Carine De Vriese

Influence of ghrelin on food intake and energy homeostasis.

Purpose of reviewThe purpose of this review is to provide updated information on the role of ghrelin in food intake and energy homeostasis, and on its mechanism of action. Moreover, the potential of ghrelin as a target for drugs to treat cachexia and obesity will be discussed. Recent findingsWhereas the effects of ghrelin in the regulation of appetite, food intake and energy homeostasis have been fairly well documented, the pathways responsible for the effects of ghrelin are now increasingly being understood. As a consequence, clinical applications of ghrelin are now being developed. SummaryGhrelin is an endogenous orexigenic peptide recently discovered in the stomach. Ghrelin is involved in short-term regulation of food intake since its plasma levels increase before meals and decrease strongly postprandially. Ghrelin is also involved in long-term body-weight regulation by inducing adiposity. Ghrelin might be useful for cachexia and obesity treatment.

Development and evaluation of sustained-release clonidine-loaded PLGA microparticles

This work describes the encapsulation of a small, hydrophilic molecule (clonidine) into a PLGA matrix to provide sustained release over more than one month after intra-articular administration. The microparticles were prepared using a double emulsion (w(1)/o/w(2)) method followed by evaporation of the organic solvent. To optimize the efficiency of encapsulation and the mean size of the microparticles, which was targeted around 30 μm, the following parameters were modulated: the viscosity and the volume of the organic phase, the molecular weight of the polymer, the volume of the internal and external aqueous phases, the drug loading, the concentration of surfactant, and the stirring parameters. Blends of polymers characterized by different molecular weights (34000-96000 Da) as well as copolymers of PLGA-PEG were used to enhance the entrapment of the drug. The pH of the aqueous phases was adjusted to obtain suitable encapsulation efficiency. Characterization was made of the physico-chemical properties of the microparticles, such as their crystallinity (DSC and PXRD) and microstructure (SEM). When performing in vitro dissolution studies, controlled release for up to approximately 30 days was achieved with several of the formulations developed. Diffusion was found to be the dominant drug release mechanism at early time points.

Focus on the short- and long-term effects of ghrelin on energy homeostasis

The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28-amino-acid peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelin results from its synthesis and secretion by the X/A-like endocrine cells from the stomach and proximal small intestine. Besides its potent growth hormone secretory action, ghrelin is a highly pleiotropic hormone, contributing significantly to the regulation of appetite and food intake control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secretions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic processes. The purpose of this review is to consider the orexigenic effects of ghrelin on short-term regulation of food intake and long-term regulation of body weight, the implications of genetic ghrelin and growth hormone secretagogue receptor polymorphism, and the use of antagonists and agonists of ghrelin in pathophysiological conditions.

New sustained-release intraarticular gel formulations based on monolein for local treatment of arthritic diseases.

Inflammatory osteoarthritis (OA) is characterized by painful and destructive inflammatory flares of a single joint, mainly in the back, the knees, the wrists or the hips. Monoarthritis is generally treated by intraarticular (IA) injections of corticosteroids or hyaluronic acid (HA). However, due to their toxicity, the chronic use of corticosteroids should be avoided. The aim of this work was to develop a new slow-release formulation for a parenteral route of administration (e.g., IA). The development’s strategy was based on the use of amphiphilic ingredients such as glyceryl monooleate (GMO), which is able to generate viscous crystalline phase structures upon contact with an aqueous fluid (e.g., synovial fluid) to sustain the drug activity over weeks. Clonidine (CLO) was suggested as a small and hydrophilic model drug and HA as a hydrophilic viscoelastic scaffold. Thermal analyses showed that the stability of GMO, HA, and CLO in mixtures with a ratio of 1:1 (wt/wt) was not affected in comparison with the raw materials. In order to obtain a formulation presenting suitable syringeability and containing GMO, CLO, and HA, two elements were found to be essential: a minimum of about 15% (wt/wt) water content and the use of co-solvents such as ethanol (ET) and propylene glycol (PG), approved by the FDA for parenteral use. Several developed gels presented pseudoplastic flow behavior. Moreover, the best composition provided an in vitro release of CLO for about 1 week that was similar to a cubic reference formulation, described by many authors as presenting poor syringeability but the best sustained-release capacity.

Evaluation of the degradation of clonidine-loaded PLGA microspheres

Abstract Context: The release of an encapsulated drug is dependent on diffusion and/or degradation/erosion processes. Objective: This work aimed to better understand the degradation mechanism of clonidine-loaded microparticles. Methods: Gel permeation chromatography was used to evaluate the degradation of the polymer. The water-uptake and the weight loss were determined gravimetrically. The swelling behaviour and the morphological changes of the formulations were observed by microscopy. The glass transition temperature and the crystallinity were also determined by differential scanning calorimetry and X-ray diffraction, respectively. The pH of the medium and inside the microspheres was assessed. Results: The microspheres captured a large amount of water, allowing a decrease in the molecular weight of the polymer. The pH of the medium decreased after release of the degradation products and the pH inside the microparticles remained constant due to the neutralization of these acidic products. Conclusion: Clonidine and buffers both had an action on the degradation.

Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia

The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose–brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N-(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose–brain delivery of ghrelin.

Development and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis.

