Surgical complications and technical failure of simultaneous pancreas-kidney transplantation: A 22-year experience from a single center.

Simultaneous pancreas-kidney transplantation (SPKT) is the best treatment for selected individuals with type 1 diabetes mellitus and end-stage renal disease. Despite advances in surgical techniques, donor and recipient selection, and immunosuppressive therapies, SPKT remains a complex procedure with associated surgical complications and adverse consequences. We conducted a retrospective study that included 263 SPKT procedures performed between May 2000, and December 2022. A total of 65 patients (25%) required at least one relaparotomy, resulting in an all-cause relaparotomy rate of 2.04 events per 100 in-hospital days. Lower donor body mass index was identified as an independent factor associated with reoperation (OR .815; 95% CI:  .725-.917, p = .001). Technical failure (TF) occurred in 9.9% of cases, primarily attributed to pancreas graft thrombosis, intra-abdominal infections, bleeding, and anastomotic leaks. Independent predictors of TF at 90 days included donor age above 36 years (HR 2.513; 95% CI 1.162-5.434), previous peritoneal dialysis (HR 2.503; 95% CI 1.149-5.451), and specific pancreas graft reinterventions. The findings highlight the importance of carefully considering donor and recipient factors in SPKT. The incidence of TF in our study population aligns with the recent series. Continuous efforts should focus on identifying and mitigating potential risk factors to enhance SPKT outcomes, thereby reducing post-transplant complications.

Psychometric properties of the Decisional Conflict Scale in a sample of perinatal women with depressive symptoms: A study in Portugal and Norway.

OBJECTIVE: To assess the psychometric properties, i.e., reliability and construct validity of the 16-item Decisional Conflict Scale (DCS) and sub-scales in women with perinatal depressive symptoms in Norway and Portugal. METHODS: We included 415 women in Portugal and 163 in Norway (≥18 years) who were pregnant or had given birth in the last 12 months and presenting with active depressive symptoms. Women replied to the original DCS items. We conducted confirmatory factor analysis, estimated internal consistency reliability, and examined factorial invariance across country, perinatal status, and treatment uptake. RESULTS: The DCS factor model had good fit to the data, with all items loading significantly on their respective factor (.585 to .958). There was configural invariance of the DCS across countries, treatment, and perinatal status. The internal consistency of the total DCS (Cronbach's alpha) was .958, and for the subscales it ranged from .798 to .947. CONCLUSIONS: The DCS is a valid and reliable measure of the decisional conflict in women with perinatal depressive symptoms in Portugal and Norway. PRACTICE IMPLICATIONS: Measuring the extent of decisional conflict regarding treatment and the effect of multiple interventions towards its reduction, is critical to facilitate the decision-making process of women with perinatal mental illness.

In vitro studies into establishing therapeutic bioequivalence of complex topical products: Weight of evidence.

Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.

Drilling into "Quality by Design" Approach for Analytical Methods.

The need for consistency in analytical method development reinforces the dependence of pharmaceutical product development and manufacturing on robust analytical data. The Analytical Quality by Design (AQbD), akin to the product Quality by Design (QbD) endows a high degree of confidence to the method quality developed. AQbD involves the definition of the analytical target profile as starting point, followed by the identification of critical method variables and critical analytical attributes, supported on risk assessment and design of experiment tools for the establishment of a method operable design region and control strategy of the method. This systematic approach moves away from reactive troubleshooting to proactive failure reduction. The objective of this review is to highlight the elements of the AQbD framework and provide an overview of their implementation status in various analytical methods used in the pharmaceutical field. These methodologies include but are not limited to, high-performance liquid chromatography, UV-Vis spectrophotometry, capillary electrophoresis, supercritical fluid chromatography, and high-performance thin-layer chromatography. Finally, a critical appraisal is provided to highlight how regulators have encouraged AQbD principles application to boost the prevention of method failures and a better understanding of the method operable design region (MODR) and control strategy, ultimately resulting in cost-effectiveness and regulatory flexibility.

Parenteral Ready-to-Use Fixed-Dose Combinations Including NSAIDs with Paracetamol or Metamizole for Multimodal Analgesia-Approved Products and Challenges.

