VAS) was used to measure alertness and calmness. The B&L-VAS is a self-administered scale for evaluation of mood. The participant is required to mark on a horizontal 100 mm line to describe his/her state of mind as per the 16 dimensions of mood at that particular time. The 16 dimensions are anchored at either end by adjective pairing, e.g., Alert to Drowsy, and higher scores represent a more positive mood state. The participant responses were recorded and combined for 2 dimensions that represent alertness and calmness. An average of the same was calculated and a total score was also quantified. Assessment of B&L-VAS was conducted at 0 (pre-consumption) and 3 hours (post-consumption) on day 0, 28, 56, and 84. Furthermore, a single B&L assessment was performed after 6 days of product abstinence on day 90.
At day 0, the pre-consumption (pre-IP) mean±SD alertness score for EnXtra®, EnXtra® plus Caffeine and placebo group was 31.69±07.38, 30.82±6.92 and 34.78±14.96, respectively; p>0.05. Three hours after the first dose administration (post-IP), the mean±SD alertness score for EnXtra® as well as EnXtra® plus caffeine groups significantly increased to 61.40±11.74 (p<0.001) and 62.27±10.11 (p<0.001) from baseline. The change in placebo was not significant with a score of 40.14±17.47; p>0.05. Similarly, 3 hours after the last designated dose (day 84), the alertness score for EnXtra® group was 68.02±08.52 (p<0.001) and 74.25±11.96 (p<0.001) for the EnXtra® plus caffeine group. Thees groups significantly differed from placebo the placebo, and this increase in the alertness score of EnXtra® and EnXtra® plus Caffeine group substantiates their consistent effect on alertness. This data is shown in the Table in
At day 0, pre-IP mean±SD calmness score for EnXtra®, EnXtra® plus caffeine, and placebo groups was 38.70±08.29, 39.78±08.05 and 41.52±15.11, respectively; p>0.05. Three hours after IP consumption on the same visit, the calmness score for the EnXtra®, EnXtra® plus caffeine, and placebo groups significantly increased to 71.30±12.27 (p<0.001) and 71.09±13.98 (p<0.001) from baseline. Comparatively, there was no increase in calmness score of the placebo group that was 46.74±15.71; p>0.05. Similarly on day 84, the calmness score of the EnXtra® group was 70.65±11.80 (p<0.001) and in the EnXtra® plus caffeine group, it further increased to 77.39±12.87 (p<0.001). The score of the placebo group was 43.70±13.59 (p>0.05) indicating a decrease in comparison to baseline. The improved calmness scores of groups administered EnXtra®, with and without caffeine, implies significant improvement in the calmness attribute of these groups, as compared to the placebo group. The Bond and Lader—Alertness, and Calmness scores for before and after IP intervention are provided in
As shown in
Statistical Analysis
In the present study, the type I error probability associated with the test of the null hypothesis was set at 0.05. Per-protocol analysis was used for conducting comparisons, and only participants completing assessment visits without any major protocol deviations were analyzed. A descriptive and exploratory analysis of the variables was conducted, where their distribution, outliers and missing data were evaluated. The data normality was evaluated using the Shapiro—Wilk test. The summary (mean, standard deviation, minimum and maximum) and analysis of change (mean difference, standard error) of efficacy and safety parameters was compiled using Analysis of Variance (ANOVA), Paired Sample T test, and Bonferroni test.
Subjects were divided into four treatment arms and randomized for allocation to one of the interventional products (IPs) on each study visit, and a similar trend was followed for subsequent visits. The remaining interventions on consecutive visits were administered only after a sufficient washout period of not less than 5 half-lives of caffeine in the blood to avoid a carryover effect.
IPs included placebo, A. galanga proprietary extract (E-AG-01), caffeine, and a combination of E-AG-01 with caffeine (composite). All treatments were administered to subjects in the form of capsules that were identical in appearance and packed in duly labeled high-density polyethylene bottles. Subjects receiving only A. galanga, caffeine, or placebo were coassigned to an additional placebo capsule to achieve a double-dummy design identical to the caffeine+E-AG-01 regime. The composition details of all IPs are listed below.
Gastronomic use of A. galanga has generally been well documented in the form of spice. It has also been reported to improve cognitive performance in animals; however, the current study aimed to explore the role of this A. galanga rhizome extract in decreasing errors made during high-demand cognitive tasks.
