Cognitive Impairment, Elderly
Conditions
Brief summary
This study will measure the oral bioavailability and pharmacokinetics of known bioactive compounds from a standardized Centella asiatica water extract product (CAP) in mildly demented elders on cholinesterase inhibitor therapy. Compound levels will be measured in human plasma and urine over 10 hours after acute oral administration of two doses of the botanical extract product. The dose giving maximum plasma levels (Cmax)closest to those observed in the investigator's mouse studies, the area under the curve (AUC0-12), as well as the rate of clearance (t ½) of the known compounds and time of maximum concentration (tmax), will be identified. These data will be used to inform decisions on the dosage and dosing frequency for future clinical trials.
Detailed description
PRIMARY OBJECTIVES: 1. To assess the bioavailability and rate of clearance of Centella asiatica derived compounds in mildly demented elders on cholinesterase inhibitor therapy through a pharmacokinetic study. 2. To determine the acute tolerability of a Centella asiatica product in mildly demented elders on cholinesterase inhibitor therapy. OUTLINE: Participants will orally consume a single administration of a standardized Centella asiatica water extract product (CAP). Two doses (2g and 4g CAW) will be administered on separate occasions, at least two weeks apart. The levels of known bioactive compounds present in Centella asiatica will be measured in human plasma and urine over 10 hours after administration of each of the doses.
Interventions
2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Sponsors
National Center for Complementary and Integrative Health (NCCIH)
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SCREENING
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Randomization will use an arm equivalence design to promote equal numbers of participants for each order schema. All participants will be blinded to the dose they will be receiving at each visit. The investigators have developed a formulation that tastes and looks very similar at each dose. The investigator administering the intervention and the analyst performing the liquid chromatography analysis of collected plasma will be blinded as to the dose of the product administered. The liquid chromatography analyst will also be blinded as to the time point of collection.
Intervention model description
This is an outpatient open-label clinical study using a blinded randomized crossover design of two doses.
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age 65-85, male and female 2. Meet the National Institute of Aging - Alzheimer's Association core clinical criteria for mild cognitive impairment or probable Alzheimer's disease dementia with a Clinical Dementia Rating (CDR) score of 0.5-1 and MMSE score of 20-28 3. Report a history of subjective memory decline with gradual onset and slow progression over the last one year before screening; MUST be corroborated by an informant 4. On cholinesterase inhibitor therapy for Alzheimer's disease (AD) and must be on a stable dose for at least 12 weeks prior to baseline 5. Caregiver/study partner that can accompany participant to all study visits 6. Sufficient English language skills to complete all tests 7. Sufficient vision and hearing to complete all tests 8. No known allergies to Centella asiatica or CAP excipients 9. Willingness to discontinue all botanical dietary supplements for one week prior to and during each study visit 10. Willingness to comply with a 48-hour low plant diet for each study visit 11. Absence of significant depression symptoms (Geriatric Depression Scale-15 score of \<12) 12. Body Mass Index (BMI) greater than 17 and less than 35 at screening 13. General health status that will not interfere with the ability to complete the study
Exclusion criteria
1. Current smoking, alcohol or substance abuse according to DSM-V criteria 2. Women who are pregnant, planning to become pregnant or breastfeeding 3. Men who are actively trying to conceive a child or planning to within three months of study completion 4. Severe aversion to venipuncture 5. Abnormal laboratory evaluation indicating asymptomatic and untreated urinary tract infection 6. Cancer within the last five years, with the exception of localized prostate cancer (Gleason Grade \<3) and non-metastatic skin cancers 7. Comorbid conditions such as diabetes mellitus, kidney failure, liver failure, hepatitis, blood disorders, clinical symptomatic orthostatic hypotension, and unstable or significantly symptomatic cardiovascular disease 8. Significant disease of the central nervous system such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke 9. Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-V criteria 10. Medications: sedatives (except those used occasionally for sleep), central nervous system active medications that have not been stable for two months (including beta blockers, cimetidine, SSRIs, SNRIs), anticoagulants (i.e. Warfarin), investigational drugs used within five half-lives of baseline visit, systemic corticosteroids, neuroleptics, anti-Parkinsonian agents, narcotic analgesics, nicotine (tobacco, patches, gum, lozenges, etc.), Cannabis sativa (herb or edibles) 11. Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus or Parkinson's disease 12. Mini Mental State Examination (MMSE) score of \<20 or \>28 or CDR score \>1 or zero 13. Unwilling to maintain stable dosage of AD medications throughout study duration 14. Inability or unwillingness of individual or legal guardian/representative to give written informed consent. 15. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes). | Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (maximum concentration) for each of the two doses (2g and 4g). |
| Time of Maximum Concentration (Tmax) | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes). | The time of maximum concentration (Tmax) of the known bioactive compounds and their metabolites will be calculated from the concentrations measured by high performance liquid chromatography tandem mass spectrometry in order to help determine dosage intervals |
| Half-life (t1/2) | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes). | The half-life (t1/2) of the known bioactive compounds and their metabolites will be calculated from the plasma concentrations measured by high performance liquid chromatography tandem mass spectrometry to help determine dosage intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes). | Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (area under the curve) for each of the two doses (2g and 4g). |
| Total Urinary Excretion | Total 10 hours | All urine produced over the 10 hours post-administration was collected into a single container. The concentration of bioactive compounds from Centella asiatica (triterpenes, caffeoylquinic acids, and their metabolites) was measured in the single total urine sample collected over 10 hours after CAP administration. Urine samples were treated with glucuronidase and sulfatase enzymes to release analyte from conjugated (Phase II metabolite) forms of the analyte. All samples were analyzed using high performance liquid chromatography tandem mass spectrometry. The concentrations obtained were multiplied by total urine volume to obtain the total amount of that analyte excreted. The total amount (free and conjugated forms) in micrograms of of each analyte in the 10h urine sample is reported. |
| NRF2 Expression | 0, 1, 2, 3, 4, and 6h following study intervention | NRF2 gene expression was measured in peripheral blood mononuclear cells following consumption of 2g and 4g of Centella asiatica water extract product (CAP). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Baseline values for all participants before randomization | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study discontinuation due to pandemic restrictions | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Alanine aminotransferase | 32 U/L STANDARD_DEVIATION 3 |
| Albumin | 3.8 g/dL STANDARD_DEVIATION 0.1 |
| Alkaline phosphatase | 87 U/L STANDARD_DEVIATION 12 |
| Anion gap | 5 mEq/L STANDARD_DEVIATION 1 |
| Aspartate aminotransferase | 26 U/L STANDARD_DEVIATION 3 |
| Blood glucose | 81 mg/dL STANDARD_DEVIATION 3 |
| Blood urea nitrogen | 17 mg/dL STANDARD_DEVIATION 3 |
| Body mass index | 28 kg/m^2 STANDARD_DEVIATION 2 |
| Body temperature | 36.7 Celsius STANDARD_DEVIATION 0.1 |
| Calcium | 9.3 mg/dL STANDARD_DEVIATION 0.1 |
| Chloride | 108 mmol/L STANDARD_DEVIATION 1 |
| Creatinine | 0.9 mg/dL STANDARD_DEVIATION 0.1 |
| Diastolic blood pressure | 81 mmHg STANDARD_DEVIATION 3 |
| Heart rate | 68 beats per minute STANDARD_DEVIATION 5 |
| Hematocrit | 44 percentage STANDARD_DEVIATION 2 |
| Hemoglobin | 14.3 g/dL STANDARD_DEVIATION 0.6 |
| Platelets | 259 x10^3 platelets/uL STANDARD_DEVIATION 20 |
| Potassium | 3.8 mmol/L STANDARD_DEVIATION 0.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Red blood cells | 4.64 x10^6 cells/uL STANDARD_DEVIATION 0.21 |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
| Sodium | 141 mmol/L STANDARD_DEVIATION 1 |
| Systolic blood pressure | 132 mmHg STANDARD_DEVIATION 7 |
| Total bilirubin | 0.6 mg/dL STANDARD_DEVIATION 0.1 |
| Total CO^2 | 29 mmol/L STANDARD_DEVIATION 1 |
| Total protein | 7.7 g/dL STANDARD_DEVIATION 0.1 |
| White blood cells | 7.28 x10^3 cells/uL STANDARD_DEVIATION 0.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Half-life (t1/2)
The half-life (t1/2) of the known bioactive compounds and their metabolites will be calculated from the plasma concentrations measured by high performance liquid chromatography tandem mass spectrometry to help determine dosage intervals.
