Clinical outcomes in individuals hospitalized with SARS-CoV-2 Delta variant (B.1.617.2) who had been vaccinated with Covishield (ChAdOx1) and Covaxin (BBV-152).

Background: Covishield (ChAdOx) and Covaxin (BBV-152) are the mainstream vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) used in India and a few other countries. Objective: To assess the clinical outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19) who had been vaccinated with either Covishield or Covaxin. Methods: This prospective, single-centre, observational cohort study of 1160 patients hospitalized with COVID-19 was conducted between April and June 2021. Severity of disease at admission and during hospitalization, requirement for intensive care unit (ICU) admission and ventilatory support, inflammatory markers (C-reactive protein, ferritin, lactate dehydrogenase, D-dimer), neutralizing antibody levels and mortality were assessed in vaccinated and unvaccinated patients. Results: More than 90% of patients in this study harboured the Delta variant (Pango lineage B.1.617.2) of SARS-CoV-2. Severity of disease at admission and during hospitalization (3.44% vs 7.51%; P=0.0032) and requirement for ICU admission and ventilatory support (2.83% vs 5.86%; P=0.0154) were significantly lower in vaccinated patients compared with unvaccinated patients. Vaccinated patients also had significantly (P<0.0001) higher antibody levels and lower inflammatory marker levels compared with unvaccinated patients. A subset of vaccinated, deceased patients mounted minimal antibody response ['non-responders': 4.53 (standard deviation 1.40) AU/mL]. Conclusion: These results demonstrate the effectiveness of Covishield and Covaxin against severe disease in patients hospitalized with COVID-19 with breakthrough infections caused by the Delta variant. Strategies targeting non-responders are desirable to minimize morbidity and mortality.

Shilajit extract reduces oxidative stress, inflammation, and bone loss to dose-dependently preserve bone mineral density in postmenopausal women with osteopenia: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Accelerated bone loss associated with aging and estrogen withdrawal is mediated in part by increased oxidative stress and inflammation. OBJECTIVE: Investigate dietary supplementation with a standardized aqueous extract of shilajit with clinically demonstrated antioxidant, anti-inflammatory, and collagen-promoting activity on attenuating bone loss in postmenopausal women with osteopenia. DESIGN: Sixty postmenopausal women aged 45 - 65 years with osteopenia were randomized to receive 1 of 3 treatments daily for 48 weeks: (1) placebo, (2) 250 mg shilajit extract, or (3) 500 mg shilajit extract. Bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) were measured at weeks 0, 24, and 48, and circulating markers of bone turnover (CTX-1, BALP, RANKL, OPG), oxidative stress (MDA, GSH), and inflammation (hsCRP) at weeks 0, 12, 24, and 48. RESULTS: BMD of both the LS and FN progressively decreased in women receiving placebo but was dose-dependently attenuated with shilajit extract supplementation, resulting in significantly increased percentage changes from baseline in BMD at 24- and 48-weeks in both supplemented groups compared to placebo (p < 0.001). CTX-1, BALP, and RANKL decreased, whereas OPG increased, in both groups supplemented with the shilajit extract, but not in the placebo group, resulting in significantly decreased or increased percentage changes from baseline, respectively. MDA was significantly decreased (p < 0.001) and GSH was significantly increased (p < 0.001) in both supplemented groups compared to placebo from week 12 for the duration of the study. Progressive reductions in hsCRP were observed in both supplemented groups, resulting in significantly decreased percentage changes from baseline in supplemented women compared to placebo (p < 0.001). CONCLUSION: Daily supplementation with this shilajit extract supports BMD in postmenopausal women with osteopenia in part by attenuating the increased bone turnover, inflammation and oxidative stress that coincides with estrogen deficiency in this population at increased risk for osteoporosis and bone fractures.

Aqueous Azadirachta indica (Neem) Extract Attenuates Insulin Resistance to Improve Glycemic Control and Endothelial Function in Subjects with Metabolic Syndrome.

