Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.

Background: There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. Discussion: Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. Trial Registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

US Dietary Supplement Labeling Rules and the Possibility of Medical Cost Reduction.

US dietary supplements classified as foods are regulated under the Dietary Supplement Health and Education Act (DSHEA) and other rules. After the DSHEA established in 1994, the supplement market grew by about 4 times and reached $32 billion as of 2012. One of the major reasons for this market expansion is that consumers can recognize functions of the supplements by the structure/function (S/F) claims. S/F claims must not be false or misleading, and must be based upon reliable scientific evidence, especially clinical studies. At the same time, disclaimers must be shown on the package, which are "These statements have not been evaluated by the Food and Drug Administration (FDA). These products are not intended to diagnose, treat, cure or prevent any disease." Both the FDA and Federal Trade Commission (FTC) are responsible for label claims and advertisement of dietary supplements. S/F claims are not medical claims, but these may have impact on people's mindset to be healthier. Recent research shows utilizing dietary supplements in 4 major areas with 10 popular ingredients could hypothetically reduce medical costs by over $50 billion in the US in the period of 2013-2020. Predicted fewer health problems and reduced medical cost information will further increase awareness of supplement usage and thus may raise quality of life. These may reduce the medical cost significantly, if the products are used appropriately with sufficient consumer education.

A meta-analysis of clinical improvements of general well-being by a standardized Lycium barbarum.

Four randomized, blind, placebo-controlled clinical trials were pooled to study the general effects of oral consumption of Lycium barbarum at 120 mL/day, as a standardized juice, GoChi(®) (FreeLife International, Phoenix, AZ, USA). A questionnaire consisting of symptoms graded 0-5 was given to the participants. For each question, the score changes in the questionnaire between pre- and postintervention were summarized by the standardized mean difference and associated SE to perform the meta-analysis. The change was also characterized into a binary outcome, improved or not, to derive odds ratio (OR) and associated SE derived by a binary outcome using the Mantel-Haenszel method. The meta-analysis and heterogeneity were evaluated with the R program using the rmeta package. Statistical significance was set at 5%. In total, 161 participants (18-72 years old) were included in the meta-analysis. Compared with the placebo group (n=80), the active group (n=81) showed significant improvements in weakness, stress, mental acuity, ease of awakening, shortness of breath, focus on activity, sleep quality, daydreaming, and overall feelings of health and well-being under a random effects model. A fixed effects model showed additional improvements in fatigue, depression, circulation, and calmness. The OR indicated significantly higher chance to improve fatigue, dizziness, and sleep quality. Three studies had statistically significant heterogeneity in procrastination, shoulder stiffness, energy, and calmness. The present meta-analysis confirmed the various health effects of L. barbarum polysaccharides-standardized L. barbarum intake found in the previous randomized, double-blind, placebo-controlled human clinical trials and revealed it resulted in statistically significant improvements in neurological/psychological performance and overall feelings of health and well-being compared with the placebo group under both the fixed and the random effects models of the R program.

Lycium barbarum increases caloric expenditure and decreases waist circumference in healthy overweight men and women: pilot study.

BACKGROUND: Lycium barbarum (L. barbarum), a traditional Asian medicinal therapy for diabetes and other conditions, has been shown to increase metabolic rate and to reduce body-weight gains in rodent models, as well as to produce clinical improvements in general feelings of well-being including energy level. OBJECTIVE: To investigate the impact of L. barbarum consumption on (1) caloric expenditure and (2) changes in morphometric parameters (waist circumference) in healthy human adults. METHOD: Two separate randomized, double-blind, placebo-controlled, small clinical studies were conducted using a standardized L. barbarum fruit juice, GoChi, and assessing its effects on (1) resting metabolic rate (RMR) and postprandial energy expenditure (PPEE) as measured by indirect calorimetry after single-bolus intake of 3 doses of L. barbarum (30, 60, and 120 ml) and placebo; and (2) waist circumference and other morphometric changes in a 14-day intervention trial (120-ml daily intake) in the subjects (age = 34 years, body mass index = 29 kg/m(2)). RESULTS: (1) A single bolus of L. barbarum intake increased PPEE 1 through 4 hours postintake over the baseline level in a dose-dependent manner and was significantly higher than the placebo group by 10% at 1 hour postintake of 120 ml (p < 0.05). (2) In a 14-day intervention trial, L. barbarum was found to significantly decrease waist circumference by 5.5 ± 0.8 cm (n = 15) compared with the preintervention measurements and placebo group at postintervention day 15 (p < 0.01). By contrast, the changes in the placebo group (n = 14) from preinterventions was 0.9 ± 0.8 cm, which was not statistically significant. CONCLUSIONS: These results show that L. barbarum consumption increases metabolic rate and reduces the waist circumference, relative to placebo treated control subjects.