Time frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | Half-life (t1/2) | Asiatic acid | 3.8 hours | Standard Error 1 |
| 2g CAP | Half-life (t1/2) | Caffeic acid | 2.6 hours | Standard Error 1 |
| 2g CAP | Half-life (t1/2) | Dihydrocaffeic acid | 4.8 hours | Standard Error 1.3 |
| 2g CAP | Half-life (t1/2) | Dihydroferulic acid | 4.5 hours | Standard Error 1.6 |
| 2g CAP | Half-life (t1/2) | Dicaffeoylquinic acids | 0 hours | Standard Error 0 |
| 2g CAP | Half-life (t1/2) | Ferulic acid | 13.4 hours | Standard Error 5.3 |
| 2g CAP | Half-life (t1/2) | 3-(3-hydroxyphenyl)propionic acid | 2.3 hours | Standard Error 0.3 |
| 2g CAP | Half-life (t1/2) | Isoferulic acid | 8.8 hours | Standard Error 5.7 |
| 2g CAP | Half-life (t1/2) | Madecassic acid | 1.7 hours | Standard Error 0.5 |
| 2g CAP | Half-life (t1/2) | Monocaffeoylquinic acids | 2 hours | Standard Error 0.5 |
| 4g CAP | Half-life (t1/2) | Isoferulic acid | 2.9 hours | Standard Error 0.6 |
| 4g CAP | Half-life (t1/2) | Asiatic acid | 2.2 hours | Standard Error 0.5 |
| 4g CAP | Half-life (t1/2) | Ferulic acid | 7 hours | Standard Error 1.2 |
| 4g CAP | Half-life (t1/2) | Caffeic acid | 3.5 hours | Standard Error 1.2 |
| 4g CAP | Half-life (t1/2) | Monocaffeoylquinic acids | 3 hours | Standard Error 0.3 |
| 4g CAP | Half-life (t1/2) | Dihydrocaffeic acid | 1.1 hours | Standard Error 0.4 |
| 4g CAP | Half-life (t1/2) | 3-(3-hydroxyphenyl)propionic acid | 1.8 hours | Standard Error 0.7 |
| 4g CAP | Half-life (t1/2) | Dihydroferulic acid | 2.5 hours | Standard Error 0.3 |
| 4g CAP | Half-life (t1/2) | Madecassic acid | 1.7 hours | Standard Error 0.9 |
| 4g CAP | Half-life (t1/2) | Dicaffeoylquinic acids | 3 hours | Standard Error 2 |
Comparison: Asiatic acidp-value: 0.34t-test, 2 sided
Comparison: Dihydrocaffeic acidp-value: 0.08t-test, 2 sided
Comparison: Dihydroferulic acidp-value: 0.23t-test, 2 sided
Comparison: Ferulic acidp-value: 0.14t-test, 2 sided
Comparison: 3-(3-hydroxyphenyl)propionic acidp-value: 0.28t-test, 2 sided
Comparison: Isoferulic acidp-value: 0.17t-test, 2 sided
Comparison: Madecassic acidp-value: 0.98t-test, 2 sided
Comparison: Monocaffeoylquinic acidsp-value: 0.16t-test, 2 sided
Primary
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax)
Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (maximum concentration) for each of the two doses (2g and 4g).
Time frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes).
