An Overview of Biosimilars-Development, Quality, Regulatory Issues, and Management in Healthcare.

Biological therapies have transformed high-burden treatments. As the patent and exclusivity period for biological medicines draws to a close, there is a possibility for the development and authorization of biosimilars. These products boast comparable levels of safety, quality, and effectiveness to their precursor reference products. Biosimilars, although similar to reference products, are not identical copies and should not be considered generic substitutes for the original. Their development and evaluation involve a rigorous step-by-step process that includes analytical, functional, and nonclinical evaluations and clinical trials. Clinical studies conducted for biosimilars aim to establish similar efficacy, safety, and immunogenicity, rather than demonstrating a clinical benefit, as with the reference product. However, although the current knowledge regarding biosimilars has significantly increased, several controversies and misconceptions still exist regarding their immunogenicity, extrapolation, interchangeability, substitution, and nomenclature. The development of biosimilars stimulates market competition, contributes toward healthcare sustainability, and allows for greater patient access. However, maximizing the benefits of biosimilars requires cooperation between regulators and developers to ensure that patients can benefit quickly from access to these new therapeutic alternatives while maintaining high standards of quality, safety, and efficacy. Recognizing the inherent complexities of comprehending biosimilars fully, it is essential to focus on realistic approaches, such as fostering open communication between healthcare providers and patients, encouraging informed decision-making, and minimizing risks. This review addresses the regulatory and manufacturing requirements for biosimilars and provides clinicians with relevant insights for informed prescribing.

Nanoclays for wound management applications.

Nanotechnology has been comprehensively applied as a new approach to managing wound healing. Particularly, nanoclays are being used to improve traditional wound healing approaches or new therapies. Nanoclays are nanoscale aluminosilicates with remarkable intrinsic properties, including the capacity to promote hemostatic response, anti-inflammatory effects, angiogenesis, and re-epithelization. The main purpose of the present review is focusing on skin lesions, post-surgical wounds, burn wounds, and chronic ulcer skin wounds that can be treated using nanoclays, not only as vehicles for therapeutic molecules' efficacy improvement but also alone due to their native beneficial features. A systematic search of the PubMed, ScienceDirect, Scopus, Web of Science, and Google Scholar databases revealed several studies satisfying the purpose of our study. In addition, the selected keywords were used to refine the information. Non-planar hydrous phyllosilicates have been compared with other nanoclays considering their acute specific surface area and loading capacity are strongly influenced by their structure. Nanocomposites in the powder form may be directly incorporated in polymers to form gels, biofilms, and scaffolds that may be adjustable to wound sites. Also, nanoclays can be directly incorporated into polymer mats. Regarding hydrogels/films and mats, nanoclays can improve their mechanical strength, thermal stability, viscosity, and cohesive strength. Additionally, nanoclays are able to control drug release, as well as their skin bioavailability, and seem to be promising candidates to overcome cytotoxicity problems; further in vivo toxicity studies are required.

Application of nanotechnology in management and treatment of diabetic wounds.

Diabetic wounds are one of the most common health problems worldwide, enhancing the demand for new management strategies. Nanotechnology, as a developing subject in diabetic wound healing, is proving to be a promising and effective tool in treatment and care. It is, therefore, necessary to ascertain the available and distinct nanosystems and evaluate their performance when topically applied to the injury site, especially in diabetic wound healing. Several active ingredients, including bioactive ingredients, growth factors, mesenchymal stem cells, nucleic acids, and drugs, benefit from improved properties when loaded into nanosystems. Given the risk of problems associated with systemic administration, the topical application should be considered, provided stability and efficacy are assured. After nanoencapsulation, active ingredients-loaded nanosystems have been showing remarkable features of biocompatibility, healing process hastening, angiogenesis, and extracellular matrix compounds synthesis stimulation, contributing to a decrease in wound inflammation. Despite limitations, nanotechnology has attracted widespread attention in the scientific community and seems to be a valuable technological ally in the treatment and dressing of diabetic wounds. The use of nanotechnology in topical applications enables efficient delivery of the active ingredients to the specific skin site, increasing their bioavailability, stability, and half-life time, without compromising their safety.

Nanocarriers for the topical treatment of psoriasis - pathophysiology, conventional treatments, nanotechnology, regulatory and toxicology.

Psoriasis is a chronic inflammatory non-contagious disease normally characterized by a multisystemic inflammation with reddish plaques and whitish scales with greater incidence in the knees, feet and hands, elbow, scalp, and sacral areas. The global incidence of psoriasis rounds about 2% of the population and it is established that the pathophysiology of this skin disease is quite complex and still misunderstood. Nowadays, this pathology still has no cure, however, efforts are being made to find more effective and safe treatments as well as trying to decrease the occurrence of crises and complications. Nanotechnology is increasingly becoming an innovating and promising new approach for the study of various dermatological diseases, such as psoriasis. In this case, the interest in the use of nanocarriers arises in order to decrease the side effects associated with conventional therapy, as well as improve its effectiveness. Nanotechnology allows for better solubility and better delivery of the drugs, as well as an increase in their tolerance. Besides psoriasis pathophysiology and its conventional treatments, this manuscript will also be present and discusse nanotechnological strategies for topical application that intend to increase the effectiveness of treatment, as well as its regulatory and toxicological context. Regulatory issues as well as nanotoxicological concerns and long-term safeness, both for the user and for the environment will be discussed.

Dispositivos intraorais no tratamento da apneia obstrutiva do sono em pacientes desdentados: uma revisão sistematizada de literatura / Intraoral devices in the treatment of obstructive sleep apnea in edentulous patients: a systematized literature review

Objetivo: elucidar aspectos envolvidos no uso dos dispositivos intraorais para apneia obstrutiva do sono em indivíduos desdentados totais, como a eficácia dos dispositivos, o conforto e retenção/estabilidade. Metodologia: essa revisão seguiu o checklist do PRISMA, no qual foram incluídos estudos clínicos em inglês, sem restrição de tempo, em que foram utilizados dispositivos para apneia obstrutiva do sono em pacientes desdentados bimaxilares. As buscas foram realizadas nas bases de dados PubMed / MEDLINE, Cochrane e SCOPUS até março de 2021. Resultados: Após as diferentes etapas do processo de seleção dos artigos, foram selecionados 6 estudos para esta revisão, sendo 5 relatos de caso e 1 ensaio clínico. Os estudos relataram uma redução no índice apneia-hipopneia. Em três estudos houve redução expressiva, proporcionando a redução no grau de apneia, de severa para moderada e moderada para leve. A protrusão alcançada com os dispositivos foi adequada para o efeito desejado, em todos os dispositivos. Os estudos não reportam deslocamento do dispositivo e apenas um relata desconforto temporário. Conclusão: Os dispositivos intraorais foram eficazes no tratamento da apneia obstrutiva do sono em pacientes desdentados e os usuários não tiveram queixas quanto ao conforto e estáveis... (AU)

Objective: to elucidate aspects involved in the use of intraoral devices for obstructive sleep apnea in complete edentulous patients, such as the effectiveness of these devices, comfort and retention/stability. Methodology: this review followed the PRISMA checklist, included clinical studies in English, without publication restrictions, in which intraoral devices were used for obstructive sleep apnea in edentulous bimaxillary patients. The search was carried out in PubMed/MEDLINE, Cochrane and SCOPUS databases, until March 2021. Results: After the different stages of the article selection process, 6 studies were selected for this review, 5 case reports and 1 clinical trial. The studies reported a reduction in the apnea-hypopnea index. In three studies there was a significant reduction in the degree of apnea, from severe to moderate and moderate to mild. The protrusion achieved with the devices was adequate for the desired effect, in all devices. Studies did not report displacement of the device and only one reports temporary discomfort. Conclusion: Intraoral devices were effective in treating obstructive sleep apnea in edentulous patients and users had no complaints about comfort and stability... (AU)

Existe relação entre doenças respiratórias e próteses dentárias removíveis contaminadas? Uma revisão sistematizada da literatura / Relationship between respiratory diseases and contaminated removable dental prostheses

Objetivo: O objetivo dessa revisão sistematizada da literatura foi analisar a associação entre o uso de próteses dentárias removíveis e doenças respiratórias prevalentes. Materiais e métodos: Este estudo foi conduzido seguindo os critérios do PRISMA check-list (Preferred Reporting Items for Systematic Review and Meta-Analysis). A base de dados eletrônica selecionada foi a PubMed/MEDLINE, sem restrições do ano de publicação. Estudos prospectivos e retrospectivos (ensaios clínicos randomizados, ensaios clínicos controlados, estudos de coorte, estudos caso-controle e estudos transversais), estudos in vitro e publicados em inglês foram escolhidos como critérios de elegibilidade. Resultados: A busca inicial na base de dados obteve 553 artigos e 8 deles foram selecionados baseados nos critérios de elegibilidade e subdivididos em dois tópicos: doença pulmonar obstrutiva crônica e pneumonia por aspiração. Conclusão: Com base nos estudos avaliados existe associação entre as próteses dentárias removíveis contaminadas e doenças respiratórias... (AU)

