Sveinbjörn Gizurarson

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Background Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low‐dose aspirin during pregnancy reduces the risk of preterm preeclampsia. Methods In this multicenter, double‐blind, placebo‐controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention‐to‐treat principle. Results A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow‐up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between‐group differences in the incidence of neonatal adverse outcomes or other adverse events. Conclusions Treatment with low‐dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013‐003778‐29; Current Controlled Trials number, ISRCTN13633058.)

The relevance of nasal physiology to the design of drug absorption studies

Abstract The parenteral administration of drugs is often associated with complications. For example, low patient acceptance of these routes leading to non-compliance can be a particular risk when self-administration is needed for chronic therapy. Consequently, alternatives such as the nasal, buccal, ocular and vaginal routes have been considered, e.g. for systemic peptide and protein drug delivery. This review focusses on the relevance of the intranasal administration of drugs, peptides and vaccines, and looks at some physiological factors that present a barrier to the use of this route. A brief overview is given of the pharmacokinetics of drugs administered to the nasal cavity, including some of the physiological factors that may influence the kinetics, and on the major intranasal drug absorption models used today. Physiological factors highlighted are (1) mucus and mucociliary clearance; (2) enzymatic degradation; (3) immunological factors; (4) blood flow and (5) deposition of drugs in the nasal cavity.

Stimulation of the transepithelial flux of influenza HA vaccine by cholera toxin B subunit

Secretory antibodies in mucosal surfaces are known to play an essential role in protection against various infectious diseases. To enhance the production of such antibodies, influenza HA vaccine was inoculated intranasally into rabbits, together with cholera toxin B subunit (CTB) which is known to augment antibody response to an unrelated antigen. This combination resulted in high levels of serum IgG antibody responses against HA and CTB molecules, 3-4 weeks after inoculation, compared with the inoculation of HA vaccine alone. The adjuvant mechanism for CTB was studied by using Ussing chambers, in which nasal mucosa from rabbits were mounted. CTB was found to enhance the transepithelial flux of HA vaccine, from the mucosal side (lumen) into the serosal side (lamina propria), indicating that the permeability of the membrane was changed by CTB. Moreover, to achieve effective flux of HA vaccines, some interactions between the vaccine and CTB across the membrane were found, which may effect the effectiveness of the vaccine formulation. The results suggest that one of the mechanisms by which CTB enhances the production of mucosal antibody response is to enhance the transepithelial influx of vaccine into the nasal mucosa, where the cells involved in the antibody production are located. CTB may be used as a potent adjuvant to induce antibody response, by nasal vaccination, against pathogens impinging on mucosal surfaces.

Intranasal booster vaccination against diphtheria and tetanus in man

The booster responses of three different formulations of intranasal (i.n.) diphtheria-tetanus (D-T) vaccines were determined in military recruits and compared with a conventional subcutaneous D-T vaccine. The vaccines for mucosal delivery were sprayed into one nostril and contained D and T toxoids in an enhancer mixture of polysorbate and caprylic/capric glycerides. All of the vaccines gave rise mainly to a systemic IgG response. Among 51 persons with anti-D antibody concentrations in serum below a protective level of 0.01 international units (IU ml-1) before vaccination, all except two attained protective antibody concentrations 4 weeks after vaccination. The median increase in anti-D antibody concentration was 113-fold with the most efficient i.n. formulation. The median increase in anti-T antibody level was 2.4-fold, however, the pre-vaccination levels for this antigen were very high. Within the examined levels, the booster response depended mainly on the dose of the antigen in the vaccine rather than on the concentration of the vehicle mixture. Compared with the parenteral D-T vaccine containing aluminium hydroxide as an adjuvant, all of the tested i.n. formulations showed somewhat lower immunogenicity in man as well as in pre-clinical guinea-pig studies. Among 215 persons immunized i.n., 61% preferred this route of administration rather than a parenteral injection, although the formulations were all associated with varying local symptoms, frequently stinging and pronounced, nasal secretion.

Pharmacokinetic and Pharmacodynamic Response after Intranasal Administration of Diazepam to Rabbits

Nasal application of drugs might be an alternative to intravenous administration in acute situations such as epileptic or fever seizures. In the search for a nasal formulation leading to a peak plasma concentration of diazepam at a tmax ≤5 min bioavailability in rabbits has been studied after intranasal administration of the drug in ten vehicles of different polarity.

