CDC Guidelines for the Prevention and Treatment of Anthrax, 2023.

This report updates previous CDC guidelines and recommendations on preferred prevention and treatment regimens regarding naturally occurring anthrax. Also provided are a wide range of alternative regimens to first-line antimicrobial drugs for use if patients have contraindications or intolerances or after a wide-area aerosol release of: Bacillus anthracis spores if resources become limited or a multidrug-resistant B. anthracis strain is used (Hendricks KA, Wright ME, Shadomy SV, et al.; Workgroup on Anthrax Clinical Guidelines. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20:e130687; Meaney-Delman D, Rasmussen SA, Beigi RH, et al. Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 2013;122:885-900; Bradley JS, Peacock G, Krug SE, et al. Pediatric anthrax clinical management. Pediatrics 2014;133:e1411-36). Specifically, this report updates antimicrobial drug and antitoxin use for both postexposure prophylaxis (PEP) and treatment from these previous guidelines best practices and is based on systematic reviews of the literature regarding 1) in vitro antimicrobial drug activity against B. anthracis; 2) in vivo antimicrobial drug efficacy for PEP and treatment; 3) in vivo and human antitoxin efficacy for PEP, treatment, or both; and 4) human survival after antimicrobial drug PEP and treatment of localized anthrax, systemic anthrax, and anthrax meningitis. Changes from previous CDC guidelines and recommendations include an expanded list of alternative antimicrobial drugs to use when first-line antimicrobial drugs are contraindicated or not tolerated or after a bioterrorism event when first-line antimicrobial drugs are depleted or ineffective against a genetically engineered resistant: B. anthracis strain. In addition, these updated guidelines include new recommendations regarding special considerations for the diagnosis and treatment of anthrax meningitis, including comorbid, social, and clinical predictors of anthrax meningitis. The previously published CDC guidelines and recommendations described potentially beneficial critical care measures and clinical assessment tools and procedures for persons with anthrax, which have not changed and are not addressed in this update. In addition, no changes were made to the Advisory Committee on Immunization Practices recommendations for use of anthrax vaccine (Bower WA, Schiffer J, Atmar RL, et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices, 2019. MMWR Recomm Rep 2019;68[No. RR-4]:1-14). The updated guidelines in this report can be used by health care providers to prevent and treat anthrax and guide emergency preparedness officials and planners as they develop and update plans for a wide-area aerosol release of B. anthracis.

Allene Trifunctionalization via Amidyl Radical Cyclization and TEMPO Trapping.

Radical-mediated trifunctionalizations of allenes are virtually unknown, in contrast to well-studied radical difunctionalizations of alkenes and alkynes. In this article, we describe a light-promoted reaction that transforms all three allene carbons to new carbon-heteroatom bonds in one pot with no expensive transition-metal catalyst. Formation of an electron donor-acceptor complex between an electron-deficient aryl and K2CO3, followed by photochemical generation of an amidyl radical and cyclization, yields a vinyl radical that can be trapped by TEMPO to ultimately furnish the product. Insights into the impact of the allene substitution pattern, radical source, and donor are presented, along with studies to unravel the mechanism of this unusual transformation.

Mechanistic Aspects and Synthetic Applications of Radical Additions to Allenes.

More than 50 years have passed since Haszeldine reported the first addition of a trifluoromethyl radical to an allene; in the intervening years, both the chemistry of allenes and the reactivity of single-electron species have become topics of intense interest. In this Review, we provide an overview of the fundamentals of radical additions to allenes and highlight the emergence of theoretical and experimental evidence that reveals unique reactivity patterns for radical additions to allenes as compared with other unsaturated compounds. Factors capable of exerting control over the chemo-, regio-, and stereoselectivities of the attack of carbon- and heteroatom-based radicals at each of the three potential reactive sites in an allene substrate are described. These include reaction conditions, the nature of the attacking radical, the substitution pattern of the allene, and the length of the linker between the radical center and the proximal allene carbon in the substrate. Cycloaddition reactions between allenes and partners containing π-bonds, which are likely to proceed through radical pathways, are presented to highlight their ability to rapidly access complex polycyclic scaffolds. Finally, the synthetic utility of the products arising from these chemistries is described, including their applications to the construction of complex molecules.

Regioselective Intramolecular Allene Amidation Enabled by an EDA Complex*.

The addition of radicals to unsaturated precursors is a powerful tool for the synthesis of both carbo- and heterocyclic organic building blocks. The recent advent of mild ways to generate N-centered radicals has reignited interest in exploiting highly regio-, chemo-, and stereoselective transformations that employ these reactive intermediates. While the additions of aminyl, iminyl, and amidyl radicals to alkenes and alkynes have been well-studied, analogous additions to allenes are scarce. Allenes offer several attractive features, including potential for selective amidation at three distinct sites via judicious choice of precursor or radical source, the opportunity for axial-to-point chirality transfer, and productive trapping of vinyl or allyl radical intermediates to diversify functionality in the products. In this article, we report a regioselective addition of amidyl radicals to allenes to furnish an array of valuable N-heterocycle scaffolds.