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) with non-opioid analgesics is common in clinical practice for the treatment of acute painful conditions like post-operative and post-traumatic pain. Despite the satisfactory results achieved by oral analgesics, parenteral analgesia remains a key tool in the treatment of painful conditions when the enteral routes of administration are inconvenient. Parenteral ready-to-use fixed-dose combinations of non-opioid analgesics combinations, including NSAIDs and paracetamol or metamizole, could play a central role in the treatment of painful conditions by combining the advantages of multimodal and parenteral analgesia in a single formulation. Surprisingly, only in 2020, a parenteral ready-to-use fixed-dose combination of ibuprofen/paracetamol was launched to the market. This review aims to investigate the current availability of combinations of NSAIDs with paracetamol or metamizole in both European and American markets, and how the combination of such drugs could play a central role in a multimodal analgesia strategy. Also, we explored how the parenteral formulations of NSAIDs, paracetamol, and metamizole could serve as starting elements for the development of new parenteral ready-to-use fixed-dose combinations. We concluded that, despite the well-recognized utility of combining NSAIDs with paracetamol or metamizole, several randomized clinical trial studies demonstrate no clear advantages concerning their efficacy and safety. Future clinical trials specifically designed to assess the efficacy and safety of pre-formulated fixed-dose combinations are required to generate solid evidence about their clinical advantages.

Rheology of Complex Topical Formulations: An Analytical Quality by Design Approach to Method Optimization and Validation.

Analytical method validation ensures that a method provides trustworthy information about a particular sample when applied in accordance with the predefined protocol. According to regulatory standards, the rheological characteristics of topically applied semisolid formulations are one of the key elements involved in microstructure equivalence documentation. Therefore, for generic drug product manufacturers, it is a dire need to take a step forward in rheology method development and validation procedures. This paper aims to apply Analytical Quality by Design (AQbD) principles towards the development and validation of rheology methods for topical creams, as complex semisolid formulations. Risk assessment was carried out through an Ishikawa diagram and an estimate failure mode, effects, and criticality analysis (FMECA). Sample application, peltier temperature control, and sample rest time were identified as critical method variables (CMVs), and a 23 full factorial design was applied to understand their impact on rotational, creep recovery and, oscillatory measurements. The development of the method was carried out as per the ICH Q8-Q10, and Q14 guidelines and validated according to ICH Q2 (R2) guideline. The method demonstrated adequate precision (RSD < 15%), as well as selectivity. AQbD provided a comprehensive framework for developing a reliable and effective rheology method for this type of formulation.

Morphogeometric Evaluation of the Left Ventricle and Left Atrioventricular Ring in Dogs: A Computerized Anatomical Study.

In veterinary, there is scarce availability of morphogeometric studies in normal and remodeled hearts; furthermore, ventricular geometry acts as an indicator of cardiac function. It is a highly necessary field of knowledge for the development of therapeutic protocols, especially surgical ones. The objectives of this study were: to obtain measurements of the left atrioventricular valve ring and left ventricle, to analyze the proportionality between the segments of the left cardiac chamber of normal hearts and to describe reference values for morphogeometric analysis of the left ventricle. For this, 50 hearts from small (Group 1-G1) and medium to large (Group 2-G2) dogs were laminated in the apical, basal and equatorial segments, and submitted to computer analysis to identify the perimeter of each segment and the left atrioventricular ring, wall thickness and distance from the atrioventricular sulcus to the apex. The largest internal perimeter was that of the equatorial. The basal segment had the highest mean for ventral parietal wall thickness, suggesting greater contractile reserve at that location. Considering the proportionality relationships, there was no statistical difference between the intersegmental perimeter indices for the two groups. This suggests that despite the animals' weight variations, the proportions between the left ventricular segments are maintained. Therefore, it is concluded that the data can be used as a standard of comparison for cardiac geometric assessments, as well as a basis for the development of therapeutic measures in the context of adverse cardiac remodeling.

COSMO models for the pharmaceutical development of parenteral drug formulations.

The aqueous solubility of active pharmaceutical ingredients is one of the most important features to be considered during the development of parenteral formulations in the pharmaceutical industry. Computational modelling has become in the last years an integral part of pharmaceutical development. In this context, ab initio computational models, such as COnductor-like Screening MOdel (COSMO), have been proposed as promising tools for the prediction of results without the effective use of resources. Nevertheless, despite the clear evaluation of computational resources, some authors had not achieved satisfying results and new calculations and algorithms have been proposed over the years to improve the outcomes. In the development and production of aqueous parenteral formulations, the solubility of Active Pharmaceutical Ingredients (APIs) in an aqueous and biocompatible vehicle is a decisive step. This work aims to study the hypothesis that COSMO models could be useful in the development of new parenteral formulations, mainly aqueous ones.

Drilling down the bioequivalence assessment of topical antifungal products: Microstructure and release.

In recent years, the regulatory mechanisms for topical generic product bioequivalence (BE) assessment have been subjected to noteworthy changes, with the FDA issuing product specific guidances, and the EMA adopting a more universal approach with the quality and equivalence of topical products draft guideline. The agencies advise on a modular strategy for BE documentation. Nevertheless, their scope, data analysis and criteria are rather distinct. This study aims to tackle bioequivalence assessment issues of complex topical formulations starting by statistical implications of the EMA/FDA approaches concerning the documentation of qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance requirements (Q4). As a model drug product, a bifonazole 10 mg/g cream formulation was selected. For this specific formulation, the commercially available Reference Product (RP) was compared with two comparator products, also commercially available, referred to as comparator product A (CPA) and comparator product B (CPB). The former displays Q1 sameness and Q2 differences, whilst CPB is categorically considered as Q1/Q2 different. Furthermore, intending to establish a regulatory rationale for the submission of a generic product according to the updated regulatory requirements, the RP was likewise compared with a Test Product (TP). This formulation was designed to display equal Q1/Q2 profile to that of the RP. Validated rheology and in vitro release test (IVRT) methods were used to infer on Q3/Q4 characteristics. During rheology studies, statistically significant RP batch to batch differences were observed. Therefore, in an attempt to surpass this heterogeneity, the initial pool of RP batches was expanded to include RP product batches at different lifecycle stages. Despite this effort, it was not possible to classify the RP/TP, RP/CPA or RP/CPB as rheologically equivalent products. Nevertheless, product performance results, retrieved from IVRT, were able to sustain equivalence between the RP and the formulations exhibiting Q1 sameness (TP and CPA). It should however be mentioned, that for some RP batch combinations, the IVRT results failed to demonstrate equivalence according to the EMA requirements. Enlarging the RP batch pool was then a critical step in further understanding an optimum statistical approach for establishing equivalence in product performance. This study highlights the need to that a 'one-fits-all approach' may not be an optimum path way for establishing the regulatory strategy and requirements to support generic product bioequivalence.

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.

Hemorrhagic Versus Ischemic Risk in Patients with Atrial Fibrillation on Hemodialysis

Abstract Background Hemodialysis (HD) patients with atrial fibrillation (AF) have a particularly high risk of stroke and bleeding, but no high-quality evidence-based recommendations exist to properly manage these patients. Objectives We aim to evaluate the ischemic versus the hemorrhagic risk in a HD population with AF. Methods We selected incident patients that started hemodialysis between 2011 and 2015. All patients that had AF before HD, or developed AF during the follow-up, were included. Both CHA2DS2 -VASC and HAS-BLED scores were calculated at the time of beginning of HD or AF diagnosis and correlated with the outcomes using a logistic regression model. The outcomes were hemorrhagic events, ischemic events and death related to any of these events. A p-value < 0.05 was set as statistically significant. Results Forty-six patients were included. Most of them had had AF before they started hemodialysis. Twenty-two patients were on oral anticoagulation (OAC). There was no significant difference between the incidence of ischemic and hemorrhagic events, regardless of the use of OAC. Previous stroke, transient ischemic attack, and thromboembolic event significantly increased the risk of an ischemic event (OR 6.78, p=0.028). Conclusions In this population, we did not observe any difference between the incidence of ischemic and hemorrhagic events, which was also true in patients with OAC. Therefore, the benefit of OAC in such patients remains questionable. However, patients with previous stroke, transient ischemic attack, or thromboembolic event seem to have a higher risk of new ischemic events and might benefit from anticoagulation.

Reconstructed Human Epidermis: An Alternative Approach for In Vitro Bioequivalence Testing of Topical Products.

The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two "negative controls" dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

Cyclodextrin-based delivery systems in parenteral formulations: A critical update review.

Parenteral formulations are indispensable in clinical practice and often are the only option to administer drugs that cannot be administrated through other routes, such as proteins and certain anticancer drugs - which are indispensable to treat some of the most prevailing chronic diseases worldwide (like diabetes and cancer). Additionally, parenteral formulations play a relevant role in emergency care since they are the only ones that provide an immediate action of the drug after its administration. However, the development of parenteral formulations is a complex task owing to the specific quality and safety requirements set for these preparations and the intrinsic properties of the drugs. Amongst all the strategies that can be useful in the development of parenteral formulations, the formation of water-soluble host-guest inclusion complexes with cyclodextrins (CDs) has proven to be one of the most advantageous. CDs are multifunctional pharmaceutical excipients able to form water-soluble host-guest inclusion complexes with a wide variety of molecules, particularly drugs, and thus improve their apparent water-solubility, chemical stability, and bioavailability, to make them suitable for parenteral administration. Besides, CDs can be employed as building blocks of more complex injectable drug delivery systems with enhanced characteristics, such as nanoparticles and supramolecular hydrogels, that has been found particularly beneficial for the delivery of anticancer drugs. However, only a few CDs are considered safe when parenterally administered, and some of these types are already approved to be used in parenteral dosage forms. Therefore, the application of CDs in the development of parenteral formulations has been a more common practice in the last few years, due to their significant worldwide acceptance by the health authorities, promoting the development of safer and more efficient injectable drug delivery systems.

