Ground Calcium Carbonate as a Low Cost and Biosafety Excipient for Solubility and Dissolution Improvement of Praziquantel

Calcium carbonate is an abundant mineral with several advantages to be a successful carrier to improve oral bioavailability of poorly water-soluble drugs, such as praziquantel. Praziquantel is an antiparasitic drug classified in group II of the Biopharmaceutical Classification System hence characterized by high-permeability and low-solubility. Therefore, the dissolution rate is the limiting factor for the gastrointestinal absorption that contributes to the low bioavailability. Consequently, the therapeutic dose of the praziquantel must be high and big tablets and capsules are required, which are difficult to swallow, especially for pediatric and elderly patients. Mixtures of praziquantel and calcium carbonate using solid-solid physical mixtures and solid dispersions were prepared and characterized using several techniques (X-ray diffraction differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, laser diffraction, Fourier transform infrared and Raman spectroscopies). Solubility of these formulations evidenced that the solubility of praziquantel-calcium carbonate interaction product increased in physiological media. In vitro dissolution tests showed that the interaction product increased the dissolution rate of the drug in acidic medium. Theoretical models were studied to understand this experimental behavior. Cytotoxicity and cell cycle studies were performed, showing that praziquantel-calcium carbonate physical mixture and interaction product were biocompatible with the HTC116 cells, because it did not produce a decrease in cell viability or alterations in the cell cycle.We also acknowledge for financial support the MINECO, for projects FIS2016-77692-C2-2-P and CGL2016-80833-R, and the Andalusian government, for project RNM1897

The Preclinical discovery and development of opicapone for the treatment of Parkinson's Disease

Introduction: Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson's disease (PD) associated with L-DOPA / L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favours more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. Areas covered: This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data were extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000-2019). Clinical and post-marketing data were also evaluated. Expert opinion: OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Abbreviations: 3-OMD, 3-O-methyldopa; 6-OHDA, 6-hydroxydopamine; BG, basal ganglia; COMT, Catechol-O-methyltransferase; DDI, decarboxylase inhibitors; ENT, Entacapone; FDA, Food and Drug Administration; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OPC, Opicapone; PD, Parkinson's disease; TOL, Tolcapone; GDNF, Glial cell-line-derived neurotrophic factor; NTN, neurturin; ICV, Intracerebroventricular; PDUFA, Prescription Drug User Fees Act; EMA, European Medicine Administration; AE, Adverse event BG, Basal ganglia. QD, once a day

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer's Disease Dementia

Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the 'peripheral' symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors

A metabolic perspective of late onset Alzheimer's disease

After decades of research, the molecular neuropathology of Alzheimer's disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid β (Aβ) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aβ oligomers as mere aggravators, with an arguable role in the origin of the disease. In this line of research, the relative contribution of soluble Aβ oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aβ production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment. The present review summarizes the current understanding on the neuropathological role of Aβ associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD). Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia.

Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile

High Dispersivity Bacterial Cellulose/Carbon Nanotube Nanocomposite for Sensor Applications

Bacterial cellulose (BC) has established to be a remarkably versatile biomaterial and can be used in wide variety of applied scientific endeavors, especially for medical devices. In fact, biomedical devices recently have gained a significant amount of attention because of increased interesting tissue-engineered products for both wound care and the regeneration of damaged or diseased organs. The architecture of BC materials can be engineered over length scales ranging from nano to macro by controlling the biofabrication process, besides, surface modifications bring a vital role in in vivo performance of biomaterials. In this work, bacterial cellulose fermentation was modified with carbon nanotubes for sensor applications and diseases diagnostic. SEM images showed that polymer modified-carbon nanotube (PVOH-carbon nanotube) produced well dispersed system and without agglomeration. Influences of carbon nanotube in bacterial cellulose were analyzed by FTIR. TGA showed higher thermal properties of developed bionanocomposites

