Making Sense of Composite Endpoints in Clinical Research.

Multiple drugs currently used in clinical practice have been approved by regulatory agencies based on studies that utilize composite endpoints. Composite endpoints are appealing because they reduce sample size requirements, follow-up periods, and costs. However, interpreting composite endpoints can be challenging, and their misuse is not uncommon. Incorrect interpretation of composite outcomes can lead to misleading conclusions that impact patient care. To correctly interpret composite outcomes, several important questions should be considered. Are the individual components of the composite outcome equally important to patients? Did the more and less important endpoints occur with similar frequency? Do the component endpoints exhibit similar relative risk reductions? If these questions receive affirmative answers, the use and interpretation of the composite endpoint would be appropriate. However, if any component of the composite endpoint fails to satisfy the aforementioned criteria, interpretation can become difficult, necessitating additional steps. Regulatory agencies acknowledge these challenges and have specific considerations when approving drugs based on studies employing composite endpoints. In conclusion, composite endpoints are valuable tools for evaluating the efficacy and net clinical benefit of interventions; however, cautious interpretation is advised.

Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of amyloid-ß (Aß), and selective neurodegeneration are the anatomopathological hallmarks of this disease. The dysregulation of calcium may be present in all the stages of AD, and it is associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, and chronic neuroinflammation. Although the cytosolic calcium alterations in AD are not completely elucidated, some calcium-permeable channels, transporters, pumps, and receptors have been shown to be involved at the neuronal and glial levels. In particular, the relationship between glutamatergic NMDA receptor (NMDAR) activity and amyloidosis has been widely documented. Other pathophysiological mechanisms involved in calcium dyshomeostasis include the activation of L-type voltage-dependent calcium channels, transient receptor potential channels, and ryanodine receptors, among many others. This review aims to update the calcium-dysregulation mechanisms in AD and discuss targets and molecules with therapeutic potential based on their modulation.

Definition of self-medication: a scoping review.

Self-medication (SM) is a global and growing phenomenon. It represents a public health problem due to antibiotic resistance, risk of adverse drug reactions, drug-drug interactions, disease masking, and increased morbidity. There is not a consensus on the definition of SM. The definitions found in different studies make it difficult to address this problem from a theoretical perspective and therefore find an adequate solution to this public health problem. The aim of this article is to search the medical literature to characterize the current understanding of SM in the medical community. We conducted a scoping review of definitions of SM by searching on PubMed - Medline, Embase, and LILACS using the following combination of keywords: 'self-prescription' or 'self prescription', 'self-medication' or 'self medication', or 'automedication' and 'definition' or 'explanation'. The search was limited to articles containing the definition of SM, with no limit on language or year. Duplicate studies and those that did not mention the definition of SM were excluded from the final review. A total of 65 studies were included in the final selection. We found a vast heterogeneity in the definition of SM. Most articles based their definition of SM on the process of obtaining the drug, the nonparticipation of a specific health professional, the source of the medication, and the reason for SM. Other interesting concepts such as self-care, nonadherence to a prescription, reuse of stored drugs, and sharing and lending medicines were also considered forms of SM by other authors, however. This study highlights the need to reach a consensus regarding the definition of SM to adequately propose strategies to address this global health problem. This study shows the diverse concepts that need to be included in a future definition of SM. Plain Language Summary: Definition of self-medication: a review with systematic methodology Self-medication (SM) is a global and growing phenomenon that represents a public health problem due to antibiotic resistance, risk of dangerous side effects, interactions between drugs, and disease masking. Currently, there is not a consensus on the definition of SM, which makes it difficult to address this problem and therefore find an adequate solution. Making a standard definition would allow the development of programs focused on addressing drug-related problems associated with self-medication behavior. The purpose of this article is to search the medical literature to define the current understanding of SM in the medical community. We included a total of 65 studies and found a great variance in the definition of SM. Most articles based their definition of SM on the process of obtaining the drug, the nonparticipation of a specific health professional, the source of the medication, and the reason for SM. Other interesting concepts such as self-care, not following a prescription, reuse of stored drugs, and sharing and lending medicines were also considered forms of SM by other authors, however. Furthermore, this study highlights that SM is a wider concept that goes beyond aiming to promote and restore health, as aesthetic and recreational purposes are also reasons for SM that can put individuals at risk and compromise the correct and safe use of medications.

Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.

The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 318.15 K) determined by UV-vis spectrophotometry. From the solubility data, the thermodynamic solution, mixing, and transfer functions were calculated in addition to performing the enthalpy-entropy compensation analysis. The solubility of isoniazid depends on the concentration of PEG 200 (positive cosolvent effect) and temperature (endothermic process) reaching its maximum solubility in pure PEG 200 at 318.15 K and the lowest solubility in pure water at 278.15 K. The solution process is favored by the solution entropy and according to the enthalpy-entropy compensation analysis it is driven by entropy in mixtures rich in water and by enthalpy in mixtures rich in PEG 200.