Objective: The purpose of this review was to analyze the association between the use of removable dental prostheses and the prevalence of respiratory diseases. Methodology: This study was conducted following the criteria of PRISMA check-list (Preferred Reporting Items for Systematic Review and Meta-Analysis). The database selected was PubMed/MEDLINE, with no restrictions on the year of publication. Prospective and retrospective studies (randomized clinical trials, controlled clinical trials, cohort studies, case-control studies and cross-sectional studies), in vitro studies and published in English were selected in tehe eligibility criteria. Results: The search in the database obtained 553 articles and 8 of them were selected based on the eligibility criteria and subdivided into two topics: chronic obstructive pulmonary disease and aspiration pneumonia. Conclusion: Based on the studies evaluated, there is an association between contaminated removable dental prostheses and respiratory diseases... (AU)

Infecção cervical complicada com mediastinite descendente necrosante: análise de 25 casos / Descending necrotizing mediastinitis: analysis of 25 cases

As infecções cervicais profundas são afecções de origembacteriana que acometem os espaços cervicais profundos.Apesar de sua ocorrência pouco comum, constituem quadrosgraves que, se não forem tratados pronta e adequadamente,podem determinar a morte. Essas infecções podem apresentaruma evolução rápida para uma complicação muito temível,a mediastinite descendente necrosante, associada com umaalta morbidade e mortalidade. Apresentamos uma série de 47casos de mediastinite descendente necrosante tratados pelaDisciplina de Cirurgia de Cabeça e Pescoço da Irmandade daSanta Casa de Misericórdia de São Paulo no período de 1997 a2010. A toracotomia esteve associada a uma melhor sobrevidados doentes onde 68% sobreviveram à infecção (p=0,024). Apneumonia e a insuficiência respiratória estiveram associadas amaior letalidade da mediastinite.

The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain.

BACKGROUND AND PURPOSE: In adults, neurogenesis persists in the hippocampus and the subventricular zone (SVZ), and this is important for learning and memory. Inhibitors of COX-2 suppress ischaemia-induced neurogenesis in the hippocampus. Here, we have determined the effects of COX-2 inhibitors on neurogenesis throughout the normal adult mouse brain. EXPERIMENTAL APPROACH: Young adult mice were treated with COX-2 inhibitors, and the proliferation of neural progenitor cells was measured in the SVZ and hippocampus. In addition, the local uptake of lentiviral vectors in the rostral migratory stream enabled the formation of new neurons in the olfactory bulb (OB) to be assessed. KEY RESULTS: The COX-2 inhibitor meloxicam suppressed progenitor cell proliferation in the SVZ and hippocampus. A significant decrease in the appearance of new neurons in the OB was also observed. Similar effects on progenitor proliferation in the SVZ were seen with nimesulide. The absence of COX-2 expression in the proliferating progenitors in vivo, and the lack of effect of the COX-2 inhibitors on the growth rate of a cultured progenitor cell line, suggest that the effect is indirect. The specific expression of COX-2 in resting microglia that closely associate with the proliferating progenitor cells provides for a possible site of action. CONCLUSIONS AND IMPLICATIONS: Treatment with a COX-2 inhibitor results in a substantial inhibition of adult neurogenesis. Studies on human tissues are warranted in order to determine if this effect extends to humans, and whether inhibition of neurogenesis should be considered as an adverse effect of these drugs.

Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.

Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.

Sequential RARbeta and alpha signalling in vivo can induce adult forebrain neural progenitor cells to differentiate into neurons through Shh and FGF signalling pathways.

We show here the role of retinoic acid receptor (RAR) beta and alpha signalling in proliferation and differentiation of endogenous adult forebrain neural progenitor cells (NPCs). RARbeta activation stimulates Sonic hedgehog signalling (Shh), and induces the proliferation of the NPCs. They can be induced to become Doublecortin (DCX) expressing migrating neuroblasts by RARalpha signalling, some of which differentiate into cholinergic neurons. The same signalling pathways cause the proliferation of embryonic forebrain NPCs. These cells express glial fibrillary acidic protein (GFAP) and are predominantly uni/bipolar, two characteristics of neuronal progenitor cells. We further show that fibroblast growth factor (FGF) signalling, induces the expression of the retinoic acid degrading enzyme cytochrome P450 (cyp) 26a1, and that one of its products, 4-oxo-RA, mimics the action of the RARalpha agonist in the differentiation of the NPCs into cholinergic neurons.

A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner.