Nanoderm Extracellular Matrix for Reconstructive Surgery Applications

Introduction: Bacterial cellulose (BC) can be used in wide area of applied scientific, especially for tissue regeneration and regenerative medicine, lately, bacterial cellulose mats are used in the treatment of skin conditions such as burns and ulcers, because of the morphology of fibrous biopolymers serving as a support for cell proliferation, its pores allow gas exchange between the organism and the environment. Moreover, the nanostructure and morphological similarities with collagen make BC attractive for cell immobilization, cell support and Natural Extracellular Matrix (ECM) Scaffolds. In this scope, Natural ECM is the ideal biological scaffold since it contains all the components of the tissue.The development of mimicking biomaterials and hybrid biomaterial can further advance directed cellular differentiation without specific induction.&nbsp;Methods: The acetic fermentation process was achieved by using glucose as a carbohydrate source. Results of this process are vinegar and a nanobiocellulose biomass. The modifying process is based on the addition of hyaluronic acid and chondroitin sulfate (1% w/w) to the culture medium before the bacteria is inoculated. After, vegetal stem cells were added in the system, which were chosen because has wound healing properties that help new skin formation. (Casearia Sylvestris).Result: Bacterial cellulose (Nanoskin®) was successfully modified by changing the fermentation medium as shown by FTIR and TGA, which produced necessary materials for regenerative medicine. Nanoskin Natural extracellular matrix (ECMs) perform the tasks necessary for tissue formation,maintenance, regulation and function, providing a powerful means of controlling the biological performance of regenerative materials.Conclusion: Nanoderm® Natural extracellular matrix (ECMs) perform the tasks necessary for tissue formation, maintenance, regulation and function, providing a powerful means of controlling the biological performance of regenerative materials. Understanding how cells interact with these to assemble their own ECM and how the scaffolds can be used to control delivery of signals in a temporal and spatial manner to guide or maintain cell differentiations need future investigation. But,undoubtedly, natural-origin polymers or nature-inspired materials appear as the natural and desired choice for medical applications.</p

Gabriel Molina de Olyveira Novel Natural Transdermal Otoliths/Collagen/Bacterial Cellulose Patch for Osteoporosis Treatment

In the present work, we report the novel natural transdermal otoliths/collagen/bacterial cellulose patch for osteoporosis treatment. This biomaterial is an osteoinductor, or be, stimulates the bone regeneration, enabling bigger migration of the cells for formation of the bone fabric. Otolith is a typical biomaterial that is composed of calcium carbonate and organic matrix. Otoliths are calcareous concrescences present in the inner ear of fishes. Since they are rich in minerals, they are considered essential to the bone mineralization process on a protein matrix (otolin). The objective in this study was to analyze the regeneration capacity of bone defects treated with otoliths network preparation. Collagen and nano-otoliths influences in bacterial cellulose was analyzed using transmission infrared spectroscopy (FTIR). In vivo analysis shows bone surface tissue with high regularity, higher osteoblast activity, and osteo-reabsorption activities areas. These results indicated that the transdermal permeation of otollith using this patch system was sufficient for the treatment of bone diseases. These findings indicate that our novel transdermal delivery system for otolith/collagen/bacterial cellulose is a promising approach to improve compliance and quality of life of patients in the treatment of bone diseases

Bionanocomposites from electrospun PVA/pineapple nanofibers/Stryphnodendron adstringens bark extract for medical applications

Tissue engineering has been defined as an interdisciplinary field that applies the principles of engineering and life sciences for the development of biological substitutes to restore, maintain or improve tissue function. This area is always looking for new classes of degradable biopolymers that are biocompatible and whose activities are controllable and specific, more likely to be used as cell scaffolds, or in vitro tissue reconstruction. In this paper, we developed a novel bionanocomposite with homogeneous porous distribution and prospective natural antimicrobial properties by electrospinning technique using Stryphodedron barbatimao extract (Barbatimão). SEM images showed equally distribution of nanofibres. DSC and TGA showed higher thermal properties and change crystallinity of the developed bionanocomposite mainly because these structural modification. © 2012 Elsevier B.V