Neem (Azadirachta indica) exhibits multiple therapeutic benefits in preclinical studies, but clinical studies are lacking. This clinical study investigated the efficacy and safety of an aqueous A. indica leaf and twig extract (NEEM) on metabolic parameters in subjects with metabolic syndrome (MetS). Subjects were randomized to receive (1) placebo or (2) 125 mg, (3) 250 mg, or (4) 500 mg of NEEM twice daily (n = 20/group) for 12 weeks. Fasting blood sugar (FBS) and insulin, postprandial blood sugar (PPBS), insulin resistance (IR), hemoglobin A1c (HbA1c), endothelial function, circulating markers of inflammation and oxidative stress, lipid profiles, and platelet aggregation were measured at weeks 0, 4, 8, and 12. NEEM supplementation dose dependently improved the trajectories for FBS, PPBS, IR, and HbA1c over time, as well as endothelial function and most markers of inflammation and oxidative stress. Therefore, NEEM may be considered a promising therapeutic to attenuate the hyperglycemia and associated cardiometabolic derangements in people with MetS. Clinical trial registration no.: CTRI/2019/03/018034 [registered on: March 12, 2019].

Effect of Omega-3 Fatty Acid Alone and in Combination with Proprietary Chromium Complex on Endothelial Function in Subjects with Metabolic Syndrome: A Randomized, Double-Blind, Parallel-Group Clinical Study.

Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities that include hypertension, central obesity, insulin resistance, and dyslipidemia and is strongly associated with an increased risk of diabetes, cardiovascular diseases (CVD), and all-cause mortality. Early diagnosis is important to employ lifestyle and risk factor modification. Existing therapies are limited. Studies report positive effect of omega-3 fatty acids (ω-3FA) on symptoms of metabolic syndrome. The present study was undertaken to evaluate the effect of ω-3FA alone and in combination with proprietary chromium complex (PCC) on endothelial function in subjects with metabolic syndrome. In this randomized, double-blind, parallel-group study, subjects were enrolled into the study after ethics committee (EC) approval and informed consent. Eligible subjects were randomized to receive ω-3FA concentrate 2000 mg (Group A-18 subjects), ω-3FA concentrate 2000 mg + PCC200 mcg (Group B-19 subjects), and ω-3FA concentrate 2000 mg + PCC400 mcg (Group C-21 subjects) daily for 12 weeks. Endothelial dysfunction as measured by reflection index (RI), biomarkers of oxidative stress (NO, MDA, and glutathione), and inflammation (hsCRP, endothelin-1, ICAM-1, and VCAM-1) were evaluated at baseline, 4, and 12 weeks. Lipid-profile and platelet-aggregation tests were performed at baseline and 12 weeks. Adverse drug reactions were recorded. Compliance was assessed by pill count method. GraphPad Prism8 was used for statistical analysis. Significant changes were seen from 4 weeks onwards in all the parameters evaluated. Significant improvement in RI% (mean ± SD = -2.56 ± 0.77 to -3.27 ± 0.67-group A, -2.33 ± 0.76 to 4.72 ± 0.79-group B; -2.39 ± 1.13 to 6.46 ± 1.00-group C) was seen at 12 weeks. Significant improvement in biomarkers of oxidative stress and inflammation was seen with all the treatment groups. Similarly, significant improvement in lipid profile was seen in group B and group C, while group A showed change in HDL, VLDL, and TG. Group C demonstrated the best response in the parameters evaluated. Three patients in group C reported gastrointestinal adverse events, which resolved spontaneously; none stopped the therapy. So, the addition of PCC to ω-3FA may prove to have beneficial effect in reducing cardiovascular morbidity in MetS patients.

Evaluation of the Effect of an Aqueous Extract of Azadirachta indica (Neem) Leaves and Twigs on Glycemic Control, Endothelial Dysfunction and Systemic Inflammation in Subjects with Type 2 Diabetes Mellitus - A Randomized, Double-Blind, Placebo-Controlled Clinical Study.

