Advances In Pharmacotherapy Research Articles

Efficacy of Janus Kinase Inhibitors (JAKi) in the treatment of biologic-naive and biologic-experienced patients with ulcerative colitis

Abstract Introduction Janus kinase inhibitors (JAKi) are an orally available treatment for patients with moderately to severe ulcerative colitis (UC). There are currently 3 JAKi for UC: tofacitinib, filgotinib and upadacitinib with variable selectivity to JAK-11. There is limited data comparing the outcomes between biologic-naive and biologic-experienced patients. This study describes the effectiveness of JAKi according to biologic exposure. Aim To investigate the effectiveness of 3 the JAKi’s, tofacitinib, filgotinib and upadacitinib according to biologic exposure. Method We undertook a retrospective study of UC patients treated with JAKi within a tertiary hospital. Clinical endpoints were assessed at week 8-12. Baseline disease activity, previous advanced therapies and use of corticosteroids were documented. Clinical response was defined as reduction in SCCAI score by ≥3 points from baseline or a sustained score of <2.5. Clinical remission was defined as a SCCAI score of < 2.5, and/ or a calprotectin level of <250 mg/g with a CRP of < 5mg/L. Ethical approval has been granted by HRA and Health and Care Research Wales (HCRW) (REC ref: 24/HRA/1198) Results 52 patients were reviewed at week 8-12 following their first dose. 15, 15 and 22 patients were on tofacitinib, filgotinib, and upadacitinib respectively. 3 (20%) of patient in the tofacitinib group were exposed to at least 3 biologics prior to initiating the JAK Inhibitor, followed by upadacitinib which was 3 (14%) of patients. In the tofacitinib group, most patients were exposed to 2 previous biologics (n=7, 47%), whereas majority of patients on filgotinib and upadacitinib had exposure to 1 previous biologic, 7 (47%) and 8 (36%) patients respectively. For the patient group exposed to 3 or more biologics (n=7, 14%), 100% patients on tofacitinib (n=3) and upadacitinib (n=3) achieved clinical remission by week 8-12, whereas none of the patients on filgotinib achieve clinical remission. In biologic naïve patients, filgotinib demonstrated the greatest improvement in calprotectin score with a reduction in 30% from baseline (n=2, 100%). In patients exposed to ≥3 biologics, upadacitinib achieved higher rates of improvement in faecal calprotectin score (n=2, 100%). Conclusion Our observations suggest that patients exposed to at least 3 biologics, tofacitinib and upadacitinib were the most effective, whereas filgotinib seems to be more effective in biologic naïve patients. Our patient cohort is small. We will continue to collect data and undertake further statistical analysis to examine the significance of the observations and factors associated with effectiveness. Reference 1. Goetsch, A et al. Advances in pharmacotherapy for ulcerative colitis: a focus on JAK1 inhibitors. Expert Opinion on Pharmacotherapy, 2023, 24(7), 849–861.

Advancements in Pharmacotherapy: Novel Approaches for Treating Sickle Cell Disease

Advancements in Pharmacotherapy: Novel Approaches for Treating Sickle Cell Disease

O USO DOS INIBIDORES DO COTRANSPORTADOR DE SÓDIO-GLICOSE-2 (SGLT2) NA INSUFICIÊNCIA CARDÍACA: UMA REVISÃO BIBLIOGRÁFICA

Heart failure (HF) is not a single pathological diagnosis, but a clinical syndrome caused by a structural and/or functional abnormality of the heart, resulting in elevated intracardiac pressure or inadequate cardiac output at rest or during exercise. It is a common clinical condition found in various healthcare settings, with a vast socio-economic impact. In Brazil, HF is the leading cardiovascular cause of hospital morbidity. Thus, heart failure studies play a crucial role in the development of new drugs, enabling significant improvements in the efficacy, safety and tolerability of treatment, as well as the personalization of care for individual patients. Recent advances in pharmacotherapy have led to the evolution of new therapeutic agents with a decrease in hospitalization and mortality rates in HF. The 2023 update of the European Society of Cardiology (ESC) guidelines recommends (class IA) the administration of sodium-glucose transporter 2 inhibitors (SGLT2i) for patients with heart failure with preserved ejection fraction (HFpEF) and mildly reduced EF (HFpEF). This study aims to analyze the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure. In order to arrive at these topics, articles were collected from the PUBMED and SCIELO databases, and an analysis was carried out based on the material found in order to be able to explain the information relevant to the topic.

