Double Cervical Adjacent Hydrated Nucleus Pulposus Extrusion (HNPE) in a Yorkshire Terrier.

A 9-year-old Yorkshire terrier was brought to the emergency department for inability to maintain the correct station with acute onset. Neurological examination showed a non-ambulatory tetraparesis, spontaneous proprioceptive deficit in all limbs, and decreased flexor reflex in the forelimbs. The neurological symptoms suggested a cranial cervical spinal cord with suspicion of spinal shock. The clinical differential diagnoses included degenerative (intervertebral disc extrusion), vascular, inflammatory, or neoplastic disease. No pathological findings were evident in the hematobiochemical tests or in the radiograph examination. MRI examination of the cervical spine showed the presence of two adjacent hydrated nucleus pulposus extrusions at C3-C4 and C4-C5 tracts. Treatment included analgesic and non-steroidal anti-inflammatory therapy; movement restriction was initially necessary, followed by physiotherapy. Follow-up at 4 weeks showed complete recovery. A telephone follow-up after 3 months with the owner confirmed the absence of symptoms. This article reports the first double cervical HNPE case in a dog, adding the possibility that the disease may present in this form and the success of conservative treatment as described in the literature.

The piper at the gates of brain: A systematic review of surface modification strategies on lipid nanoparticles to overcome the Blood-Brain-Barrier.

The Blood-Brain Barrier (BBB) significantly impedes drug delivery to the central nervous system. Nanotechnology, especially surface-functionalized lipid nanoparticles, offers innovative approaches to overcome this barrier. However, choosing an effective functionalization strategy is challenging due to the lack of detailed comparative analysis in current literature. Our systematic review examined various functionalization strategies and their impact on BBB permeability from 2041 identified articles, of which 80 were included for data extraction. Peptides were the most common modification (18) followed by mixed strategies (12) proteins (9), antibodies (7), and other strategies (8). Interestingly, 26 studies showed BBB penetration with unmodified or modified nanoparticles using commonly applied strategies such as PEGylation or surfactant addition. Statistical analysis across 42 studies showed correlation between higher in vivo permeation improvements and nanoparticle type, size, and functionalization category. The highest ratios were found for nanostructured lipid carriers or biomimetic systems, in studies with particle sizes under 150 nm, and in those applying mixed functionalization strategies. The interstudy heterogeneity we observed highlights the importance of adopting standardized evaluation protocols to enhance comparability. Our systematic review aims to provide a comparative insight and identify future research directions in the development of more effective lipid nanoparticle systems for drug delivery to the brain to help improve the treatment of neurological and psychiatric disorders and brain tumours.

Application of Galenic Strategies for Developing Gastro-Resistant Omeprazole Formulation for Pediatrics.

OBJECTIVES: This study addresses a critical need in pediatric pharmacotherapy by focusing on the development of an enteric formulation of omeprazole for pediatric use. Omeprazole, a widely used proton pump inhibitor, is essential for treating various gastrointestinal disorders in children. The main objective is to design a compounding formula that can be prepared in hospital pharmacy services without the need for industrial equipment, which is often unavailable in these settings. METHODS: The research applied different galenic strategies to overcome the challenges of omeprazole's instability in acidic environments and its complex pharmacokinetic and physicochemical properties. The experiments were conducted sequentially, employing salting out, ionic gelation, and matrix granulation strategies. Based on the results obtained, the control conditions and parameters for the various trials were established. RESULTS: Among the techniques used, wet granulation proved to be the most promising, achieving a gastro-resistance level of 44%. In contrast, the ionic gelation and salting-out techniques did not yield satisfactory results. CONCLUSIONS: The findings of this study underscore the need to adopt alternative formulation strategies to ensure the stability of omeprazole. This goal requires a multidisciplinary approach and continuous effort to design omeprazole formulations that meet quality standards and appropriate gastro-resistance requirements.

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram.

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM. In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.

Evaluation of the neuroprotective effect of antipsychotics by serum quantification of protein S100B.