Population: The pharmacokinetic parameter (Cmax) and time curves was calculated using non-compartmental analysis of plasma concentration versus time data using Excel software PK-solver (version 2.0).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dihydrocaffeic acid | 1 ng/mL | Standard Error 0.4 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Ferulic acid | 1 ng/mL | Standard Error 0.2 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Caffeic acid | 0.3 ng/mL | Standard Error 0.2 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | 3-(3-hydroxyphenyl)propionic acid | 32 ng/mL | Standard Error 18 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dihydroferulic acid | 11 ng/mL | Standard Error 5 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Isoferulic acid | 0.9 ng/mL | Standard Error 0.3 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Madecassic acid | 38 ng/mL | Standard Error 3 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Asiatic acid | 124 ng/mL | Standard Error 29 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Monocaffeoylquinic acids | 14 ng/mL | Standard Error 7 |
| 2g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dicaffeoylquinic acids | 18 ng/mL | Standard Error 10 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Monocaffeoylquinic acids | 7 ng/mL | Standard Error 2 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Asiatic acid | 259 ng/mL | Standard Error 24 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Caffeic acid | 1 ng/mL | Standard Error 0.1 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dihydrocaffeic acid | 2 ng/mL | Standard Error 0.2 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dihydroferulic acid | 20 ng/mL | Standard Error 6 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Dicaffeoylquinic acids | 3 ng/mL | Standard Error 0.3 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Ferulic acid | 1.4 ng/mL | Standard Error 0.1 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | 3-(3-hydroxyphenyl)propionic acid | 42 ng/mL | Standard Error 18 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Madecassic acid | 63 ng/mL | Standard Error 10 |
| 4g CAP | Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) | Isoferulic acid | 2 ng/mL | Standard Error 0.1 |
Comparison: Asiatic acidp-value: 0.01t-test, 2 sided
Comparison: Caffeic acidp-value: 0.23t-test, 2 sided
Comparison: Dihydrocaffeic acidp-value: 0.001t-test, 2 sided
Comparison: Dihydroferulic acidp-value: 0.05t-test, 2 sided
Comparison: Ferulic acidp-value: 0.07t-test, 2 sided
Comparison: 3-(3-hydroxyphenyl)propionic acidp-value: 0.09t-test, 2 sided
Comparison: Isoferulic acidp-value: 0.003t-test, 2 sided
Comparison: Madecassic acidp-value: 0.1t-test, 2 sided
Comparison: Monocaffeoylquinic acidsp-value: 0.11t-test, 2 sided
Primary
Time of Maximum Concentration (Tmax)
The time of maximum concentration (Tmax) of the known bioactive compounds and their metabolites will be calculated from the concentrations measured by high performance liquid chromatography tandem mass spectrometry in order to help determine dosage intervals
Time frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | Time of Maximum Concentration (Tmax) | Dihydrocaffeic acid | 3.25 hours | Standard Error 0.5 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Ferulic acid | 5 hours | Standard Error 0.6 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Caffeic acid | 4 hours | Standard Error 2 |
| 2g CAP | Time of Maximum Concentration (Tmax) | 3-(3-hydroxyphenyl)propionic acid | 6 hours | Standard Error 1.4 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Dihydroferulic acid | 3.4 hours | Standard Error 1 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Isoferulic acid | 1.3 hours | Standard Error 0.6 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Asiatic acid | 2 hours | Standard Error 0.6 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Madecassic acid | 2 hours | Standard Error 0.5 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Monocaffeoylquinic acids | 4 hours | Standard Error 2 |
| 2g CAP | Time of Maximum Concentration (Tmax) | Dicaffeoylquinic acids | 6 hours | Standard Error 2 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Monocaffeoylquinic acids | 2 hours | Standard Error 0.4 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Caffeic acid | 4 hours | Standard Error 1 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Asiatic acid | 2 hours | Standard Error 0.6 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Dihydrocaffeic acid | 3.5 hours | Standard Error 0.5 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Dihydroferulic acid | 3.5 hours | Standard Error 0.5 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Dicaffeoylquinic acids | 0.6 hours | Standard Error 0.3 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Ferulic acid | 5.5 hours | Standard Error 0.5 |
| 4g CAP | Time of Maximum Concentration (Tmax) | 3-(3-hydroxyphenyl)propionic acid | 5.5 hours | Standard Error 1.7 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Isoferulic acid | 1 hours | Standard Error 0.4 |
| 4g CAP | Time of Maximum Concentration (Tmax) | Madecassic acid | 2 hours | Standard Error 0.5 |
Comparison: Asiatic acidp-value: 0.82t-test, 2 sided
Comparison: Caffeic acidp-value: 0.4t-test, 2 sided
Comparison: Dihydrocaffeic acidp-value: 0.2t-test, 2 sided
Comparison: Dihydroferulic acidp-value: 0.48t-test, 2 sided
Comparison: Ferulic acidp-value: 0.2t-test, 2 sided
Comparison: 3-(3-hydroxyphenyl)propionic acidp-value: 0.32t-test, 2 sided
Comparison: Isoferulic acidp-value: 0.35t-test, 2 sided
Comparison: Madecassic acidp-value: 0.52t-test, 2 sided
Comparison: Monocaffeoylquinic acidsp-value: 0.13t-test, 2 sided
Secondary
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica
Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (area under the curve) for each of the two doses (2g and 4g).
