Randomized, double-blind, placebo-controlled trial to examine the safety, pharmacokinetics and effects of Epimedium prenylflavonoids, on bone specific alkaline phosphatase and the osteoclast adaptor protein TRAF6 in post-menopausal women.

BACKGROUND: Fragility fractures due to menopausal osteoporosis are a major cause of morbidity and mortality. Osteoporotic medications have substantial side effects that limit long term use. HYPOTHESES: Ingestion of a purified extract of Epimedium spp. (EP) is safe, can increase serum levels of prenylflavonoid metabolites, exert positive changes in bone specific alkaline phosphatase (BSAP), suppress of tumor necrosis factor receptor associated factor 6 (TRAF6) protein in osteoclast-precursor monocytes in peripheral blood and therefore have the potential to reduce post-menopausal bone loss. STUDY DESIGN & METHODS: Healthy postmenopausal women were randomized in a double-blind fashion to consume either EP prenylflavonoid extract (740 mg daily) or placebo daily for 6 weeks. The main outcome measures were safety and pharmacokinetics of EP flavonoids. Fasting blood was collected at 3- and 6-weeks, and two weeks after stopping medication for safety evaluations and measurement of BSAP. Peripheral blood monocytes were harvested for measurement of TRAF6 levels. Serum levels of the EP metabolites icariin, icariside I & II, icaritin and desmethylicaritin were measured using tandem mass spectrometry, and non-compartmental pharmacokinetic analyses performed using WinNonlin software. RESULTS: Between October 2018 and Jun 2020, 58 postmenopausal women, aged 57.9 ± 8.9 years, were randomized and completed the study. Consumption of EP prenylflavonoids was not associated with any significant adverse symptoms, with no changes in hepatic, hematological, and renal parameters observed. The main metabolites detected in sera after ingestion of EP prenylflavonoid capsules were desmethylicaritin, icaritin and icariside II. Icariin and icariside I were below detection levels. Ingestion of EP prenylflavonoids induced a median Cmax and AUC0→∞ for desmethylicaritin of 60.9 nM, and 157.9 nM ×day, respectively; and were associated with higher levels of BSAP (p < 0.05) and a trend (p = 0.068) towards lower levels of TRAF6 in peripheral blood monocytes eight weeks after commencing prenylflavonoid ingestion. Prenylflavonoid metabolites were not detected in the sera of placebo participants. CONCLUSIONS: Despite the widespread consumption of EP extracts, the safety, mechanisms of action of their bioactive compounds, and therapeutic indications in humans are unknown. Daily consumption of EP prenylflavonoids for six weeks was safe. The predominant metabolite in sera was desmethylicaritin. Rise in prenylflavonoid metabolites was associated with higher levels of the bone anabolic marker BSAP, suggesting potential therapeutic value for post-menopausal osteoporosis.

Predictors of circulating vitamin D levels in healthy mid-life Singaporean women.