PURPOSE: Neem tree (Azadirachta indica) offers different bioactives ranging from pesticides to therapeutic molecules, depending on which part of the plant is used and the extraction methodology and the solvent used. This study was aimed at evaluating the safety and efficacy of a standardized aqueous extract of Azadirachta indica leaves and twigs (NEEM) on glycemic control, endothelial dysfunction, and systemic inflammation in patients with type 2 diabetes mellitus (T2DM). METHODS: In this randomized, double-blind, placebo-controlled clinical study (RCT), 80 T2DM subjects, who have already been on standard metformin therapy, received either 125 mg, 250 mg, 500 mg of NEEM or placebo twice daily for 12 weeks. Postprandial blood sugar level (PPBS), fasting blood sugar level (FBS), glycosylated hemoglobin (HbA1c), insulin resistance (IR), endothelial function, oxidative stress, systemic inflammation, IL-6 and TNF-α, platelet aggregation and lipid profile were assessed. Adverse drug reactions, if any, were noted. GraphPad Prism 8 was used to perform statistical analysis. RESULTS: NEEM at the doses of 125, 250, and 500 mg BID significantly reduced PPBS (from 194.4±14 to 173.1±12.8mg/dL, 192.3±17.1 to 161.8±9.7mg/dL, and 205.9±7.2 to 159.3±7.1mg/dL, respectively), FBS (from 119.2±5.0 to 109.2±5.7mg/dL, 115.5±4.4 to 103.7±4.2mg/dL, and 120.7±4.2 to 97.3±3.7mg/dL, respectively), HbA1c (from 6.87 ± 0.4% to 6.64 ± 0.4%, 7.52 ± 0.4% to 6.86 ± 0.3%, and 7.78 ± 0.2% to 6.26 ± 0.4%, respectively), and IR (from 4.5 ± 1.2 to 3.4 ± 0.9, 3.8 ± 1.1 to 2.5 ± 0.6, and 4.6 ± 1.3 to 2.0 ± 0.6, respectively) compared to placebo. Also, NEEM significantly improved endothelial function, decreased oxidative stress and systemic inflammation compared to placebo. The efficacy was significant with all the doses, but no effect on platelet aggregation or lipid profile was observed. CONCLUSION: NEEM may significantly ameliorate hyperglycemia, endothelial dysfunction, and systemic inflammation, on top of what metformin could do, in subjects with T2DM.

A randomized, double-blind, positive-controlled, prospective, dose-response clinical study to evaluate the efficacy and tolerability of an aqueous extract of Terminalia bellerica in lowering uric acid and creatinine levels in chronic kidney disease subjects with hyperuricemia.

