Part Two: Pharmacokinetic Evaluation of E-Liquid Flavors of Vuse Solo Electronic Nicotine Delivery System, An Unblinded, Parallel, Randomized Study To Assess Nicotine Uptake In Smokers

This paper reports the findings of a randomized nicotine pharmacokinetic (PK) study of a closed electronic nicotine delivery system (ENDS). The study evaluated four flavor variants of Vuse Solo ENDS where subjects used their randomized investigational product (IP) for 10 minutes ad libitum and blood samples were collected for PK assessments that included maximum plasma nicotine concentration (Cmax) and area under the nicotine concentration-vs-time curve up to 60 minutes (AUCnic0–60). Baseline-adjusted mean Cmax ranged from 6.53 to 8.21 ng/mL, and mean AUCnic0–60 ranged from 206.87 to 263.52 ng*min/mL for all ENDS IPs. Results for Cmax and AUCnic0-60 values were consistent among the ENDS IP flavor variants tested and results indicate that flavors did not affect nicotine uptake in human subjects.

Serotype Distribution of Remaining Pneumococcal Meningitis in the Mature PCV10/13 Period: Findings from the PSERENADE Project

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5–7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites (N = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites (N = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed.

Use of growth inhibitor chlormequat chloride in potato culture in vitro

The publication presents data on the use of growth inhibitor chlormequat chloride in in vitro potato culture on varieties of different maturity groups: Meteor (early), Zekura (mid-early), and Northern Lights (mid-season). Five dosages of the investigational product were studied, ranging from 0.1125 to 1.8 g/l. It was found that in maximum doses of the product there was a strong inhibition of all growth processes in all varieties. The research results showed that the most optimal concentration of chlormequat chloride is 0.225 g per 1 liter of Murashige and Skoog medium. At this dose, on 30th day of cultivation, there was a decrease in the height of microplants from the control by 63.2-85.1%, in the root length - up to 15.0% and their number - up to 22.8% and an increase in the number of internodes by 6.5-22,0 % depending on the variety. The investigational product had an effect on formation of microtubers; in the Meteor variety, their largest number was 89.5% in the nutrient medium with a dose of 1.8 g/l, in the Zekura variety - 93.0% in the nutrient medium with a dose of 0.9 g/l. The new technique makes it possible to lengthen the periods between cuttings of test-tube plants by 2.3 times. This, in turn, reduces the cost of maintaining the in vitro collection material of potatoes in the summer-autumn period, and improves its quality, since each additional cutting cycle affects a more rapid degeneration of the variety. Also, microplants grown with growth inhibitor during subsequent relocation to a standard Murashige and Skoog medium did not show an aftereffect.

Safety and efficacy of herbal extracts to restore respiratory health and improve innate immunity in COVID-19 positive patients with mild to moderate severity: A structured summary of a study protocol for a randomised controlled trial

Objectives Primary Objective • To assess the efficacy of herbal extracts in boosting innate immunity of patients with COVID-19 infection. Secondary Objectives • To assess the efficacy of herbal extracts in restoring respiratory health • To assess the efficacy of Cap. IP in early recovery of patients and decline in viral load • To assess the safety of herbal extracts Trial design This is a single centre, randomized, 2-arm, parallel group, double blind, 1:1 ratio, controlled, exploratory trial with a study period of 30 days from the day of enrolment. Participants Patients attending the COVID treatment centre at Yashwantrao Chavan Memorial Hospital, Nehrunagar, Pimpri, Pune, India were screened for their participation in the study. Patients who were known COVID-19 positive (with positive RT-PCR), eligible and willing were enrolled in the study. Intervention and comparator The intervention in the trial has a background in ‘Ayurved’. Intervention Arm: Two capsules, Investigational Product (IP) - 1 - 400mg and Investigational Product - 2 - 450mg, containing herbal extracts (a blend of water and CO2 extracts) of Shunthi (Zingiber officinale (Ginger), Vidanga (Embelia ribes), Yashtimadhu (Glycyrrhiza glabra), Haritaki (Terminalia chebula), Guduchi (Tinospora cordifolia), Shatavari (Asparagus racemosus), Aamalaki (Emblica officinalis), Pippali (Piper longum) and calcined Zinc, Shankha bhasma. Placebo Arm: Edible starch ~ 450 mg. The look and feel of IP and of Placebo boxes were very similar. Patients are to take two capsules (one each of IP-1 and IP-2) twice a day for 15 days, and from the 16th day, one capsule of IP-2 twice a day up-to day 30. Capsules are to be administered orally with plain water. The IP is to be taken with all other concomitant medicines prescribed by the treating physician/doctor. The dose of each component in the IP is very safe to administer. The investigational products are registered products with the Indian Government and have been used for more than 6 months in various health conditions but not for COVID-19. Main outcomes Primary Outcome: Efficacy of the herbal extracts in COVID 19 positive patients (in declining viral load: time-point: 4 days and early recovery) Secondary Outcomes: Efficacy of the herbal extracts as an immune-modulator - TH1, TH2, Th17, IL6, NK Cells and CD markers; Immunoglobulin IGG (Serum); Immunoglobulin IGM (Serum) - at 30 days. Efficacy of the investigational product in reducing sequela of the disease Safety analysis (Liver Function Test and Kidney Function Test) including serious allergic reaction of: rash, itching/swelling, severe dizziness, trouble breathing. Randomisation An alphanumeric coded set of IP/Placebo containers will be used. Participants will be automatically randomized to two groups in the ratio 1:1. Blinding (masking) Participants, caregivers and investigators were blinded. Numbers to be randomised (sample size) A total of more than 60 and up to 75 patients were to be enrolled in the study into the two groups, considering drop-outs. 72 were enrolled with 37 into the intervention group and 35 into the placebo group. Trial Status Protocol number: CoviQuest-01 Protocol version number: 1.2 Protocol Date: 1st July 2020 The recruitment period is completed for the trial. Date of 1st patient enrolment was 11th Aug 2020 and the last patient was enrolled on 3rd of September 2020. This is to state that it was a late submission from authors for publication of the protocol to the BMC, after enrolment in the study was over. Last Participant’s last follow-up is scheduled on 5th October 2020 Trial registration The trial was prospectively registered with the CTRI (Clinical Trial Registry of India). Registration number is CTRI/2020/07/026570. Registered on 14 July 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