OBJECTIVE: This research delves into the intricate interplay between antipsychotic medications and neuroprotection focusing on the S100B protein-a central player in the regulation of neuroapoptotic activity. METHOD: Blood samples were collected to assess serum S100B protein levels using an immunoassay of immunoelectrochemiluminescence. The first two samples were collected with a 3-month interval between each, and the third sample was obtained 6 months after the previous one. Changes in S100B protein levels throughout the study were assessed using Friedman's ANOVA test. This was followed by the Wilcoxon signed-rank test with Bonferroni correction to account for multiple comparisons. RESULTS: This study involved 40 patients diagnosed with severe mental disorders (34 schizophrenia, 4 schizoaffective disorder, 1 bipolar disorder, and 1 borderline personality disorder). These patients had been receiving antipsychotic treatment for an average duration of 17 years. The results revealed that the S100B protein remained within physiological levels (median values 39.0 ng/L for the first sample, median values 41.0 ng/L for the second sample, and median values 40.5 ng/L for the third sample) with no significant changes (p = 0.287), with all anti-psychotic medicaments values consistently below 50 ng/L, a lower value compared to maximum range of 105 ng/L. Importantly, there were no significant differences in S100B protein levels between patients on monotherapy and those on combination antipsychotic therapy (p = 0.873), suggesting that combination therapy did not increase neuroapoptotic activity. CONCLUSIONS: These findings provide compelling evidence for the potential neuroprotective effects of long-term antipsychotic treatment in individuals with severe mental disorders. By maintaining physiological levels of the S100B protein, antipsychotic medications may help protect against neuronal damage and dysfunction. This research contributes valuable insights into the neuroprotective mechanisms of antipsychotic drugs, enhancing our understanding of their potential benefits in the treatment of severe mental disorders.

Development of cationic solid lipid nanoparticles incorporating cholesteryl-9-carboxynonanoate (9CCN) for delivery of antagomiRs to macrophages.

Lipid-based nanoparticles are a useful tool for nucleic acids delivery and have been regarded as a promising approach for diverse diseases. However, off-targets effects are a matter of concern and some strategies to improve selectivity of solid lipid nanoparticles (SLNs) were reported. The goal of this study was to test formulations of SLNs incorporating lipid cholesteryl-9-carboxynonanoate (9CCN) as "eat-me" signal to target antagomiR oligonucleotides to macrophages. We formulate four SLNs, and those with a mean diameter of 200 nm and a Z-potential values between 25 and 40 mV, which allowed the antagomiR binding, were selected for in vitro studies. Cell viability, transfection efficiency and cellular uptake assays were performed within in vitro macrophages using flow cytometry and confocal imaging and the SLNs incorporating 25 mg of 9CCN proved to be the best formulation. Subsequently, we used a labeled antagomiR to study tissue distribution in in-vivo ApoE-/- model of atherosclerosis. Using the ApoE-/- model we demonstrated that SLNs with phagocytic signal 9-CCN target macrophages and release the antagomiR cargo in a selective way.

Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.

The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.

Comparative Analysis of the Physicochemical and Biological Characteristics of Freeze-Dried PEGylated Cationic Solid Lipid Nanoparticles.

Cationic solid-lipid nanoparticles (cSLNs) have become a promising tool for gene and RNA therapies. PEGylation (PEG) is crucial in enhancing particle stability and protection. We evaluated the impact of PEG on the physicochemical and biological characteristics of cholesteryl-oleate cSLNs (CO-cSLNs). Several parameters were analyzed, including the particle size, polydispersity index, zeta potential, shape, stability, cytotoxicity, and loading efficiency. Five different formulations with specific PEGs were developed and compared in both suspended and freeze-dried states. Small, homogeneous, and cationic suspended nanoparticles were obtained, with the Gelucire 50/13 (PEG-32 hydrogenated palm glycerides; Gelucire) and DSPE-mPEG2000 (1,2-distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjungate-2000; DSPE) formulations exhibiting the smallest particle size (~170 nm). Monodisperse populations of freeze-dried nanoparticles were also achieved, with particle sizes ranging from 200 to 300 nm and Z potential values of 30-35 mV. Notably, Gelucire again produced the smallest particle size (211.1 ± 22.4), while the DSPE and Myrj S100 (polyoxyethylene (100) stearate; PEG-100 Stearate) formulations had similar particle sizes to CO-cSLNs (~235 nm). The obtained PEGylated nanoparticles showed suitable properties: they were nontoxic, had acceptable morphology, were capable of forming SLNplexes, and were stable in both suspended and lyophilized states. These PEG-cSLNs are a potential resource for in vivo assays and have the advantage of employing cost-effective PEGs. Optimizing the lyophilization process and standardizing parameters are also recommended to maintain nanoparticle integrity.