A retrospective analysis of patients with very HIGH level of LDL-C and the predictors of mortality (HIGH-LDL-PM Registry)

Abstract Introduction Elevated levels of LDL cholesterol (LDL-C) significantly contribute to the development and progression of cardiovascular diseases (CVDs). In HIGH-LDL-PM Registry, we aimed to investigate the demographics and clinical characteristics of patients with very high level of LDL-C and the predictors of mortality, retrospectively. Methods We retrospectively searched the electronic database of Istanbul University-Cerrahpasa Institute of Cardiology and included patients with very high level of LDL-C (>190 mg/dl) in HIGH-LDL-PM registry. The study group were classified as patients with high probability of familial hypercholesterolemia (FH) and low probability of FH according to Dutch Lipid Clinic Network Score (DLCNS). Results The study group were consisted of 1127 patients and almost two thirds (61.5%) were female. The mean age was 56.5 12.2 years. Hypertension, diabetes, chronic kidney disease (CKD) were seen in 55.8%, 23.5% and 3.7%, respectively. One third of study group (31.1%) had coronary artery disease (CAD) and rest of them were primary prevention patients. the main rhythm was sinus in most of the patients (92,2) and 7.8% patients had atrial fibrillation (AF). Only minority of patients (3.9%) had stigmata for elevated cholesterol levels. While 41.8% of patients had high clinical probability for FH, 58.2% of them had low probability according to DLCNS. While 69% of patients were using lipid lowering treatments (LLTs), 42% of them had drug adherence. High dose (HD) statins (atorvastatin 40-80 and rosuvastatin 20-40 mg) were prescribed in more than half (55.2%) of patients with LLTs. Ezetimibe was the preferred agent as combination therapy in 6.9% and PCSK-9is were prescribed only in 2.5% of patients with LLTs. In 38.8% of study population, ASA was prescribed. 50% decrease in LDL-C levels or decreasing LDL-C below 70 or 100 mg/dl as a treatment goal were achieved in 37.1% and 15% of study population. MACE (MI, stroke, PCI or peripheral revascularization) was recorded in 21% of study population and the mortality rate was 10.4% at 12-years FU (6-145 months). Patients with low probability of FH had better survival than patient with high probability (91.4% vs 88.4%). The age, low dose statin use and higher level of LDL-C at FU were predictors of mortality in Cox-regression analysis. Conclusion Our retrospective analysis of patients with very high levels of LDL-C underscores the multifaceted nature of dyslipidemia management and its impact on cardiovascular outcomes. Despite advancements in pharmacotherapy, suboptimal adherence to lipid-lowering treatments remains a significant challenge, contributing to a notable burden of major adverse cardiovascular events and mortality. Identification of predictors of mortality, such as age, statin dosage, and LDL-C levels, highlights the importance of individualized risk assessment and tailored treatment approaches in this high-risk population.

Transforming respiratory diseases management: a CMO-based hospital pharmaceutical care model.

Respiratory diseases encompass a diverse range of conditions that significantly impact global morbidity and mortality. While common diseases like asthma and COPD exhibit moderate symptoms, less prevalent conditions such as pulmonary hypertension and cystic fibrosis profoundly affect quality of life and mortality. The prevalence of these diseases has surged by approximately 40% over the past 3decades. Despite advancements in pharmacotherapy, challenges in drug administration, adherence, and adverse effects persist. This study aimed to develop and perform an interim validation of a Capacity-Motivation-Opportunity (CMO) model tailored for respiratory outpatients to enhance pharmaceutical care, which is the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient's quality of life, and overall wellbeing. This cross-sectional, multicenter study was conducted from March 2022 to March 2023. It comprised four phases: 1) forming an expert panel of 15 hospital pharmacists, 2) selecting respiratory pathologies based on prevalence and severity, 3) developing the CMO model's pillars, and 4) integrating and conducting an interim validation of the model. The Capacity pillar focused on patient stratification and personalized care; the Motivation pillar aligned therapeutic goals through motivational interviewing; and the Opportunity pillar promoted the use of information and communication technologies (ICTs) for telemedicine. The model included eight respiratory diseases based on expert assessment. For the Capacity pillar, 22 variables were defined for patient stratification, leading to three priority levels for personalized pharmaceutical care. In a preliminary test involving 201 patients across six hospitals, the stratification tool effectively classified patients according to their needs. The Motivation pillar adapted motivational interviewing techniques to support patient adherence and behavior change. The Opportunity pillar established teleconsultation protocols and ICT tools to enhance patient monitoring and care coordination. The CMO model, tailored for respiratory patients, provides a comprehensive framework for improving pharmaceutical care. By focusing on patient-centered care, aligning therapeutic goals, and leveraging technology, this model addresses the multifaceted needs of individuals with respiratory conditions. Future studies are necessary to validate this model in other healthcare systems and ensure its broad applicability.