Immune-related adverse events of biological immunotherapies used in COVID-19.

The use of biological immunotherapeutic drugs is one of the options currently being evaluated and employed to manage COVID-19, specifically monoclonal antibodies, which have shown benefit by regulating the excessive immune response seen in patients with severe infection, known as a cytokine storm. Tocilizumab has received particular importance for this clinical application, as has sarilumab. Both drugs share a substantial similarity in terms of pharmacodynamics, being inhibitors of the interleukin six receptor (IL-6Rα). Furthermore, sotrovimab, a neutralizing anti-SARS CoV-2 antibody, has gained the attention of the scientific community since it has recently been authorized under certain circumstances, positioning itself as a new therapeutic alternative in development. However, despite their clinical benefit, biological immunotherapies have the potential to generate life-threatening immune-related adverse events. Therefore it is essential to review their incidence, mechanism, and risk factors. This review aims to provide a comprehensive understanding of the safety of the biological immunotherapeutic drugs currently recommended for the treatment of COVID-19, provide a review of the known immune-mediated adverse events and explore the potential immune-related mechanisms of other adverse reactions.

Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics.

Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer's disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases.

Type III Kounis Syndrome Secondary to Ciprofloxacin-Induced Hypersensitivity.

Kounis syndrome (KS) is a rare syndrome characterized by the co-occurrence of acute coronary syndromes in the setting of mast cell and platelet activation in response to hypersensitivity reactions. It can be manifested as coronary vasospasms, acute myocardial infarction, or stent thrombosis triggered by drugs, vaccines, foods, coronary stents, and insect bites. It is a life-threatening condition that needs to be adequately recognized for early diagnosis and appropriate treatment. In this case report, we present a 71-year-old patient with a history of arterial hypertension and non-ST elevation myocardial infarction six months earlier that was treated percutaneously with angioplasty plus stent implantation in the circumflex artery, who subsequently presented to the emergency department due to generalized itching associated with tongue swelling, dyspnea, and chest pain after ingestion of ciprofloxacin for the treatment of a urogenital infection. An electrocardiogram showed ST elevation in II, III, and aVF leads, and positive troponin; thus, a coronary arteriography was performed that showed complete thrombotic stent occlusion in the circumflex artery. Consequently, diagnosis of type 4b inferolateral acute myocardial infarction secondary to ciprofloxacin-triggered type III Kounis syndrome was made. The aim of this report is to understand the relationship between the allergic reaction to ciprofloxacin and the acute coronary syndrome, and to create awareness of the importance of early diagnosis and treatment of this potentially fatal syndrome.

Prescription for COVID-19 by non-medical professionals during the pandemic in Colombia: a cross-sectional study.

Background: The COVID-19 pandemic has led to an increase in the behavior of self-medication (SM). Given the massive release of misleading information during the pandemic, some pharmacies recommend drugs such as ivermectin, azithromycin, and hydroxychloroquine that are not useful for preventing or treating COVID-19 and could expose patients to unnecessary adverse drug reactions (ADRs), drug-drug interactions (DDIs), disease masking, and antibiotic resistance. Rationale: SM with drugs advertised for COVID-19 can have consequences, and people should be aware of approved uses, potential contraindications, and ADRs. Thus, the aim of this study was to know the drug therapies including natural products and homeopathic drugs offered by Colombian pharmaceutical establishments for the prevention and treatment of COVID-19, as well as the information provided on the safe use of the product. Methods: An observational, cross-sectional mystery shopping study was carried out to determine the pharmaceutical alternatives for the management of COVID-19 offered by pharmaceutical establishments (drugstores, pharmacies, homeopathic pharmacies, and nutritional supplements stores) in Colombia, and information related to the safe use of the product. The study included 482 pharmaceutical establishments from 16 Colombian departments. Data collection was done through telephone calls to each of the establishments following an interview protocol pretending to be a patient who presents symptoms related to COVID-19. Results: About 57.3% (276) of the establishments recommended a product for the treatment of COVID-19 infection, 66.6% (321) asked whether the caller had COVID-19 symptoms and what they are, and 44.2% (213) suggested taking a COVID-19 test. Of 59 drugs suggested by pharmacies, the most recommended were azithromycin, ivermectin, acetaminophen, ibuprofen, and ASA (aspirin). From the establishments that recommended a product, dosage was indicated in 85.5% (236) of the pharmaceutical establishments and 14.5% (40) of the establishments reported the most common adverse effects of this substance. About 9.4% (26) of the establishments reported possible interactions of the recommended drugs and substances with food, beverages, or supplements.Conclusion: Pharmaceutical establishments in Colombia seem to have significantly contributed to self-medication for COVID-19 in Colombia during the pandemic. This behavior is inappropriate, since the mild forms of the disease do not have a specific treatment. Plain Language Summary: Self-medication induced by pharmaceutical establishments in Colombia during the COVID-19 pandemic Background: The COVID-19 pandemic has led to an increase in the behavior of self-medication (SM). Given the massive release of misleading information during the pandemic, some pharmacies recommend drugs such as ivermectin, azithromycin, hydroxychloroquine among others, which are not useful for preventing or treating COVID-19 and could expose patients to unnecessary side effects and interactions with other medications. People should be aware of the approved and non-approved uses, and potential side effects of these drugs. Rationale: The aim of this study was to know the drugs, including natural products and homeopathic drugs, offered by Colombian pharmaceutical establishments for the prevention and treatment of COVID-19, as well as the information provided on the safe use of the product. Methods: The study was done using the mystery shopping method, collecting data through telephone calls to each of the establishments by a trained individual pretending to be a patient with COVID-19 symptoms. The study included 482 pharmaceutical establishments from 16 Colombian departments. Results: Of 59 drugs suggested by pharmacies, the most recommended were azithromycin, ivermectin, acetaminophen, ibuprofen, and aspirin. The recommended dose was indicated in 85.5% (236) of the pharmaceutical establishments, and 14.5% (40) of them reported the most common adverse effects of the recommended product. About 9.4% (26) of the establishments reported possible interactions of the recommended drugs and substances with food, beverages, or supplements. Conclusion: The majority of the pharmaceutical establishments included in the study promoted inadequate self-medication for COVID-19 in Colombia during the pandemic.

Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients. Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations. Consequently, a therapeutic target concentration that may be useful for one patient may not be appropriate for another. Regular doses do not take into account the important PK variations in the critically ill, and the need to select an effective dose while minimising toxicity advocates for the use of therapeutic drug monitoring (TDM). This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.

Drug safety of frequently used drugs and substances for self-medication in COVID-19.

During the COVID-19 pandemic, the behavior of self-medication has increased. The dissemination of misleading information regarding the efficacy of certain drugs or substances for the prevention and treatment of COVID-19 has been the major contributing factor for this phenomenon. Alongside with the increase in self-medication behavior, the inherent risks to this act such as drug-drug interactions, adverse events, drug toxicity, and masking of symptoms have also increased. Self-medication in the context of COVID-19 has led to drug misuse leading in some cases to the development of fatal adverse drug reactions. It is important that during this ongoing pandemic drugs with potential clinical efficacy against COVID-19 are adequately analyzed regarding their efficacy, safety, and monitoring. The aim of this review is to describe the available evidence regarding the efficacy, safety, and monitoring of the drugs and substances that have been shown to be frequently used for self-medication in patients with COVID-19 (hydroxychloroquine, non-steroidal anti-inflammatory drugs, ivermectin, azithromycin, vitamins, aspirin, and chlorine dioxide) to adequately characterize their risks, safe use, monitoring strategies, and to reinforce the concept that these substances should not be used for self-medication and require a medical prescription. Plain Language Summary: Drug safety of frequently used drugs and substances for self-medication in COVID-19 Dissemination of information about potential COVID-19 treatments has led individuals to self-medicate and expose themselves to risks such as drug-drug interactions, side effects, antibiotic resistance, and misdiagnosis. There is a need to review the medical literature to evaluate the safety and efficacy of the drugs and substances commonly used by the population for the treatment and prevention of SARS CoV-2 infection. In this review, we included drugs that are frequently used for self-medication and commonly advertised such as ivermectin, hydroxychloroquine, chlorine dioxide, azithromycin, and non-steroidal anti-inflammatory drugs, among others. A brief introduction of the drug and its mechanism of action, followed by a summary of the efficacy in COVID-19 and safety, will be described for each drug in order to promote their responsible use.

Revisiting Excitotoxicity in Traumatic Brain Injury: From Bench to Bedside.

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality. Consequences vary from mild cognitive impairment to death and, no matter the severity of subsequent sequelae, it represents a high burden for affected patients and for the health care system. Brain trauma can cause neuronal death through mechanical forces that disrupt cell architecture, and other secondary consequences through mechanisms such as inflammation, oxidative stress, programmed cell death, and, most importantly, excitotoxicity. This review aims to provide a comprehensive understanding of the many classical and novel pathways implicated in tissue damage following TBI. We summarize the preclinical evidence of potential therapeutic interventions and describe the available clinical evaluation of novel drug targets such as vitamin B12 and ifenprodil, among others.

Synthetic Pharmacotherapy for Systemic Lupus Erythematosus: Potential Mechanisms of Action, Efficacy, and Safety.

The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy.

Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation.

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.