Useful Role of a New Generation of Dexamethasone, Vitamin E and Human Serum Albumin Microparticles in the Prevention of Excitotoxicity Injury in Retinal Ocular Diseases.

Excitotoxicity has been linked to the pathogenesis of several serious degenerative ocular diseases. Long-term overactivation of the NMDA receptor by glutamate in retinal ganglion cells (RGCs) results in degeneration, apoptosis and loss of function leading to blindness. NMDA receptor antagonists have been proposed as a pharmacological blockage of glutamate excitotoxicity. However, an inhibition of the pathway activated by glutamate receptors has intolerable side effects. An interesting pharmacological alternative would be the use of antiapoptotic compounds as RGCs' neuroprotective active substances. Several mechanisms have been proposed to explain neuroprotection, including anti-inflammatory and scavenging activities. Here, the role of dexamethasone in neuroprotection was studied. For this purpose, original controlled release systems composed of microparticles containing dexamethasone with or without vitamin E and human serum albumin (HSA) were designed. The particles were prepared by the solid-in-oil-in-water (S/O/W) emulsion-evaporation technique. After properly characterization of the particles, they were intravitreally injected into an rat model of acute ocular excitotoxicity injury. The functionality of the retina was determined by electroretinography and RGCs were counted after cell immunohistochemistry. These microparticulate systems showed the ability to maintain normal electroretinal activity and promoted significant protection of RGCs. Through this proof of concept, we demonstrated that dexamethasone could be a useful anti-inflammatory agent to avoid the progression of degenerative ocular diseases. Furthermore, when administered in controlled release systems that provide low concentrations during prolonged periods of time, not only can the patient's comfort be increased but the cytotoxicity of the drugs can also be avoided.

Retinal Cell Protection in Ocular Excitotoxicity Diseases. Possible Alternatives Offered by Microparticulate Drug Delivery Systems and Future Prospects.

Excitotoxicity seems to play a critical role in ocular neurodegeneration. Excess-glutamate-mediated retinal ganglion cells death is the principal cause of cell loss. Uncontrolled glutamate in the synapsis has significant implications in the pathogenesis of neurodegenerative disorders. The exploitation of various approaches of controlled release systems enhances the pharmacokinetic and pharmacodynamic activity of drugs. In particular, microparticles are secure, can maintain therapeutic drug concentrations in the eye for prolonged periods, and make intimate contact by improving drug bioavailability. According to the promising results reported, possible new investigations will focus intense attention on microparticulate formulations and can be expected to open the field to new alternatives for doctors, as currently required by patients.

A Reassessment of the Marrubium Vulgare L. Herb's Potential Role in Diabetes Mellitus Type 2: First Results Guide the Investigation toward New Horizons.

Despite the wide variety of pharmacological activities described for the Marrubium vulgare L. herb, amazingly, only one clinical trial can be found in scientific literature. It was designed for the evaluation of its antidiabetic activity. Worse, the outcomes of this trial were contradictory to what previous in vivo mice assays had concluded. Therefore, should Marrubium vulgare be ruled out due to its lack of therapeutic potential in diabetes? The authors suggest a reevaluation of the clinical trial methodology to establish valid and final results.

Solving the puzzle: What is behind our forefathers' anti-inflammatory remedies?

Inflammation is a ubiquitous host response in charge of restoring normal tissue structure and function but is a double-edged sword, as the uncontrolled or excessive process can lead to the injury of host cells, chronic inflammation, chronic diseases, and also neoplastic transformation. Throughout history, a wide range of species has been claimed to have anti-inflammatory effects worldwide. Among them, Angelica sinensis, Tropaeolum majus, Castilleja tenuiflora, Biophytum umbraculum, to name just a few, have attracted the scientific and general public attention in the last years. Efforts have been made to assess their relevance through a scientific method. However, inflammation is a complex interdependent process, and phytomedicines are complex mixtures of compounds with multiple mechanisms of biological actions, which restricts systematic explanation. For this purpose, the omics techniques could prove extremely useful. They provide tools for interpreting and integrating results from both the classical medical tradition and modern science. As a result, the concept of network pharmacology applied to phytomedicines emerged. All of this is a step toward personalized therapy.

Experimental and Clinical Pharmacology of Ziziphus jujuba Mills.

Ziziphus jujuba Mills, 'annab' in Iran, 'ber' in India or 'pomme sourette' in France, is a species whose fruit (known warmly as 'the fruits of life' in China) has been consumed for centuries for its nutritional value. The food industry used it as a food additive and flavoring. The dry seeds, the crude leaves and the stem bark are still used in ethnopharmacology to treat digestive disorders and gastric ulcers as antitussive, laxative and hypotensive drugs; even now, it is used in China to treat children who suffer from typhoid fever, furuncle and ecthyma. In Taiwan, the dry seeds for the variety spinosa (Suan Zao Ren) are the second most commonly prescribed and used phytomedicine for insomnia. Its popularity and production have increased worldwide in recent years, especially in Europe. The European Pharmacopoeia Commission has been unable to elaborate upon the EP monograph on Ziziphi spinosae semen as was planned. The EMA has not made its recommendations yet. Is it still a gap in the scientific knowledge? Or is difficult for traditional Chinese medicinal herbs to fulfill the style and quality parameters that are required? Copyright © 2017 John Wiley & Sons, Ltd.