Advancements in the Treatment of Diuretic Resistance in Congestive Heart Failure.

This narrative evaluates the dynamic developments that have significantly transformed treatment strategies in the constantly evolving domain of diuretic resistance (DR) management in congestive heart failure (CHF). The discourse explores historical challenges and the current state of therapeutic approaches as it investigates the crucial matter of DR in patients with CHF. An introduction provides a synopsis of the pivotal function diuretics performed in the management of fluid excess and the intricacies associated with CHF. The narrative explores the progressive exposure of the constraints that traditional treatments face, thus underscoring the persistent issue of DR and the imperative for innovative methodologies. The text underscores advancements in pharmacotherapy that demonstrate efficacy in surmounting resistance, including innovative diuretics and combination therapies. Furthermore, it outlines the pivotal shift towards personalized medicine, an approach that transforms the results of treatments through the integration of genetic knowledge and individualized strategies. Furthermore, the text delves into nonpharmacological strategies, including ultrafiltration and renal denervation, that enhance the overall comprehension of the intricate battle against diuretic resistance. In summary, this narrative exemplifies resolute perseverance in the pursuit of solutions, presenting a promising future wherein various developments converge to restore hope in regard to the control of DR and the improvement of the health status of chronic heart failure patients.

Clinical and economic studies of pharmacotherapy for multiple myeloma: literature review data

Among hematological diseases, Multiple myeloma (MM) is the second most common malignancy in adults worldwide. In the vast majority of cases, MM remains incurable, despite improvements in progression-free survival and overall survival due to advances in pharmacotherapy, as well as the emergence of innovative drugs in recent years. Unfortunately, this does not prevent patients from relapse and, ultimately, multidrug resistance and poor prognosis. In conditions of limited funding, one of the determining factors for the success of therapy is the cost of treatment. There is a need to conduct a clinical and economic analysis of the use of targeted drugs to determine the most economically feasible treatment option. The purpose of the review is to provide an overview of current and experimental treatments for relapsed/refractory MM (RRMM), with an emphasis on their pharmacoeconomic availability to assist clinicians in their decision-making process. Let's look at the latest data that will help improve approaches to the treatment of this still incurable disease and analyze pharmacoeconomic studies of modern expensive treatment regimens for RRMM in various countries.

Advances in pharmacotherapy of dyslipidemia

Abstract: Dyslipidaemia is a group of disorders of lipoprotein metabolism with consequences of endothelial dysfunction, atherosclerosis and increase in thrombogenecity of blood. Management of dyslipidaemia include diet and lifestyle modifications followed by pharmacotherapy. There are multiple drugs used for the management of dyslipidaemia with statins as most widely used therapeutic class. There are other class of drugs like resins, fibrates, drugs like niacin, ezetimibe being the established drugs in treatment of dyslipidaemia. With identification of mutations in specific genes of the lipoprotein receptors and on observation of adverse effects due to the established treatment modalities available, there is a need for new therapeutic targets to find an alternative treatment. Thus, new agents are approved for the treatment like the microsomal triglyceride transfer protein inhibitors, proprotein convertase substillin/klexin type 9 inhibitors, omega 3 fatty acid ethyl esters, antisense inhibition of Apo B-100 synthesis. Although the available drugs have well defined actions and effects, yet still in some patients either they could not fulfil the desired lipid lowering goals or the patients are intolerant/ non respondent to treatment or there is an imbalance between the risk-benefit profile. Thus, new drugs are being developed, described as pipeline drugs. Some of these are the cholesteryl ester transfer protein inhibitor, ATP citrate lyase inhibitor, antisense oligonucleotide inhibitor of lipoprotein A and Apo C–III, angiopeptin-like-3 inhibitors, AMP kinase activators, cylodextrins, thyroid receptor beta agonists, peroxisome proliferator-activated receptor agonists, acetyl CoA carboxylase inhibitor, diacylglycerol transferase inhibitor, acetyl coenzyme A cholesterol acetyl transferase-1 inhibitors, gene therapy and active immunisations.