Optimisation of the Manufacturing Process of Organic-Solvent-Free Omeprazole Enteric Pellets for the Paediatric Population: Full Factorial Design.

Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee quality and stability; this is the case, for example, with omeprazole. Omeprazole is used as a model drug due to the lack of a paediatric formulation meeting gastro-resistance requirements, which remains a challenge today. In this experimental study, the development of enteric polymer-coated pellets is proposed. It is proposed to use aqueous coating dispersions without the use of organic solvents, which are commonly used in fluidised bed coatings. To do this, the design of experiments method is used as a statistical tool for experiment creation and the subsequent analysis of the responses. In particular, this study uses a randomised full factorial design. The mean weight increases of the protective layer and the enteric coating are chosen as factors. Each factor is assigned two levels. Therefore, the design of the used experiments is a 22 + 1 central point. Overall, the obtained pellets can be an alternative to the compounding formulas of omeprazole that are currently used in the paediatric population, which do not meet the gastro-resistance specifications necessary to guarantee the therapeutic efficacy of this active ingredient.

Methods for Developing a Process Design Space Using Retrospective Data.

Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that certain guidelines are followed to enhance and ensure proper statistical modeling. This article presents a methodology for constructing a design space using process data, while avoiding the common pitfalls associated with retrospective data analysis. For this study, data from a real wet granulation process were collected to pragmatically illustrate all the concepts and methods developed in this article.

Development of a Carvedilol Oral Liquid Formulation for Paediatric Use.

Carvedilol (CARV) is an 'off-label' ß-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/mL CARV-malic acid solution. A design of experiment (DoE) was used to optimize the CARV solution's preparation parameters. A 1 mg/mL CARV solution containing malic acid was stable for up to 12 months at 25 °C and 30 °C and 6 months at 40 °C. An equation associating malic acid with CARV concentrations was obtained using DoE. Microbiological data showed that the use of methylparaben was not necessary for this period of time. We successfully developed an aqueous CARV solution suitable for paediatrics and proven to be stable over a 12-month period.

Pellets and gummies: Seeking a 3D printed gastro-resistant omeprazole dosage for paediatric administration.

The production of 3D printed pharmaceuticals has thrived in recent years, as it allows the generation of customised medications in small batches. This is particularly helpful for patients who need specific doses or formulations, such as children. Compounding pharmacies seek alternatives to conventional solid oral doses, opting for oral liquid formulations. However, ensuring quality and stability, especially for pH-sensitive APIs like omeprazole, remains a challenge. This paper presents the application of semi-solid extrusion 3D printing technology to develop patient-tailored medicinal gummies, with an eye-catching appearances, serving as an innovative omeprazole pharmaceutical form for paediatric use. The study compares 3D printing hydrogels with dissolved omeprazole to hydrogels loaded with gastro-resistant omeprazole pellets, a ground-breaking approach.. Gastro-resistance and dissolution profiles were studied using different methods for better comparison and to emphasize the significance of the assay's methodology. Both developed formulas exhibit proper rheology, good printability, and meet content and mass uniformity standards. However, the high gastro-resistance and suitable release profile of 3D printed chewable semi-solid doses with enteric pellets highlight this as an effective strategy to address the challenge of paediatric medication.

SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening.

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source.

Palatability and Stability Studies to Optimize a Carvedilol Oral Liquid Formulation for Pediatric Use.

