Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS: In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS: The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS: Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

Tramadol SR Formulations : Pharmacokinetic Comparison of a Multiple-Units Dose (Capsule) versus a Single-Unit Dose (Tablet).

INTRODUCTION: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet). METHODS: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC(12)) and maximum concentration (C(max)), as well as the mean AUC(12) and C(max) for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC(12) of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment. RESULTS: The two formulations were equivalent in the area under the curve (AUC(infinity): 2411 vs 2527 mug . h/L). However, capsules led to a lower C(max) (148.6 vs 183.2 mug/L), to a later time to reach C(max) (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC(12) was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05). CONCLUSION: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.

Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment.

An acute pharyngitis is characterised by mild to severe sore throat mostly accompanied by inflammation, throat pain, pain on swallowing, and burning. This randomised, double-blind, placebo-controlled phase III study was conducted for comparison of the efficacy and safety of a newly developed lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, CAS 137-58-6) 8 mg lozenge formulation (Trachisan Halsschmerztabletten) for the treatment of acute sore throat not necessarily to be treated with antibiotics. 240 patients of both genders were enrolled. The study was performed in a single centre setting and consisted of two parts. A 2-h stationary phase (single dose treatment) was directly followed by a 46-h ambulatory phase, where patients were allowed to take up to a maximum of 11 further lozenges (multiple dose treatment). Pain intensity was assessed via Visual Analogue Scale during the course of the study. Moreover, the global efficacy and tolerability of the treatments were assessed. Lidocaine 8 mg sore throat lozenges were found to be superior to placebo for all efficacy parameters investigated. For the primary efficacy parameter, area under the curve of pain intensity from baseline over 2 h (AUC(0-2h)), i.e. after single-dose treatment, a significant treatment difference with a p-value of p < 0.001 in favour of the verum treatment could be demonstrated. Significant superiority could also be demonstrated for the descriptive AUC(0-48h) values, reflecting the treatment effect during the ambulatory multiple dose phase. Pain relief, minimum pain intensity, meaningful pain relief and the time of onset of meaningful pain relief as well as the assessments of global efficacy underlined the superiority of the treatment with lidocaine 8 mg sore throat lozenges. Global tolerability of the verum treatment was rated as "good" or "very good" in the majority of cases, the number of study drug related adverse events was low and evenly distributed to both treatment groups. Therefore, the results of the trial emphasise lidocaine 8 mg sore throat lozenges to be a favourable option in the treatment of pain symptoms of an acute sore throat.

[Application of quantifying scoring systems for the determination of changes in the mucosa of the upper gastrointestinal tract. A comparative study of a diclofenac effervescent tablet with conventional diclofenac preparations and acetylsalicylic acid after repeated administration]. / Einsatz quantifizierender Scoring-Systeme zur Ermittlung von Schleimhautveränderungen des oberen Gastrointestinaltraktes. Vergleichende Untersuchung einer Diclofenac-Brausetablette, konventioneller Diclofenac-Zubereitungen sowie von Acetylsalicylsäure nach wiederholter Anwendung.

UNLABELLED: Application of Quantifying Scoring Systems for the Determination of Changes of the Mucosa of the Upper Gastrointestinal Tract/A comparative study of a diclofenac effervescent tablet with conventional diclofenac preparations and acetylsalicylic acid after repeated administration. BACKGROUND AND AIM: A new diclofenac effervescent tablet (DIC-BT) was developed in order to circumvent the high variable delay in delivery of the drug in enteric coated tablets of diclofenac (CAS 15307-86-5). The gastrointestinal side effects of the effervescent tablet were investigated in comparison to two other galenic principles of DIC preparations (DIC entero coated dragees = DIC-mrD) and dispersible tablets (DIC-DispT) and to acetylic salicylic acid (ASA (CAS 50-78-2). For the assessment of gastrointestinal side effects, two score systems were used simultaneously. The Lanza-scores were compared with our HEU-criteria system (Haemorrhage, Erosion, Ulceration) to find out if the pattern and the localisation of the lesions differ between the drugs tested. METHODS: In a single-blind, randomised, controlled, parallel study design healthy volunteers (27 females, 33 males; mean age 26.9 years, mean b.w. 72.5 kg, Helicobacter pylori antibody negative) were treated by 150 mg/d DIC or 1500 mg ASA (as positive control group) for 7 days. DIC-BT (n = 20 subjects), DIC enteric coated dragees (DIC-mrD) (n = 20), DIC-Dispers tablets (DIC-DispT) (n = 10) and ASA (n = 10) were administered t.i.d. The effects were investigated by videoendoscopy with chromoscopy before and after treatment. Mucosa lesions were assessed according to the Lanza-scores and HEU-criteria system. The results were calculated as pre-post comparison and assessed as paired test between treatment groups. RESULTS: DIC preparations caused mostly erosions and scarcely haemorrhages, but different from ASA only few combined lesions of haemorrhages and lesions in Corpus ventriculi and Bulbus duodeni. The number of mucosal lesions was different with regard to the region (Antrum ventriculi > Corpus ventriculi > Bulbus duodeni). The spreading with Helicobacter pylori (histological assessment at the end of study) varied between 20% and 50% (7/20 subjects in DIC-BT and DIC-msrD, respectively, 5/10 in DIC-dispT group, 2/10 subjects in the ASA group). Based on the HEU-criteria, erosions were seen in 9/20 subjects in DIC-BT, 10/20 subjects in DIC-mrD, 4/10 in DIC-DispT, and 3/10 subjects in ASA group, respectively, the combination of haemorrhages and erosions is seen in 2/20 subjects in DIC-BT, 6/20 in DIC-mrD, 4/10 subjects in DIC-DispT, and in 7/10 subjects in the ASA group, respectively. The difference is significantly between DIC-BT and ASA (p < 0.05) to the sum of all lesions in stomach. Based on Lanza-scores (score values > 2), (a) erosions were seen in 7/20 subjects in DIC-BT, 15/20 subjects in DIC-mrD, 7/10 in DIC-DispT, and 9/10 subjects in ASA group; (b) haemorrhages were seen in 0/20 subjects in DIC-BT, 5/20 subjects in DIC-mrD, 2/10 in DIC-DispT, and 4/10 subjects in ASA group, (c) combined type in 3/20 subjects in DIC-BT, 8/20 subjects in DIC-mrD, 5/10 in DIC-DispT, and 8/10 subjects in ASA group, respectively. Independent of the scoring systems, the difference was significant between DIC-BT and DIC-mrD, as well as between all DIC preparations and ASA. At the end of the study Helicobacter pylori infections were observed by biopsy in 20-50% of volunteers (DIC-BT and DIC-mrD in 7/20 subjects, each, and DIC-DispT in 5/10, and ASA in 2/10 subjects, respectively) and between Dic-BT and ASA (p < 0.05) for all categories. CONCLUSION: Mucosal lesions induced by DIC-BT were significantly less than by DIC-mrD and DIC-DispT. The effect was confirmed by both scoring systems, i.e. Lanza scores and HEU-criteria system. Using the HEU-criteria the pattern and the localization of the lesions could be characterized. There were remarkable differences between the effects of DIC and ASA. The assessment of gastrointestinal side effects using the HEU-criteria was superior to Lanza-scores because there was no bias according to the type of lesion and the type of drug.