A narrative review of advances in pharmacotherapy for depression and suicidal behavior in youth within the era of heightened social media

A narrative review of advances in pharmacotherapy for depression and suicidal behavior in youth within the era of heightened social media

Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice

Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.

Advancements In Pharmacotherapy for Hyperlipidemia: A Comprehensive Review of Recent Drug Innovations and Clinical Outcomes

Hyperlipidemia, characterized by elevated blood lipid levels, significantly contributes to cardiovascular diseases (CVDs), the leading cause of global mortality per the World Health Organization (WHO). Studies reveal a 20-30% increase in coronary heart disease risk for every 1 mmol/L rise in LDL-C levels. While statins are widely used, novel pharmacotherapeutic approaches are necessary for effective hyperlipidemia management and CVD risk reduction. Recent clinical trials demonstrate the efficacy of innovative drugs like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in lowering LDL-C levels and reducing adverse cardiovascular events. These findings highlight the potential of new therapies to enhance existing treatments for hyperlipidemia. Additionally, safety evaluations of emerging lipid-lowering agents address concerns about adverse effects and long-term risks. Despite progress, challenges persist in refining treatment strategies and ensuring equitable access to advanced therapies, especially for marginalized populations. Incorporating innovative pharmacotherapies into current approaches offers personalized and efficient hyperlipidemia management. Continued research and interdisciplinary collaborations are vital for advancing our understanding of lipid metabolism and translating scientific discoveries into improved patient outcomes and cardiovascular health. Ongoing innovation and investment in tailored hyperlipidemia therapies are crucial for better outcomes in individuals at risk of CVDs.
 Keywords: hyperlipidemia, pcsk9 inhibitors, bempedoic acid, evinacumab, inclisiran mipomersen, volanesorsen

Current advances in pharmacotherapy for schizophrenia

Background: Schizophrenia is a complex psychiatric disorder characterized by hallucinations, delusions, and cognitive deficits, often leading to functional decline. Pharmacotherapy has long played a central role in schizophrenia management with our evolving understanding shaping the treatment.Current Concepts: Antipsychotic agents are the mainstay of the pharmacological treatment of schizophrenia. Although second-generation antipsychotics (atypical) reduce extrapyramidal side effects, they give rise to metabolic concerns. Personalized treatment, guided by the response and side effects of the patient, determines suitable medications and dosages. Long-acting injectable antipsychotics have enhanced medication adherence, and the consideration of clozapine is warranted for treatment-resistant cases. In addition, potential combination therapies with other psychotropic medications could be explored to address specific symptoms or comorbidities.Discussion and Conclusion: Antipsychotics are pivotal in acute intervention and schizophrenia treatment maintenance. Individualized plans, accounting for drug response, side effects, and adherence, are essential when selecting specific antipsychotic agents. Long-acting injectables and clozapine with combination therapies for treatment resistance offer effective and tolerable management. Ongoing studies and novel antipsychotic development hold promise for improving schizophrenia treatment and patient life quality.

Pharmacologic Management of Parkinsonism and Other Movement Disorders

Parkinsonism and other movement disorders constitute a diverse group of neurodegenerative conditions characterized by disturbances in motor control. This abstract provides an overview of the pharmacologic management strategies employed in the treatment of these disorders. Parkinson's disease, the most prevalent form of Parkinsonism, is primarily managed through dopaminergic therapies aimed at replenishing dopamine levels or enhancing its effects in the central nervous system. Levodopa, a precursor of dopamine, remains the gold standard, often combined with dopaminergic agonists or monoamine oxidase-B inhibitors for optimal efficacy.In addition to Parkinson's disease, other movement disorders such as essential tremor, dystonia, and chorea pose unique challenges. Beta-blockers and anticonvulsants, like primidone, are commonly prescribed for essential tremor, while dystonia may respond to anticholinergic agents or botulinum toxin injections. Huntington's disease, characterized by chorea, is managed through dopamine-depleting agents, tetrabenazine being a notable example.Recent advances in pharmacotherapy include the development of adenosine A2A receptor antagonists and glutamate receptor modulators, providing promising alternatives and adjuncts to traditional therapies. However, challenges such as medication-induced side effects, disease progression, and the need for personalized treatment plans persist.This abstract underscore the evolving landscape of pharmacologic interventions for managing Parkinsonism and other movement disorders. A comprehensive understanding of the underlying pathophysiology, coupled with ongoing research efforts, promises to enhance therapeutic options and improve the quality of life for individuals affected by these debilitating conditions.

