Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone. MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals. PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates. CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure. THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.

Development of biosensors for detection of fibrinogen: a review.

Fibrinogen as a major inflammation marker and blood coagulation factor has a direct impact on the health of humanity. The variations in fibrinogen content lead to risky conditions such as bleeding and cardiovascular diseases. So, accurate methods for monitoring of this glycoprotein are of high importance. The conventional methods, such as the Clauss method, are time consuming and require highly specialized expert analysts. The development of fast, simple, easy to use, and inexpensive methods is highly desired. In this way, biosensors have gained outstanding attention since they offer means for performing analyses at the points-of-care using self-testing devices, which can be applied outside of clinical laboratories or hospital. This review indicates that different electrochemical and optical sensors have been successfully implemented for the detection of fibrinogen under normal levels of fibrinogen in plasma. The biosensors for the detection of fibrinogen have been designed based on the quartz crystal microbalance, field-effect transistor, electrochemical impedance spectroscopy, amperometry, surface plasmon resonance, localized surface plasmon resonance, and colorimetric techniques. Also, this review demonstrates the utility of the application of nanoparticles in different detection techniques.

Laser Therapy Effects on Periodontal Status: A Randomized Study Using Gaussian Network Analysis and Structural Equation Modeling Approach.

Background and Objectives: This paper aims to assess the role of laser therapy in periodontitis through an innovative approach involving computational prediction and advanced modeling performed through network analysis (Gaussian graphical models-GGMs) and structural equations (SEM). Materials and Methods: Forty patients, exhibiting periodontal pockets with a minimum depth of 5 mm, were randomly divided into two groups: a control group and a laser group. Four specific indicators were measured for each tooth, namely periodontal pocket depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque index (PI), and the mean of six measured values was recorded at five time markers (baseline, 6 months, 1 year, 2 years, and 4 years). The assessment algorithm included enrollment, measurements, and differential non-surgical periodontal treatment, according to the group allocation. Scaling, root planing, and chlorhexidine 1% were conducted for the control group, and scaling, root planing and erbium, chromium:yttrium-scandium-gallium-garnet (Er,CR:YSGG) laser therapy were conducted for the laser group. Results: The main results highlight that the addition of laser treatment to scaling and root planing led to notable clinical improvements, decreasing the PPD values, reducing the BOP scores, and increasing the CAL. Conclusions: Notable relationships between the specific indicators considered were highlighted by both the GGMs and by SEM, thus confirming their suitability as proxies for the success of periodontal treatment.

Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is ranked as the third most prevalent skin condition with a worldwide prevalence of 2.4%. Atopic dermatitis is a common form of eczema. It develops in infancy or childhood and continues into adulthood with symptoms ranging from mild to severe. Pruritis and inflammation are the hallmark symptoms of AD. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Abrocitinib is a JAK1 selective inhibitor; inhibition results in a decreased interleukin (IL) 4 activation and decreased pruritis in a patient with AD. Abrocitinib is hepatically metabolized by multiple cytochrome P450 enzymes, and dose modification may be required when administered with concurrent medications. CLINICAL TRIALS: At least 6 JAK1 Atopic Dermatitis Efficacy and Safety (JADE) trials were conducted evaluating Investigator's Global Assessment and Eczema Area and Severity Index score for efficacy. All JADE trials showed abrocitinib 100 mg and 200 mg doses efficacious when compared with placebo. Common adverse reactions were related to gastrointestinal disturbances, headache, and acne. Serious adverse reactions to assess risk for include serious infections, malignancy, major adverse cardiovascular events, and venous thromboembolisms. THERAPEUTIC ADVANCE: Abrocitinib provides a valuable treatment option for patients with moderate-to-severe AD unresponsive to other therapies for those candidates without a high risk for significant adverse reaction associated with its use.

Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

BACKGROUND: Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. CLINICAL TRIALS: The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. THERAPEUTIC ADVANCE: Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

Anakinra-An Interleukin-1 Receptor Antagonist for COVID-19.