Carvedilol (CARV) is a blocker of α- and ß- adrenergic receptors, used as an "off-label" treatment for cardiovascular diseases in pediatrics. Currently, there is no marketed pediatric-appropriate CARV liquid formulation, so its development is necessary. Palatability (appreciation of smell, taste, and aftertaste) is a key aspect to be considered during the development of pediatric formulations since only formulations with good palatability also have adequate acceptability in this population. Consequently, the aim of this research was to assess the palatability and acceptability of different CARV formulations using an in vivo taste assessment (ID Number PR103/22) in order to select the highest palatability-rated CARV formulation. The preparation of CARV formulations was based on a reference 1 mg/mL CARV solution, which contains malic acid as a solubilizing agent. Subsequently, sucralose and flavoring agents were added and mixed until complete dissolution to the corresponding formulations. Adult volunteers participated in this study and evaluated the taste and odor of various CARV formulations through a questionnaire and a sensory test. The mean palatability score, measured on a 10-point scale, increased from 1.60 for the unflavored control to 7.65 for the highest-rated flavored formulation. Moreover, the bitterness of the optimized CARV formulation was reduced from 66.67% to 17.86%, and the taste pleasantness was increased from 25/100 to 73/100. This optimized CARV formulation contains a sweetening agent, sucralose, in addition to two flavoring agents at appropriate concentrations for pediatrics. Furthermore, the physicochemical and microbiological stability of the optimized CARV formulation were evaluated for 6 months at 25, 30, and 40 °C, in addition to in-use stability for 15 days at 25 °C, whose results were confirmed. Thus, we successfully developed a palatable CARV liquid solution that contains excipients appropriate for pediatrics and is stable under the studied conditions.

Development of a Standardized Method for Measuring Bioadhesion and Mucoadhesion That Is Applicable to Various Pharmaceutical Dosage Forms.

Although some methods for measuring bioadhesion/mucoadhesion have been proposed, a standardized method is not yet available. This is expected to hinder systematic comparisons of results across studies. This study aimed to design a single/systematic in vitro method for measuring bioadhesion/mucoadhesion that is applicable to various pharmaceutical dosage forms. To this end, we measured the peak force and work of adhesion of minitablets, pellets, and a bioadhesive emulsion using a texture analyzer. Porcine tissue was used to simulate human stomach/skin conditions. The results of these formulations were then compared to those for formulations without the bioadhesive product. We conducted a case study to assess the stability of a bioadhesive emulsion. The results for the two parameters assessed were contact time = 60 s and contact force = 0.5 N at a detachment speed of 0.1 mm/s. Significant differences were observed between the bioadhesive and control formulations, thus demonstrating the adhesive capacity of the bioadhesive formulations. In this way, a systematic method for assessing the bioadhesive capacity of pharmaceutical dosage forms was developed. The method proposed here may enable comparisons of results across studies, i.e., results obtained using the same and different pharmaceutical formulations (in terms of their bioadhesion/mucoadhesion capacity). This method may also facilitate the selection of potentially suitable formulations and adhesive products (in terms of bioadhesive properties).

Mechanism-Driven Modeling to Aid Non-invasive Monitoring of Cardiac Function via Ballistocardiography.

Left ventricular (LV) catheterization provides LV pressure-volume (P-V) loops and it represents the gold standard for cardiac function monitoring. This technique, however, is invasive and this limits its applicability in clinical and in-home settings. Ballistocardiography (BCG) is a good candidate for non-invasive cardiac monitoring, as it is based on capturing non-invasively the body motion that results from the blood flowing through the cardiovascular system. This work aims at building a mechanistic connection between changes in the BCG signal, changes in the P-V loops and changes in cardiac function. A mechanism-driven model based on cardiovascular physiology has been used as a virtual laboratory to predict how changes in cardiac function will manifest in the BCG waveform. Specifically, model simulations indicate that a decline in LV contractility results in an increase of the relative timing between the ECG and BCG signal and a decrease in BCG amplitude. The predicted changes have subsequently been observed in measurements on three swine serving as pre-clinical models for pre- and post-myocardial infarction conditions. The reproducibility of BCG measurements has been assessed on repeated, consecutive sessions of data acquisitions on three additional swine. Overall, this study provides experimental evidence supporting the utilization of mechanism-driven mathematical modeling as a guide to interpret changes in the BCG signal on the basis of cardiovascular physiology, thereby advancing the BCG technique as an effective method for non-invasive monitoring of cardiac function.

Left hepatic lobe agenesis, a rare anatomical condition.

Left hepatic lobe agenesis is a rare congenital disorder, first reported by Wakefield in 1898. Since then, less than 40 cases have been described in the literature. We present the case of a man with a left hepatic lobe agenesis diagnosed during the study of obstructive jaundice.