Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.
ABSTRACT: OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF-?, IL-1? and NF-?B. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.
Project description:Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action.CD(+)4CD45RB(high) T cells were transferred into Rag1(-/-) mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression.Mice treated with MC developed colitis within 4-7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-?), interleukin (IL)-1?, interferon-gamma (IFN-?), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4(+) T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4(+), and IL-17(+), and IFN-? T(+) cells. Furthermore, HMPL-004 inhibited the proliferation of CD4 T cells and differentiation into TH1/TH17 cells in vitro.HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH(1)/TH(17) responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.
Project description:To evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures.This randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ?16 years and had uncontrolled partial-onset seizures despite treatment with 1-2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries.Standardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p < 0.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p = 0.38) or diary version (p = 0.76). Responder rate (?50% reduction in SSF) was significantly higher with ESL 1,200 mg (42.6%, p < 0.001) but not ESL 800 mg (30.5%, p = 0.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia.Adjunctive ESL 1,200 mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800 mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used.
Project description:Andrographis paniculata (A. paniculata), a medicinal plant, has shown anti-inflammatory, neuroprotective and antifibrotic effects in animal models as well as clinical efficacy in different studies, including an anti-fatigue effect in autoimmune diseases such as rheumatoid arthritis. In multiple sclerosis (MS), fatigue is rated as one of the most common and disabling symptoms. In the present trial, we investigated the effect of A. paniculata on relapse rate and fatigue in relapsing-remitting MS (RRMS) patients receiving interferon beta.A randomised double-blind placebo-controlled trial assessed the effects of 170 mg of A. paniculata dried extract tablet b.i.d. p.o. on relapse rate and fatigue using the Fatigue Severity Scores (FSS) over 12 months in RRMS patients receiving interferon. The Expanded Disability Status Scale (EDSS) score, inflammatory parameters and radiological findings were also investigated. Twenty-five patients were enrolled, and twenty-two patients were ultimately analysed and randomised to the active or placebo group.Patients treated with A. paniculata showed a significant reduction in their FSS score as compared to the placebo, equivalent to a 44 % reduction at 12 months. No statistically significant differences were observed for relapse rate, EDSS or inflammatory parameters, with a trend in reducing new lesions among the A. paniculata group. One patient in the A. paniculata group presented with a mild and transient skin rash, which was alleviated with anti-histamine treatment for three weeks.A. paniculata was well tolerated in patients and no changes in clinical parameters were observed. A. paniculata significantly reduces fatigue in patients with RRMS receiving interferon beta in comparison to placebo and only interferon beta treatment.ClinicalTrials.gov Identifier: NCT02280876 ; Trial registration date: 20.10.2014.
Project description:Objective:To investigate whether adjunctive eslicarbazepine acetate (ESL) could lead to exacerbation of seizures in some patients. Methods:Post-hoc analysis of data pooled from three Phase III trials of adjunctive ESL (studies 301, 302, and 304) for refractory partial-onset seizures (POS). Following an 8-week baseline period, patients were randomized to receive placebo or ESL 400, 800, or 1,200 mg once daily (2-week titration, 12-week maintenance, 2-4 week tapering-off periods). Patient seizure diary data and seizure treatment-emergent adverse event (TEAE) reports were pooled for analysis. Results:The modified intent-to-treat and safety populations comprised 1,410 patients and 1,447 patients, respectively. Titration period: Compared with placebo (32/21%), significantly smaller proportions of patients taking ESL 800 mg (20/15%) and 1,200 mg (22/12%) had a ?25/?50% increase in standardized seizure frequency (SSF) from baseline; there was no significant difference between placebo and ESL 400 mg. Maintenance period: Compared with placebo (20%), significantly smaller proportions of patients taking ESL (400 mg, 12%; 800 mg, 12%; 1,200 mg, 14%) had an increase in SSF ?25%. When evaluating ?50% increases in SSF, only ESL 800 mg (7%) was significantly different from placebo (12%). Some patients had no secondarily generalized tonic-clonic (sGTC) seizures during baseline but had ?1 sGTC seizure during maintenance treatment (placebo, 11%; ESL 400 mg, 5%; 800 mg, 10%; 1,200 mg, 5%). Fewer patients had a ?25% increase in sGTC seizure frequency with ESL (400 mg, 11%; 800 mg, 9%; 1,200 mg, 14%) versus placebo (19%). The incidence of seizures reported as TEAEs was low in all treatment groups; incidences were generally lower with ESL versus placebo. Tapering-off period: Similar proportions of patients taking ESL and placebo had a ?25/?50% increase in SSF. Seizure TEAE incidence was numerically higher with ESL versus placebo. Significance:Treatment with adjunctive ESL does not appear to aggravate POS or sGTC seizures.
Project description:Budesonide foam is used for the topical treatment of distal ulcerative colitis. This phase III study was performed to confirm mucosal healing and other therapeutic effects of twice-daily budesonide 2-mg foam in patients with mild-to-moderate ulcerative colitis including left-sided colitis and pancolitis.This was a multicenter, randomized, placebo-controlled, double-blind trial. A total of 126 patients with mild-to-moderate ulcerative colitis with active inflammation in the distal colon were randomized to two groups receiving twice-daily budesonide 2 mg/25 ml foam or placebo foam. The primary endpoint was the percentage of complete mucosal healing of distal lesions (endoscopic subscore of 0) at week 6. Some patients continued the treatment through week 12. Drug efficacy and safety were evaluated.The percentages of both complete mucosal healing of distal lesions and clinical remission were significantly improved in the budesonide as compared with the placebo group (p = 0.0003 and p = 0.0035). Subgroup analysis showed similar efficacy of budesonide foam for complete mucosal healing of distal lesions and clinical remission regardless of disease type. The clinical remission percentage tended to be higher in patients achieving complete mucosal healing of distal lesions than in other patients. There were no safety concerns with budesonide foam.This study confirmed for the first time complete mucosal healing with twice-daily budesonide 2-mg foam in mild-to-moderate ulcerative colitis with distal active inflammation. The results also indicated that complete mucosal healing of distal lesions by budesonide foam promotes clinical remission of ulcerative colitis. Clinical trial registration no.: Japic CTI-142704.