BACKGROUND: Hyperuricemia is an independent risk factor in chronic kidney disease (CKD). Allopurinol and febuxostat are prescription medicines used to treat hyperuricemia but suffer side-effects. Earlier clinical study has shown that an aqueous extract of Terminalia bellerica (TBE), significantly reduced uric acid levels with no serious adverse effects in hyperuricemic subjects. The objective of this study is to determine the efficacy and tolerability of TB in reducing uric acid and creatinine levels in CKD subjects. METHODS: 59-subjects were randomized to three groups-40 mg-once-daily febuxostat, 500 mg-twice-daily and 1000 mg-twice-daily of TBE. Serum uric acid, creatinine levels and estimated-glometular-filtration-rate were measured at baseline, 4, 8, 12, 16, 20, 24-weeks. Biomarkers of oxidative-stress, endothelial function, systemic inflammation, and platelet-aggregation were evaluated at baseline, 4, 8, 12, 24-weeks. Adverse drug reactions were recorded. Statistical analysis evaluated using GraphPadPrism4. RESULTS: 55-subjects completed 24-week study. Starting at 4-weeks, all treatment groups showed a significant decrease in serum uric acid levels from baseline (p ≤ 0.0001). At 24-weeks, febuxostat, T.bellerica 500 mg-twice-daily, and T.bellerica 1000 mg-twice-daily doses decreased mean-percentage serum uric acid by 63.70 ± 4.62, 19.84 ± 6.43 and 33.88% ± 4.95% respectively (p ≤ 0.0001). Significant decrease in serum creatinine with all the groups starting at 16-weeks was seen (p ≤ 0.005-p ≤ 0.0001). At 24-weeks, the mean-percentage change in creatinine levels was 23.71 ± 12.50, 11.70 ± 9.0, and 24.42 ± 8.14, respectively with febuxostat, T.bellerica 500 mg-twice-daily and T.bellerica 1000 mg-twice-daily. Statistically significant (p ≤ 0.05) increase in estimated glomerular filtration rate-(eGFR) was seen at 20 (p ≤ 0.05) and 24-weeks (p ≤ 0.01) for both febuxostat vs T.bellerica 500 mg-twice-daily and T.bellerica 1000 mg-twice-daily vs T.bellerica 500 mg-twice-daily. There was no statistically significant difference between febuxostat and T.bellerica 1000 mg-twice-daily, with an increase of eGFR of 41.38 and 40.39 ml/min/1.73m2 respectively, with the inference that T.bellerica at 1000 mg-twice-daily dose is as good as febuxostat 40 mg-once-daily. Positive improvements were made by all the groups in endothelial function and the related biomarkers and high-sensitivity C-reactive protein. None of the products showed effect on platelet aggregation. CONCLUSION: In this 24-week study Febuxostat 40 mg, T. bellerica 500 mg-twice-daily and 1000 mg-twice-daily, significantly decreased the serum uric acid and creatinine levels, increased eGFR in CKD subjects. T. bellerica 500 mg-twice-daily and 1000 mg-twice-daily were one-third and more than half as effective at 24-weeks, respectively. T. bellerica extract may be considered a natural alternative for reducing serum uric acid levels. TRIAL REGISTRATION: This study was registered with the Clinical Trials Registry - India (CTRI) with the registration number: CTRI/2019/11/022093 [Registered on: 21/11/2019] Trial Registered Retrospectively.

Effect of an aqueous extract of Terminalia chebula on endothelial dysfunction, systemic inflammation, and lipid profile in type 2 diabetes mellitus: A randomized double-blind, placebo-controlled clinical study.

Endothelial dysfunction is a crucial complication in type 2 diabetic patients, related to cardiovascular risk. Terminalia chebula (TC), a traditional ayurvedic herb, is known for its antioxidant and antihyperlipidemic activity. A prospective, randomized, double-blind, placebo-controlled clinical study was undertaken to evaluate the effects of an aqueous extract of T. chebula 250 and 500 mg versus placebo on endothelial dysfunction and biomarkers of oxidative stress in type 2 diabetic patients. A total of 60 eligible patients were randomized to receive either T. chebula 250 mg, T. chebula 500 mg, or placebo twice daily for 12 weeks. The subjects were assessed based on the endothelial function, the levels of nitric oxide, malondialdehyde, glutathione, high sensitivity C-reactive protein, glycosylated hemoglobin, and lipid profile at baseline and after 12 weeks of treatment. Treatment with T. chebula 250 mg and T. chebula 500 mg for 12 weeks significantly improved the endothelial function (reflection index) compared to placebo (absolute changes: - T. chebula 250: -2.55 ± 1.82% vs. T. chebula 500: -5.21 ± 2.41% vs. placebo: 1.40 ± 2.11%). Other cardiovascular risk indicators were also significantly ameliorated in the treatment groups compared to placebo. In conclusion, T. chebula (especially, 500 mg BID dose) significantly minimized the cardiovascular risk factors in patients with type 2 diabetes compared to placebo.

Evaluation of the Effect of Fish Oil Alone and in Combination with a Proprietary Chromium Complex on Endothelial Dysfunction, Systemic Inflammation and Lipid Profile in Type 2 Diabetes Mellitus - A Randomized, Double-Blind, Placebo-Controlled Clinical Study.