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma.

Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control.

Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates.

The study of medications among pediatric patients has increased worldwide since 1997 in response to new legislation and regulations, but these studies have not yet adequately addressed the therapeutic needs of neonates. Additionally, extant guidance developed by regulatory agencies worldwide does not fully address the specificities of neonatal drug development, especially among extremely premature newborns who currently survive. Consequently, an international consortium from Canada, Europe, Japan, and the United States was organized by the Critical Path Institute to address the content of guidance. This group included neonatologists, neonatal nurses, parents, regulators, ethicists, clinical pharmacologists, specialists in pharmacokinetics, specialists in clinical trials and pediatricians working in the pharmaceutical industry. This group has developed a comprehensive, referenced White Paper to guide neonatal clinical trials of medicines - particularly early phase studies. Key points include: the need to base product development on neonatal physiology and pharmacology while making the most of knowledge acquired in other settings; the central role of families in research; and the value of the whole neonatal team in the design, implementation and interpretation of studies. This White Paper should facilitate successful clinical trials of medicines in neonates by informing regulators, sponsors, and the neonatal community of existing good practice.

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy.

AIMS: Caffeine concentrations in preterm infants are usually measured in the blood. However, salivary assays may provide a valid and practical alternative. The present study explored the validity and clinical utility of salivary caffeine concentrations as an alternative to blood concentrations and developed a novel plasma/salivary caffeine distribution model. METHODS: Paired salivary and plasma samples were obtained in 29 infants. Salivary samples were obtained using a commercially available salivary collection system. Caffeine concentrations in the saliva and plasma were determined using high-performance liquid chromatography. A population pharmacokinetic (PK) model was developed using NONMEM 7.3. RESULTS: The mean (± standard deviation) gestational age (GA) at birth and birth weight were 27.9 ± 2.1 weeks and 1171.6 ± 384.9 g, respectively. Paired samples were obtained at a mean postmenstrual age (PMA) of 35.5 ± 1.1 weeks. The range of plasma caffeine concentrations was 9.5-54.1 µg ml(-1) , with a mean difference (95% confidence interval) between plasma and salivary concentrations of -0.18 µg ml(-1) (-1.90, 1.54). Salivary and plasma caffeine concentrations were strongly correlated (Pearson's correlation coefficient = 0.87, P < 0.001). Caffeine PK in plasma and saliva was simultaneously described by a three-compartment recirculation model. Current body weight, birth weight, GA, PMA and postnatal age were not significantly correlated with any PK parameter. CONCLUSIONS: Salivary sampling provides an easy, non-invasive method for measuring caffeine concentrations. Salivary concentrations correlate highly with plasma concentrations. Caffeine PK in saliva and plasma are well described by a three-compartment recirculation model.

Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma.

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Optimal design in pediatric pharmacokinetic and pharmacodynamic clinical studies.

It is not trivial to conduct clinical trials with pediatric participants. Ethical, logistical, and financial considerations add to the complexity of pediatric studies. Optimal design theory allows investigators the opportunity to apply mathematical optimization algorithms to define how to structure their data collection to answer focused research questions. These techniques can be used to determine an optimal sample size, optimal sample times, and the number of samples required for pharmacokinetic and pharmacodynamic studies. The aim of this review is to demonstrate how to determine optimal sample size, optimal sample times, and the number of samples required from each patient by presenting specific examples using optimal design tools. Additionally, this review aims to discuss the relative usefulness of sparse vs rich data. This review is intended to educate the clinician, as well as the basic research scientist, whom plan on conducting a pharmacokinetic/pharmacodynamic clinical trial in pediatric patients.

Effects of unbound mycophenolic acid on inosine monophosphate dehydrogenase inhibition in pediatric kidney transplant patients.

BACKGROUND: Mycophenolic acid (MPA) is a key immunosuppressive drug that acts through inhibition of inosine monophosphate dehydrogenase (IMPDH). MPA is commonly measured, as part of therapeutic drug monitoring, as the total concentration in plasma. However, it has been postulated that the free (unbound) fraction of MPA (fMPA) is responsible for the immunosuppressive effects. In this study, a sensitive low volume high-performance liquid chromatography (HPLC) assay was developed to measure fMPA concentrations to explore the relationship between fMPA and IMPDH activity. METHODS: To obtain fMPA concentrations, plasma samples were filtrated using Centrifree ultrafiltration devices. The ultrafiltrate was analyzed by HPLC using a Kinetex C18 column (2.6 µm, 3.0 × 75 mm). fMPA concentrations were compared with the total MPA concentrations available in 28 pediatric kidney transplant patients at 3 consecutive occasions after transplantation. The relationship between fMPA and IMPDH activity was analyzed using an Emax model. RESULTS: The HPLC assay, using 25 µL of the ultrafiltrates, was validated over a range from 2.5 to 1000 µL with good accuracy, precision, and reproducibility. Total and free MPA concentrations were well correlated (R = 0.85, P < 0.0001), although large intraindividual and interindividual variability in the bound MPA fractions was observed. The overall relationship between fMPA concentrations and IMPDH inhibition using the Emax model was comparable with that of total MPA, as previously reported. The model estimated EC50 value (164.5 µL) is in good agreement with reported in vitro EC50 values. CONCLUSIONS: This study provides a simple HPLC method for the measurement of fMPA and a pharmacologically reasonable EC50 estimate. The good correlation between the total and free MPA concentrations suggests that routine measurement of fMPA to characterize mycophenolate pharmacokinetic and pharmacodynamic does not seem warranted, although the large variability in the bound fractions of MPA warrants further study.