Project description:In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).
Project description:BACKGROUND:Sutherlandia frutescens (L.) R. Br. is widely used as an over the counter complementary medicine and in traditional medications by HIV seropositive adults living in South Africa; however the plant's safety has not been objectively studied. An adaptive two-stage randomized double-blind placebo controlled study was used to evaluate the safety of consuming dried S. frutescens by HIV seropositive adults with CD4 T-lymphocyte count of >350 cells/?L. METHODS:In Stage 1 56 participants were randomized to S. frutescens 400, 800 or 1,200 mg twice daily or matching placebo for 24 weeks. In Stage 2 77 additional participants were randomized to either 1,200 mg S. frutescens or placebo. In the final analysis data from Stage 1 and Stage 2 were combined such that 107 participants were analysed (54 in the S. frutescens 1,200 mg arm and 53 in the placebo arm). RESULTS:S. frutescens did not change HIV viral load, and CD4 T-lymphocyte count was similar in the two arms at 24 weeks; however, mean and total burden of infection (BOI; defined as days of infection-related events in each participant) was greater in the S. frutescens arm: mean (SD) 5.0 (5.5) vs. 9.0 (12.7) days (p = 0.045), attributed to two tuberculosis cases in subjects taking isoniazid preventive therapy (IPT). CONCLUSION:A possible interaction between S. frutescens and IPT needs further evaluation, and may presage antagonistic interactions with other herbs having similar biochemical (antioxidant) properties. No other safety issues relating to consumption of S. frutescens in this cohort were identified. TRIAL REGISTRATION:ClinicalTrials.gov NCT00549523.
Project description:Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, crossover thorough QT study in healthy subjects who were administered intravenous (i.v.) gepotidacin as a therapeutic (1,000-mg) dose and supratherapeutic (1,800-mg) dose, placebo, and 400 mg oral moxifloxacin in 4 separate treatment periods. Gepotidacin caused a mild effect on heart rate, with a largest placebo-corrected change-from-baseline heart rate of 7 and 10 beats per minute at the end of the 1,000-mg and 1,800-mg infusion, respectively. Gepotidacin caused an increase of change-from-baseline QTcF (?QTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ?QTcF (??QTcF) was 12.1 ms (90% confidence interval [CI], 9.5 to 14.8) and 22.2 ms (90% CI, 19.6 to 24.9) after 1,000 mg and 1,800 mg, respectively. ??QTcF rapidly fell after the end of the infusion, with a mean ??QTcF of 6.1 ms 60 min after the 1,800-mg dose. Exposure-response analysis demonstrated a statistically significant positive relationship between gepotidacin plasma levels and ??QTcF, with a slope of 1.45 ms per ?g/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ??QTcF can be predicted to be 11 and 20 ms at the observed mean peak plasma concentration after the infusion of gepotidacin at 1,000 mg (7 ?g/ml) and 1,800 mg (13 ?g/ml), respectively. In conclusion, gepotidacin caused QT prolongation in this thorough QT study, and a mean effect can be predicted to less than 15 ms at the highest expected plasma concentration, 9 ?g/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.).
Project description:Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300?mg once daily (QD), 300?mg twice daily (BD), 600?mg QD, 600?mg BD, 1,200?mg QD, 1,200?mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log10(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200?mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600?mg BD (4.1%; BCI, 2.5 to 5.7), 600?mg QD (4.1%; BCI, 2.9 to 5.3), 300?mg BD (3.3%; BCI, 1.9 to 4.7), 300?mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200?mg TIW (2.2%; BCI, 1.1 to 3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over MIC. There were no unexpected adverse events. All linezolid doses showed bactericidal activity. For the same total daily dose, once-daily dosing proved to be at least as effective as a divided twice-daily dose. An intermittent dosing regimen, with 1,200?mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.).
Project description:Flavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of the study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg EGCG from green tea extract, 220 mg EPA and 180 mg DHA from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 ug folic acid) would reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Women were assigned using a randomized double-blinded placebo-controlled trial to Q-Mix or placebo groups. Overnight fasted blood samples were collected and subjected to RNA expression analysis on Affymetrix Hugene ST1_1 arrays. Randomized, double-blinded, placebo controlled study.Subjects were randomized to either mixed flavonoid-fish oil supplement group (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg EGCG from green tea extract, 400 mg n3-PUFAs (220 mg EPA and 180 mg DHA) from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 µg folic acid) or placebo (n=29 samples, including pre- and post-treatment samples in the Q-Mix and placebo arms).The placebo did not contain quercetin, vitamin C, and niacin. Subjects were instructed to ingest two soft chew supplements twice daily (upon awakening, and between 6:00-7:00 pm) for 70 days. A three-day food record was used to assess typical energy and nutrient intake. No restrictions were placed on diet, supplement usage or medications with the exception that subjects agreed to avoid any non-steroidal anti-inflammatory drugs and dietary supplements that influence inflammation or oxidative stress.