Explore the vast range of titles available.

Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0–6; 78·7 mg.h/L [95% CI 71·0–87·3] vs 26·0 mg.h/L [19·0–35·6]), maximum plasma concentrations (Cmax; 22·1 mg/L [19·9–24·6] vs 6·3 mg/L [4·9–8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46–0·78] vs 0·21 mg/L [0·16–0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0–6 (31·5 mg.h/L [24·1–41·1] vs 15·1 mg.h/L [12·8–17·7]), Cmax (7·4 mg/L [5·6–9·6] vs 3·9 mg/L [3·2–4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81–3·27] vs 1·52 mg/L [1·28–1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20–0·91; p=0·03). These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Delafloxacin is a novel anionic fluoroquinolone in Phase III development for the treatment of serious skin infections. The objective of this study was to evaluate the effects of delafloxacin on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A substrate. CYP3A activity using midazolam as a probe was assessed before and after multiple doses of delafloxacin to reach steady state. In this nonrandomized, open-label, single-sequence, Phase I study, 22 healthy male and female subjects were administered a single 5-mg oral dose of midazolam on days 1 and 8, with oral delafloxacin 450 mg every 12 hours administered from days 3 to 8. Full pharmacokinetic profiles were obtained on days 1 and 8 (midazolam and 1-hydroxymidazolam) and days 3 and 7 (delafloxacin). The geometric mean ratios (90% CIs) for AUC0–∞ and Cmax of midazolam coadministered with delafloxacin versus midazolam alone were 89.4 (83.2–96.0) and 93.6 (83.7–104.6). Similarly, the geometric ratio for the AUC0–∞ of 1-hydroxymidazolam, the primary metabolite of midazolam, was 105.7 (97.7–114.3); the ratio of Cmax was not equivalent at 116.1 (101.7–132.4), which was outside the CI of 80% to 125%. Multiple doses of oral delafloxacin for 6 days were generally well tolerated. Steady-state dosing of delafloxacin produced no significant changes in midazolam pharmacokinetics, except for a small but not clinically relevant change in the Cmax of 1-hydroxymidazolam. ClinicalTrials.gov identifier: NCT02505997.

Objectives: To evaluate safety, tolerability and systemic pharmacokinetics of escalating doses of SPL7013 Gel in healthy women. Design: Randomized, double-blind, placebo-controlled dose-escalation trial. Methods: Thirty-seven healthy women were randomized to receive 3.5 g of 0.5% (N = 8), 1% (N = 8), or 3% (N = 9) SPL7013 Gel or placebo gel (N = 12), applied vaginally once daily for 7 consecutive days. Genital toxicity was determined by interview, physical examination, assessment of vaginal microflora and colposcopy. Systemic toxicity was determined by nongenital adverse events (AEs) and laboratory assessments. Plasma was collected for pharmacokinetic analysis. Results: Genital AEs considered potentially product-related were all mild and reported by 5 (20%) women receiving SPL7013 Gel and 2 (17%) women receiving placebo gel. The most common were abdominal pain or discomfort, with no reports of vaginal burning or malodour, or genital-tract pain. There were no clinically significant colposcopic findings, including of genital inflammation or epithelial disruption. Lower concentrations of normal lactobacillary flora occurred during SPL7013 Gel and placebo gel use, with a decrease in anaerobes in the SPL7013 Gel groups. There were no reported cases of bacterial vaginosis, and lactobacilli returned to predose levels in most women after treatment. All nongenital AEs were of mild or moderate severity, expect for a severe tension headache in a woman receiving placebo. There was no absorption of SPL7013 into the systemic circulation. Conclusions: SPL7013 Gel applied vaginally once daily for 7 days at concentrations of 0.5% to 3% was safe and well tolerated in healthy, sexually abstinent women, with no evidence of systemic toxicity or absorption.

Our objective was to prospectively determine the factors influencing the probability of a good microbiological or clinical outcome in patients with nosocomial pneumonia treated with a fluoroquinolone. Levofloxacin was administered as an infusion of 500 mg/h for 1.5 h (total dose, 750 mg). For patients with Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus, a second drug was added (ceftazidime or piperacillin/tazobactam for P. aeruginosa and vancomycin for methicillin-resistant S. aureus). Population pharmacokinetic studies of 58 patients demonstrated that this population handled the drug differently from populations of volunteers. Multivariate logistic regression analysis (n=47 patients) demonstrated that only the age of the patient and the achievement of an area under the curve:minimum inhibitory concentration ratio of ⩾87 had a significant effect on eradication of the pathogen (P<.001). Achieving the breakpoint made the patient 4 times more likely to achieve eradication. The effect was greatest in patients ⩾67 years old.

