Aspirin causes endothelium-dependent vasodilation of resistance arteries from non-gravid and gravid rats

Abstract Objective The objective of this study was to understand the effect of acetylsalicylic acid (aspirin) on resistance arteries from mesentery and uterus. During pregnancy, the uterine vasculature undergoes consistent growth to provide sufficient uteroplacental blood flow, a process whose failure is associated with pregnancy complications characterized by high uterine vascular resistance. Methods Uterine arcuate (UA) and mesenteric arteries (MA; diameter Results Aspirin dilated both UA and MA in a dose dependent manner. Pregnancy increased aspirin vasodilation in MA and UA from mid-gravid rats, an effect that was reduced in vessels from late gravid animals at concentrations >10−7 M. Further, uterine vasodilation was significantly reduced when the endothelium was removed (p  Conclusion This is the first study to show a direct vasodilatory effect of aspirin on rat uterine artery that is mediated by a combination of cellular – primarily endothelial - mechanisms. Our results in UA suggest that the use of aspirin may be effective in enhancing uteroplacental blood flow, while its vasodilation effect on MA may lower peripheral resistance

Evaluation of intranasal delivery route of drug administration for brain targeting

Publisher's version (útgefin grein)The acute or chronic drug treatments for different neurodegenerative and psychiatric disorders are challengingfrom several aspects. The low bioavailability and limited brain exposure of oral drugs, the rapid metabolism,elimination, the unwanted side effects and also the high dose to be added mean both inconvenience for thepatients and high costs for the patients, their family and the society. The reason of low brain penetration of thecompounds is that they have to overcome the blood-brain barrier which protects the brain against xenobiotics.Intranasal drug administration is one of the promising options to bypass blood-brain barrier, to reduce thesystemic adverse effects of the drugs and to lower the doses to be administered. Furthermore, the drugs ad-ministered using nasal route have usually higher bioavailability, less side effects and result in higher brainexposure at similar dosage than the oral drugs. In this review the focus is on giving an overview on the ana-tomical and cellular structure of nasal cavity and absorption surface. It presents some possibilities to enhance thedrug penetration through the nasal barrier and summarizes somein vitro,ex vivoandin vivotechnologies to testthe drug delivery across the nasal epithelium into the brain. Finally, the authors give a critical evaluation of thenasal route of administration showing its main advantages and limitations of this delivery route for CNS drugtargetingThe authors thank the Faculty of Information Technology andBionics, Pázmány Péter Catholic University, Budapest, for the supportof the publication costs of this article. This work was partly supportedby the European Union through grant no. EFOP-3.6.3-VEKOP-16-2017-00002 co-financed by the European Social Fund and also by theNational Bionics Program of Hungary.Peer Reviewe

Improving unbiased left/right training of rats and use of physostigmine to counteract scopolamine-induced short-term memory impairment

Rationale: The DNMTP task measures short-term / working memory uncontaminated by learning capacity,  spatial abilities, motor performance or general motivational and arousal factors. However, DNMTP training  of rats can take two months, and we aimed to reduce this. Methods: Two experiments were conducted on rats  in an operant DNMTP task. Improvements were made on the training procedure. The method was validated  by replicating the effect of scopolamine on working memory. The experiments also explored the influence  of physostigmine in reversing impairment induced by scopolamine. Thus in experiment 1, ten Lewis rats  were trained in an operant DNMTP task (1, 2, 4 and 8 s delay intervals) before 9 of them received vehicle,  scopolamine, saline or combinations of scopolamine and physostigmine. In experiment 2, ten Lewis rats (5  old and 5 young) were trained in the same task (1, 2, 4, 8 and 16 s delay intervals). There were six treatments:  0.05 mg/kg scopolamine, 0.1 mg/kg physostigmine or 0.15 mg/kg physostigmine, control involving  saline or involving no injection and no handling, and finally a combined treatment of 0.05mg/kg scopolamine  and 0.15 mg/kg physostigmine. In both experiments scopolamine significantly reduced correct  responses, nose-pokes and lever presses compaired to control conditions. Furthermore, in experiment 2,  there was insignificant difference between saline and combined scopolamine/physostigmine for correct  responses and for delay prior to pressing the sample lever. As expected, there was significant difference  between scopolamine and combined scopolamine/physostigmine for correct responses, for delay prior to  pressing the sample lever and for delay prior to pressing the non-matching lever. As a result, the animals  were ready for drug injection after 17 days from habituation and the method ensured that there were no dropouts  due to left or right lever preference. This is a shorter training period than previously thought necessary.  The brief training method was validated by replicating the effect of scopolamine on working memory.

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits

Introduction: Human placental protein 13 (PP13) is a galectin predominantly expressed by the placenta. Low serum concentrations of PP13 in early pregnancy indicate a higher risk of developing preeclampsia. Methods: The pharmacokinetic disposition and bioavailability of PP13 were determined by single intravenous and subcutaneous administration to 12 healthy New Zealand White rabbits. The serum pharmacokinetic values were determined by enzyme-linked immunosorbent assay, and are best described by a two-compartment model. Results: Both volume of distribution and the area under the curve were dose dependent for the intravenous group (p < 0.01). PP13 elimination half-life was also found to be different between the groups (p < 0.01). The bioavailability of PP13 following subcutaneous administration was found to be 57%. Conclusion: This study shows that the concentration of total PP13 released into the maternal circulation during pregnancy might be much higher than previously estimated.The authors thank Hy Laboratories for providing PP13 to this study through support provided by the European Union through the ASPRE project (# 601852). This study was mainly sponsored by Hananjaehf and the Icelandic Research Fund (Rannis; grant number 163403-052).Peer Reviewe