Time frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Madecassic acid | 101 ng x h/mL | Standard Error 16 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dicaffeoylquinic acids | 18 ng x h/mL | Standard Error 10 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Monocaffeoylquinic acids | 18 ng x h/mL | Standard Error 6 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Asiatic acid | 364 ng x h/mL | Standard Error 114 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Caffeic acid | 1 ng x h/mL | Standard Error 1 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dihydrocaffeic acid | 3 ng x h/mL | Standard Error 0.4 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dihydroferulic acid | 42 ng x h/mL | Standard Error 18 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Ferulic acid | 7 ng x h/mL | Standard Error 2 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | 3-(3-hydroxyphenyl)propionic acid | 100 ng x h/mL | Standard Error 46 |
| 2g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Isoferulic acid | 5 ng x h/mL | Standard Error 2 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | 3-(3-hydroxyphenyl)propionic acid | 189 ng x h/mL | Standard Error 77 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dihydroferulic acid | 77 ng x h/mL | Standard Error 25 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Madecassic acid | 187 ng x h/mL | Standard Error 48 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dicaffeoylquinic acids | 6 ng x h/mL | Standard Error 4 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Monocaffeoylquinic acids | 23 ng x h/mL | Standard Error 4 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Asiatic acid | 935 ng x h/mL | Standard Error 178 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Ferulic acid | 10 ng x h/mL | Standard Error 1 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Caffeic acid | 3 ng x h/mL | Standard Error 0.3 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Isoferulic acid | 8 ng x h/mL | Standard Error 0.4 |
| 4g CAP | Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica | Dihydrocaffeic acid | 6 ng x h/mL | Standard Error 1 |
Comparison: Asiatic acidp-value: 0.04t-test, 2 sided
Comparison: Caffeic acidp-value: 0.01t-test, 2 sided
Comparison: Dihydrocaffeic acidp-value: 0.06t-test, 2 sided
Comparison: Dihydroferulic acidp-value: 0.08t-test, 2 sided
Comparison: Dicaffeoylquinic acidsp-value: 0.56t-test, 2 sided
Comparison: Ferulic acidp-value: 0.21t-test, 2 sided
Comparison: 3-(3-hydroxyphenyl)propionic acidp-value: 0.05t-test, 2 sided
Comparison: Isoferulic acidp-value: 0.05t-test, 2 sided
Comparison: Madecassic acidp-value: 0.23t-test, 2 sided
Comparison: Monocaffeoylquinic acidsp-value: 0.16t-test, 2 sided
Secondary
NRF2 Expression
NRF2 gene expression was measured in peripheral blood mononuclear cells following consumption of 2g and 4g of Centella asiatica water extract product (CAP).
Time frame: 0, 1, 2, 3, 4, and 6h following study intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | NRF2 Expression | 0 h | 1 fold change in expression from time 0h | Standard Error 0 |
| 2g CAP | NRF2 Expression | 1 h | 2 fold change in expression from time 0h | Standard Error 0.2 |
| 2g CAP | NRF2 Expression | 2 h | 32 fold change in expression from time 0h | Standard Error 4 |
| 2g CAP | NRF2 Expression | 3 h | 22 fold change in expression from time 0h | Standard Error 9 |
| 2g CAP | NRF2 Expression | 4 h | 12 fold change in expression from time 0h | Standard Error 7 |
| 2g CAP | NRF2 Expression | 6 h | 4 fold change in expression from time 0h | Standard Error 2 |
| 4g CAP | NRF2 Expression | 4 h | 2 fold change in expression from time 0h | Standard Error 1 |
| 4g CAP | NRF2 Expression | 0 h | 1 fold change in expression from time 0h | Standard Error 0 |
| 4g CAP | NRF2 Expression | 3 h | 3 fold change in expression from time 0h | Standard Error 1 |
| 4g CAP | NRF2 Expression | 1 h | 2 fold change in expression from time 0h | Standard Error 0.3 |
| 4g CAP | NRF2 Expression | 6 h | 1 fold change in expression from time 0h | Standard Error 0.3 |
| 4g CAP | NRF2 Expression | 2 h | 5 fold change in expression from time 0h | Standard Error 2 |
Comparison: 1 hourp-value: 0.1t-test, 1 sided
Comparison: 2 hoursp-value: 0.1t-test, 1 sided
Comparison: 3 hoursp-value: 0.3t-test, 1 sided
Comparison: 4 hoursp-value: 0.5t-test, 1 sided
Comparison: 6 hoursp-value: 0.5t-test, 1 sided
Secondary
Total Urinary Excretion
All urine produced over the 10 hours post-administration was collected into a single container. The concentration of bioactive compounds from Centella asiatica (triterpenes, caffeoylquinic acids, and their metabolites) was measured in the single total urine sample collected over 10 hours after CAP administration. Urine samples were treated with glucuronidase and sulfatase enzymes to release analyte from conjugated (Phase II metabolite) forms of the analyte. All samples were analyzed using high performance liquid chromatography tandem mass spectrometry. The concentrations obtained were multiplied by total urine volume to obtain the total amount of that analyte excreted. The total amount (free and conjugated forms) in micrograms of of each analyte in the 10h urine sample is reported.