BACKGROUND: Coronavirus disease (COVID-19) caused by SARS-CoV-2 virus caused a global pandemic in 2019. There are limited pharmacologic options available. The Food and Drug Administration initiated an emergency use authorization process to expedite pharmacologic agents to treat COVID-19. There are several agents available through the emergency use authorization process, ritonavir-boosted nirmatrelvir, remdesivir, and baricitinib. Anakinra is an interleukin (IL)-1 receptor antagonist that exhibits properties in fighting against COVID-19. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Anakinra is a recombinant IL-1 receptor antagonist. The epithelial cell damage that may occur with COVID-19 enhances the release of IL-1, which plays a central role in severe cases. Thus, drugs that inhibit the IL-1 receptor may be beneficial in the management of COVID-19. Anakinra has good bioavailability after subcutaneous injection and a half-life of up to 6 hours. CLINICAL TRIALS: The SAVE-MORE, double-blind, randomized controlled trial, phase 3 evaluated the efficacy and safety of anakinra. Anakinra 100 mg was given subcutaneously daily for up to 10 days in patients with moderate and severe COVID-19 and plasma suPAR ≥6 ng/mL. Anakinra group had a 50.4% fully recovered with no viral RNA detected on day 28 versus 26.5% for placebo, and more than 50% of relative decrease in mortality. A significantly decreased risk of worse clinical outcome was observed. THERAPEUTIC ADVANCE: COVID-19 causes global pandemic and a serious viral disease. There are limited therapy options to combat this deadly disease. Anakinra is an IL-1 receptor antagonist and shown to be effective for the treatment of COVID-19 in some trials but not others. Anakinra, the first in this class, seems to have a mix result for the treatment of COVID-19.

Tirzepatide: A Dual Glucose-dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 Agonist for the Management of Type 2 Diabetes Mellitus.

BACKGROUND: Diabetes is a chronic disease that can lead to many complications, and controlling glucose balance is essential. Incretin hormones are produced in the gut and are essential to maintaining glucose homeostasis. Their effects range from increasing insulin synthesis, insulin secretion, and glucose sensing and decreasing glucagon secretion to promote satiety and suppressing appetite. Tirzepatide is a first in class dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP) analog approved for the management of adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise. PHARMACODYNAMICS AND PHARMACOKINETICS: Tirzepatide is a synthetic chemical structure based on the GIP sequence and consists of 39 amino acid peptides. Tirzepatide increases insulin secretion, reduces glucagon release in a glucose-dependent manner, decreases fasting and postprandial glucose levels, promotes satiety, decreases body weight, and delays gastric emptying. Pharmacodynamics and pharmacokinetics properties of tirzepatide were similar in patients with kidney and hepatic impairment, and its metabolites are excreting through urine and feces. CLINICAL TRIALS: The SURPASS trials are pivotal phase 3 trials assessing the efficacy and safety of tirzepatide as monotherapy and as an add-on to different antihyperglycemic drugs for the management of T2DM. Tirzepatide consistently showed reductions in HbA1c, as well as benefits with weight loss, with common adverse events reported related to gastrointestinal issues. THERAPEUTIC ADVANCE: Tirzepatide is a novel first in class dual GIP and glucagon-like peptide-1 agonist that improves overall glycemic control as an adjunct to diet and exercise. It has the potential benefits in other therapeutic areas such as obesity.