Anticoagulants for atrial fibrillation: from warfarin and DOACs to the promise of factor XI inhibitors.

Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.

The Utah Pharmacy Summit: Collaborating to Optimize Patient Care

Pharmacy has evolved significantly over the past 20 years, despite advances in pharmacotherapy and the expanding scope of pharmacy practice, pharmacists have struggled to collaborate across disciplines to create improved processes that enable the best outcomes from these innovations. A lack of innovation at any part of the healthcare system could inhibit the progress of practice innovations thereby leading to suboptimal patient medication and health outcomes. The Utah Pharmacy Summit was held in late 2022 with the goal of promoting pharmacist collaboration and a unified pharmacist voice within the state. The success of the Summit leads us to encourage collaborative forums across the Globe.

Oral Complications in Patients With Psychiatric Illness Undergoing Electroconvulsive Therapy in Istanbul, Turkey.

Despite advances in pharmacotherapy, electroconvulsive therapy (ECT) remains a mainstay treatment option in psychiatry. This study aims to determine the occurrence of oral injury from ECT modified with the use of an inexpensive, disposable, hand-made oral protector customized to the dental needs of the individual patient. Based on data collected between January 1, 2013, and December 31, 2018, registered patients who had received ECT were evaluated retrospectively. We investigated the incidence of oral complications such as dental fractures, dental avulsion, temporomandibular joint dislocation, jaw pain, and soft tissue, lip, and tongue injuries in a single center. There were 1750 male patients (59.6%) and 1187 female patients (40.4%), with a mean age of 35.20 ± 11.59 years. The incidence of oral injury was 0.1% per patient (4/2937) and 0.01% per session (4/22135). Oral complication characteristics included mucosal abrasion in 2 patients, dental fracture in 1 patient, and tooth avulsion in one. No dental fracture or avulsion in our patient population has resulted in aspiration. We found no evidence of jaw pain, temporomandibular joint dislocation, or injury to the lip or tongue. Our results demonstrate a minimum risk of oral complications during ECT and also provide additional justification for an adequate oral assessment by the ECT team before the procedure.

Chapter 1: The Burden of Heart Failure

Heart failure (HF) affects an estimated 6 million American adults, and the prevalence continues to increase, driven in part by the aging of the population and by increases in the prevalence of diabetes. In recent decades, improvements in the survival of patients with HF have resulted in a growing number of individuals living longer with HF. HF and its comorbidities are associated with substantial impairments in physical functioning, emotional well-being, and quality of life, and also with markedly increased rates of morbidity and mortality. As a result, the management of patients with HF has a substantial economic impact on the health care system, with most costs arising from hospitalization. Clinicians have an important role in helping to reduce the burden of HF through timely diagnosis of HF as well as increasing access to effective treatments to minimize symptoms, delay progression, and reduce hospital admissions. Prevention and early diagnosis of HF will play a fundamental role in efforts to reduce the large and growing burden of HF. Recent advances in pharmacotherapies for HF have the potential to radically change the management of HF, offering the possibility of improved survival and quality of life for patients.