Time frame: Total 10 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 2g CAP | Total Urinary Excretion | Madecassic acid | 8 micrograms | Standard Error 2 |
| 2g CAP | Total Urinary Excretion | Ferulic acid | 18 micrograms | Standard Error 6 |
| 2g CAP | Total Urinary Excretion | Dihydrocaffeic acid | 47 micrograms | Standard Error 25 |
| 2g CAP | Total Urinary Excretion | 3-(3-hydroxyphenyl)propionic acid | 16 micrograms | Standard Error 10 |
| 2g CAP | Total Urinary Excretion | Asiatic acid | 3 micrograms | Standard Error 4 |
| 2g CAP | Total Urinary Excretion | Monodicaffeoylquinic acids | 17 micrograms | Standard Error 8 |
| 2g CAP | Total Urinary Excretion | Dihydroferulic acid | 145 micrograms | Standard Error 60 |
| 2g CAP | Total Urinary Excretion | Madecassoside | 1 micrograms | Standard Error 8 |
| 2g CAP | Total Urinary Excretion | Isoferulic acid | 18 micrograms | Standard Error 6 |
| 4g CAP | Total Urinary Excretion | Madecassoside | 7 micrograms | Standard Error 3 |
| 4g CAP | Total Urinary Excretion | Isoferulic acid | 24 micrograms | Standard Error 5 |
| 4g CAP | Total Urinary Excretion | Madecassic acid | 14 micrograms | Standard Error 4 |
| 4g CAP | Total Urinary Excretion | Asiatic acid | 4 micrograms | Standard Error 2 |
| 4g CAP | Total Urinary Excretion | Dihydrocaffeic acid | 41 micrograms | Standard Error 7 |
| 4g CAP | Total Urinary Excretion | Dihydroferulic acid | 242 micrograms | Standard Error 54 |
| 4g CAP | Total Urinary Excretion | Ferulic acid | 24 micrograms | Standard Error 5 |
| 4g CAP | Total Urinary Excretion | 3-(3-hydroxyphenyl)propionic acid | 13 micrograms | Standard Error 7 |
| 4g CAP | Total Urinary Excretion | Monodicaffeoylquinic acids | 13 micrograms | Standard Error 7 |
Comparison: Asiatic acidp-value: 0.7t-test, 2 sided
Comparison: Madecassic acidp-value: 0.09t-test, 2 sided
Comparison: Asiaticosidep-value: 0.4t-test, 2 sided
Comparison: Madecassosidep-value: 0.6t-test, 2 sided
Comparison: Monocaffeoylquinic acidsp-value: 0.4t-test, 2 sided
Comparison: Dicaffeoylquinic acidsp-value: 0.1t-test, 2 sided
Comparison: 3-(3-hydroxyphenyl)propionic acidp-value: 0.9t-test, 2 sided
Comparison: Caffeic acidp-value: 0.03t-test, 2 sided
Comparison: Ferulic acidp-value: 0.9t-test, 2 sided
Comparison: Isoferulic acidp-value: 0.6t-test, 2 sided
Comparison: Dihydroferulic acidp-value: 0.4t-test, 2 sided
Comparison: Dihydrocaffeic acidp-value: 0.8t-test, 2 sided