Immunomodulatory effects of a standardized Lycium barbarum fruit juice in Chinese older healthy human subjects.

Lycium barbarum has been traditionally used in combination with several herbs for medicinal properties, but systematic modern clinical evaluation as a single herb has not been reported. To examine the systematic effects of L. barbarum on immune function, general well-being, and safety, we tested the effects of a standardized L. barbarum fruit juice (GoChi, FreeLife International, Phoenix, AZ, USA) at 120 mL/day, equivalent to at least 150 g of fresh fruit, the amount traditionally used, or placebo for 30 days in a randomized, double-blind, placebo-controlled clinical study in 60 older healthy adults (55-72 years old). The GoChi group showed a statistically significant increase in the number of lymphocytes and levels of interleukin-2 and immunoglobulin G compared to pre-intervention and the placebo group, whereas the number of CD4, CD8, and natural killer cells or levels of interleukin-4 and immunoglobulin A were not significantly altered. The placebo group showed no significant changes in any immune measures. Whereas the GoChi group showed a significant increase in general feelings of well-being, such as fatigue and sleep, and showed a tendency for increased short-term memory and focus between pre- and post-intervention, the placebo group showed no significant positive changes in these measures. No adverse reactions, abnormal symptoms, or changes in body weight, blood pressure, pulse, visual acuity, urine, stool, or blood biochemistry were seen in either group. In conclusion, daily consumption of GoChi significantly increased several immunological responses and subjective feelings of general well-being without any adverse reactions.

Lycium barbarum (goji) juice improves in vivo antioxidant biomarkers in serum of healthy adults.

Although Lycium barbarum (goji) and active compounds, Lycium barbarum polysaccharides (LBP), have a high in vitro antioxidant score as determined by simple chemical reaction methods, their in vivo antioxidant effects in humans have not been extensively examined. After our earlier report that an LBP-standardized Lycium barbarum preparation (GoChi) helps prevent oxidant stress-related conditions in humans, our present study examined the hypothesis that the antioxidant effects of GoChi result from its ability to enhance endogenous antioxidant factors. We investigated the effects of GoChi in a 30-day randomized, double-blind, placebo-controlled clinical study. The study population included 50 Chinese healthy adults aged 55 to 72 years. In vivo antioxidant markers, consisting of serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and lipid peroxidation (indicated by decreased levels of malondialdehyde, MDA) were examined preintervention and postintervention with GoChi or placebo (120 mL/d). In the GoChi group, antioxidant markers significantly increased by 8.4% for SOD and 9.9% for GSH-Px between the preintervention and postintervention measurements, whereas MDA were significantly decreased by 8.7%. In addition, the SOD, GSH-Px, and MDA levels in the GoChi group were significantly different from those in the placebo group at the postintervention time point, with increases of 8.1% and 9.0% and a decrease of 6.0%, respectively. No significant differences were detected between the preintervention and postintervention time points in the placebo group. These results indicate that GoChi increased antioxidant efficacies in humans by stimulating endogenous factors and suggest that continued use beyond 30 days might help prevent or reduce free radical-related conditions.

A randomized, double-blind, placebo-controlled, clinical study of the general effects of a standardized Lycium barbarum (Goji) Juice, GoChi.

