scholarly journals Developing a Rational, Optimized Product of Centella asiatica for Examination in Clinical Trials: Real World Challenges

2022 ◽  
Vol 8 ◽  
Author(s):  
Kirsten M. Wright ◽  
Janis McFerrin ◽  
Armando Alcázar Magaña ◽  
Joanne Roberts ◽  
Maya Caruso ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dose Range ◽  
Water Extract ◽  
Centella Asiatica ◽  
Placebo Control ◽  
Mitochondrial Activity ◽  
Pharmacokinetic Studies ◽  
Active Compounds ◽  
Chemical Complexity ◽  
Botanical Products

Botanical products are frequently sold as dietary supplements and their use by the public is increasing in popularity. However, scientific evaluation of their medicinal benefits presents unique challenges due to their chemical complexity, inherent variability, and the involvement of multiple active components and biological targets. Translation away from preclinical models, and developing an optimized, reproducible botanical product for use in clinical trials, presents particular challenges for phytotherapeutic agents compared to single chemical entities. Common deficiencies noted in clinical trials of botanical products include limited characterization of the product tested, inadequate placebo control, and lack of rationale for the type of product tested, dose used, outcome measures or even the study population. Our group has focused on the botanical Centella asiatica due to its reputation for enhancing cognition in Eastern traditional medicine systems. Our preclinical studies on a Centella asiatica water extract (CAW) and its bioactive components strongly support its potential as a phytotherapeutic agent for cognitive decline in aging and Alzheimer's disease through influences on antioxidant response, mitochondrial activity, and synaptic density. Here we describe our robust, scientific approach toward developing a rational phytotherapeutic product based on Centella asiatica for human investigation, addressing multiple factors to optimize its valid clinical evaluation. Specific aspects covered include approaches to identifying an optimal dose range for clinical assessment, design and composition of a dosage form and matching placebo, sourcing appropriate botanical raw material for product manufacture (including the evaluation of active compounds and contaminants), and up-scaling of laboratory extraction methods to available current Good Manufacturing Practice (cGMP) certified industrial facilities. We also address the process of obtaining regulatory approvals to proceed with clinical trials. Our study highlights the complexity of translational research on botanicals and the importance of identifying active compounds and developing sound analytical and bioanalytical methods for their determination in botanical materials and biological samples. Recent Phase I pharmacokinetic studies of our Centella asiatica product in humans (NCT03929250, NCT03937908) have highlighted additional challenges associated with designing botanical bioavailability studies, including specific dietary considerations that need to be considered.

scholarly journals Ecklonia cava Attenuates PM2.5-Induced Cognitive Decline through Mitochondrial Activation and Anti-Inflammatory Effect

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 131
Author(s):  
Seon Kyeong Park ◽  
Jin Yong Kang ◽  
Jong Min Kim ◽  
Hyun-Jin Kim ◽  
Ho Jin Heo
Keyword(s):  
Water Extract ◽  
Ecklonia Cava ◽  
Mitochondrial Activity ◽  
Memory Decline ◽  
Mitochondria Membrane Potential ◽  
Mitochondrial Ros ◽  
Ifn Γ ◽  
Related Proteins ◽  
The Brain ◽  
Pro Inflammatory Cytokines

To evaluate the effects of Ecklonia cava (E. cava) on ambient-pollution-induced neurotoxicity, we used a mouse model exposed to particulate matter smaller than 2.5 µm in aerodynamic diameter (PM2.5). The intake of water extract from E. cava (WEE) effectively prevented the learning and memory decline. After a behavioral test, the toll-like receptor (TLR)-4-initiated inflammatory response was confirmed by PM2.5 exposure in the lung and brain tissues, and the WEE was regulated through the inhibition of nuclear factor-kappa B (NF-κB)/inflammasome formation signaling pathway and pro-inflammatory cytokines (IL-6 and IFN-γ). The WEE also effectively improved the PM2.5-induced oxidative damage of the lungs and brain through the inhibition of malondialdehyde (MDA) production and the activation of mitochondrial activity (mitochondrial ROS content, mitochondria membrane potential (MMP), adenosine triphosphate (ATP) content, and mitochondria-mediated apoptotic molecules). In particular, the WEE regulated the cognition-related proteins (a decreased amyloid precursor protein (APP) and p-Tau, and an increased brain-derived neurotrophic factor (BDNF)) associated with PM2.5-induced cognitive dysfunction. Additionally, the WEE prevented the inactivation of acetylcholine (ACh) synthesis and release as a neurotransmitter by regulating the acetylcholinesterase (AChE) activity, choline acetyltransferase (ChAT), and ACh receptor (AChR)-α3 in the brain tissue. The bioactive compounds of the WEE were detected as the polysaccharide (average Mw; 160.13 kDa) and phenolic compounds including 2′-phloroeckol.