Mitapivat: A Quinolone Sulfonamide to Manage Hemolytic Anemia in Adults With Pyruvate Kinase Deficiency.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare enzyme-linked glycolytic defect resulting in mild-to-severe chronic persistent erythrocyte hemolysis. The disease is an autosomal recessive trait caused by mutations in the PK liver and red blood cell gene characterized by insufficient erythrocyte PK activity. PK deficiency is most diagnosed in persons of northern European descent and managed with packed red blood cell transfusions, chelation, and splenectomy with cholecystectomy. Mitapivat is the first approved therapy indicated for hemolytic anemia in adults with PK deficiency with the potential for delaying splenectomy in mild-moderate disease. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Mitapivat is a PK activator that acts by allosterically binding to the PK tetramer and increases PK activity. The red blood cell form of PK is mutated in PK deficiency, which leads to reduced adenosine triphosphate, shortened red blood cell lifespan, and chronic hemolysis. The half-life of elimination is 3-5 hours, with 73% bioavailability, 98% plasma protein binding, and a median duration of response of 7 months. CLINICAL TRIALS: Mitapivat has been investigated through various clinical trials for different therapeutic indications. Pivotal trials that serve the primary focus throughout this article are ACTIVATE, ACTIVATE-T, and RISE. ACTIVATE is a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of mitapivat in adult patients who were not receiving regular blood transfusions. Contrarily, ACTIVATE-T explored the safety and efficacy of mitapivat in adults with PK deficiency who received regular blood transfusions. Both trials demonstrated favorable use of mitapivat in PK deficiency. Focusing on another indication, the ongoing RISE trial investigates the optimal dosage of mitapivat in sickle cell disease. THERAPEUTIC ADVANCE: Mitapivat is an appropriate treatment for adults with PK deficiency requiring transfusions and may be considered for patients with symptomatic anemia who do not require transfusions and/or PK deficiency with compensated hemolysis without overt anemia.

Nivolumab/Relatlimab-rmbw: A Novel Dual Combination Therapy to Treat Adult and Pediatric Patients With Unresectable or Metastatic Melanoma.

BACKGROUND: Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma. MECHANISM OF ACTION PHARMACOKINETICS/PHARMACODYNAMICS: The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure-response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe. CLINICAL TRIALS: In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) and hazard ratio of 0.75 (95% CI, 0.62-0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone. THERAPEUTIC ADVANCE: The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.

Roflumilast 0.3% Cream: a Phosphodiesterase 4 Inhibitor for the Treatment of Chronic Plaque Psoriasis.

BACKGROUND: Plaque psoriasis is a chronic dermatologic autoimmune disease that affects adults and children. Roflumilast 0.3% cream is currently the only topical phosphodiesterase 4 inhibitor indicated for the treatment of plaque psoriasis in patients 12 years or older. PHARMACODYNAMICS AND PHARMACOKINETICS: Roflumilast inhibits phosphodiesterase 4 inhibitor enzyme leading to the accumulation of cyclic adenosine monophosphate, which suppresses the inflammatory mediators interferon-γ and tumor necrosis factor-α. Roflumilast, applied once daily, reaches steady state by day 15 and has a half life of approximately 4 days in adults. Roflumilast undergoes extensive hepatic metabolism by cytochrome P450 enzymes and conjugation. Roflumilast is 99% bound to plasma proteins. CLINICAL TRIALS: Roflumilast efficacy and safety were evaluated in the DERMIS-1 and DERMIS-2 clinical trials. These identically designed, double-blind, vehicle-controlled phase 3 trials randomized 881 patients to roflumilast 0.3% cream or vehicle, applied once daily for 8 weeks. In DERMIS-1, the Investigator Global Assessment success rate was 42.4% with roflumilast 0.3% cream compared with 6.1% with the vehicle (32.3%-46.9%; P <0.001). Similarly, in DERMIS-2, the Investigator Global Assessment success rate was 37.5% with roflumilast 0.3% cream compared with 6.9% with the vehicle (20.8%-36.9%; P <0.001). Of 881 participants, 1% discontinued treatment with roflumilast cream due to adverse reactions compared with 1.3% treated with vehicle. Urticaria at the application site (0.3%) was the most common adverse reaction that led to discontinuation of roflumilast. THERAPEUTIC ADVANCE: To date, topical corticosteroids are the most commonly used agents to treat mild plaque psoriasis. Sensitive areas are often challenging to treat with existing topical therapy, including corticosteroids. Topical roflumilast has shown to be effective in treating sensitive areas, including skin folds, and may be an alternative to systemic therapy for some patients. The Food and Drug Administration approved topical roflumilast for the treatment of plaque psoriasis, including intertriginous areas, for patients 12 years or older.