PURPOSE: This study was conducted to evaluate the effectiveness of fish oil alone and with an adjunct, a proprietary chromium complex (PCC), on cardiovascular parameters - endothelial dysfunction, lipid profile, systemic inflammation and glycosylated hemoglobin - in a 12-week randomized, double-blind, placebo-controlled clinical study in type 2 diabetes mellitus subjects. PATIENTS AND METHODS: In this randomized, double-blind, parallel group study, 59 subjects in three groups completed the study: Group A, fish oil 2000 mg; Group B, fish oil 2000 mg + PCC 10 mg (200 µg of Cr3+); and Group C, fish oil 2000 mg + PCC 20 mg (400 µg of Cr3+) daily for 12 weeks (2000 mg of fish oil contained 600 mg of eicosapentaenoic acid [EPA] and 400 mg of docosahexaenoic acid [DHA], the omega-3 fatty acids). Endothelial function, by estimating reflection index (RI), biomarkers of oxidative stress (nitric oxide [NO], malondialdehyde [MDA], glutathione [GSH]) and inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], endothelin-1) were evaluated at baseline, and 4 and 12 weeks. Lipid profile, platelet aggregation and glycosylated hemoglobin [HbA1c) were tested at baseline and 12 weeks. Any reported adverse drug reactions were recorded. Statistical analysis was performed using GraphPad Prism 8. RESULTS: The present study shows that fish oil by itself, at a dose of 2000 mg (600 mg of EPA + 400 mg of DHA) per day, led to significant, but only modest, improvement in cardiovascular parameters (RI from -2.38±0.75 to -3.92±0.60, MDA from 3.77±0.16 to 3.74±0.16 nM/mL, NO from 30.60±3.18 to 32.12±3.40 µM/L, GSH from 568.93±5.91 to 583.95±6.53 µM/L; p≤0.0001), including triglyceride levels. However, when PCC was added to fish oil, especially at the 20 mg dose, there were highly significant improvements in all the parameters tested (RI from -2.04±0.79 to -8.73±1.36, MDA from 3.67±0.39 to 2.89±0.34 nM/mL, NO from 28.98±2.93 to 40.01±2.53 µM/L, GSH from 553.82±8.18 to 677.99±10.19 µM/L; p≤0.0001), including the lipid profile. It is noteworthy that the triglycerides were decreased significantly by addition of 20 mg of PCC although the dose of fish oil was only 2 g/day and the baseline triglyceride levels were only about 200 mg/dL. Fish oil alone did not significantly decrease the HbA1c, whereas the addition of 20 mg of PCC did. CONCLUSION: Addition of PCC, especially at 20 mg dose, significantly improves the efficacy of fish oil in addressing cardiovascular risk factors compared to fish oil given alone.

Evaluation of the effects of a standardized aqueous extract of Phyllanthus emblica fruits on endothelial dysfunction, oxidative stress, systemic inflammation and lipid profile in subjects with metabolic syndrome: a randomised, double blind, placebo controlled clinical study.

