Fluorescence Properties of Photonic Crystals Doped with Perylenediimide

This study aims to present the fabrication of colloidal photonic crystals (PC) with increased fluorescence properties. The use of a highly fluorescent perylenediimide derivate (PDI) during the soap-free emulsion polymerization of styrene–acrylic acid resulted in monodisperse core–shell particles which allowed the fabrication of PC films. The properties of the hybrid material were studied in comparison with hybrid materials obtained by impregnation of films with chromophore solutions. In both cases an increase of the fluorescence response was observed in addition to a blue shift for the PDI core particles, proving the incorporation of the dye inside the copolymer particles

A new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP)

The PanACEA consortium was funded by the European Developing Country Partnership through grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013. PN is supported by the NIAID of the National Institutes of Health (R01AI104589) and the TBTC. KED is supported by NIAID/NID (R01AI111992) and the TBTC.Background The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world’s greatest infectious disease killer. Methods We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. Results With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Conclusions Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.Publisher PDFPeer reviewe

A dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosis

The study was funded by the EDCTP (European & Developing Countries Clinical Trials Partnership), NACCAP (Netherlands-African partnership for Capacity development and Clinical interventions Against Poverty-related diseases) and the Bill & Melinda Gates Foundation.Rationale: Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment. Objectives: To evaluate the safety and tolerability, the pharmacokinetics and the extended early bactericidal activity of increasing doses of rifampin. Methods: Patients with drug-susceptible tuberculosis were enrolled into a control group of 8 patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20 mg/kg, 25 mg/kg, 30 mg/kg and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed. Measurements and Main Results: Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were 5 grade 3 events of which 1 was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10CFU/ml sputum in the 10, 20, 25, 30 and 35 mg/kg groups respectively. Conclusions: Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a non-linear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registration available at www.clinicaltrials.gove, ID NCT01392911.PostprintPeer reviewe

Reversible physical interaction between CdSe quantum dots and perylenediimide (PDI) aggregates in aqueous media

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Anionic polymerization by an electron transfer process from a CdSe quantum dot–perylenediimide (PDI) system

Reversible physical interactions between CdSe quantum dots (QDs) and perylenediimide (PDI) derivatives have been investigated. Original processes, dependent on the concentration of the two species, contact time, temperature and pH, were observed. The combining of the two solutions resulted in the formation of an electron transfer complex (ETC) due to the transfer of an electron from CdSe nanoparticles to PDI, followed by the formation of the final particularly stable dianion PDI2− species through another electron transfer process. The anionic species was employed for the polymerization initiation of glycidyl methacrylate (GMA). Some aspects of the anionic polymerization mechanism have been investigated

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis

BACKGROUND Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs — bedaquiline, pretomanid, and linezolid — that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799. opens in new tab.

Effect of C-2 substitution on the stability of non-traditional cephalosporins in mouse plasma

This work is licensed under a Creative Commons Attribution 4.0 International License.A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to β-lactam cleavage in mouse plasma

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p