Adhesion Prevention to Polypropylene Meshes Using Combined Icodextrin Four Percent and Dimetindene Maleate.

BACKGROUND: The use of surgical meshes in ventral hernia repair has significantly reduced hernia recurrence rates. However, when placed intraperitoneally prosthetic materials can trigger the development of peritoneal adhesions. The present experimental study evaluated the combined icodextrin 4% and dimetindene maleate treatment in preventing peritoneal adhesion formation to polypropylene and titanium-coated polypropylene meshes. MATERIALS AND METHODS: Sixty female white rabbits were divided into four groups. A 2 × 2 cm piece of mesh was fixed to intact peritoneum in all animals through a midline laparotomy. A lightweight polypropylene mesh was implanted in groups 1 and 2 and a titanium-coated polypropylene mesh in groups 3 and 4. Groups 2 and 4 were treated, intraoperatively, with intravenous dimetindene maleate (0.1 mg/kg) and intraperitoneal solution of icodextrin 4% (20 mL/kg) and for the next 6 d with dimetindene maleate intramuscularly. The observation period lasted 15 d. Adhesion scores, percentage of mesh affected surface, tissue hydroxyproline levels, and tissue histopathology were examined. RESULTS: All animals in group 1 and 57% of animals in group 3 presented postoperative adhesions. The combination of antiadhesives significantly reduced the extent and severity of adhesions as well as the hydroxyproline levels in groups 2 and 4 compared with groups 1 and 3. On microscopic evaluation, animals in group 1 exhibited higher inflammation scores compared with group 2, whereas animals in groups 2 and 4 had better mesotheliazation compared with groups 1 and 3. CONCLUSIONS: The combined administration of icodextrin 4% and dimetindene maleate reduces the extent and severity of adhesions and may be successfully used to prevent adhesion formation after mesh intraperitoneal placement.

Targeted Use of Placebo Effects Decreases Experimental Itch in Atopic Dermatitis Patients: A Randomized Controlled Trial.

Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to "hidden drug administration.​" In a randomized controlled trial, we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN-DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN-DRUG+INST+COND) or infused drug without any information or sight (i.e., hidden administration (control group 1: HIDDEN-DRUG)). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary end point: experimental itch intensity, numeric rating scale), and objective level (secondary end point: wheal size, mm2 ). Experimental-induced itch intensity decreased in all groups but at different rates (P < 0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN-DRUG group (OPEN-DRUG+INST+COND: P < 0.001; OPEN-DRUG+INST: P = 0.009; and PLAC+INST+COND: P < 0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (P = 0.001). Results on wheal size were similar (P = 0.048), however, no significant difference between the HIDDEN-DRUG group and the PLAC+INST+COND group (P = 0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice.

Are antihistamines effective in children? A review of the evidence.

BACKGROUND AND AIMS: During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H1-antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions. METHODS: Review of the Summary of Product Characteristics of first-generation H1-antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature. RESULTS: This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children. CONCLUSIONS: Many of the licensed indications of first-generation antihistamines do not appear to be evidence based.

Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis.

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

[Premedication with H1- and H2-receptor antagonists for intravenous urography using contrast media]. / Prämedikation mit H1- und H2-Rezeptorantagonisten vor intravenöser Kontrastmitteldarstellung der ableitenden Harnwege.

Intravenous urography using Telebrix was performed on 500 patients. Two hundred patients (group I) received no pre-medication; 300 patients (group II) were premedicated with H1 and H2 receptor antagonists. All patients were examined for signs of contrast reactions, blood pressure, pulse rate and plasma histamine levels. These were measured before and three minutes after the administration of the antihistamine substances and/or the contrast medium, and also at the end of the examination. Following the administration of H1 and H2 receptor antagonists, a slight, transient and insignificant rise in plasma histamine could be demonstrated. Both groups showed a significant rise in plasma histamine levels after the injection of the contrast medium. Although the pre-medicated group contained a higher percentage of high risk patients, there were significantly fewer patients with contrast reactions. Pre-medication with H1 and H2 receptor antagonists in high risk patients is therefore advisable.

[Prescription and safety of dimethindene maleate micropellet capsules in Hungary]. / Dimethinden maleat-tartalmú, késleltetett felszívódású mikropellet kapszula alkalmazása és biztonságossága Magyarországon.

INTRODUCTION: Dimethindene maleate, the active substance of the extended-release Fenistil 24 capsule, is a first-generation histamine receptor antagonist, which is marketed in 10 European countries. In Hungary approximately 200,000 boxes are sold yearly from this product, which is mainly used for treatment of symptoms associated with allergic diseases (urticaria, itch, hay fever) The aim of the present study was to gather information with the help of medical doctors about the indications, efficacy and primarily the safety of use, observed side effects and frequency of adverse events associated with this product. METHOD: During the study 4574 questionnaires were evaluated out of the 5578 filled by 249 doctors. Responses were included into the evaluation only if the address and type of polyclinic of the doctor filling the questionnaire, indication of the use of the product could be precisely identified and the patient returned for control visit at least once. RESULTS: Based on the study results in Hungary in most cases the product is prescribed according to the indications and dosing schedule given in the SPC. In this study participating doctors found the drug to be effective in 95% of cases. Unexpected, new adverse events were not observed during the study. Approximately 22% of patients reported adverse events, tiredness and sleepiness being the most frequent ones. Occurrence of sedative adverse events was more frequent among those who were prone to tiredness (51 vs. 17%). The adverse events most frequently were reported 10-12 hours after intake. The average length of treatment was 4 weeks or less. The medicine is taken usually at night, before going to sleep. CONCLUSIONS: In Hungary in most cases the product is prescribed according to the indications and dosing schedule given in the current approved Summary of Product Characteristics.

Efficacy of dimetinden and hydroxyzine/chlorpheniramine in atopic dogs: a randomised, controlled, double-blinded trial.

Antihistaminic drugs are commonly used as symptomatic therapy of atopic dermatitis in dogs. Unfortunately, their clinical benefit is largely unsubstantiated. In a double-blinded, placebo-controlled, cross-over trial, the influence of dimetinden and of a combination of chlorpheniramine and hydroxyzine on pruritus and lesions was evaluated in 19 dogs. They were treated with either product or a placebo orally for 14 days, each time followed by a 14-day washout period. Before and after each period, the dogs were examined and the Canine Atopic Dermatitis Extent and Severity Index (CADESI) determined by a clinician, and the pruritus and general condition by the owner. Dimetinden improved the pruritus significantly (P=0.014) but not the CADESI (P=0.087), the combination of hydroxyzine and chlorpheniramine improved the CADESI (P=0.049) and pruritus (P=0.05) significantly. Ten of 17 dogs improved by more than 25 per cent in pruritus with the combination of hydroxyzine and chlorpheniramine, 12 of 18 with dimetindenmaleate and only 2 of 19 with placebo. Antihistamines can help to reduce pruritus in atopic dogs, but in most cases, the improvement is limited and additional treatment may be needed.

Matrix metaloproteinase-2 and -9 serum levels as potential markers of intraperitoneal adhesions.

OBJECTIVE: To assess the value of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) as prognostic serum markers for intraperitoneal adhesions. BACKGROUND: Postoperative adhesions are associated with serious complications responsible for increased patient's morbidity. METHODS: Forty-eight rabbits were used and randomized into groups A, B, C, and D. Abdominal laparotomy and experimental adhesion formation model was carried out. In group A, 60 mL of N/S 0.9% were instilled intraperitoneally, in group B 60 mL of icodextrin 4% were instilled intraperitoneally, in group C 0.1 mL/kg of dimetindene maleate were administered intravenously, and in group D both agents were administered. Prior to euthanasia 0.5 mL of blood was obtained. The type, the surface area of adhesions, and serum concentration of MMPs were assessed. RESULTS: The mean surface area and Zuhlke classification of adhesions of groups B, C, and D has been proved to be significantly lower compared to group A. Serum MMP-2 levels were significantly higher in groups B and D than in group A, while group D was higher when compared to group C. Serum MMP-9 levels were significantly higher in group D compared to groups A, B, and C. Serum MMP-9 was the most accurate test to differentiate between animals with and without adhesions with a sensitivity of 81.8% and a specificity of 100% at a cut-off point of 21.5 (AUC = 0.934). CONCLUSIONS: The administration of icodextrin 4% and dimetindene maleate seems to prevent postoperative adhesion formation. Serum levels of MMP-2 and MMP-9 may serve as prognostic markers to identify postoperative adhesions.