Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is a chronic disease characterized by intense, persistent and debilitating itch, resulting in sleep deprivation, signs of anxiety and depression, impaired quality of life and reduced productivity. The Peak Pruritus Numerical Rating Scale (NRS) was developed and validated as a single-item, patient-reported outcome (PRO) of itch severity. OBJECTIVES: To describe the content validity and psychometric assessment (test-retest reliability, construct validity, known-groups validity, sensitivity to change) of the Peak Pruritus NRS, and to derive empirically a responder definition to identify adults with a meaningful change in itch. METHODS: Content validity was assessed through in-depth patient interviews. Psychometric assessments used data from phase IIb and phase III dupilumab clinical trials and included test-retest reliability, construct validity, known-groups validity and sensitivity to change in patients with moderate-to-severe AD. RESULTS: Interview participants indicated that the Peak Pruritus NRS was a relevant, clear and comprehensive assessment of itch severity. Peak Pruritus NRS scores showed large, positive correlations with existing PRO measures of itch, and weak or moderate correlations with clinician-reported measures assessing objective signs of AD. Peak Pruritus NRS score improvements were highly correlated with improvements in other itch PROs, and moderately correlated with improvements in clinician-reported measures assessing objective signs of AD. The most appropriate threshold for defining a clinically relevant, within-person response was ≥ 2-4-point change in the Peak Pruritus NRS. CONCLUSIONS: The Peak Pruritus NRS is a well-defined, reliable, sensitive and valid scale for evaluating worst itch intensity in adults with moderate-to-severe AD.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Steady state pharmacokinetics, metabolism and pharmacodynamics of theophylline in children after unequal twice-daily dosing of a new sustained-release formulation.

This was an open-label study in 19 children aged 9-13 years, weighing 27-44 kg, with bronchial asthma. Twenty-four-hour steady-state concentrations of theophylline and its metabolites 1,3-dimethyl uric acid, 3-methyl xanthine and 1-methyl uric acid were assessed after daily dosing of 600 mg (ca 18 mg/kg/day) of the sustained-release theophylline micro-pellet sprinkle system BY158K, for 4 days. The dosing regimen used was an unequal twice-daily dose of 200 mg in the morning after breakfast and 400 mg in the evening after dinner. Twenty-four-hour peak expiratory flow (PEF) profiles were compared before treatment and at steady-state, along with lung function parameters after bronchial provocation. Mean values +/- SD (n = 16) of the steady-state characteristics were Cmin 6.8 +/- 2.1 mg/l, Cmax 14.5 +/- 4.8 mg/l and Cav 10.5 +/- 2.9 mg/l, the plateau time was 11.7 +/- 4.8 hr and peak-trough fluctuation and swing were 72 +/- 21 and 118 +/- 52%, respectively. There was an excellent reproducibility of theophylline pre-dose levels at corresponding time points of the 24-hr sampling period [r = 0.864 (p less than 0.001)]. Mean values +/- SD of the 24 hr average serum metabolite levels were 0.9 +/- 0.2 mg/1 for 1,3-dimethyl uric acid, 0.6 +/- 0.1 mg/1 for 3-methyl xanthine and 0.4 +/- 0.1 mg/1 for l-methyl uric acid. Lung function (n = 17) following bronchial provocation, improved in 10 children after theophylline treatment of 4 days, remained stable in 2 patients and deteriorated in 5 patients. Serum theophylline profiles and PEF profiles ran largely in parallel over the 24-hr period. Six children exhibited typical theophylline induced side-effects, headache (n = 3), nausea (n = 4), dizziness (n = 1), vomiting (n = 4), sleep disturbances (n = 1), pallor (n = 1) and tremor (n = 1), necessitating in 3 children one dose omission/reduction (n = 2) or subsequent dose reduction (n = 1). It has been shown that a twice daily dosing regimen with unequal doses of anhydrous theophylline (BY158K) is well suited to this population of fast metabolisers. The patients were well protected throughout the day, including the critical early morning hours.

[Structure and function of the endoplasmic reticulum]. / Struktur und Funktion des endoplasmatischen Retikulums

After a general review of enzyme topology and the molecular architecture of endoplasmic reticulum the latest research results are discussed. Microsomal enzymes do not occur in specialized regions of the endoplasmic reticulum but are uniformly distributed over the entire membrane system. Functionally associated enzymes are also located in the direct vicinity of the membrane. It has been shown that the catalytic activity of integral enzyme proteins depends on phospholipid and membrane structure. These membrane-bound lipoproteid complexes exert specific effects as vectorial enzyme catalysts. The endoplasmic reticulum is active is active in the intracellular transport of metabolites.

A 4-methoxybenzoate O-demethylase from Pseudomonas putida. A new type of monooxygenase system.