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

BACKGROUND: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). METHODS: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. RESULTS: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) . CONCLUSIONS: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Solvent Effects on the Chemo- and Site-Selectivity of Transition Metal-Catalyzed Nitrene Transfer Reactions: Alternatives to Chlorinated Solvents.

Transition metal-catalyzed, non-enzymatic nitrene transfer (NT) reactions to selectively transform C-H and C=C bonds to new C-N bonds are a powerful strategy to streamline the preparation of valuable amine building blocks. However, many catalysts for these reactions use environmentally unfriendly solvents that include dichloromethane, chloroform, 1,2-dichloroethane and benzene. We developed a high-throughput experimentation (HTE) protocol for heterogeneous NT reaction mixtures to enable rapid screening of a broad range of solvents for this chemistry. Coupled with the American Chemical Society Pharmaceutical Roundtable (ACSPR) solvent tool, we identified several attractive replacements for chlorinated solvents. Selected catalysts for NT were compared and contrasted using our HTE protocol, including silver supported by N-dentate ligands, dinuclear Rh complexes and Fe/Mn phthalocyanine catalysts.

Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes.

Inhaled glucocorticoids, such as beclomethasone dipropionate (BDP), are the mainstay treatment of asthma. However, ≈ 30% of patients exhibit little to no benefit from treatment. It has been postulated that glucocorticoid resistance, or insensitivity, is attributable to individual differences in glucocorticoid receptor-mediated processes. It is possible that variations in cytochrome P450 3A enzyme-mediated metabolism of BDP may contribute to this phenomenon. This hypothesis was explored by evaluating the contributions of CYP3A4, 3A5, 3A7, and esterase enzymes in the metabolism of BDP in vitro and relating metabolism to changes in CYP3A enzyme mRNA expression via the glucocorticoid receptor in lung and liver cells. CYP3A4 and CYP3A5 metabolized BDP via hydroxylation ([M4] and [M6]) and dehydrogenation ([M5]) at similar rates; CYP3A7 did not metabolize BDP. A new metabolite [M6], formed by the combined action of esterases and CYP3A4 hydroxylation, was also characterized. To validate the results observed using microsomes and recombinant enzymes, studies were also conducted using A549 lung and DPX2 liver cells. Both liver and lung cells produced esterase-dependent metabolites [M1-M3], with [M1] correlating with CYP3A5 mRNA induction in A549 cells. Liver cells produced both hydroxylated and dehydrogenated metabolites [M4, M5, and M6], but lung cells produced only the dehydrogenated metabolite [M5]. These studies show that CYP3A4 and CYP3A5 metabolize BDP to inactive metabolites and suggest that differences in the expression or function of these enzymes in the lung and/or liver could influence BDP disposition in humans.

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

OBJECTIVE: To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. STUDY DESIGN: The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well controlled to 15=poorly controlled), determined using a questionnaire modified from the National Heart Lung and Blood Institute's Expert Panel 3 guidelines. RESULTS: Our study cohort comprised 734 children with asthma (mean age, 8.8±4.3 years) and was predominantly male (61%) and non-Hispanic white (53%). More than one-half of the children (56%; n=413) were receiving an inhaled glucocorticoid daily, with FP the most frequently prescribed agent (65%). Among the children receiving daily FP, single nucleotide polymorphisms in CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved in the 20 children (7%) with the CYP3A4*22 allele (median, 3; range, 0-6) compared with the 201 children without the CYP3A4*22 allele (median, 4; range, 0-15; P=.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI, 0.5-3.8). CONCLUSION: The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control in the FP-treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

Metabolic pathways of inhaled glucocorticoids by the CYP3A enzymes.

Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6ß-hydroxylation and Δ(6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Δ(6)-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.

Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk.

BACKGROUND: Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia, and reduced severe retinopathy of prematurity in two randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed before efficacy trials. METHODS: Infants born in 23-29 wk of gestation were randomized to a single intravenous (i.v.) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed-effects approach. Safety outcomes were recorded. RESULTS: A single-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age strata, and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance was 0.0679 l/kg/h, endogenous production was 2.67 mg/kg/h, and the half-life was 5.22 h when modeled without the covariates. During the first 12 h, renal inositol excretion quadrupled in the 120 mg/kg group, returning to near-baseline value after 48 h. There was no diuretic side effect. No significant differences in adverse events occurred among the three groups (P > 0.05). CONCLUSION: A single-compartment model accounting for endogenous production satisfactorily described the PK of i.v. inositol.