Topical bioequivalence: Experimental and regulatory considerations following formulation complexity.

Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products. For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used. For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75-133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.

Topical fixed-dose combinations: Current in vitro methodologies for pre-clinical development.

The combination of two or more active pharmaceutical ingredients in the same dosage form - fixed-dose combination products - for topical administration represents a promising therapeutic approach for treating several pathologies, including pain. The pre-clinical development of fixed-dose combination products aims to characterize the interactions between the different APIs and ensure that the final medicinal product has the required safety characteristics. To this end, there are several regulatory accepted in vitro tests to assess the safety of medicinal products intended for cutaneous administration. In turn, the evaluation of anti-inflammatory activity should be based on models described in the scientific literature, as there are no models fully validated by competent entities. Therefore, this work presents the information regarding accepted in vitro tests to assess the safety of topical products and the most used methods to assess anti-inflammatory activity. Additionally, a new approach to select a fixed-dose combination product with the potential to enhance the therapeutic effects of the individual active pharmaceutical ingredients is rationalized by integrating the overall effects on several targets relevant for inflammation and pain management in one numeric index.

In vivo methodologies to assist preclinical development of topical fixed-dose combinations for pain management.

The combination in a fixed dose of two or more active pharmaceutical ingredients in the same pharmaceutical dosage form is an approach that has been used successfully in the treatment of several pathologies, including pain. In the preclinical development of a topical fixed-dose combination product with analgesic and anti-inflammatory activities for pain management, the main objective is to establish the nature of the interaction between the different active pharmaceutical ingredients while obtaining data on the medicinal product safety and efficacy. Despite the improvement of in vitro assays, animal models remain a fundamental strategy to characterise the interaction, efficacy and safety of active pharmaceutical ingredients at the physiological level, which cannot be reached by in vitro assays. Thus, the main goal of this review is to systematise the available animal models to evaluate the efficacy and safety of a new fixed-dose combination product for topical administration indicated for pain management. Particular emphasis is given to animal models that are accepted for regulatory purposes.

Enlightening clinical and therapeutic heterogeneity in thoracic actinomycosis: A review in bronchiectasis and non-bronchiectasis patients.

Actinomycosis is a rare chronic infection triggered by species of Actinomyces. Although thoracic involvement represents about 15% of human actinomycosis, its true incidence may be underestimated, not only because of its challenging diagnosis, but also because it can be treated unintentionally with antibiotics for other diseases. In this sense, this work aims at providing an up-to-date literature review on thoracic actinomycoses, with particular emphasis on presentation, diagnostic and therapeutic approaches, also paving upcoming clinical interventions from findings obtained of a presentation of a case series. Data discussed here clearly denote the rarity, non-specificity and heterogeneity of clinical presentations of the disease, reinforcing the need for individualized therapeutic approaches.

Topical Fixed-Dose Combinations: A Way of Progress for Pain Management?

Pain, a severe public health problem, can affect patient quality of life when inadequately controlled. Considering that pain pathophysiological mechanisms are complex, combining active pharmaceutical ingredients (APIs) with multiple and synergistic mechanisms of action represents a potentially more effective therapeutic approach than conventional monotherapy treatments. In turn, topical drug delivery has clear advantages over other routes of administration, such as high levels of efficacy, better safety profile and great patient compliance. In this context, the combination of two or more APIs in a single dosage form - fixed-dose combination product (FDC) - for topical administration may represent a promising therapeutic option in the field of pain management. Considering the above mentioned, the purpose of this manuscript is to address an overview of some general aspects regarding pain management and FDCs, as well as the regulatory environment that has to be taken into consideration during their development. Special emphasis will be given to fixed-dose combinations for topical administration with analgesic and/or anti-inflammatory activity. Market drivers of the topical FDC currently approved are ultimately pointed out, and new opportunities in pain management highlighted.