BACKGROUND: This randomized, double-blind, placebo-controlled clinical trial is the first study reported from outside China that has examined the general effects of the orally consumed goji berry, Lycium barbarum, as a standardized juice (GoChi; FreeLife International LLC, Phoenix, AZ) to healthy adults for 14 days. METHODS: Based upon the medicinal properties of Lycium barbarum in traditional Asian medicine, we examined by questionnaire subjective ratings (0-5) of general feelings of well-being, neurologic/psychologic traits, gastrointestinal, musculoskeletal, and cardiovascular complaints as well as any adverse effects. Also, measures of body weight, body-mass index, blood pressure, pulse rate, and visual acuity were assessed before and after consuming 120 mL of GoChi/day or placebo control solution. Data were statistically analyzed for changes between day 1 and day 15. RESULTS: Significant differences between day 1 and day 15 were found in the GoChi group (N = 16) in increased ratings for energy level, athletic performance, quality of sleep, ease of awakening, ability to focus on activities, mental acuity, calmness, and feelings of health, contentment, and happiness. GoChi also significantly reduced fatigue and stress, and improved regularity of gastrointestinal function. In contrast, the placebo group (N = 18) showed only two significant changes (heartburn and happiness). No significant changes in musculoskeletal or cardiovascular complaints were observed in either group. All parametric data (body weight, etc.) were not significantly different between groups or between day 1 and day 15 for either group. CONCLUSIONS: These results clearly indicate that daily consumption of GoChi for 14 days increases subjective feelings of general well-being, and improves neurologic/psychologic performance and gastrointestinal functions. The data strongly suggest that further research is indicated to confirm and extend knowledge of the potential effects of Lycium barbarum upon human health.

Current marketplace for probiotics: a Japanese perspective.

In Japan, probiotics are available as both foods and drugs. Unlike in the United States, probiotics have a long history of cultural acceptance and safe use in Japan. Sales are booming, which may reflect the inception of the regulatory category "foods for specialized health use" (FOSHU), which permits labeling with claims that describe health benefits. A total of 65 probiotic products, containing 16 different strains, are listed among the 579 FOSHU products. Since the US market for probiotics is still small, it has substantial room to grow.

A randomized factorial study of the effects of long-term garlic and micronutrient supplementation and of 2-wk antibiotic treatment for Helicobacter pylori infection on serum cholesterol and lipoproteins.

BACKGROUND: Little is known about the long-term effects of garlic or micronutrient supplementation on total, HDL, and LDL cholesterol in disease-free persons. OBJECTIVE: We aimed to assess the effects of long-term supplementation with garlic and micronutrients and of short-term amoxicillin and omeprazole treatment on serum total, HDL, and LDL cholesterol in a rural Chinese population. DESIGN: We conducted a randomized, double-blind, placebo-controlled, 2 x 2 x 2 and 2 x 2 factorial study of precancerous gastric lesions in 3411 subjects in Linqu County, Shandong Province, China. Thirty-four subjects were randomly selected from each of 12 treatment strata. Sera were analyzed at 3.3 and 7.3 y to measure effects on total, HDL, and LDL cholesterol after 2-wk twice-daily treatment with 1 g amoxicillin and 20 mg omeprazole and supplementation throughout the study with 1) 2 capsules twice daily, each containing 200 mg aged garlic extract and 1 mg steam-distilled garlic oil, or 2) twice-daily micronutrient capsules containing 250 mg vitamin C, 100 IU vitamin E, and 37.5 mg selenium. RESULTS: Regressions adjusted for covariates indicated increases of 0.22 mmol total cholesterol/L (P = 0.01) and 0.19 mmol LDL/L (P = 0.02) after 7.3 y of micronutrient supplementation, but no effect of garlic supplementation or short-term amoxicillin and omeprazole treatment. CONCLUSIONS: In this rural Chinese population with low meat intake and moderate cholesterol concentrations, long-term garlic supplementation had no effect on lipid profiles, whereas micronutrient supplementation was associated with small but significant increases in total and LDL-cholesterol concentrations at 7.3 y.