A strain of Pseudomonas putida grown on 4-methoxybenzoate as sole carbon source contains an enzyme system for the O-demethylation of this substrate. The enzyme system is purifiable and can be separated into two components: an NADH-dependent reductase and an iron-containing and acid-labile-sulfur-containing monooxygenase. The reductase, of molecular weight 42000 and containing two chromophores, an FMN and an iron-sulfur complex (EPR at g = 1.95), reduces both one-electron and two-electron acceptors (i.e., ferricyanide, 2,6-dichloroindophenol, cytochrome c, and cytochrome b5) at an optimum pH of 8.0. Increasing ionic strength affects these activities differently. The absolute spectrum of the oxidized displays distinct absorption peaks at 409 and 463 nm and a small shoulder between 538 and 554 nm. Treatment with dithionite or NADH reduces the absorbance throughout the visible range, yielding a spectrum with small maxima at 402 and 538 nm. Spectroscopic characteristics of the reductase indicate a tight coupling between its two chromophores. The iron-containing and acid-labile-sulfur-containing monooxygenase, which has a molecular weight of about 120000, contains an iron-sulfur chromophore with an EPR signal at g = 1.90. This protein is a dimer whose subunits each have a molecular weight of about 50000 and are perhaps identical. The optical absorption properties are somewhat unusual. In contrast to other iron-sulfur proteins, there is no significant peak near 415 nm in the absorption spectrum of the oxidized protein, but rather one at 455 nm. The presence of the substrate 4-methoxybenzoate increases both the NADH-dependent reductase. Hydroxylation can be achieved by the monooxygenase also in absence of the reductase with artifical reductants. This enzyme opens a new group of oxygenases within the classification scheme, i.e., iron-containing and labile-sulfur-containing monooxygenases. From the reported data, a scheme for the interaction of the isolated pigments and their relationship to various acceptors is proposed.

Theophylline therapeutic drug monitoring in the case of a new sustained-release pellet formulation for once-daily evening administration.

In view of the large interindividual differences in theophylline clearance and the narrow therapeutic range it is essential to individualize the theophylline dose. In order to do so, estimation of minimum and maximum serum theophylline concentrations during one dosing interval from one or two blood samples is desirable, particularly in the case of once-daily administration. Whereas the minimum (trough) concentration can be readily estimated from the pre-dose level, the maximum (peak) concentration occurs at night. For Euphylong, a new sustained-release theophylline pellet formulation, administered once-daily in the evening, for example between 7 p.m. and 8 p.m., the nocturnal maximum concentration can be calculated as 110-120% of the serum theophylline concentration determined from a blood sample taken in the early morning, for example between 7 a.m. and 8 a.m. This procedure works not only for mean data but also on an individual basis. The procedure is based on the extended nocturnal plateau profile of Euphylong with its high reproducibility and cannot be transferred to other formulations.

Pharmacokinetic profile of a new sustained-release theophylline pellet formulation for once-daily evening administration.

Euphylong is a new anhydrous theophylline sustained-release pellet formulation developed for once-daily administration in the evening in normal and slow metabolizers, and unequally divided twice-daily administration in fast metabolizers. Its pharmacokinetics have been investigated with respect to bioavailability, peak-trough fluctuation, nocturnal plateau profile, food effects, predictability and reproducibility between subjects and from day to day. To this end, 7 single-dose and 4 multiple-dose, randomized, cross-over studies were performed in a total of 168 healthy, normal, male volunteers. In order to match the dosage strengths of three reference products, capsules containing different amounts of pellets--also referred to as Euphylong pellets--have been used. Absolute bioavailability of theophylline from Euphylong was 88 and 100%, depending on the rate and the total dose of the intravenous reference infusions. Relative bioavailability ranged between 85 and 112%, depending on the reference formulations. The peak-trough fluctuation was reduced for Euphylong pellets in comparison with other once-daily theophyllines, by more than 30% in the case of a reference tablet. In contrast to another once-daily theophylline capsule, Euphylong pellets seem to be hardly affected by meals. Moreover, in view of the known variability of theophylline pharmacokinetics both between subjects and from day to day, the nocturnal plateau profile, which is characteristic of Euphylong, is extremely reproducible. The nocturnal excess is consistently 30-40% and the plateau time is consistently 11-12 h in normal metabolizers. The long nocturnal plateau profile together with the high reproducibility of Euphylong pharmacokinetics enable an easy and safe adjustment of the dose tailored to the needs of the individual patient. In addition, the time of the evening dose and its relationship to meals is not critical in the case of Euphylong pellets. Particularly patients presenting with nocturnal asthma, which is one of the major areas of theophylline therapy, should have a clinically relevant benefit from Euphylong.