Vitamin D levels were lowest in Indian and Malay compared to Chinese women, and in younger and employed women. The main reason for hypovitaminosis D in study women was deficient cutaneous production. Supplementation in regions with abundant sunshine should consider ethnicity and opportunities for exposure to sunlight. INTRODUCTION: Little is known about variations in circulating vitamin D levels in multiethnic mid-life women living in communities with year-round sunlight. Our study describes the circulating vitamin D levels and their sociodemographic predictors in mid-life Singaporean women. METHODS: Prospective cross-sectional study of healthy Singaporean women, age 45-69 years, who were not consuming vitamin D supplements. Total 25-hydroxyvitaminD [25(OH)D], the sum of 25(OH)D2 and 25(OH)D3, was measured by liquid chromatography-tandem mass spectrometry. RESULTS: The analytic cohort of 721 women, mean age 55.2±6.0 (±SD) years, was of Chinese (82%), Indian (11%), and Malay (7%) ethnicity. Their mean 25(OH)D level was 24.8±7.8ng/mL. One-third (32.6%) of the women had deficient 25(OH)D (≤20ng/mL) and 3.5% were severely deficient (<12ng/mL). 25(OH)D3 comprised 98% of the total circulating 25(OH)D level. Adjusted mean total 25(OH)D levels were significantly lower for women of Indian and Malay (vs Chinese) ethnicity, who were premenopausal or working outside the home. Indian and Malay women had higher odds (adjusted OR 5.58 (95% CI 3.22, 9.87) and 3.83 (95% CI 1.97, 7.57), respectively) of low 25(OH)D compared to Chinese women. Obesity was not an independent predictor of low 25(OH)D, as its strong crude association was confounded by ethnicity. The adjusted odds of low 25(OH)D was reduced in women ≥65 years (adjusted OR 0.37 (95% CI 0.14, 0.87)) compared to those aged 45-55 years. CONCLUSION: One-third of mid-life Singaporean women were 25(OH)D deficient, and the major independent predictors of deficiency were Indian or Malay ethnicity and younger age. Vitamin D supplementation in mid-life women should be targeted to those with documented deficiency or limited cutaneous production.

Antibiotic-Resistant Acinetobacter baumannii Is Susceptible to the Novel Iron-Sequestering Anti-infective DIBI In Vitro and in Experimental Pneumonia in Mice.

Acinetobacter baumannii is a major cause of nosocomial infections especially hospital-acquired pneumonia. This bacterium readily acquires antibiotic resistance traits and therefore, new treatment alternatives are urgently needed. The virulence of A. baumannii linked to iron acquisition suggests a potential for new anti-infectives that target its iron acquisition. DIBI, a 3-hydroxypyridin-4-one chelator, is a purpose-designed, iron-sequestering antimicrobial that has shown promise for treating microbial infection. DIBI was investigated for its in vitro and in vivo activities against clinical A. baumannii isolates. DIBI was inhibitory for all isolates tested with very low MICs (2 µg/ml, equivalent to 0.2 µM), i.e., at or below the typical antibiotic MICs reported for antibiotic-sensitive strains. DIBI inhibition is Fe specific, and it caused an iron-restricted bacterial physiology that led to enhanced antibiotic killing by several discrete antibiotics. DIBI also strongly suppressed recovery growth of the surviving population following antibiotic exposure. A low intranasal dose (11 µmol/kg) of DIBI after intranasal challenge with hypervirulent ciprofloxacin (CIP)-resistant A. baumannii LAC-4 significantly reduced bacterial burdens in mice, and DIBI also suppressed the spread of the infection to the spleen. Treatment of infected mice with CIP alone (20 mg/kg, equivalent to 60 µmol/kg) was ineffective given LAC-4's CIP resistance, but if combined with DIBI, the treatment efficacy improved significantly. Our evidence suggests that DIBI restricts host iron availability to A. baumannii growing in the respiratory tract, bolstering the host innate iron restriction mechanisms. DIBI has potential as a sole anti-infective or in combination with conventional antibiotics for the treatment of A. baumannii pneumonia.

Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans.

Leaves of the Epimedium plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined Epimedium prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized Epimedium prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial. Serum samples were collected over a 48-h period and analyzed by liquid chromatography-tandem mass spectrometry and non-compartmental pharmacokinetic modelling. Epimedium prenylflavonoid extracts were well tolerated and no adverse effects were observed. The principle metabolites detected in the serum were icariside II and desmethylicaritin. Icariside II had a T max of between 4.1 - 4.3 h, reaching a maximum AUC0→∞ of 23.0 (17.5, 29.9) h×ng/mL (median [IQR: interquartile range]) with the highest dose of the Epimedium prenylflavonoid. On the other hand, desmethylicaritin had a delayed T max of 24.1 - 24.4 h and reached a maximum AUC0→∞ of 126.1 (62.4, 202.9) h×ng/mL. The median maximum plasma concentration and AUC0→∞ of desmethyliciaritin showed an increase with higher doses of the Epimedium prenylflavonoid (p < 0.05). Icariin, icariside I, and icaritin levels were below detection limits. Levels of Epimedium prenylflavonoid metabolites observed in this study were consistent with levels demonstrated to have anti-osteoporotic effects in cellular and animal studies. Coupled with the favorable safety profile of the extract observed, further studies are required to explore the utility of Epimedium prenylflavonoid extracts to prevent osteoporosis in postmenopausal women.