The subventricular zone (SVZ) is a major site of neurogenesis in the adult. We now show that ependymal and proliferating cells in the adult mouse SVZ express diacylglycerol lipases (DAGLs), enzymes that synthesise a CB1/CB2 cannabinoid receptor ligand. DAGL and CB2 antagonists inhibit the proliferation of cultured neural stem cells, and the proliferation of progenitor cells in young animals. Furthermore, CB2 agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals. A similar response was seen with a fatty acid amide hydrolase (FAAH) inhibitor that limits degradation of endocannabinoids. The effects on proliferation were mirrored in changes in the number of neuroblasts migrating from the SVZ to the olfactory bulb (OB). In this context, CB2 antagonists reduced the number of newborn neurons appearing in the OB in the young adult animals while CB2 agonists stimulated this in older animals. These data identify CB2 receptor agonists and FAAH inhibitors as agents that can counteract the naturally observed decline in adult neurogenesis that is associated with ageing.

Desempenho de novilhos de corte em pastagem nativa com níveis de suplementação de farelo de arroz integral / Beef steers performance in natural pasture with levels of full fat rice brain supplementation

Este trabalho teve por objetivo avaliar o desempenho de novilhos de corte em pastagem nativa (PN), suplementados com níveis de farelo de arroz integral (FAI) de 0; 0,5; 1,0 e 1,5 por cento do peso vivo dos animais, num delineamento inteiramente casualizado em parcelas subdivididas, durante 126 dias. Na parcela principal, foram alocados os níveis de suplemento e, nas subparcelas, os períodos de tempo (6 períodos de 21 dias). A suplementação foi oferecida de forma individual, duas vezes por dia, às 7h e às 15h:30min. O método de pastejo empregado foi o contínuo com lotação fixa e carga variável. As médias encontradas para proteína bruta foram de 6,8 e 14,9 por cento, e para os coeficientes de digestibilidade "in vitro" da matéria orgânica, foram de 59,54 e 71,47 por cento na PN e no FAI, respectivamente (dados expressos na matéria seca). Os ganhos médios diários dos animais foram de 0,35; 0,55; 0,53; e 0,63kg animal-1 dia-1 para os níveis de inclusão de farelo de arroz de 0; 0,5; 1,0 e 1,5 por cento do peso vivo dos animais, diferindo entre animais suplementados e não-suplementados. Os resultados de rendimento e peso de carcaça fria dos animais não diferiram entre os tratamentos. A suplementação com FAI nos níveis entre 0,5 a 1,5 por cento proporcionou incremento no ganho médio diário de aproximadamente 60 por cento, quando comparado com os animais que não receberam suplemento.

This study was aimed at investigating steers performance on native pasture supplemented with levels of full fat rice bran: 0; 0.5; 1.0 and 1.5 percent of body weight of the animals, in a completely randomized design, with a split plot arrangement, during 126 days. In main plots were allocated the levels of supplement and in a split plot, the periods of time (6 periods of 21 days each). The supplementation was individual, offered twice a day, at 7am and 3.3pm. The system of pasture was continuous grazing with fix stocking density and variable stocking rate. The average percent of crude protein were 6.8 percent and 14.9 percent and the in vitro digestibility coefficients were 59.54 percent and 71.47 percent in native pasture and rice bran, respectively (in the dry matter). The live weight gains of the animals were 0.35; 0.55; 0.53 and 0.63kg d-1 with the rice bran daily inclusion of 0.0; 0.5; 1.0 and 1.5 percent of the animals live weigh differing only when it was considered the use or not use of the supplement. The carcass yield and weigh do not differ among the treatments. The supplementation with full fat rice bran in the levels between 0.5 percent and 1.5 percent of live weight proportioned an increase on the live weigh gain of approximately 60 percent when compared with the animals that did not receive supplement.

Timing of the retinoid-signalling pathway determines the expression of neuronal markers in neural progenitor cells.

By culturing neural progenitor cells in the presence of retinoid receptor agonists, we have defined the components of the retinoid-signalling pathway that are important for the birth and maintenance of neuronal cells. We provide evidence that depending on the order and combination of retinoid receptors activated, different neuronal cells are obtained. Astrocytes and oligodendrocytes are predominantly formed in the presence of activated retinoic acid receptor (RAR) alpha, whereas motoneurons are formed when RARbeta is activated. We have looked at the regulation of two transcription factors islet-1/2 which are involved in neuronal development. We find that activated RARbeta up-regulates islet-1 expression, whereas activation of RARalpha can either act in combination with RARbeta signalling to maintain islet-1 expression or induce islet-2 expression in the absence of activated RARbeta. RARgamma cannot directly regulate islet-1/2 but can down-regulate RARbeta expression, which results in loss of islet-1 expression. We finally show that activated RARalpha is one of the final steps required for a mature motoneuron phenotype.