A study of effect of Centella asiatica on oxidative markers in the hippocampus of offsprings born to alcohol-fed pregnant rats and the correlation with their cognitive functions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mitha K.V. ◽  
Saraswati Jaiswal Yadav ◽  
Ganaraja Bolumbu
Keyword(s):  
Brain Damage ◽  
Water Extract ◽  
Centella Asiatica ◽  
Protein Carbonyl ◽  
Memory Retention ◽  
Pregnant Rats ◽  
Shuttle Box ◽  
Cognitive Efficiency ◽  
Beneficial Effects ◽  
Oxidative Markers

Abstract Objectives Alcohol consumption causes several harmful effects on the organs, which is hugely understated. Many deformities occur in the fetus when pregnant mothers indulge in alcoholism. Alcohol is a known teratogen, hence organ formation, particularly development of parts brain critical for cognitive function may be affected. The oxidative brain damage also could contribute to reduced cognitive efficiency of brain exposed to alcohol. In this study, effect of Centella asiatica in relieving the oxidative brain damage in offspring of alcohol fed mother rats was evaluated. Methods In this study we fed alcohol (5 g/kg body weight, 30% w/v) to a group of pregnant Wistar rats during gestation period, and another group served as control. Four groups of rats (n = 6 each) were selected from the offspring of these mother rats. The groups were, control, positive (treated) control, untreated and treated from alcohol-fed mother. Their cognitive parameters were tested in water maze, shuttle box and compared. Further their oxidative status was evaluated by estimating malondialdehyde (MDA), protein carbonyl, total antioxidants and glutathione reductase (GSH) in hippocampus. Results The results suggested that there was significantly high cognitive performance in maze test and shuttle box memory retention in rats treated with C. asiatica water extract and the antioxidant levels were high in their hippocampus. Conclusions The outcome of the study suggested that C. asiatica produced beneficial effects in reversing the alcohol induced brain damage in pregnancy.

scholarly journals Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 630 ◽  
Author(s):  
Donald G Matthews ◽  
Maya Caruso ◽  
Charles F Murchison ◽  
Jennifer Y Zhu ◽  
Kirsten M Wright ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyloid Β ◽  
Water Extract ◽  
Centella Asiatica ◽  
Antioxidant Response ◽  
Plaque Burden ◽  
Heme Oxygenase 1 ◽  
Synaptic Density ◽  
Cognitive Benefits ◽  
5Xfad Mice

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

Use of a placebo in clinical trials

1998 ◽  
Vol 13 (5) ◽  
pp. 254-263 ◽  
Author(s):  
G Emilien ◽  
JM Maloteaux ◽  
A Seghers ◽  
G Charles
Keyword(s):  
Clinical Trials ◽  
Placebo Response ◽  
Drug Efficacy ◽  
Placebo Treatment ◽  
High Response Rate ◽  
Experimental Methodology ◽  
Necessary Condition ◽  
Control Group ◽  
Placebo Control ◽  
Experimental Drug

SummaryThe use of a placebo control group in the evaluation of a new product is today considered by most as a necessary condition of experimental drug research. Placebo response is an essential consideration in all clinical trials. If not properly controlled, incorrect and dangerous conclusion may be inferred for a product efficacy and safety profile. However, the inclusion of a placebo group in clinical trials in neuropsychiatric research raises several ethical and scientific questions. Whereas in certain indications, such as suicidal patients and severe and psychotic depression, the use of a placebo is generally not accepted, it is difficult to assess drug efficacy. This article discusses the concept of placebo in clinical trials, the occurrence of adverse events after placebo treatment and the high response rate of placebo in neuropsychiatric clinical research. The experimental methodology to adequately control all the factors involved is also analysed and discussed.

scholarly journals Health Benefits of Ganoderma lucidum as a Medicinal Mushroom

2019 ◽  
Vol 7 (sp1) ◽  
pp. 84 ◽  
Author(s):  
Sanem Bulam ◽  
Nebahat Şule Üstün ◽  
Aysun Pekşen
Keyword(s):  
Clinical Trials ◽  
Ganoderma Lucidum ◽  
International Markets ◽  
Biologically Active ◽  
Medicinal Mushroom ◽  
Pharmacological Activities ◽  
Active Compounds ◽  
Plastic Bags ◽  
Ethanol Extracts ◽  
Diverse Groups