Pharmaceutical technology can turn a traditional drug, dexamethasone into a first-line ocular medicine. A global perspective and future trends.

Dexamethasone is one of the most prescribed glucocorticoids. It is effective and safe in the treatment of a wide variety of ocular conditions, including anterior and posterior segment inflammation. However, its half-life in the vitreous humor is very short, which means that it typically requires frequent administrations, thus reducing patient adherence and causing therapeutic failure. Innovative dexamethasone delivery systems have been designed in an attempt to achieve sustained release and targeting. The FDA has approved dexamethasone implants for the treatment of macular edema secondary to retinal vein occlusion and posterior segment noninfectious uveitis. Lenses, micro- and nanoparticles, liposomes, micelles and dendrimers are also proving to be adequate systems for maintaining optimal dexamethasone levels in the site of action. Pharmaceutical technology is turning a classical drug, dexamethasone, into a fashionable medicine.

Dendrimers as a promising tool in ocular therapeutics: Latest advances and perspectives.

Dendrimers have called the attention of scientists in the area of drug and gene delivery over the last two decades for their versatility, complexity and multibranching properties. Some strategies for optimizing drug pharmacokinetics and site-specific targeting using dendrimers have been proposed. Among them, those related to treating and managing ocular diseases are of special interest. Ocular therapies suffer from significant disadvantages, including frequent administration, poor penetration and/or rapid elimination. This review provides an overview of the recent and promising progress in the dendrimers field, focusing on both the anterior and posterior segments of the eye ocular targets, the use of dendrimers as a strategy for overcoming obstacles to the traditional treatment of ocular diseases and an outlook on future directions. Finally, a first approach to ocular safety with dendrimers is intended that accounts for the state-of-the-art science to date.

An Insight into a Blockbuster Phytomedicine; Marrubium vulgare L. Herb. More of a Myth than a Reality?

Aerial parts and the root of Marrubium vulgare L. (white horehound) have been traditionally used in Europe and in southern and eastern Mediterranean countries. During colonization, the plant was introduced in America to great levels of popularity because of the simplicity of its growing; it was especially popular in Mexico and Brazil, where it has been known as 'maromba', 'marroio' or 'marroio-branco'. Ethnopharmacological uses of M. vulgare include treating respiratory diseases such as acute or chronic bronchitis, colds and asthma. The plant is also used in cases where there is a lack of appetite or dyspepsia and for diagnosed type II diabetes. It has even been used for antihypertensive therapy. For decades, scientists have carried out extensive research trying to explain these and other pharmacologic actions. It is time to systematize and critically analyse the quality of results found to date. Copyright © 2016 John Wiley & Sons, Ltd.

Optimising the controlled release of dexamethasone from a new generation of PLGA-based microspheres intended for intravitreal administration.

Successful therapy for chronic diseases affecting the posterior segment of the eye requires sustained drug concentrations at the site of action for extended periods of time. To achieve this, it is necessary to use high systemic doses or frequent intraocular injections, both associated with serious adverse effects. In order to avoid these complications and improve patient's quality of life, an experimental study has been conducted on the preparation of a new generation of biodegradable poly(D,L-lactide-co-glycolide) (50:50) (PLGA) polymer microspheres (MSs) loaded with Dxm, vitamin E and/or human serum albumin (HSA). Particles were prepared according to a S/O/W encapsulation method and the 20-40µm fraction was selected. This narrow size distribution is suitable for minimally invasive intravitreal injection by small calibre needles. Characterisation of the MSs showed high Dxm loading and encapsulation efficiency (> 90%) without a strong interaction with the polymer matrix, as revealed by DSC analysis. MSs drug release studies indicated a small burst effect (lower than 5%) during the first five hours and subsequently, drug release was sustained for at least 30days, led by diffusion and erosion mechanisms. Dxm release rate was modulated when solid state HSA was incorporated into MSs formulation. SDS-PAGE analysis showed that the protein maintained its integrity during the encapsulation process, as well as for the release study. MSs presented good tolerance and lack of cytotoxicity in macrophages and HeLa cultured cells. After 12months of storage under standard refrigerated conditions (4±1°C), MSs retained appropriate physical and chemical properties and analogous drug release kinetics. Therefore, we conclude that these microspheres are promising pharmaceutical systems for intraocular administration, allowing controlled release of the drug.