Clarifying the real bioactive constituents of garlic.

Compounds in garlic work synergistically to produce various effects, but, because of garlic's chemical complexity, processing methods yield preparations with differing efficacy and safety. Although thiosulfinates such as allicin have been long misunderstood to be active compounds due to their characteristic odor, it is not necessary for garlic preparations to contain such odorous compounds to be effective, and they decompose and disappear during any processing. Garlic exhibits hypolipidemic, antiplatelet, and procirculatory effects. It prevents cold and flu symptoms through immune enhancement and demonstrates anticancer and chemopreventive activities. In addition, aged garlic extract possesses hepatoprotective, neuroprotective, antioxidative activities, whereas other preparations may stimulate oxidation. Additional effects may be caused by S-allylcysteine, S-allyl mercaptocysteine), saponins, Nalpha-fructosyl arginine, and other substances formed during a long-term extraction process. Although not all of active ingredients of garlic are known, and allicin-like transient components are not directly active, ample research suggests that an allicin-free garlic preparation that is standardized with a bioavailable component such as S-allylcysteine, is active and various effects of garlic may be attributed to it. Furthermore, various chemical constituents in garlic products, including nonsulfur compounds such as saponins, may contribute to the essential biological activities of garlic. Further studies are needed to confirm their bioavailability and associated activities.

Aged garlic extract may be safe for patients on warfarin therapy.

Garlic has been known to have antiplatelet properties. Because of the lack of major clinical data regarding the safety of concomitant use of garlic supplements and anticoagulants, we decided to evaluate the safety of using garlic extract along with oral anticoagulation therapy. During this project we tested aged garlic extract (AGE), a commercial garlic preparation, with warfarin (Coumadin). Sixty-six (66) patients were screened for a double-blind, randomized, placebo-controlled pilot study. Fifty-two (52) patients were randomized for the project. Forty-eight patients (30 men and 18 women, with a mean age of 56+/-10 years) completed the study. Eighteen patients (14 before randomization, 4 after randomization) were dropped from the study. The study medication (AGE or placebo) was administered at a dose of 5 mL twice a day for 12 wk. Potential bleeding and thromboembolic episodes were monitored. There was no evidence of increased hemorrhage in either the placebo or the AGE group. Adverse events included headache, fatigue, colds, and dizziness. However, no significant difference was found in the incidence of these minor adverse events between the groups. Thus, the adverse events are unlikely to be attributable to AGE. The results suggest that AGE is relatively safe and poses no serious hemorrhagic risk for closely monitored patients on warfarin oral anticoagulation therapy. Although the risk-benefit ratio of AGE use needs to be considered carefully when warfarin therapy is necessary, its positive effects may be beneficial to people with a high-risk background or who are taking cardiovascular medications.

Aged garlic extract is a potential therapy for sickle-cell anemia.

Sickle-cell anemia is one of the most prevalent hereditary disorders with prominent morbidity and mortality. Oxidative phenomena play a significant role in the disorder's pathophysiology. A forumlation of garlic (Allium sativum), AGE, has been reported to exert an antioxidant effect in vitro. We evaluated the antioxidant effect of AGE on sickle red blood cells (RBCs). Five patients (two men and three women, mean age 40+/-15 years, range 24-58 years) with sickle-cell anemia participated in the study. AGE was administered at a dose of 5 mL daily. Whole blood samples were obtained at baseline and at 4 wk, primarily for Heinz body analysis. In all patients, the number of Heinz bodies decreased over the 4-wk period (58.9+/-20.0% at baseline to 29.8+/-15.3% at follow-up; P=0.03). These data suggest that AGE has a significant antioxidant activity on sickle RBCs. AGE may be further evaluated as a potential therapeutic agent to ameliorate complications of sickle-cell anemia.

Aged garlic extract has potential suppressive effect on colorectal adenomas in humans.