Ganoderma lucidum (Curtis) P. Karst., known as “Lingzhi” in China or “Reishi” in Japan, is a well-known medicinal mushroom and traditional Chinese medicine, which has been used for the prevention and treatment of bronchitis, allergies, hepatitis, immunological disorders and cancer. G. lucidum is rarely collected from nature and mostly cultivated on wood logs and sawdust in plastic bags or bottles to meet the demands of international markets. Diverse groups of chemical compounds with pharmacological activities, isolated from the mycelia and fruiting bodies of G. lucidum are triterpenoids, polysaccharides (β-D-glucans), proteins, amino acids, nucleosides, alkaloids, steroids, lactones, lectins, fatty acids, and enzymes. The biologically active compounds as primarily triterpenoids and polysaccharides of G. lucidum have been reported to possess hepatoprotective, antihypertensive, hypocholesterolemic, antihistaminic effects and antioxidant, antitumor, immunomodulatory, and antiangiogenic activities. Several formulations have been developed, patented and used as nutraceuticals, nutriceuticals and pharmaceuticals from G. lucidum’s water or ethanol extracts and rarely purified active compounds. As the result of clinical trials, various products have commercially become available as syrup, injection, tablet, tincture or bolus of powdered medicine and an ingredient or additive in dark chocolate bars and organic fermented medicinal mushroom drink mixes such as green teas, coffees, and hot cacaos. This review has intended to give and discuss recent knowledge on phytochemical and pharmacological compositions, therapeutic and side effects, clinical trials, and commercial products of G. lucidum.

Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art

2021 ◽  
Vol 16 ◽  
Author(s):  
John J. Sramek ◽  
Michael F. Murphy ◽  
Sherilyn Adcock ◽  
Jeffrey G. Stark ◽  
Neal R. Cutler
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Healthy Volunteers ◽  
Small Molecules ◽  
Phase 1 ◽  
Dose Range ◽  
Pharmacodynamic Modeling ◽  
Inpatient Setting ◽  
Conducting Phase ◽  
Safe Dose

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

scholarly journals Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Aβ-Exposed Hippocampal Neurons

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Nora E. Gray ◽  
Jonathan A. Zweig ◽  
Donald G. Matthews ◽  
Maya Caruso ◽  
Joseph F. Quinn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Neuroblastoma Cells ◽  
Water Extract ◽  
Centella Asiatica ◽  
Antioxidant Response ◽  
And Oxidative Stress

Centella asiatica has been used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) protects against the deleterious effects of amyloid-β (Aβ) in neuroblastoma cells and attenuates Aβ-induced cognitive deficits in mice. Yet, the neuroprotective mechanism of CAW has yet to be thoroughly explored in neurons from these animals. This study investigates the effects of CAW on neuronal metabolism and oxidative stress in isolated Aβ-expressing neurons. Hippocampal neurons from amyloid precursor protein overexpressing Tg2576 mice and wild-type (WT) littermates were treated with CAW. In both genotypes, CAW increased the expression of antioxidant response genes which attenuated the Aβ-induced elevations in reactive oxygen species (ROS) and lipid peroxidation in Tg2576 neurons. CAW also improved mitochondrial function in both genotypes and increased the expression of electron transport chain enzymes and mitochondrial labeling, suggesting an increase in mitochondrial content. These data show that CAW protects against mitochondrial dysfunction and oxidative stress in Aβ-exposed hippocampal neurons which could contribute to the beneficial effects of the extract observed in vivo. Since CAW also improved mitochondrial function in the absence of Aβ, these results suggest a broader utility for other conditions where neuronal mitochondrial dysfunction occurs.

scholarly journals Inhibition of cPLA2 and sPLA2 Activities in Primary Cultures of Rat Cortical Neurons by Centella asiatica Water Extract

2012 ◽  
Vol 7 (7) ◽  
pp. 1934578X1200700 ◽  
Author(s):  
Patrícia P. Defillipo ◽  
André H. Raposo ◽  
Alessandra G. Fedoce ◽  
Aline S. Ferreira ◽  
Hudson C. Polonini ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Leaf Extract ◽  
Primary Cultures ◽  
Water Extract ◽  
Centella Asiatica ◽  
Long Time ◽  
Rat Cortical Neurons ◽  
Low Toxicity ◽  
The Brain