Evaluation of Weigh Forward: A group intervention delivered by dietitians and psychologists within a National Health Service specialist weight management service.

There is limited evidence of the effectiveness of non-surgical interventions for severe obesity. Our aim was to evaluate a group intervention delivered by a National Health Service (NHS) specialist weight management service to contribute to the evidence base and inform the development of future services. Participants in this prospective cohort study were patients attending NHS Grampian Specialist Weight Management Services. The intervention was an interactive 12-session group programme based on evidence-based psychological model, with combined dietetic and psychological knowledge and support provided. The primary outcome was mean weight change at the end of the intervention and for 12-mo follow-up (including programme completers, baseline observation carried forward [BOCF], last observation carried forward). Secondary outcome measures included mood, anxiety, binge eating and quality of life. A total of 166 patients accepted a place on the group programme, mean body mass index was 48.9 kg/m2 . Mean weight loss at 6 mo was 5.6 kg and 35.2% of those who completed the group (n = 88) lost ≥5%. Using BOCF, 18.7% lost ≥5% at 6 mo. Those who remained in the programme maintained their weight loss 12 and 18 mo after the start of the intervention. Significant improvements were also found in psychological variables, including reduced depression, anxiety, binge eating and improved emotion regulation. This real-world evaluation of an NHS intervention for patients with severe obesity suggests that individuals who engage achieve a moderate weight loss, which most maintain a year later, although further research is needed to strengthen this conclusion.

Caring for the Uninsured with Prostate Cancer: A Comparison of Four Policy Alternatives in California.

The IMPACT Program seeks to improve access to prostate cancer care for low-income, uninsured men. The objective of the current study was to compare the cost-effectiveness of four policy alternatives in treating this population. We analyzed the cost-effectiveness of four policy alternatives for providing care to low-income, uninsured men with prostate cancer: (1) IMPACT as originally envisioned, (2) a version of IMPACT with reduced physician fees, (3) a hypothetical Medicaid prostate cancer treatment program, and (4) the existing county safety net. We calculated cost-effectiveness based on incremental cost-effectiveness ratios (ICERs) with the formula ICER = (Cost(alternative strategy) - Cost(baseline strategy)) / (QALY(alternative strategy) - QALY(baseline strategy)). We measured outcomes as quality-adjusted life years (QALYs). "Best-case" scenarios assumed timely access to care in 50% of cases in the county system and 70% of cases in any system that reimbursed providers at Medicaid fee-for-service rates. "Worst-case" scenarios assumed timely access in 35 and 50% of corresponding cases. In fiscal year 2004-2005, IMPACT allocated 11% of total expenditures to administrative functions and 23% to fixed clinical costs, with an overall budget of $5.9 million. The ICERs ($/QALY) assuming "best-case" scenarios for original IMPACT, modified IMPACT, and a hypothetical Medicaid program were $32,091; $64,663; and $10,376; respectively. ICERs assuming "worst-case" scenarios were $27,189; $84,236; and $10,714; respectively. County safety net was used as a baseline. In conclusion, IMPACT provides underserved Californians with prostate cancer care and value-added services with only 11% of funds allocated to administrative fixed costs. Both the original IMPACT program and the hypothetical Medicaid prostate cancer program were cost-effective compared to the county safety net, while the reduced-fees version of IMPACT was not.