Efficacy and safety of long-acting pasireotide in Japanese patients with acromegaly or pituitary gigantism: results from a multicenter, open-label, randomized, phase 2 study.

A multicenter, open-label, phase 2 study was conducted to investigate the efficacy and safety of long-acting pasireotide formulation in Japanese patients with acromegaly or pituitary gigantism. Medically naïve or inadequately controlled patients (on somatostatin analogues or dopamine agonists) were included. Primary end point was the proportion of all patients who achieved biochemical control (mean growth hormone [GH] levels<2.5µg/L and normalized insulin-like growth factor-1 [IGF-1]) at month 3. Thirty-three patients (acromegaly, n=32; pituitary gigantism, n=1) were enrolled and randomized 1:1:1 to receive open-label pasireotide 20mg, 40mg, or 60mg. The median age was 52 years (range, 31-79) and 20 patients were males. At month 3, 18.2% of patients (6/33; 90% confidence interval: 8.2%, 32.8%) had biochemical control (21.2% [7/33] when including a patient with mean GH<2.5µg/L and IGF-1< lower limit of normal). Reductions in the median GH and IGF-1 levels observed at month 3 were maintained up to month 12; the median percent change from baseline to month 12 in GH and IGF-1 levels were -74.71% and -59.33%, respectively. Twenty-nine patients completed the 12-month core phase, 1 withdrew consent, and 3 discontinued treatment due to adverse events (AEs; diabetes mellitus, hyperglycemia, liver function abnormality, n=1 each). Almost all patients (97%; 32/33) experienced AEs; the most common AEs were nasopharyngitis (48.5%), hyperglycemia (42.4%), diabetes mellitus (24.2%), constipation (18.2%), and hypoglycemia (15.2%). Serious AEs were reported in 7 patients with the most common being hyperglycemia (n=2). Long-acting pasireotide demonstrated clinically relevant efficacy and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

[The possibilities for the rational pharmacotherapy of adenoiditis in the children]. / Vozmozhnosti ratsional'noi farmakoterapii adenoidita u detei.

The available literature data give evidence that viral infection is the main cause underlying the development of inflammatory nasopharyngeal pathology in the children. According to ICD-10, nether acute nor chronic adenoiditis should be considered as a self-consistent nosological entity. Acute adenoiditis is usually regarded as a form of acute nasopharyngitis (J02) or acute respiratory viral infection (J06.9) whereas chronic adenoiditis is commonly referred to as representing other chronic diseases of the tonsils and adenoids (J 35.8). The reactive changes in the nasopharyngeal tonsils begin to be manifested on days 3-5 after the onset of acute respiratory viral infection; thereafter, they persist and gradually disappear within the next 2-3 weeks. In the majority of the cases, acute adenoiditis is actually a physiological reaction of the nasopharyngeal tonsils as the organs of regional mucosal immunity to antigenic stimulation. There is no universally accepted opinion as regards the duration of the inflammatory process which would allow these pathological changes to be considered as turned into chronic ones. This condition is actually not a serious pathology provided it is not associated with the concomitant complications and produces no clinically significant effect on the child's quality of life. Under practical conditions, such children are most frequently treated with the use of irrigation therapy. Taking into account that otorhinolaryngologists all over the world do not consider chronic adenoiditis as an independent nosological entity but distinguish only hypertrophy of adenoid vegetations or chronic rhinosinusitis (in the presence of inflammatory changes in the nasopharynx), it appears correct to speak about chronic adenoiditis provided the clinical manifestations of the disease persist for more than 12 weeks. Based on the predominant etiological component, the viral, bacterial, and allergic forms of nasopharyngeal adenoiditis can be distinguished even though it is rather difficult to actually determine which etiological factor prevails in each concrete case. The aforedescribed situation poses a large number of questions pertaining to the choice of either systemic or topical antibacterial therapy.

Nonacog alfa: an analysis of safety data from six prospective clinical studies in different patient populations with haemophilia B treated with different therapeutic modalities.

Nonacog alfa is a recombinant factor IX (FIX) product indicated for treatment and prevention of bleeding episodes in patients with haemophilia B. This posthoc analysis evaluated the safety of nonacog alfa in key clinical studies across 15 years. Data were pooled from six prospective studies that utilized on-demand, prophylactic and preventive nonacog alfa regimens: three open-label, nonrandomized studies that assessed efficacy and safety; a bioequivalence study of original and reformulated nonacog alfa; an open-label, randomized study that compared on-demand and prophylactic treatment; and a noninterventional observational registry study that evaluated safety. Safety assessments included adverse events, serious adverse events (SAEs) and events of special interest. In total, 412 patients received nonacog alfa treatment. Adverse events occurred in 220 patients (53.4%), the most common being pyrexia (n = 63), nasopharyngitis (n = 53) and cough (n = 52). Forty-eight patients (11.7%) experienced treatment-related adverse events; the most common were hypersensitivity (n = 6), urticaria (n = 6), FIX inhibition (n = 5) and pyrexia (n = 4). Seventy-four patients (18.0%) developed SAEs. Thirty-seven events of special interest occurred in 31 (7.5%) patients. Events of special interest included allergic-type manifestations (n = 15), inhibitor development (n = 5), lack of effect (n = 8), red blood cell agglutination in tubing or syringe (n = 7), and thrombogenicity (n = 2). Six patients (1.5%) withdrew due to seven adverse events: hypersensitivity (n = 3), drug eruption, pruritic rash, urticaria and decreased therapeutic response (n = 1 each). Four patients died during the study; no deaths were related to study medication. This pooled safety analysis in haemophilia B patients confirmed the safety of nonacog alfa across various patient populations.

Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder.

OBJECTIVE: The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine (Lu AA21004) in the long-term treatment of patients with major depressive disorder. METHODS: Patients entered this 52-week, open-label extension study after completing an 8-week lead-in study. Safety and tolerability were evaluated at regular intervals on the basis of spontaneously reported adverse events (AEs), clinical safety laboratory tests, vital signs, ECG and physical examination. Effectiveness of treatment was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. RESULTS: A total of 535 patients were treated and 61.3% (n = 328) completed the study, resulting in 393 patient years of exposure to vortioxetine. AEs reported by ≥10% of patients were nausea, headache, and nasopharyngitis. Taken together, six patients had eight AEs related to sexual dysfunction. There were no clinically significant safety findings with respect to mean changes of vital signs, weight, ECG parameters, or clinical laboratory values. Patients entered the extension study with a mean MADRS total score of 13.5 ± 8.7. The mean MADRS total score decreased (improved) by approximately 8 points to 5.5 ± 6.0 at Week 52 (OC). By the end of the study, the proportion of responders had increased from 63% to 94% (OC), as had the proportion in remission (MADRS ≤10), increasing from 42% to 83% (OC). Patients in remission (n = 226) at the start of this study had a relapse rate (MADRS ≥22) of 9.7%. CONCLUSIONS: As with all open-label studies, the conclusions that can be drawn are limited by the lack of a placebo control, making it difficult to assess causality of any changes in outcome measures. However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment. TRIAL REGISTRATION: This study has the ClinicalTrials.gov identifier: NCT00694304.

Role of IgE-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations.

A pathophysiologic model of otitis media with effusion secondary to IgE-mediated hypersensitivity is described. Specific mediators of inflammation are released by mucosal mast cells in the nasal mucosa following the interaction of antigen and specific IgE antibody. These mediators increase vascular permeability, mucosal blood flow, and, most important, mucus production. Furthermore, accessory cell types are recruited by colony-stimulating factors that in turn provide an autocrine-positive feedback for the influx of further inflammatory cells. The eustachian tube is then effectively obstructed by both intrinsic venous engorgement and extrinsic mucus plugs, isolating the middle ear space from the ambient environment. The net result is the increased exchange of nitrogen into the middle ear mucosa from the middle ear cavity. This causes the development of a significant middle ear underpressure that disrupts tight junctions and allows for transudation of fluids into the middle ear space. The prolonged obstruction of the eustachian tube with mucus results in middle ear inflammation, mucosal metaplasia, and increased glandular activities, all of which are hallmarks of chronic otitis media with effusion.

