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Learn More. Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4- methylnitrosamino 3-pyridyl butanone NNK as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage.
Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of Smoking kava root 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4- methylnitrosamino 3-pyridyl butanol NNAL plus its glucuronides, major metabolites of NNK before and after kava administration as an indicator of NNK detoxification. Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine 3-mA in participants, suggestive of its ability to reduce the carcinogenicity of NNK.
Kava also reduced urinary total nicotine equivalents TNEindicative of its Smoking kava root to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents TCE were reduced upon kava use, which may contribute to reductions in tobacco use.
These demonstrate the potential of kava Smoking kava root to reduce lung cancer risk among smokers. In spite of recent advances in immunotherapy, lung cancer remains the leading cause of cancer-related deaths, with an estimateddeaths and overnew cases annually in the U. Cigarette smoking is the major risk factor and tobacco cessation is the only strategy to date proven to mitigate lung cancer risk. The success rate of tobacco cessation with currently available therapies, however, remains low 2.
Novel approaches, such as the integration of lung cancer prevention in conjunction with tobacco cessation, are urgently needed. Tobacco smoke contains various carcinogens and co-carcinogens, collectively contributing to the increased lung cancer risk.
Ample evidence support NNK as a key causative factor of human lung adenocarcinoma development 4 — 7. Polymorphisms of genes involved in NNK metabolism both bioactivation and detoxification are also associated with differential lung cancer risk 8.
Prospective cohort studies found that urinary NNAL was positively associated with lung cancer risk in smokers 910after correcting for cigarettes smoked per day and years of smoking, directly linking NNK exposure to lung cancer development. The mechanism of NNK carcinogenesis has been well characterized Fig. Some Smoking kava root DNAs DNA adductshowever, are not stable and are excreted in urine, which could serve as non-invasive surrogates to estimate the level of DNA damage in tissues.
Among various urinary DNA adducts, we and others demonstrated that human urinary 3-methyladenine 3-mA appeared to be highly tobacco-dependent 14 — 16 and may be indicative of NNK bioactivation Kava is traditionally consumed by the South Pacific Islanders to promote natural calmness 17 It is also marketed as a dietary supplement in the U. A group of kava-specific lactones kavalactones, particularly kavain and dihydrokavain, Fig. S1 have been proposed to be responsible for this pharmacodynamic effect 19 Epidemiological observations 2122 and pre-clinical animal studies 23 — 25 indicate that kava consumption may reduce cancer risk, particularly lung cancer 2326 — We herein report a pilot clinical trial in healthy smokers to test the hypothesis that short-term kava administration will result in increased levels of urinary NNAL, reflective of enhanced NNK detoxification.
The Smoking kava root endpoint was a comparison of urinary NNAL before and after a 7-day course of kava.
Twenty bottles of kava capsules from the Smoking kava root manufacturing lot were obtained directly from Gaia Herbs Brevard, NC. Each capsule was labeled to contain no less than 75 mg kavalactones. Louis, MO. Louis, MO unless stated otherwise. Our method to quantify five major kavalactones kavain, dihydrokavain, methysticin, DHM, and desmethoxyyangonin in kava products was published elsewhere The same method was also used to quantify DHM in the urine samples from the trial participants to assess kava exposure.
Twenty-one participants completed the clinical trial Clinicaltrials. The study de is shown in Figure 2. All participants had normal blood counts, electrolytes, and liver function. The study was approved by the University of Minnesota Institutional Review Board and was conducted in accordance with recognized ethical guidelines.
All participants provided informed, written consent. Demographic information, tobacco use history, medical history, and medication use history were obtained.
All participants underwent a screening physical exam by a study physician. Height and weight were measured. Blood for safety or biomarker evaluation were collected at screening, baseline, and on days 4 and 7 of kava intervention. Twenty-four hour urine collections were obtained at baseline, and on days 1—2, 4—5 and 6—7 of kava intervention for urinary NNAL and other urinary biomarker analysis, broken down into 0—6 and 6—24 h time periods. Volume was recorded to the nearest millimeter. Participants were instructed to continue their usual smoking habits, record dietary intake, and keep a smoking diary throughout the kava intervention.
Additionally, participants completed the modified Cigarette Evaluation Questionnaire mCEQa Smoking kava root tool that assesses the degree to which a smoker experiences the reinforcing effects of smoking 31at baseline and on day 7 of the kava intervention. The kava manufactured by Gaia Herb was chosen because it had the same preparation as the kava product used in our pre-clinical mouse studies 23 Based on the surface area normalization method, the dose of three capsules per day recommended by the manufacturer standardized to mg kavalactones per 3 capsules is comparable to the dose utilized Smoking kava root the mouse studies.
Fasting except water was required at least 1 h before and 1 h after each dose. A dosing diary was maintained by the participant.
Compliance was measured by pill counts at study visits, review of the dosing diary, and by measuring urinary DHM. Missed doses were not made up. Participants were asked to abstain from cruciferous vegetables which contain phytochemicals that may alter NNK metabolismalcohol, medications with special attention paid to acetaminophensupplements and herbs.
Topical and inhaled medications were permitted. The SPE column was washed with 0.
Urinary 3-mA was quantified as ly described with slight modifications Briefly, urine was diluted 10x with phosphate buffer mM, pH 6. The samples were washed with 0. Urinary TCE was measured as described ly Plasma cortisol was quantified following the same procedures with slight modifications. Urinary Smoking kava root NNAL was Smoking kava root following a published procedure For urinary NNAL, the separation and analysis followed ly published procedures Urinary creatinine was measured using a modified Jaffe reaction method 34 by three lab members independently and the mean values were used.
Absorbance was recorded at nm using spectrophotometer. Calibration curves, limit of detection LOD and limit of quantification LOQ of kavalactones, 3-mA, cortisol and cortisol metabolites have been established as ly described 1530 Performance of these methods were validated by specificity, precision, accuracy, within-day and between-day reproducibility using the pure standards added into the blank matrix at three to four different concentrations on three different days.
Demographic information was summarized using frequency and percentage. The mCEQ was summarized using mean and standard deviation before and after kava intervention and compared using a two-tailed paired t-test for means.
The primary endpoint, total urinary NNAL, and other biomarkers of interest were summarized using geometric mean, minimum and maximum due to the skewedness of the data. To investigate the change in these biomarkers before and after kava, a two-sided paired t-test was performed on the log-transformed values. Measures of liver function were summarized using mean and standard deviation at screening, four days after kava and seven days after kava.
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A ificance level of 0. Statistical analyses of biomarkers were performed using R version 3. The characteristics of the 21 eligible participants who completed the study are summarized in Table 1. DHM, a kava-specific lactone, was not detected in any of the baseline urine samples before kava and was detected in all urine samples after kava initiation Fig.
Overall, kava demonstrated excellent safety. Kava had no impact on liver function Fig. Seven of the 21 participants experienced an AE Table S5 that was at least possibly Smoking kava root to the kava.
All were grade 1 and none of these AEs observed occurred in the same participant. These support 1 the safety and tolerability of short-term kava intervention; 2 the potential use of urinary DHM as a measure of kava exposure; and 3 feasibility of high compliance.
In order to quantitatively and objectively evaluate the impact of kava on the biomarkers of NNK-mediated carcinogenesis risk, the potential effect of kava on tobacco use needs to be characterized. We therefore quantified urinary TNE before and on day 7 of kava ingestion.
Nineteen of 21 participants had reductions in 0—6h urinary TNE Fig. The reduction on nicotine, cotinine, 3-hydroxycotine and nicotine-N-oxide the four components for TNE by kava was similar Supporting InformationFig. S4suggesting that the reduction of tobacco use by kava is not likely mediated via inhibiting nicotine metabolism. There were, however, no changes in self-reported cigarettes per day CPD among the participants Table 2which is intriguing.
The effect of kava on tobacco dependence was assessed using the mCEQ As shown in Table 2kava ificantly reduced mCEQ scores for smoking satisfaction and enjoyment of respiratory tract sensation although the extent of reductions was small. Kava use did not have ificant effects on psychological rewards, craving reduction or aversion.
It should be noted that the participants enrolled in this pilot trial did not intend to quit smoking while mCEQ was deed for participants active in Smoking kava root cessation.
Two-tailed paired t-test was performed on the log-transformed data for each measure. Most blood samples were collected between 11 am — 2 pm, reducing circadian influence on plasma cortisol levels. As shown in Fig. We also quantified the sum of the major metabolites of cortisol in the urine samples termed total cortisol equivalent, TCE following our recently reported methods Kava use resulted in a