Drug‐delivery contact lenses

The prevalence of ocular chronic diseases, like those associated to diabetes (diabetic retinopathy, macular edema and glaucoma), has increased significantly in the last years. They affect quite negatively people's quality of life, leading to extremely high economic costs both for patients and society. Recent advances in pharmacotherapy have greatly improved their prognosis. However, the efficacy and safety of the treatments currently available are still a concern. Topical drug delivery (DD) is useful to treat diseases of the anterior segment of the eye, but new strategies are needed to increase drug's bioavailability, which is quite low, and to overcome the difficulties that e.g. elderly people face in topical administration. Regarding the posterior segment, the challenge is to reach the target tissues due to the eye's natural barriers. Topical treatments are generally useless in this case. Systemic administration requires large doses to achieve local therapeutic levels and may induce undesirable side effects. Intravitreal route provides direct access to the intraocular environment and is highly effective, but is rather invasive and may origin serious complications, such as endophthalmitis, retinal detachment, intravitreal haemorrhage and cataract. In BioMat Research Group of IST, and within the frame of ORBITAL and SOL projects, we are making efforts to develop and optimize new DD systems for the treatment of diabetic ocular diseases that use noninvasive routes and present sustained drug release capabilities, increasing the drug's bioavailability at the target tissues. We propose the use of soft contact lenses (SCLs) as DD vehicles, due to their high biocompatibility and prolonged contact with the eye. Being frequently replaced, SCLs may be used as drug reservoirs for continued treatments, not only of diseases of the anterior part of the eye, but also of the posterior, using innovative techniques that enhance the drug penetration in the eye. Although in the last years much research has been done on this type of devices, they are still not available in the market due to a number of reasons, such as the need of improving systems efficiency, the difficulty in transposing to industry the preparation methodologies, issues related with sterilization/storage or lack of in vivo and clinical tests. In our studies, we have used different strategies to increase the bioavailability of the drugs and achieve adequate drug release profiles. Besides applying coatings and molecular imprinting techniques, we investigated the formation of prodrugs and drug inclusion in nanostructures that protect them in the biological medium. The incorporation in SCLs of cell penetrating peptides (CPP) that increase drug's ability to cross the corneal epithelium and reach the back of the eye, also led to to promising results. Ex‐vivo tests and mathematical modelling were used to predict the biological performance of the drug‐loaded devices in vivo before performing tests with animal models. Finally, alternative sterilization techniques which allow to process such challenging systems were explored.The obtained results shall contribute for the development of new forms of treatment of ocular diseases that are more predictable, safe and effective, giving response to an unmet clinical need.

The effect of antibody-mediated PCSK9 inhibitor on bare-metal stent implantation outcome

Abstract Introduction Percutaneous coronary intervention (PCI) is the gold standard for the management of acute coronary syndrome, and has been benefited from advances in pharmacotherapy and device innovation. Nevertheless, in-stent restenosis and stent thrombosis remain serious complications following PCI procedure with stent implantation. Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme known for its role in plasma cholesterol homeostasis. Efficiently reducing plasma cholesterol, PCSK9 inhibition recently became a pivotal treatment strategy for hypercholesterolemia. However, the effect of PCSK9 inhibition on stent implantation outcomes remains uninvestigated. Methods Carotid artery bare-metal stent (BMS) implantation was performed on C57Bl/6 mice, which then a parallel assessment of various inflammatory mediators was performed. To inhibit PCSK9, alirocumab was administered weekly to antiplatelet-treated mice started before stent implantation. Six weeks after the stent implantation procedure, animals were harvested and histomorphometric analysis was performed on stented arteries. In vitro cell migration and cellular senescence were also assessed on alirocumab-treated primary human aortic endothelial (EC) and vascular smooth muscle cells (VSMC). Results Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. Interestingly, the increase in PCSK9 level was confirmed in the stented vascular tissue, but not in plasma (Fig 1A). Following alirocumab treatment, PCSK9 inhibition results in an increased intimal hyperplasia in the stented vascular segment of alirocumab-treated animals compared to controls (Fig 1B). In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human VSMC, while blunted the migration and increased the senescence of EC. Conclusion The results of this study demonstrated that antibody-based PCSK9 inhibition worsen bare-metal stent implantation outcome in mice. This observed effect is mediated, in part, by the differential effect on VSMC and EC senescence, thus promoting in-stent intimal hyperplasia while blunting vascular healing. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.

Antithrombotic Treatment in Coronary Artery Disease.

Coronary artery disease exhibits growing mortality and morbidity worldwide despite the advances in pharmacotherapy and coronary intervention. Coronary artery disease is classified in the acute coronary syndromes and chronic coronary syndromes according to the most recent guidelines of the European Society of Cardiology. Antithrombotic treatment is the cornerstone of therapy in coronary artery disease due to the involvement of atherothrombosis in the pathophysiology of the disease. Administration of antiplatelet agents, anticoagulants and fibrinolytics reduce ischemic risk, which is amplified early post-acute coronary syndromes or post percutaneous coronary intervention; though, antithrombotic treatment increases the risk for bleeding. The balance between ischemic and bleeding risk is difficult to achieve and is affected by patient characteristics, procedural parameters, concomitant medications and pharmacologic characteristics of the antithrombotic agents. Several pharmacological strategies have been evaluated in patients with coronary artery disease, such as the effectiveness and safety of antithrombotic agents, optimal dual antiplatelet treatment schemes and duration, aspirin de-escalation strategies of dual antiplatelet regimens, dual inhibition pathway strategies as well as triple antithrombotic therapy. Future studies are needed in order to investigate the gaps in our knowledge, including special populations.