663 Correlation between early endpoints and overall survival in non-small-cell lung cancer: a trial-level meta-analysis

BackgroundIn clinical trials that assess novel therapeutic agents in patients with non-small-cell lung cancer (NSCLC), early endpoints (e.g. progression-free survival [PFS] and objective response rate) are often evaluated as indicators of biological drug activity, and are used as surrogate endpoints for overall survival (OS). Compiling trial-level data could help to develop a predictive framework to ascertain correlation trends between treatment effects for early (e.g. odds ratio [OR] for PFS at 6 months) and late endpoints (e.g. hazard ratio [HR] OS).MethodsA dataset was compiled, which included 81 randomized, controlled trials (RCTs; Phase II–IV) of NSCLC (Stages I–IV), with 35 drugs and 156 observations. The dataset was collected from multiple source databases, including Citeline, TrialTrove, clinicaltrials.gov, and PubMed. We applied random-effects meta-analysis to correlate a variety of treatment effects for early endpoints with HR OS. We performed meta-regression analyses across different data-strata, stratified by the mechanism of action (MoA) of the investigational product (programmed death protein-1/programmed death-ligand 1 [PD-1/PD-L1], epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor, and DNA damage response).ResultsLow (Spearman’s rho 0.3–<0.5) to moderate (rho 0.5–<0.7) correlations were observed between HR OS and (1) HR PFS, (2) OR PFS 4 months, and (3) OR PFS 6 months for PD-1/PD-L1 trials, EGFR trials, and all trials combined (Random-effects meta-regression; P<0.05). Similar correlations were observed between each of the early endpoint treatment effects and HR OS. For example, the moderate correlation observed between OR PFS 4 months and HR OS (rho-0.579; 95% confidence interval [CI]-0.800,-0.274; meta-regression R2= 72.5%) was similar to that between OR PFS 6 months and HR OS (rho-0.633; 95% CI-0.802, -0.383; R2=86.1%) for PD-1/PD-L1 trials. Note, the reported rho values are negative as a HR<1, and an OR>1, indicate benefit with the investigational product.ConclusionsUsing a comprehensive summary data set in the NSCLC space, we observed low-to-moderate correlations between treatment effects for early endpoints and HR OS across RCTs of agents with different MoAs, including trials of PD-1/PD-L1 checkpoint inhibitors. Exploration of additional endpoints, beyond RECIST, is required to identify other early indicators of efficacy that might predict HR OS. By incorporating additional trial-level parameters and building composite biomarkers using machine intelligence methods, in collaboration with innovative trial design efforts, we envisage to improve the prediction of HR OS from early endpoints.

Effect of a Calcium-Enriched Lemon Beverage on Bone Metabolism and Bone Mineral Density in Postmenopausal Women: A Double-Blind, 11-Month, Intervention Study

Background Key approaches to preventing the onset of osteoporosis are to maximize peak bone mass (PBM) in early adulthood and to minimize the inevitable loss of bone mineral density (BMD) after menopause. Consequently, osteoporosis attracts a great deal of social as well as medical attention in Japan, a country experiencing population aging. Methods The present randomized, controlled study aimed to elucidate how bone metabolism and bone mineral density (BMD) are affected by the consumption of a lemon juice-containing, calcium-enriched beverage. The effectiveness of this investigational product was evaluated in 79 postmenopausal women. The subjects were assigned to three groups. The first two groups received calcium-supplemented (LECA group) and unsupplemented lemon (LE group) beverages, respectively. The third group (control) received no intervention. The LECA and LE groups consumed one bottle (290 ml) of the appropriate investigational product every day for 11 consecutive months. Results The results showed that the regular consumption of this lemon beverage promoted Ca absorption through the chelating function of citric acid, attenuating bone resorption. The results also suggest that the suppression of bone resorption inhibits bone formation mediated by the differentiation and activity of osteoblasts and leads to the prevention of high-turnover bone metabolism. Conclusion This hypothesis is further supported by the novel finding that the regular consumption of the lemon beverage increases the BMD of both the lumbar spine and femur. We believe that the Ca-supplemented lemon beverage used in the present study will be instrumental in developing effective strategies for the prevention of osteoporosis.