Thermosensitive self-assembling block copolymers as drug delivery systems

Self-assembling block copolymers (poloxamers, PEG/PLA and PEG/PLGA diblock and triblock copolymers, PEG/polycaprolactone, polyether modified poly(Acrylic Acid)) with large solubility difference between hydrophilic and hydrophobic moieties have the property of forming temperature dependent micellar aggregates and, after a further temperature increase, of gellifying due to micelle aggregation or packing. This property enables drugs to be mixed in the sol state at room temperature then the solution can be injected into a target tissue, forming a gel depot in-situ at body temperature with the goal of providing drug release control. The presence of micellar structures that give rise to thermoreversible gels, characterized by low toxicity and mucomimetic properties, makes this delivery system capable of solubilizing water-insoluble or poorly soluble drugs and of protecting labile molecules such as proteins and peptide drugs

Evaluation of methoxy polyethylene glycol-polylactide diblock copolymers as additive in hypromellose film coating

This paper deals with a new application of diblock methoxy polyethylene glycol-polylactide block copolymers, a class of synthetic biomaterials largely studied in the pharmaceutical and biomedical fields owing to their favorable properties such as biocompatibility, biodegradability, low immunogenicity, and good mechanical properties. In this work, these materials were evaluated as additives for gastro-soluble pharmaceutical coating aimed to reduce film stiffness and water permeability. Two copolymers with different polylactide chain lengths were synthesized and characterized in term of molecular weight and solid-state properties. A series of free films with different hypromellose/copolymers ratio were prepared and characterized in terms of appearance, components miscibility, plasticity, and water vapor permeability. The obtained results demonstrate that copolymers effectively influence hypromellose film properties according to their concentration and molecular weight. Specifically, the addition of the copolymer with a molecular weight of 6.5kDa in a ratio hypromellose:polymer 5:1, allowed to obtain films with good appearance, improved plasticization, and water permeability properties. For higher molecular weight, copolymer or different ratios was not possible to observe the improvement of all the properties at the same time. The results also make possible to define the critical features to improve in order to use block copolymers as additive in hypromellose film coating. The availability of new water-soluble additives able to work as plasticizer and moisture sealer in polymeric films represents an important progress not only in the field of pharmaceutical coating but also in that of food coatings, as for example in the formulation of edible films

4WD to Travel Inside the 5-HT1A Receptor World

5-HT1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all “who” this receptor is, then “why” it continues to be a so attractive target after several years after its identification, then “where” is 5-HT1A receptor expressed within the body, and, finally, “what” effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective “drugs” might be discovered once the responses to these questions are given

Ibuprofen and Lipoic Acid Diamide as Co-Drug with Neuroprotective Activity: Pharmacological Properties and Effects in β-Amyloid (1–40) Infused Alzheimer's Disease Rat Model

Both oxidative stress and inflammation are elevated in brains of Alzheimer's disease patients, but their pathogenic significance still remains unclear. Current evidence support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease, and ibuprofen has the strongest epidemiological support. In the present work our attention was focused on (R)-α-lipoic acid considered as a potential neuroprotective agent in Alzheimer's disease therapy. In particular, we investigated a new co-drug (1) obtained by joining (R)-α-lipoic acid and ibuprofen via a diamide bond, for evaluating its potential to antagonize the deleterious structural and cognitive effects of β-amyloid (1–40) in an infused Alzheimer's disease rat model. Our results indicated that infusion of β-amyloid (1–40) impairs memory performance through a progressive cognitive deterioration; however, ibuprofen and co-drug 1 seemed to protect against behavioural detriment induced by simultaneous administration of β-amyloid (1–40) protein. The obtained data were supported by the histochemical findings of the present study: β-amyloid protein was less expressed in 1-treated than in ibuprofen and (R)-α-lipoic acid alone-treated cerebral cortex. Taken together, the present findings suggest that co-drug 1 treatment may protect against the cognitive dysfunction induced by intracerebroventricular infusion of β-amyloid (1–40) in rats. Thus, co-drug 1 could prove useful as a tool for controlling Alzheimer's disease-induced cerebral amyloid deposits and behavioural deterioration

Assessing the role of ghrelin and the enzyme ghrelin O-acyltransferase (GOAT) system in food reward, food motivation, and binge eating behavior.

Abstract The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin's functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic–pituitary–adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors

Investigating the role of the central melanocortin system in stress and stress-related disorders

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress

Design, synthesis and preliminary pharmacological evaluation of new imidazolinonesas L-DOPA prodrugs

L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson's disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of L-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release L-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a-b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a-b and 15a are also reported

Highly Potent and Selective Dopamine D4 Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma

To better understand the role of dopamine D-4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R within the series (D-2/D-4 = 8318, D-3/D-4 = 3715), and the biased ligand 29, partially activating D4R G(i)-/G(o)-protein and blocking beta-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 mu M. Interestingly, the treatment with both compounds 24 and 29 induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM