New thermoresistant polymorph from CO2 recrystallization of minocycline hydrochloride.

PURPOSE: To prepare and thoroughly characterize a new polymorph of the broad-spectrum antibiotic minocycline from its hydrochloride dehydrate salts. METHODS: The new minocycline hydrochloride polymorph was prepared by means of the antisolvent effect caused by carbon dioxide. Minocycline recrystallized as a red crystalline hydrochloride salt, starting from solutions or suspensions containing CO2 and ethanol under defined conditions of temperature, pressure and composition. RESULTS: This novel polymorph (ß-minocycline) revealed characteristic PXRD and FTIR patterns and a high melting point (of 247 ºC) compared to the initial minocycline hydrochloride hydrates (α-minocycline). Upon dissolution the new polymorph showed full anti-microbial activity. Solid-state NMR and DSC studies evidenced the higher chemical stability and crystalline homogeneity of ß-minocycline compared to the commercial chlorohydrate powders. Molecular structures of both minocyclines present relevant differences as shown by multinuclear solid-state NMR. CONCLUSIONS: This work describes a new crystalline structure of minocycline and evidences the ability of ethanol-CO2 system in removing water molecules from the crystalline structure of this API, at modest pressure, temperature and relatively short time (2 h), while controlling the crystal habit. This process has therefore the potential to become a consistent alternative towards the control of the solid form of APIs.

Triterpenes as Potential Drug Candidates for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation, swelling and pain. Although RA mainly affects the joints, the disease can also have systemic implications. The presence of autoantibodies, such as anti-cyclic citrullinated peptide antibodies and rheumatoid factors, is a hallmark of the disease. RA is a significant cause of disability worldwide associated with advancing age, genetic predisposition, infectious agents, obesity and smoking, among other risk factors. Currently, RA treatment depends on anti-inflammatory and disease-modifying anti-rheumatic drugs intended to reduce joint inflammation and chronic pain, preventing or slowing down joint damage and disease progression. However, these drugs are associated with severe side effects upon long-term use, including immunosuppression and development of opportunistic infections. Natural products, namely triterpenes with anti-inflammatory properties, have shown relevant anti-arthritic activity in several animal models of RA without undesirable side effects. Therefore, this review covers the recent studies (2017-2022) on triterpenes as safe and promising drug candidates for the treatment of RA. These bioactive compounds were able to produce a reduction in several RA activity indices and immunological markers. Celastrol, betulinic acid, nimbolide and some ginsenosides stand out as the most relevant drug candidates for RA treatment.

Triterpenes Drug Delivery Systems, a Modern Approach for Arthritis Targeted Therapy.

Arthritis is a major cause of disability. Currently available anti-arthritic drugs, such as disease-modifying anti-rheumatic drugs (DMARDs), have serious side-effects associated with long-term use. Triterpenoids are natural products with known anti-inflammatory properties, and many have revealed efficiency against arthritis both in vitro and in vivo in several animal models, with negligible cytotoxicity. However, poor bioavailability due to low water solubility and extensive metabolism upon oral administration hinder the therapeutic use of anti-arthritic triterpenoids. Therefore, drug delivery systems (DDSs) able to improve the pharmacokinetic profile of triterpenoids and achieve sustained drug release are useful alternatives for targeted delivery in arthritis treatment. Several DDSs have been described in the literature for triterpenoid delivery, including microparticulate and nanoparticulate DDSs, such as polymeric micro and nanoparticles (NPs), polymeric micelles, liposomes, micro and nanoemulsions, and hydrogels. These systems have shown superior therapeutic effects in arthritis compared to the free drugs and are similar to currently available anti-arthritic drugs without significant side-effects. This review focuses on nanocarriers for triterpenoid delivery in arthritis therapy, including osteoarthritis (OA), rheumatoid arthritis (RA) and gout that appeared in the literature in the last ten years.

Analytical Rheology of Honey: A State-of-the-Art Review.

Honey has been used as a nutraceutical product since ancient times due to its nutritional and medicinal properties. Honey rheology influences its organoleptic properties and is relevant for processing and quality control. This review summarizes the rheological behaviour of honeys of different botanical source(s) and geographical locations that has been described in the literature, focusing on the relation between rheological parameters, honey composition (moisture, water activity, sugar content, presence of colloidal matter) and experimental conditions (temperature, time, stress, shear rate). Both liquid and crystallized honeys have been addressed. Firstly, the main mathematical models used to describe honey rheological behaviour are presented highlighting moisture and temperature effects. Then, rheological data from the literature regarding distinct honey types from different countries is analysed and results are compared. Although most honeys are Newtonian fluids, interesting shear-thinning and thixotropic as well as anti-thixotropic behaviour have been described for some types of honey. Rheological parameters have also been successfully applied to identify honey adulteration and to discriminate between different honey types. Several chemometric techniques have also been employed to obtain the complex relationships between honey physicochemical and rheological properties, including partial least squares (PLS), principal component analysis (PCA) and artificial neural networks (ANN).

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy.

Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

Therapeutic Strategies Targeting Amyloid-ß in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-ß (Aß) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aß is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by ß- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aß dyshomeostasis results in the accumulation and aggregation of Aß into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aß-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aß-protein targeted AD drugs, including ß-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aß aggregation and immunotherapy targeting Aß, focusing mainly on those currently under clinical trials.

In Vitro Fracture Resistance and Bond Strength of Self-Adhesively Luted Cast Metal and Fiber-Reinforced Composite Posts and Cores: Influence of Ferrule and Storage Time.

PURPOSE: To evaluate the fracture resistance and bond strength of cast posts and cores (CPCs) and customized glass fiber posts (CFPs) with self-adhesive luting. MATERIALS AND METHODS: A total of 56 recently extracted premolars were divided into four groups for the fracture resistance test (CPC and CFP, with and without ferrule) and four groups for the bond strength test (CPC and CFP, immediate and 6 months of storage). RESULTS: Differences for fracture resistance were found between CPCs and CFPs with ferrule. For bond strength, the interaction between post and root region was significant. CONCLUSION: Self-adhesive luting increased fracture resistance of CPCs with ferrule. The ferrule decreased root fractures. Bond strength was similar for both retainers but not for the apical third. Water storage affected bond strength positively.

Anterosuperior rehabilitation with metal-free fixed prosthesis based on zirconia.

The loss of upper front dental elements causes functional and psychosocial problems to the affected individuals. In this case report, the treatment planning considered hard and soft tissue loss for a complex fixed partial denture (FPD) rehabilitation. The six-element, all-ceramic FPD was manufactured using a computer-aided design/computer-aided manufacturing system with zirconia framework, veneered with leucite-reinforced ceramic. Ceramic artificial gum was also produced to guarantee tooth-facial proportions as well as lip support, promoting both esthetics and phonetics. The material's mechanical properties allowed for the coupling of the esthetic and mechanical requirements, proving an alternative to the well-established metal-ceramic technology, optimizing biomimetic. One of the endodontic-treated abutment teeth required a radicular retainer with cast metal post, but because of the opacity of zirconia, the esthetics of the prosthesis was not compromised. The low silica content of high resistance ceramics such as zirconia hampers the adhesive cementation, with numerous studies advocating for different cementation protocols, with no clear scientific consensus so far. In the present case, the internal surface of the FPD was initially blasted with aluminum oxide, followed by the application of a universal adhesive system containing 10-methacryloyloxydecyl dihydrogen phosphate. Finally, cementation to the dental structure was conducted with dual-cure self-adhesive resin cement.

Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B.

Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γCMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (ΔGs°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone.

Transitional Era: from analogical to digital workflow in oral rehabilitation: a case report / Era de transição: do fluxo de trabalho analógico para o digital em reabilitação oral: relato de caso

ABSTRACT Digital dentistry is a ubiquitous phenomenon nowadays but it requires access to technologies and learning curve. To aid digital workflow implementation, digital steps can be progressively incorporated in conventional workflows. We aimed to demonstrate a multidisciplinary oral rehabilitation performed mixing conventional procedures with digital open-source software programs and low-cost devices. A 46-year-old female patient had photographs, intraoral scans, and cone-beam computed tomography obtained and used in combination with conventional clinical exams to develop a treatment plan. Power point software was used for digital smile planing and Horos for digital implant planning. The digital dataset were used to guide conventional clinical procedures (scaling and root planning, gingivoplasty, in-office tooth bleaching, fiber-post restoration, implant and bone graft placement, teeth preparation, and protheses design and milling). The inclusion of digital steps in the conventional workflow enabled the performance of rehabilitation procedures with reduced clinical time and increased predictability, favoring the overall workflow and the communication among the different dental specialties. A mixed workflow can progressively lead to an exclusively digital workflow as technologies become accessible and learning curve is coped.

RESUMO Atualmente, a Odontologia digital é um fenômeno onipresente, contudo exige acesso à tecnologia e curva de aprendizado. Para auxiliar na implementação de fluxos de trabalho digitais, etapas digitais podem ser progressivamente incorporadas nos fluxos de trabalho convencionais. Nosso objetivo foi demonstrar uma reabilitação oral multidisciplinar realizada combinando procedimentos convencionais e ferramentas digitais de baixo custo e acesso aberto. Uma paciente de 46 anos teve fotografias, exames intraorais e tomografia computadorizada de feixe cônico obtidos e usados em combinação com exame clínico convencional para desenvolvimento de um plano de tratamento. O software Power Point foi utilizado para o planejamento digital do sorriso e o Horos para o planejamento digital dos implantes. O conjunto de dados digitais foi usado para orientar a execução dos procedimentos clínicos convencionais (raspagem e alisamento radicular, gengivoplastia, clareamento dental, restauração com pino de fibra de vidro, inserção de implantes e enxerto ósseo, preparos protéticos e design e fresagem protética). A inclusão de etapas digitais no fluxo de trabalho convencional permitiu redução do tempo clínico na realização da reabilitação aliado à maior previsibilidade, favorecendo o fluxo de trabalho e a comunicação entre as diferentes especialidades odontológicas. O fluxo de trabalho misto pode progressivamente levar a um fluxo de trabalho exclusivamente digital à medida que as tecnologias se tornem acessíveis e a curva de aprendizado superada.

