Nitric oxide formation in gas turbine engines: A theoretical and experimental study

A modified Zeldovich kinetic scheme was used to predict nitric oxide formation in the burned gases. Nonuniformities in fuel-air ratio in the primary zone were accounted for by a distribution of fuel-air ratios. This was followed by one or more dilution zones in which a Monte Carlo calculation was employed to follow the mixing and dilution processes. Predictions of NOX emissions were compared with various available experimental data, and satisfactory agreement was achieved. In particular, the model is applied to the NASA swirl-can modular combustor. The operating characteristics of this combustor which can be inferred from the modeling predictions are described. Parametric studies are presented which examine the influence of the modeling parameters on the NOX emission level. A series of flow visualization experiments demonstrates the fuel droplet breakup and turbulent recirculation processes. A tracer experiment quantitatively follows the jets from the swirler as they move downstream and entrain surrounding gases. Techniques were developed for calculating both fuel-air ratio and degree of nonuniformity from measurements of CO2, CO, O2, and hydrocarbons. A burning experiment made use of these techniques to map out the flow field in terms of local equivalence ratio and mixture nonuniformity

A Systematic Review: Light Therapy for Individuals with Dementia and Implications for Practice

This systematic review seeks to answer the question: is light therapy an effective intervention for sundowning symptoms experienced by individuals who have dementia

Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models

Drotaverine is considered as an inhibitor of cyclic-3′,5′-nucleotide-phophodiesterase (PDE) enzymes. However, published receptor binding data supports the potential Ltype Voltage Operated Calcium Channel (L-VOCC) blocking effect of drotaverine too. Hence, in this work we are focusing on the potential L-VOCC blocking effect of drotaverine using L-VOCC associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. It was found that drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca2+- induced contraction in a concentration dependent fashion. The PDE-inhibitor theophylline had no effect on the KCl-evoked contractions indicating its lack of inhibition on inward Ca2+ flow. Drotaverine was also tested on the L-VOCC mediated resting Ca2+ refill model. In this model the extracellular Ca2+ enters the cells to replenish the emptied intracellular Ca2+ stores. Drotaverine and L-VOCC blocker reference molecules inhibited the Ca2+ replenishment of Ca2+ depleted preparations detected by agonist-induced contractions in post Ca2+ replenishment Ca2+ free medium. Theophylline didn’t modify the Ca2+ store replenishment following contraction. It seems that drotaverine but not theophylline inhibit the inward Ca2+ flux. Addition of CaCl2 to Ca2+ free medium containing the agonist, induced inward Ca2+ flow and subsequent contraction of Ca2+ depleted tracheal preparations. Drotaverine similar to the L-VOCC blockers, inhibited inward Ca2+ flow and blunted the slope of CaCl2-induced contraction in agonist containing Ca2+ free medium withCa2+ depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but unlike PDE inhibitors using L-VOCC associated in vitro experimental models

Right anterior mini-thoracotomy vs. conventional sternotomy for aortic valve replacement: A propensity-matched comparison

Background: Right anterior mini-thoracotomy (MIAVR) is a promising technique for aortic valve replacement. We aimed at comparing its outcomes with those obtained in a propensity-matched group of patients undergoing sternotomy at our two high-volume centers. Methods: Main clinical and operative data of patients undergoing aortic valve replacement between January 2010 and May 2016 were retrospectively collected. A total of 678 patients were treated with a standard full sternotomy approach, while MIAVR was performed in 502. Propensity score matching identified 363 patients per each group. Results: In-hospital mortality was not significantly different between the propensity-matched groups (1.7% in MIAVR patients vs. 2.2% in conventional sternotomy patients; P=0.79). No significant difference in the incidence of major post-operative complications was observed. Post-operative ventilation times (median 7, range 5-12 hours in MIAVR patients vs. median 7, range 5-12 in conventional sternotomy patients; P=0.72) were not significantly different between the two groups. Cardiopulmonary bypass time (61.0±21.0 vs. 65.9±24.7 min in conventional sternotomy group; P < 0.01) and aortic cross-clamping time (48.3±16.7 vs. 53.2±19.6 min in full sternotomy group; P < 0.01) were shorter in MIAVR group. EuroSCORE (OR 1.52, 95% CI, 1.12-2.06; P < 0.01) was found to be the only independent predictor of intra-hospital mortality in the whole propensity-matched population. Conclusions: Our experience shows that mini-access isolated aortic valve surgery is a reproducible, safe and effective procedure with similar outcomes and no longer operative times compared to conventional sternotomy

Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers

Background We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. Methods In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. Results Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. Conclusion This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. Clinical Trial Registration EudraCT number: 2021-006643-39

Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion

Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1’-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2–3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28–30 h followed by a steep drop to almost baseline within 1–2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, −70.6%, and −61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. Clinical Trial Registration The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14)

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (CSS,min ENDX) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target CSS,min ENDX applying conventional tamoxifen dosing. Moreover, 4–75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget CSS,min ENDX. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on CSS,min ENDX target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported CSS,min ENDX in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget CSS,min ENDX even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis