Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment

Study Overview
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Brief Summary
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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
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PRIMARY OBJECTIVES: 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. 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.

Official Title
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A Pharmacokinetic Study of Centella Asiatica Product (CAP) in Elderly Participants With Mild Cognitive Impairment Receiving Cholinesterase Inhibitor Therapy

Conditions
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Cognitive Impairment, Elderly

Intervention / Treatment
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* Drug: 2g Centella asiatica water extract product
* Drug: 4g Centella asiatica water extract product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 65-85, male and female 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 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 On cholinesterase inhibitor therapy for Alzheimer's disease (AD) and must be on a stable dose for at least 12 weeks prior to baseline Caregiver/study partner that can accompany participant to all study visits Sufficient English language skills to complete all tests Sufficient vision and hearing to complete all tests No known allergies to Centella asiatica or CAP excipients Willingness to discontinue all botanical dietary supplements for one week prior to and during each study visit Willingness to comply with a 48-hour low plant diet for each study visit Absence of significant depression symptoms (Geriatric Depression Scale-15 score of <12) Body Mass Index (BMI) greater than 17 and less than 35 at screening General health status that will not interfere with the ability to complete the study Exclusion Criteria: Current smoking, alcohol or substance abuse according to DSM-V criteria Women who are pregnant, planning to become pregnant or breastfeeding Men who are actively trying to conceive a child or planning to within three months of study completion Severe aversion to venipuncture Abnormal laboratory evaluation indicating asymptomatic and untreated urinary tract infection Cancer within the last five years, with the exception of localized prostate cancer (Gleason Grade <3) and non-metastatic skin cancers Comorbid conditions such as diabetes mellitus, kidney failure, liver failure, hepatitis, blood disorders, clinical symptomatic orthostatic hypotension, and unstable or significantly symptomatic cardiovascular disease Significant disease of the central nervous system such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-V criteria 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) Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus or Parkinson's disease Mini Mental State Examination (MMSE) score of <20 or >28 or CDR score >1 or zero Unwilling to maintain stable dosage of AD medications throughout study duration Inability or unwillingness of individual or legal guardian/representative to give written informed consent. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is an outpatient open-label clinical study using a blinded randomized crossover design of two doses.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2g CAP<br>Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. | Drug: 2g Centella asiatica water extract product<br>* 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.<br>* Other names: CAP 2g;|
| Experimental: 4g CAP<br>Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. | Drug: 4g Centella asiatica water extract product<br>* 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.<br>* Other names: CAP 4g;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes). | 
| 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 | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes). | 
| 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. | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes). | 
| 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. | Total 10 hours | 
| 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). | 0, 1, 2, 3, 4, and 6h following study intervention |