Subjects reported to the clinic during morning hours, with testing beginning early in the day (8-9 AM) for each visit to avoid the influence of daily challenges (related to mental and physical stress) on study outcomes. Also, the time of day was matched for all four visits to reduce variability in response due to diurnal patterns. Subjects reported to the clinic following 24-hour abstinence from caffeine-containing products or any psychostimulants prior to all study visits. Upon arrival at the clinic, subjects were asked to relax for 15-20 minutes, after which vital parameters were measured and a standardized meal of ˜200 ca was provided to control variations from possible confounding dietary factors. Baseline data were collected at 30 minutes post-breakfast, followed by the administration of an IP, wherein one dose of the product was administered to the subject by a trial coordinator at the investigational site.
The study tool was administered at 1, 3, and 5 hours post-IP administration and data collected. No other food or calorie-containing beverages were provided during this period. Subjects were allowed to drink water as desired and relax in an isolated room at a comfortable temperature with free access to a computer or magazines during the clinic stay. To analyze the effect of the IP on sleep architecture, a second dose of the corresponding IP was supplied in a labeled bottle to be taken before dinner during the same night of the visit, and subjects were asked to record all details pertaining to sleep quality and duration in the sleep diary. To ensure treatment compliance, product accountability was monitored by a clinical research coordinator on the following visit.
The ANT study tool was developed in 2002 by Fan et al, and is based on a well-developed neural network model of the human attention system. The test is a measure of attention designed to quantify the efficiency of vigilance, orienting, and executive-control networks through the combination of a cued reaction-time task and a flanker task. As a speed-choice task, ANT provides two measures of performance:
59 participants were enrolled in the study, as shown in
A supplemental post-study analysis was performed on the ANT data, wherein the effect of E-AG-01 on the second performance measure, ie, accuracy was analyzed in terms of change in error rate. It was calculated based on percentage correct and incorrect hits, and percentage error rate was determined from the average wrong responses registered at 1, 3, and 5 hours postingestion of E-AG-01, caffeine, a combination of the two, or placebo. Student's paired t-test was used for intergroup comparisons at different time points using SPSS 15.0 for Windows (SPSS, Chicago, Ill., USA). The effect of IPs on accuracy factors of attention, ie, focused and selective attention, served as the ultimate aim for this analysis.
The present placebo-controlled clinical trial evaluated the psychostimulant effect of E-AG-01 alone and in combination with caffeine. Based on the results, it was concluded that the stimulant effect of E-AG-01 was superior to caffeine, with a novel finding of its capacity to relieve the caffeine-withdrawal effect. Attention is a vast paradigm that involves several subcomponents, such as:
Focused attention allows a subject to prevent or avoid distractions, resulting in lower error rates and increased accuracy. When treated with placebo, participants showed an increase in error rate, a pattern that is commonly observed with increasing time on tasks. This group had a persistent error rate at 1 hour which gradually increased, reaching 27.3% over baseline at the end of 5 hours.
After ingestion of 300 mg E-AG-01, subjects were consistently able to reduce the error rate for the next 5 hours, compared to a baseline vaue. The decrease in error rate was 29.46% and 17.4% from baseline at 3 and 5 hours, respectively.
The error rate in the caffeine group initially decreased at 1 hour, but then error incidence almost tripled in magnitude (−14.0% to +6.4%) by 5 hours, owing to the caffeine crash effect.
When combined, E-AG-01+caffeine did not impact the error rate as significantly as either E-AG-01 or caffeine. The composite product of E-AG-01+caffeine showed a decrease in error rate of decrease of 7.9% 1 hour after ingestion, with an increase of in error rate 6.6% 5 hours after ingestion. However, the E-AG-01+caffeine combination was effective in averting a caffeine crash effect.
It should be apparent from the foregoing description that various embodiments of the disclosed formulation, extraction process, and use may be implemented to provide the various types of formulations described herein. The description further implements methods of administering an extract of Alpinia galanga that is free of methyl eugenol to improve cognitive performance as well as a process for preparing an extract of Alpinia galanga that is free of methyl eugenol.
Although the various embodiments have been described in detail with particular reference to certain aspects thereof, it should be understood that the disclosed formulation, extraction process, and use are capable of other embodiments and its details are capable of modifications in various obvious respects. As is readily apparent to those skilled in the art, variations and modifications can be affected while remaining within the spirit and scope of the disclosed formulation, extraction process, and use. Accordingly, the foregoing disclosure and description are for illustrative purposes only and do not in any way limit the disclosed formulation, extraction process, and use, which are defined only by the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201721004749 | Feb 2017 | IN | national |
This application is a continuation-in-part of parent U.S. application Ser. No. 15/593,093, filed on May 11, 2017. The entire disclosure of the prior application is hereby incorporated by reference herein in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15593093 | May 2017 | US |
| Child | 17203133 | US |
