Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers

Raju, K. Kanaka; Mamallapalli, Jessica; Nelson, Robyn; McCurdy, Christopher R.; Mathews, Carol A.; Xing, Chengguo; Sharma, Abhisheak

doi:10.1016/j.jep.2022.115514

Cited by 8 publications

(9 citation statements)

References 35 publications

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“…Two follow-ups (weeks 8 and 12) are designed to (1) explore the sustainable potential of AB-free kava and (2) capture delayed adverse effects if any, both of which are critical for participants and future development. AB-free kava regimen in the current trial remains the same as in the pilot trial [7], further supported by our recent pharmacokinetic results (the half-lives of the main ingredients in AB-free kava are no more than 3 h) [13]. The 4-week AB-free kava exposure is expected to provide sufficient data about AB-free kava's compliance, efficacy, and safety while minimizing potential risks among the participants.…”

Section: Trial Designsupporting

confidence: 75%

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava

Xing

Malaty

Malham

et al. 2023

Trials

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Background Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers. Methods A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 1:1 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit. Discussion Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kava’s benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence; (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis; and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases. Trial registration ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.

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Section: Trial Designsupporting

confidence: 75%

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava

Xing

Malaty

Malham

et al. 2023

Trials

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“…The active components in kava for relaxation include lactone-based compounds termed kavalactones [86] with kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin as the six major ones (Figure 2). Despite their high structural similarity, these natural kavalactones have distinct pharmacokinetic [87] and pharmacodynamic properties [88,89]. It is therefore possible that these kavalactones may be complementary to each other and none of them individually will be able to fully recapitulate the holistic beneficial properties of kava.…”

Section: A Chronic Tobacco Smoke-exposure Induced Lung Tumorigenesis ...mentioning

confidence: 99%

“…These flavokavains have not been reported to contribute to kava's relaxing property. A number of putative targets have been reported for kavalactones, including voltage-gated sodium and calcium ion channels, gamma-aminobutyric acid (GABA) type A receptors, and monoam- Despite their high structural similarity, these natural kavalactones have distinct pharmacokinetic [87] and pharmacodynamic properties [88,89]. It is therefore possible that these kavalactones may be complementary to each other and none of them individually will be able to fully recapitulate the holistic beneficial properties of kava.…”

Section: A Chronic Tobacco Smoke-exposure Induced Lung Tumorigenesis ...mentioning

confidence: 99%

“…Kavalactones have also been suspected to contribute to kava's hepatotoxic risk, potentially through drug herb interactions since various kavalactones have been reported to modulate several CYP enzymes [150,151]. The concentrations or doses of kavalactones evaluated in the biochemical or cell-based models may have limited human physiological relevance based on our recent pharmacokinetic studies of kava [87]. Nonetheless, the safety of kava needs to be closely monitored in future human translation, particularly for its potential chronic use in lung cancer risk reduction.…”

Section: Potential Risks Associated With Kava Use Particularly In The...mentioning

confidence: 99%

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Opportunities and Challenges of Kava in Lung Cancer Prevention

Freeman

Mamallapalli

Bian

et al. 2023

IJMS

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Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

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“…1) account for more than 95% of its mass balance. 44 AB-free kava has demonstrated solid safety profiles in animal models with no signs of adverse risks at dosages equivalent to human 4,000 mg kavalactones per day. 45–48…”

Section: Introductionmentioning

confidence: 99%

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice

Bian,

Lynch,

Ballas

et al. 2024

Preprint

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Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 – 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms.Graphical Abstract

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Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers

Cited by 8 publications

References 35 publications

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava

Opportunities and Challenges of Kava in Lung Cancer Prevention

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice

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