Epidemiological and animal studies suggest AGE and its organosulfur constituents, such as S-allylcysteine and S-allylmercaptocysteine have anticarcinogenic effects. To confirm these effects in humans, a preliminary double-blind, randomized clinical trial using high-dose AGE (AGE 2.4 mL/d) as an active treatment and low-dose AGE (AGE 0.16 mL/d) as a control was performed on patients with colorectal adenomas-precancerous lesions of the large bowel. The study enrolled 51 patients who were diagnosed as carrying colorectal adenomas. The patients were randomly assigned to the two groups after adenomas larger than 5 mm in diameter were removed by polypectomy. The number and size of adenomas right before intake (0 mo) and at 6 and 12 mo after intake were measured using colonoscopy. Thirty-seven patients (19 in the active group, 18 in the control group) completed the study and were evaluated for the efficacy of AGE. The number of adenomas increased linearly in the control group from the beginning (the baseline), but AGE significantly suppressed both the size and number of colon adenomas in patients after 12 mo of high-dose treatment (P=0.04). The results suggest AGE suppresses progression of colorectal adenomas in humans. It appears that AGE has multiple pathways to reduce cancer incidence and suppress its growth and proliferation.

Inhibiting progression of coronary calcification using Aged Garlic Extract in patients receiving statin therapy: a preliminary study.

BACKGROUND: Aged Garlic Extract (AGE) reduces multiple cardiovascular risk factors, including blood pressure, cholesterol, platelet aggregation and adhesion, while stimulating nitric oxide generation in endothelial cells. However, no study has evaluated the ability of AGE to inhibit vascular calcification, a marker of plaque formation in human coronary arteries. OBJECTIVE: To assess the efficacy of Aged Garlic Extract (AGE) on changing the rate of atherosclerosis progression as compared to placebo. DESIGN: A placebo-controlled, double-blind, randomized pilot study to determine whether the atherosclerotic plaque burden detected by electron beam tomography (EBT) will change at a different rate under the influence of AGE as compared to placebo. Twenty-three patients were enrolled, and 19 patients completed the study protocol. AGE 4 ml or the equivalent amount of placebo was given to subjects. Duration of the study was 1 year. S-allylcysteine (SAC), one of the active compound of AGE, was measured in the blood as a compliance marker. RESULTS: The mean change of the calcium score (volumetric method) for the AGE group (n = 9) was 7.5 +/- 9.4% over 1 year. The placebo group (n = 10) demonstrated an average increase in calcium scores of 22.2 +/- 18.5%, significantly greater than the treated cohort (P = 0.046). There were no significant differences in individual cholesterol parameters or C reactive protein between the groups. In patients randomized to AGE, there was a nonsignificant trend for improving cholesterol/high-density lipoprotein ratio (P = 0.07) and homocysteine level (P = 0.08). CONCLUSIONS: This small pilot study indicates the potential ability of AGE to inhibit the rate of progression of coronary calcification, as compared to placebo over 1 year. Should these findings be extended and confirmed in larger studies, garlic may prove useful for patients who are at high risk of future cardiovascular events.

Aged garlic extract therapy for sickle cell anemia patients.

BACKGROUND: Sickle cell anemia is one of the most prevalent hereditary disorders with prominent morbidity and mortality. With this disorder oxidative, phenomena play a significant role in its pathophysiology. One of the garlic (Allium sativum L.) formulations, aged garlic extract (AGE), has been reported to exert an anti-oxidant effect in vitro, we have evaluated the anti-oxidant effect of AGE on sickle red blood cells (RBC). METHODS: Five patients (two men and three women, mean age 40 ± 15 years, range 24-58 years) with sickle cell anemia participated in the study. AGE was administered at a dose of 5 ml a day. Whole blood samples were obtained at baseline and at 4 weeks for primarily Heinz body analysis. RESULTS: The data were consistent with our hypothesis. In all patients, the number of Heinz bodies decreased over the 4 week period (58.9 ± 20.0% at baseline to 29.8 ± 15.3% at follow-up, p = 0.03). CONCLUSIONS: These data suggest that there is a significant anti-oxidant activity of AGE on sickle RBC. AGE may be further evaluated as a potential therapeutic agent to ameliorate complications of sickle cell anemia.