BACKGROUND: Endothelial dysfunction (ED) has been observed in individuals with metabolic syndrome (MetS) and contributes to the initiation and progression of atherosclerosis. The primary management of MetS involves lifestyle modifications and treatment of its individual components with drugs all of which have side effects. Thus, it would be of advantageous if natural products would be used as adjuncts or substitutes for conventional drugs. The aim of the present study was to evaluate the effect of standardized aqueous extract of fruits of Phyllanthus emblica (P. emblica) 250 mg and 500 mg twice daily on ED, oxidative stress, systemic inflammation and lipid profile in subjects with MetS. METHODS: In this randomised, double-blind, placebo-controlled clinical study endothelial function was measured by calculating reflection index (RI) using digital plethysmograph. Oxidative stress biomarkers used were nitric oxide (NO), glutathione (GSH) and malondialdehyde (MDA). Systemic inflammation was measured by determining high sensitivity C-reactive protein (hsCRP) and dyslipidemia by lipid profile. ANOVA, paired and unpaired t-test were used. P-value < 0.05 was considered statistically significant. RESULTS: Out of 65 screened subjects all 59 enrolled completed the study. P. emblica aqueous extract (PEE), 250 mg and 500 mg twice daily dosing, showed significant reduction in mean RI, measure of endothelial function, at 8 and 12 weeks (p <  0.001) compared to baseline and placebo. Significant mean % change was seen in oxidative stress biomarkers, NO (+ 41.89%, + 50.7%), GSH (+ 24.31%, + 53.22%) and MDA (- 21.02%, - 31.44%), and systemic inflammation biomarker, hsCRP (- 39.68%, - 53.77%) (p <  0.001) at 12 weeks with 250 mg and 500 mg twice daily dosage respectively. Significant mean % change was also seen at 12 weeks with TC (- 7.71%, - 11.11%), HDL-C (+ 7.33% + 22.16%, p <  0.05), LDL-C (- 11.39%, - 21.8%) and TG (- 9.81%, - 19.22%) respectively with 250 mg and 500 mg twice daily (p <  0.001). PEE 500 mg twice daily was significantly more efficacious than the 250 mg twice daily and placebo. No participant discontinued the study because of adverse events. CONCLUSIONS: P.emblica aqueous extract significantly improved endothelial function, oxidative stress, systemic inflammation and lipid profile at both dosages tested, but especially at 500 mg twice daily. Thus, this product may be used as an adjunct to conventional therapy (lifestyle modification and pharmacological intervention) in the management of metabolic syndrome. TRIAL REGISTRATION: This study was registered with Clinical Trials Registry - India (CTRI) with the registration number of CTRI/2017/09/009606 . The study was registered retrospectively on 4th September 2017.

A randomized, double-blind, placebo-, and positive-controlled clinical pilot study to evaluate the efficacy and tolerability of standardized aqueous extracts of Terminalia chebula and Terminalia bellerica in subjects with hyperuricemia.

OBJECTIVES: To evaluate the efficacy and tolerability of standardized aqueous extracts of Terminalia chebula and Terminalia bellerica versus febuxostat and placebo on reduction in serum uric acid levels in subjects with hyperuricemia. MATERIALS AND METHODS: A total of 110 eligible subjects with hyperuricemia were enrolled and randomized to either of the five treatment groups - T. chebula 500 mg twice a day (BID), T. bellerica 250 mg BID, T. bellerica 500 mg BID, placebo BID, and febuxostat 40 mg once daily plus an identical placebo - for a duration of 24 weeks. Serum uric acid levels were measured at baseline and at the end of 4, 8, 12, 16, 20, and 24 weeks. Statistical analysis was done using GraphPad Prism Software 4. RESULTS AND INTERPRETATION: All active treatment groups showed a reduction in serum uric acid levels compared to baseline and placebo. Significant reduction in mean serum uric acid levels started as early as 4 weeks following treatment, compared to baseline, with T. bellerica (500 and 250 mg), febuxostat (P<0.001), and T. chebula 500 mg (P<0.01); an increase in serum uric acid levels was seen with placebo (P<0.05). The serum uric acid levels became steady after 16 weeks of treatment and remained the same until the end of 24 weeks. The reduction of serum uric acid levels in the T. bellerica 500 mg group was nearly twice that of the T. chebula 500 mg group as well as T. bellerica 250 mg group at all time points. T. bellerica 500 mg reduced serum uric acid levels from 8.07±0.87 to 5.78±0.25 compared to febuxostat, which reduced serum uric acid levels from 8.53±0.97 to 4.28±0.67 (P<0.001) at the end of 24 weeks. The efficacy of T. bellerica appeared to be dose dependent. All the formulations were well tolerated. CONCLUSION: T. bellerica has the potential for treating hyperuricemia as it was devoid of any serious adverse effects in the present study. Further studies are needed to confirm this potential.