Abstract Background: In cystic fibrosis (CF) patients, inhalation of alpha1-proteinase inhibitor (A1-PI) can prevent or slow down persistent infections and reduce the massive ongoing inflammation and excessive levels of NE that destroy the airway epithelium, leading to progressive loss of pulmonary function and death. It is essential for an efficient treatment with inhaled A1-PI that an adequate and reproducible dose is deposited within all regions of the lung. The I-neb AAD System provides two inhalation modes: the Target Inhalation Mode (TIM) and the Tidal Breathing Mode (TBM). Both were compared in this study for their efficiency to deliver A1-PI to the lungs. Methods: This was a randomized, open label, cross-over study to investigate the lung deposition of A1-PI in 6 healthy subjects (HS) and 15 CF subjects. The primary endpoint was to evaluate the total lung deposition relative to filling dose of A1-PI inhalation solution using the I-neb AAD System in TIM and in TBM. The main secondary endpoints were extra-thoracic deposition, exhaled drug fraction, nebulizer residue, C/P ratio, and variance of pixel counts. Additional exploratory endpoints were total treatment time and the inhalation time. Radiolabeling was performed considering GMP using a commercially available sterile labeling kit. Radiolabeling was validated using NGI data acquired by gamma scintillation and UV spectrometry. Results and Conclusions: The intrapulmonary deposition (mean ± SD) in CF subjects was 47.0% ± 6.6% and 46.7% ± 10.3% in TIM and TBM, respectively, and in healthy subjects, 50.0% ± 6.7% and 54.8% ± 7.0% in TIM and TBM, respectively. TIM resulted in an approximately 40% lower treatment time (HS 6.4 min vs. 10.3 min, CF 5.3 min vs. 10.7 min) and less extra-thoracic deposition compared to TBM, and showed a higher residue of drug in the nebulizer, compared to TBM. In both groups, inhalation of a single dose of 77 mg of A1-PI was efficient, safe, and well tolerated using TIM and TBM.

Traditional herbal remedies have been attracting attention as prospective alternative resources of therapy for diverse diseases across many nations. In recent decades, medicinal plants have been gaining wider acceptance due to the perception that these plants, as natural products, have fewer side effects and improved efficacy compared to their synthetic counterparts. Glycyrrhiza glabra L. (Licorice) is a small perennial herb that has been traditionally used to treat many diseases, such as respiratory disorders, hyperdipsia, epilepsy, fever, sexual debility, paralysis, stomach ulcers, rheumatism, skin diseases, hemorrhagic diseases, and jaundice. Moreover, chemical analysis of the G. glabra extracts revealed the presence of several organic acids, liquirtin, rhamnoliquirilin, liquiritigenin, prenyllicoflavone A, glucoliquiritin apioside, 1-metho-xyphaseolin, shinpterocarpin, shinflavanone, licopyranocoumarin, glisoflavone, licoarylcoumarin, glycyrrhizin, isoangustone A, semilicoisoflavone B, licoriphenone, and 1-methoxyficifolinol, kanzonol R and several volatile components. Pharmacological activities of G. glabra have been evaluated against various microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium falciparum, and completely eradicated P. yoelii parasites. Additionally, it shows antioxidant, antifungal, anticarcinogenic, anti-inflammatory, and cytotoxic activities. The current review examined the phytochemical composition, pharmacological activities, pharmacokinetics, and toxic activities of G. glabra extracts as well as its phytoconstituents.

To determine the steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levofloxacin and ciprofloxacin. Multiple-dose, open-label, randomized pharmacokinetic study. Thirty-six healthy, nonsmoking adult subjects were randomized either to oral levofloxacin, 500 or 750 mg once daily for five doses, or ciprofloxacin, 500 mg q12h for nine doses. Interventions: Venipuncture, bronchoscopy, and BAL were performed in each subject at 4 h, 12 h, or 24 h after the last administered dose of antibiotic. Mean plasma concentrations of levofloxacin and ciprofloxacin were similar to those previously reported. For once-daily dosing of levofloxacin, 500 mg, the mean (± SD) steady-state concentrations at 4 h, 12 h, and 24 h in ELF were 9.9 ± 2.7μμ g/mL, 6.5 ± 2.5 μμg/mL, and 0.7 ± 0.4 μμg/mL, respectively; AM concentrations were 97.9 ± 80.0 μμg/mL, 36.7 ± 23.4 μμg/mL, and 13.8 ± 16.0 μμg/mL, respectively. For levofloxacin, 750 mg, the mean steady-state concentrations in ELF were 22.1 ± 14.9 μμg/mL, 9.2 ± 5.3 μμg/mL, and 1.5 ± 0.8 μμg/mL, respectively; AM concentrations were 105.1 ± 65.5 μμg/mL, 36.2 ± 26.1 μμg/mL, and 15.1 ± 2.0 μμg/mL, respectively. The concentrations of ciprofloxacin at 4 h and 12 h in ELF were 1.9 ± 0.9 μμg/mL and 0.4 ± 0.1 μμg/mL, respectively; AM concentrations were 34.9 ± 23.2 μμg/mL and 6.8 ± 5.9 μμg/mL, respectively. The differences in the ELF concentrations of the two levofloxacin groups vs those of the ciprofloxacin group were significant (p < 0.05) at each sampling time. Levofloxacin was more extensively distributed into intrapulmonary compartments than ciprofloxacin and achieved significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration.

To evaluate the effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans. Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al(3+) and 496 mg of Mg(2+)) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe(2+)) or calcium carbonate (containing 600 mg of Ca(2+)). Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0-∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0-∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0-∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0-∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%. Metal ions, Al(3+), Mg(2+), and Fe(2+) markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca(2+) had much weaker effects. To avoid the effects of Al(3+) and Mg(2+)-containing drugs, nemonoxacin should be administered ≥2 h before them.

There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.

A series of methyl β-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich’s ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.