In vitro fracture strength and modes of cast post and cores luted with self-adhesive resin-based cement

Aim: Cast post and core (CPC) is the main used post type; however, the biomechanical behavior of CPCs adhesively luted to the dentin is still unclear. Therefore, we aimed to evaluate the fracture resistance (FR) and fracture modes of teeth restored with CPCs luted with zinc-phosphate (ZP) or resin-based self-adhesive (SA) cements, as well as the influence of the coronal remnant. Methods: For that, 24 human premolars were divided into four groups according to the cement (ZP or SA) and coronal remnant (with or without 2mm). FR was tested in a universal machine and data analyzed by two-way ANOVA and Tukey HSD (α=.05). Fracture modes were classified according to the degree of dental destruction. Results: The results showed that there was no difference in FR (p=.352); however, teeth without ferrule presented more irreparable fractures, specially in the ZP group. Conclusion: All in all, self-adhesion of CPCs does not enhance fracture resistance, however it reduces the number of irreparable fractures, compared to ZP cement

Biodegradation of acrylic based resins: A review.

OBJECTIVES: The development of different types of materials with application in dentistry is an area of intense growth and research, due to its importance in oral health. Among the different materials there are the acrylic based resins that have been extensively used either in restorations or in dentures. The objective of this manuscript was to review the acrylic based resins biodegradation phenomena. Specific attention was given to the causes and consequences of materials degradation under the oral environment. DATA AND SOURCES: Information from scientific full papers, reviews or abstracts published from 1963 to date were included in the review. Published material was searched in dental literature using general and specialist databases, like the PubMED database. STUDY SELECTION: Published studies regarding the description of biodegradation mechanisms, in vitro and in vivo release experiments and cell based studies conducted on acrylic based resins or their components were evaluated. Studies related to the effect of biodegradation on the physical and mechanical properties of the materials were also analyzed. CONCLUSIONS: Different factors such as saliva characteristics, chewing or thermal and chemical dietary changes may be responsible for the biodegradation of acrylic based resins. Release of potential toxic compounds from the material and change on their physical and mechanical properties are the major consequences of biodegradation. Increasing concern arises from potential toxic effects of biodegradation products under clinical application thus justifying an intensive research in this area.

The quaternisation reaction of phosphines and amines in aliphatic alcohols. A similarity analysis using the isokinetic, isosolvent and isoselective relationships.

Accurate second-order rate constants were measured at 5 K intervals in the temperature range 298.15-328.15 K for the quaternisation reaction of triethylphosphine with iodoethane in methanol, ethanol, propan-1-ol and butan-1-ol. These data are complemented previously reported rate constants for the quaternisation reaction of triethylamine with iodoethane in the same solvents and at similar temperatures. Each of these two reaction series is analysed in terms of the isokinetic relationship (IKR) with respect to solvent variation and of the isosolvent relationship (ISoR) with respect to temperature variation, using in the latter case five different empirical solvent scales. Statistically validated IKR and ISoR have been found for both reaction series. The resulting isokinetic temperatures of 347 K (phosphine series) and of 730 K (amine series) are discussed in terms of Linert's theory of the isokinetic relationship. The best ISoR correlation is obtained using the Dimroth-Reichardt E(T)(N) solvent scale for the phosphine series and the Kamlet-Taft alpha(KT) solvent scale for the amine series. It is demonstrated that no real solvent can be envisaged as having the characteristics of an isokinetic solvent. The selectivity of the nucleophiles triethylphosphine and triethylamine in the attack on iodoethane is examined by treating together both reaction series in terms of the isoselective relationship (ISeR). The isoselective temperature with respect to solvent is found to be 289 K, which is close to the value of 302 K predicted by Exner and Giese's formula on the basis of the individual isokinetic temperatures. A novel ISeR analysis with respect to temperature is performed. It reveals that the alpha(KT) scale is the most appropriate solvent scale for describing this selectivity series, and that it is feasible to find an isoselective solvent. A new equation is developed for predicting the isoselective solvent parameter from individual isosolvent parameters and is shown to yield realistic values. The present similarity analysis shows that there are significant differences between the courses of these quaternisation reactions. On the basis of the experimentally determined isoparameter values, in liquid alcohols as solvent it is proposed that the reaction between triethylphosphine and iodoethane follows a classic bimolecular nucleophilic substitution pathway, whereas the desolvation of triethylamine molecules has to be taken into account to describe the mechanism of the original Menshutkin reaction.