THE INFLUENCE OF INSULIN AND SOME EXCIPIENTS USED IN NASAL INSULIN PREPARATIONS ON MUCOCILIARY CLEARANCE

Abstract The potential local toxicity to the nasal mucosa of insulin, various absorption promoters and vehicles has been tested in the frog palate model. The influence on mucociliary transport rate was used as an estimate of toxicity. Full inhibition of this rate was observed with 1% l -α-lysophosphatidylcholine, 1% polyoxyethylene-9-lauryl ether, 1% sodium deoxycholate and 1% sodium dihydrotaurofusidate, whereas 1% sodium glycocholate and 1% didecanoyl- l -α-phosphatidylcholine had no effect. 0.1% sodium dihydrotaurofusidate increased the mucociliary transport rate and the insulin formulation Novolin ® reduced the rate slightly, but these latter effects were always reversible.

Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia

BACKGROUND Pre-eclampsia affects 2-7% of all pregnant women and is a major cause of maternal and fetal morbidity and mortality. The etiology of pre-eclampsia is still unknown but it is well documented that impaired placentation is a major contributor to its development. One of the placenta-specific proteins is placental protein 13 (PP13). Lower first trimester levels of maternal serum PP13 and its encoding placental mRNA are associated with the development of both early and late-onset severe pre-eclampsia. In cases where this protein is mutated, the frequency of pre-eclampsia is higher. METHODS 19 out of 68 studies on PP13, published between January 2006 and September 2012, were used to evaluate the value of maternal blood PP13 as a marker of pre-eclampsia. RESULTS A meta-analysis presented in this review shows that low serum levels of PP13 in the first trimester of pregnancy can predict the development of pre-eclampsia later in pregnancy. Although some functions of this protein have been assessed in in vitro experiments, the in vivo functions of PP13 are still unknown, especially when circulating in the maternal bloodstream. A recent pilot study has shown that in gravid rats PP13 causes significant vasodilatation, reduced blood pressure and increased maternal uterine artery remodeling. CONCLUSION Reviewing these effects of PP13, the authors propose the use of PP13 as a new drug candidate. Replenishing PP13 in those women with low serum levels early in pregnancy may help prepare their vasculature for pregnancy. This novel pharmacological approach to combat pre-eclampsia is presented as a new direction to transfer from individualized risk to personalized prevention.

INTRANASAL ADMINISTRATION OF INSULIN TO HUMANS

The purpose of this review is to summarize the information and experience at present available on the intranasal administration of insulin to human subjects and to describe some of the anatomical, physiological, pharmaceutical and technological factors which can affect the absorption of insulin. An overview is given of those absorption promoters which have been used in clinical insulin studies, and the possible absorption-promoting mechanisms are discussed. This review shows that the nasal route offers a promising alternative to parenteral administration. The easier administration and the acceptance by the patients is encouraging the development of new intranasal insulin preparations.

Anatomical and histological factors affecting intranasal drug and vaccine delivery.

The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region.

Placental Protein 13 (PP13) – A Placental Immunoregulatory Galectin Protecting Pregnancy

Galectins are glycan-binding proteins that regulate innate and adaptive immune responses, and some confer maternal-fetal immune tolerance in eutherian mammals. A chromosome 19 cluster of galectins has emerged in anthropoid primates, species with deep placentation and long gestation. Three of the five human cluster galectins are solely expressed in the placenta, where they may confer additional immunoregulatory functions to enable deep placentation. One of these is galectin-13, also known as Placental Protein 13 (PP13). It has a “jelly-roll” fold, carbohydrate-recognition domain and sugar-binding preference resembling other mammalian galectins. PP13 is predominantly expressed by the syncytiotrophoblast and released from the placenta into the maternal circulation. Its ability to induce apoptosis of activated T cells in vitro, and to divert and kill T cells as well as macrophages in the maternal decidua in situ, suggests important immune functions. Indeed, mutations in the promoter and an exon of LGALS13 presumably leading to altered or non-functional protein expression are associated with a higher frequency of preeclampsia and other obstetrical syndromes, which involve immune dysregulation. Moreover, decreased placental expression of PP13 and its low concentrations in first trimester maternal sera are associated with elevated risk of preeclampsia. Indeed, PP13 turned to be a good early biomarker to assess maternal risk for the subsequent development of pregnancy complications caused by impaired placentation. Due to the ischemic placental stress in preterm preeclampsia, there is increased trophoblastic shedding of PP13 immunopositive microvesicles starting in the second trimester, which leads to high maternal blood PP13 concentrations. Our meta-analysis suggests that this phenomenon may enable the potential use of PP13 in directing patient management near to or at the time of delivery. Recent findings on the beneficial effects of PP13 on decreasing blood pressure due to vasodilatation in pregnant animals suggest its therapeutic potential in preeclampsia.