Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients.

Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min(-1) in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide

Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database

International audienc

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice

Parameter estimates of the final population model.

<p><i>Definition of abbreviations:</i> E_max = maximal effect of the drug; A₅₀ =  amount of acetazolamide that instantaneously induces 50% of putative maximal effect on serum bicarbonate; Bicar₀ =  bicarbonate baseline level; MV₀ =  minute ventilation at baseline level; PaCO2₀ =  PaCO2 at baseline level; BSV = between-subject variability; <i>k_out</i> = first-order constant rate for acetazolamide effect kinetics; %rse = percent relative standard error; SAPS II = simplified acute physiology score II at intensive care unit admission; NA = not applicable; Furosemide₅₀ =  amount of furosemide that instantaneously induces 50% of putative maximal effect on serum bicarbonate.</p

Difference between respiratory parameters pre-acetazolamide dose and at 24 hours.

<p>Differences between pre-acetazolamide dose minute ventilation and minute ventilation at 24 hours (A) and between pre-acetazolamide dose PaCO₂ level and PaCO₂ level at 24 hours (B) in 68 COPD patients, plotted according to the total quantity of acetazolamide administered daily. Boxplots show the median values, first and third quartiles and 10th and 90th percentiles. All values are observed. Usually administered doses of acetazolamide (250–500 mg) do not have a clinically relevant effect either on minute ventilation or on PaCO₂ levels.</p

Model-predicted effect of once a day administration of 250, 500, 1000 or 2000 mg of acetazolamide.

<p>Predicted effect of the drug on minute ventilation (A) and PaCO₂ (B) in patients ventilated either by pressure support ventilation or by volume assist ventilation. Modelization of acetazolamide pharmacodynamics was derived from 68 COPD patients with metabolic alkalosis during the weaning period. The model predicts that higher acetazolamide dosage (>1000 mg) is required to significantly increase minute ventilation or to decrease PaCO₂ whatever the ventilator mode used.</p

Goodness-of-fit plots for the final model of pharmakodynamics.

<p>Observed versus model-predicted minute ventilation (A) and observed versus model-predicted PaCO₂ (B) for mean and individual predictions, and normalized prediction distribution errors (npde) versus predicted minute ventilation and PaCO₂. The regression line is represented by the solid line. The mean and variance of the npde distribution were not significantly different from respectively 0 and 1 (<i>P</i>  = 0.63 and <i>P</i>  = 0.56, respectively for PaCO₂ and <i>P</i>  = 0.59 and <i>P</i>  = 0.48 for minute ventilation; Wilcoxon signed-rank test and Fisher variance test, respectively) and from normality, illustrating robustness of minute ventilation and PaCO₂ prediction after acetazolamide administration.</p

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field