Doxycycline and Monocaprin In Situ Hydrogel: Effect on Stability, Mucoadhesion and Texture Analysis and In Vitro Release

Publisher's version (útgefin grein).The aim of this study was to develop a stable aqueous formulation containing a combination of doxycycline and monocaprin in clinically relevant concentrations. Increase in expression of Matrix metalloproteinases (MMPs) and microbial role in oral diseases is well established and the combination of above active ingredients could be potentially beneficial in treatment of oral mucosal conditions. The hydrogels containing different concentrations of doxycycline and monocaprin in the presence and absence of stabilizing excipients were developed and their stabilities were studied at 4 ◦C for up to 1 year. The drug–drug interaction was evaluated using Fourier-transform infrared spectroscopy (FTIR). The addition of monocaprin on doxycycline in situ hydrogel’s mucoadhesiveness, texture properties and drug release mechanism was studied. The addition of monocaprin negatively affected the doxycycline stability and was concentration dependent, whereas monocaprin was stable up to 1 year. Doxycycline did not interfere with the anti-Candidal activity of monocaprin. Furthermore, the presence of monocaprin significantly affected the formulation hardness, compressibility and adhesiveness. Monocaprin and doxycycline release followed zero order kinetics and the release mechanism was, by anomalous (non-Fickian) diffusion. The addition of monocaprin increased the drug release time and altered the release mechanism. It is possible to stabilize doxycycline in the presence of monocaprin up to 1 year at 4 ◦C.This work was supported by a research fund from the University of Iceland (Rannsóknarsjóður Háskóla Íslands).Peer Reviewe

Colour of Medicines and Children’s Acceptability? A Systematic Literature Review of Children’s Perceptions about Colours of Oral Dosage Forms

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient’s expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children’s opinions on colours of medicines and to what extent medicines’ colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0–18 years old), assessing children’s preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children’s medicines beyond quality purposes

Colour of medicines and children's acceptability? A systematic literature review of children's perceptions about colours of oral dosage forms

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient's expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children's opinions on colours of medicines and to what extent medicines' colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0–18 years old), assessing children's preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children's medicines beyond quality purposes

Modulation of immune responses using adjuvants to facilitate therapeutic vaccination

Publsher's version (útgefin grein)Therapeutic vaccination offers great promise as an intervention for a diversity of infectious and non-infectious conditions. Given that most chronic health conditions are thought to have an immune component, vaccination can at least in principle be proposed as a therapeutic strategy. Understanding the nature of protective immunity is of vital importance, and the progress made in recent years in defining the nature of pathological and protective immunity for a range of diseases has provided an impetus to devise strategies to promote such responses in a targeted manner. However, in many cases, limited progress has been made in clinical adoption of such approaches. This in part results from a lack of safe and effective vaccine adjuvants that can be used to promote protective immunity and/or reduce deleterious immune responses. Although somewhat simplistic, it is possible to divide therapeutic vaccine approaches into those targeting conditions where antibody responses can mediate protection and those where the principal focus is the promotion of effector and memory cellular immunity or the reduction of damaging cellular immune responses as in the case of autoimmune diseases. Clearly, in all cases of antigen-specific immunotherapy, the identification of protective antigens is a vital first step. There are many challenges to developing therapeutic vaccines beyond those associated with prophylactic diseases including the ongoing immune responses in patients, patient heterogeneity, and diversity in the type and stage of disease. If reproducible biomarkers can be defined, these could allow earlier diagnosis and intervention and likely increase therapeutic vaccine efficacy. Current immunomodulatory approaches related to adoptive cell transfers or passive antibody therapy are showing great promise, but these are outside the scope of this review which will focus on the potential for adjuvanted therapeutic active vaccination strategies.This article/publication is based upon work from COST Action CA16231 ENOVA (European Network of Vaccine Adjuvants), supported by COST (European Cooperation in Science and Technology—www.cost.eu).Peer Reviewe

Mucosal Tolerance to KLH Reduces BSA-Induced Arthritis in Rats-An Indication of Bystander Suppression.

To access Publisher full text version of this article. Please click on the hyperlink in Additional LinkMucosal tolerance has been shown to reduce disease severity in animal models mimicking human autoimmune diseases. The objective of this study was to examine whether mucosal tolerance against keyhole limpet haemocyanin (KLH) could be used to reduce bovine serum albumin (BSA)-induced arthritis in rats and whether anti-inflammatory drugs or passive cigarette smoke affected tolerance induction. Arthritis was induced by immunizing rats with BSA and then injecting BSA into one knee and saline into the other knee for comparison. Prior to BSA immunization, the rats were treated intranasally with KLH or saline and KLH then injected in the knee joints at the time of BSA injection, or the rats were treated with or without anti-inflammatory drugs or subjected to cigarette smoke prior to and during intranasal treatment with BSA. The rats that received intranasal treatment with KLH had a significantly less inflammation in their left knee joint compared to rats that received intranasal saline treatment. Beclamethasone increased the tolerance effect of BSA, whereas passive cigarette smoke abrogated the mucosal tolerance. This data suggests that bystander suppression can be used to treat arthritis and other autoimmune diseases, even when the autoantigen is not known