[A national survey on the criteria of prescription antibiotic therapy in nasopharyngitis in pediatric practice]. / Enquête nationale sur les critères de prescription d'une antibiothérapie dans les rhinopharyngites en pédiatrie de ville.

Although nasopharyngitis usually results from a viral infection, it is the leading cause of use of antimicrobials in pediatric patients. A study of the criteria used by pediatricians to prescribe antimicrobials in uncomplicated nasopharyngitis was undertaken. Each of 700 pediatricians enrolled ten consecutive patients with uncomplicated nasopharyngitis. Use of antimicrobials was left to the discretion of the physician. Antimicrobials were used in 59% of pediatric patients evaluated for nasopharyngitis. Criteria considered as the most important for deciding to use antimicrobials induced purulent secretions (87.2%), congestion of both tympanic membranes (82.8%), cough (79.2%), fever greater than 39 degrees C (77.2%), and a history of otitis media (69.8%). Data on the outcome was available for 69% of patients. Acute otitis media was the main complication, with a rate of 7.7%; this rate was lower in the treated group (5.4%) than in the untreated group (10.9%). A positive history for otitis media and the appearance of the eardrums at evaluation were the best predictors of otitis media.

[Variations of nasopharyngeal pH in nasopharyngitis in children]. / Variations du pH rhinopharyngé dans les rhinopharyngites de l'enfant.

In view of the well-known relationship between gastro-oesophageal reflux (GOR) and inflammatory diseases of the bronchi, trachea and larynx, the possibility of a pathogenic acid reflux reaching the pharynx has sometimes been suspected but never demonstrated. Paediatric E.N.T. specialists are often confronted with chronic inflammatory rhinopharyngitis of no obvious origin. In order to test the hypothesis of rhinopharyngeal contamination by gastric acid, the nycthemeral local pH was recorded in children presenting with chronic rhinopharyngitis and gastro-oesophageal reflux, and in two groups of controls without rhinopharyngitis and with or without GOR. Falls in rhinopharyngeal pH were found to be more frequent and to last longer in the 18 patients than in controls. The most significant criterion was the time during which the pH was lower than 6 compared with the total time of recording in these cases where pharyngeal pH measurements were recorded over 15 to 26 hours. It seemed most probable that this acidity resulted from the gastro-oesophageal reflux. Such variations in acid-base balance at the surface of a respiratory mucosa might be instrumental in the genesis or maintenance of the nasopharyngeal inflammatory reaction. However, these two hypotheses must be confirmed or infirmed by further studies.

Nasopharyngeal pH monitoring in infants and children with chronic rhinopharyngitis.

The etiology and mechanisms involved in determining and/or maintaining the inflammatory process along the airway mucosa remain partially obscure. The role of gastroesophageal reflux (GER) has been demonstrated in some cases of bronchitis and laryngitis especially in children. In adults, GER-related laryngitis has also been mentioned. In children, repeated rhinopharyngitis and otitis media due to GER remain a putative question. In this study, 31 infants and children underwent a day and night nasopharyngeal pH monitoring. Thirteen patients with known GER suffered from chronic or repeated rhinitis or rhinopharyngitis. Eighteen control subjects with or without GER were free of upper airway inflammatory process. In some pathological cases the pH dropped dramatically. The pH drops were more important in most of the GER/rhinitis cases than in controls. Of the reviewed criteria, the percentage of time spent below pH 6 (or pharyngeal acidity index) is the most statistically significant (P less than 0.00005). Thus, the influence of a gastro-esophago-nasopharyngeal acid reflux is strongly suggested in this common pediatric pathology, among other causes. However, the technique used does not allow us to assess the true origin of these pH changes. Further investigation with two-site pH monitoring and larger series of patients are required in order to fully assess the influence of GER on pediatric nasopharyngeal inflammation.