Leaf extract of Centella asiatica has been used as an alternative medicine for memory improvement in the Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of Alzheimer's disease, the molecular mechanism of C. asiatica on neuroprotection still remains unexplained. In this study, we investigated the effects of C. asiatica water extract on activity of subtypes of phospholipase A2 (PLA2) in primary cultures of rat cortical neurons and quantified by HPLC a possible molecule responsible for the activity. The cPLA2 and sPLA2 activities were inhibited in vitro by asiaticoside present in the water extract of C. asiatica. This extract may be a candidate for the treatment of neurodegenerative processes because of its pharmacological activity in the brain and its low toxicity, as attested by its long popular use as a natural product.

Antibiotic or Myringotomy, or Both, for Acute Otitis Media

1983 ◽  
Vol 92 (6_suppl) ◽  
pp. 32-33
Author(s):  
J. S. Supance ◽  
P. H. Kaleida ◽  
M. L. Casselbrant ◽  
M. M. Blatter ◽  
K. S. Reisinger ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Otitis Media ◽  
Acute Otitis Media ◽  
Drug Efficacy ◽  
Pharmacokinetic Studies ◽  
Controlled Clinical Trials ◽  
Randomized Controlled Clinical Trials ◽  
Surgical Methods ◽  
Potential Benefits ◽  
The Cost

Prevention and safe and effective treatment of otitis media are two of our ultimate research goals. Both of these require that a variety of medical and surgical methods of management be evaluated. The most frequent medical management of otitis media is the administration of antibiotics, decongestants, and antihistamines; therefore, several studies that are either randomized placebo-controlled clinical trials or drug efficacy studies have been undertaken. Also, pharmacokinetic studies either have been performed or are underway to determine the ability of drugs to achieve appropriate blood and middle ear levels. The most common methods of surgical management are myringotomy with or without tympanostomy tube insertion, and adenoidectomy with or without tonsillectomy. Randomized controlled clinical trials are being conducted to determine the efficacy and risk/benefit of these procedures at various stages and levels of severity of otitis media in children. In addition, we are attempting to address the problem of the cost of these methods in relation to their potential benefits.

Clinical trial feasibility assessment and start-up tool (CTFAST).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14089-e14089
Author(s):  
Amanda Tice ◽  
Richard Dima ◽  
Wasif M. Saif ◽  
Melissa Panzo ◽  
Sarah R. Vaiselbuh
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Patient Population ◽  
Feasibility Analysis ◽  
Pharmacokinetic Studies ◽  
Research Experience ◽  
Team Members ◽  
Feasibility Assessment ◽  
Start Up ◽  
The Right

e14089 Background: Selecting the right clinical trials for patients remains a challenging job. The better the match between a clinical trial and the target patient population before conducting a study, the more likely the study will successfully reach the target goal of recruitment. We developed a feasibility assessment scoring system based on our vast clinical research experience, managing multiple sites across a large health system, applicable to oncology as well. Methods: Our feasibility team (FT) is responsible for identifying clinical trials and determining if they are an appropriate match for our institution and unique patient population. Once a potential trial is identified, FT performs a feasibility assessment of the research protocol to determine the resources required to conduct the trial. We developed a Clinical Trial Feasibility Assessment & Start-up Tool (CTFAST) to help sites streamline their feasibility assessments and track their trial through the start-up phase. With CTFAST a feasibility score is generated based on the cumulative value assigned to several items such as: sponsor, study type, pharmacokinetic studies, trial phase, etc. A feasibility scale is assigned as follows: > 25 – Accepted; 15-25 – On Hold; < 15- Rejected. Accepted studies are assigned a color coded priority track (fast, intermediate, routine), that allows team members to prioritize their studies accordingly. Once a study is accepted, the study is processed for enrollment. Results: CTFAST has increased productivity and clinical trial revenues by 40%. CTFAST allows for early identification of bottlenecks in workflow, thereby improving outcomes. By appropriately matching of clinical trials to our site, enrollments increased by 50% with an expanded clinical trial portfolio across 9 different departments. Study start-up times have been reduced to a minimum of 21 days and the use of time & effort has been optimized. Conclusions: CTFAST is replicable across all clinical trial sites and provides an expansive and critical feasibility analysis that is not attainable by traditional querying of investigators and questionnaires. It is an excellent work flow improvement tool as it critically analyzes all aspects of a study, prior to enrollment. When conducting an effective feasibility analysis the clinical trial site can optimize clinical trial outcomes.

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