This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the developed hydrolipidic gels were evaluated by measuring the production of ROS by polymorphonuclear leukocytes (PMNs). In addition, the biocompatibility and effectiveness of two selected gel candidates were evaluated in vivo by evaluating the benefit of a single intraarticular injection of these new treatments in a model of osteoarthritis in rabbits. The in vitro study demonstrated that the carrier F1 did not have a pro-oxidative effect and even protected PMNs against natural auto-activation, regardless of the incorporation of either clonidine chlorhydrate or betamethasone dipropionate. The in vivo study demonstrated that F1 and F1-BDP induced a loss of cartilage quality in comparison to the control and reference groups but that the lesions of cartilage observed were generally mild, with not much full-depth erosion. Moreover, no exacerbating inflammation was observed when considering the synovial membranes and the PGE2 and CRP levels. These results seemed to demonstrate that the sustained-release formulation based on GMO could be well-tolerated after intraarticular injection. Moreover, it could have the potential to prevent inflammatory conditions while sustaining drug activity locally over weeks.

Polymorphisms for ghrelin with consequences on satiety and metabolic alterations.

Purpose of review To understand the current trend of ghrelin genetic variations on the control of satiety, eating behaviours, obesity, and metabolic alterations, and its development over the last 18 months. Recent findings Several polymorphisms of the ghrelin gene, its receptor gene and ghrelins acylating enzyme, ghrelin O-acyl transferase, have been identified and studied over the last decade in relation to control of satiety, obesity, eating behaviours, metabolic syndrome, glucose homeostasis, and type 2 diabetes. However, the effects described are either small or nonsignificant and often subjected to contradictory conclusions between studies. In the last 18 months, several of these areas of investigations have been revisited under more controlled conditions or have been subjected to meta-analysis. Summary The effects of ghrelin gene polymorphism, is a complex area of investigation, due to ghrelins interplay with a host of various factors part of an integrative network. However, taken together, results suggest that there are no or nonsignificant effects of the common genetic variants. A better understanding of the network, probably by a systems biology type approach, will be necessary to assign the exact role played by gene polymorphism of the component of the ghrelin axis.

Evaluating the implementation fidelity of New Medicines Service for asthma patients in community pharmacies in Belgium

Background: In October 2013, a New Medicines Service (NMS) was introduced in community pharmacies in Belgium to support asthma patients who are novice users of inhaler devices with corticosteroids. The protocol‐based intervention used the Asthma Control Test (ACT) and the Medication Adherence Report Scale (MARS) to assess asthma control and medication adherence. The NMS is the first initiative that puts advanced pharmaceutical care into practice in Belgium. The present study evaluated the degree to which the NMS program is delivered as intended, drawing on the concept of implementation fidelity (IF). Methods: The main dimensions of IF and potential moderating and facilitating factors for the implementation of NMS in community pharmacies were evaluated using telephone interviews with pharmacists (n = 497), semi‐structured interviews with patients eligible for NMS (n = 30), focus groups among general practitioners (n = 72) and lung specialists (n = 5), and a work system analysis in community pharmacies (n = 19). Results: The uptake of NMS in Belgian community pharmacies remains low. In addition to practical barriers, pharmacists found it difficult to identify new asthmatic patients when they were not informed about the diagnosis. A lack of commitment from physicians, patients and pharmacists was noted in the early start‐up phase of the program. Many pharmacists did not see how NMS differed from existing pharmaceutical care. Physicians considered this service as part of their own tasks and discouraged ACT for asthma follow‐up in the community pharmacy. Conclusions: The introduction of the NMS program was not sufficiently embedded in the Belgian health care organization, causing low uptake and resistance to its implementation by pharmacists, patients, and other health care professionals. To increase the uptake of this type of service and its possible extension to other patient groups, more collaboration among the different health care professionals during design and implementation is necessary, as well as systematic data collection to monitor the quality of the service, better training of pharmacists, and more information for patients and physicians.

Assessment of medication adherence and responsible use of isotretinoin and contraception through Belgian community pharmacies by using pharmacy refill data

Purpose The aims of the study were to evaluate medication adherence and the influencing factors for isotretinoin and contraception (oral, patches, and rings) and to evaluate the concomitant use of contraception and isotretinoin. Methods Reimbursed prescription data from January 2012 to August 2015 of all patients in Belgium were received from Pharmanet–National Institute for Health and Disability Insurance. Medication adherence was measured according to the medication possession ratio. The influence of gender and age was analyzed using the Mann–Whitney test and the Spearman coefficient correlation. The independence between adherence to contraception and adherence to isotretinoin was analyzed using the Pearson chi-square test of independence. Persistence was defined as the number of days between initiation and presumed end of treatment. The Kaplan–Meier method was used to plot the medication persistence curves, and the log-rank test was used to compare the curves. The concomitant use of contraception and isotretinoin was analyzed using descriptive statistics. Results The medication possession ratio was ≥0.8 for 46.1% of patients receiving isotretinoin and for 74.0% of women using contraception. For isotretinoin, this percentage decreased as the number of attempts increased (29.8% for the second attempt and 19.8% for more than two attempts). Men seemed more adherent than women, and a weak negative correlation between adherence and age was observed. The adherence data of isotretinoin and contraception were independent. The median persistence for isotretinoin treatment was 139 days (interquartile range 71–209) and was higher for men. Among women between 12 and 21 years old taking isotretinoin, 63.8% received at least one contraceptive prescription. However, 15.7% of women taking isotretinoin adhered to the use of contraception 1 month before, during, and 1 month after treatment. Conclusion Medication adherence to isotretinoin and contraception and compliance with the isotretinoin safety recommendation could be improved. Health service interventions, using pharmacy refill data, should be delivered to ensure patient safety and strict adherence to contraception when under isotretinoin treatment.