Comprehensive Targeted Treatment for Neuropathic and Nociceptive Pain in Palliative Care Patients.

BACKGROUND: Pain is a common symptom in patients with advanced, metastatic, or terminal cancer. Neuropathic pain and psycho-emotional suffering are factors that increase the difficulty of pain management. Pain control in patients with cancer remains a challenge for medical professionals. STUDY QUESTION: What is the evolution of neuropathic/mixed pain compared with nociceptive pain under standardized treatment in patients with cancer? STUDY DESIGN: A prospective, longitudinal, open-label, nonrandomized study was conducted on patients with cancer pain. MEASURES AND OUTCOMES: Pain type was assessed at admission using the modified Brief Pain Inventory, and pain intensity was assessed daily using the Numerical Rating Scale for 14 days and on days 21 and 28. Screening of depression was performed on days 1, 7, 14, 21, and 28 using the Hamilton Depression Rating Scale. Patients with pain and depression received analgesics with antidepressants, while patients without depression received analgesics or analgesics with an anticonvulsant depending on the pain subtype. RESULTS: Of 72 patients, 23 had nociceptive pain and 49 had neuropathic/mixed pain. At admission, pain intensity was higher for patients with neuropathic/mixed pain compared with nociceptive pain (mean values: 7.06 vs. 5.82) with statistical significance ( P = 0.001) and remained as such at the end of this study (mean values: 3.77 vs. 2.73). A decrease in the mean pain intensity was observed in all types of pain, but without statistical significance regardless of pain type and treatment protocol used ( P = 0.77). If depression was present, antidepressants combined with analgesics decreased pain and depression scores significantly ( P = 0.001). CONCLUSIONS: Patients with neuropathic/mixed pain have higher levels of pain and lower response to treatment. Identifying psycho-emotional suffering can improve pain control by intervening in the physical and psycho-emotional components of pain.

Switch from Olanzapine Long-Acting Injectable to its Oral Equivalent during COVID-19 Pandemic: a Real World Observational Study.

Schizophrenia is a psychiatric condition with chronic evolution, one of the most disabling diseases. The main cause for the disease's progression is considered to be the lack of compliance with the treatment. Long-acting injectable antipsychotics (LAIs) are an important treatment option for patients with schizophrenia. Olanzapine long-acting injection (OLZ-LAI) is a pamoate monohydrate salt of olanzapine that is administered by deep intramuscular gluteal injection. The aim of this paper is to report the effects of a sudden and unplanned switch from olanzapine long-acting injectable to oral olanzapine in remitted patients with schizophrenia due to restrictions caused by the COVID-19 pandemic. An observational study conducted in the Clinical Hospital of Psychiatry and Neurology of Brasov, Romania between April 2020 and March 2021. 27 patients with OLZ-LAI were entered into the study. Of 27 cases, 21 patients preferred to be switched to oral olanzapine (77.77%). Only 6 patients continued with the long-acting formulation. The main reason for the initiation of olanzapine pamoate in all the patients was non-adherence to oral medication (80.95%), and the mean age of starting LAI olanzapine was 36.42 years (SD ± 10.09). Within the following 12 months after switching from olanzapine LAI to OA, 15 patients (71.42%) relapsed, and 12 were admitted to the emergency psychiatric unit. The COVID-19 pandemic has brought multiple disservices to current medical practice. Sudden and unplanned switch from olanzapine long-acting formulation to oral olanzapine was followed by the high rate of relapse in remitted schizophrenia.

Harmonizing and improving European education in prescribing: An overview of digital educational resources used in clinical pharmacology and therapeutics.

AIM: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. METHODS: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. RESULTS: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. CONCLUSION: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials.

Rapid Titration of Clozapine in Schizophrenia and Bipolar Disorder.

Despite evidence accumulated over 30 years of clozapine efficacy in schizophrenia, its use is suboptimal. Long duration of standard titration and monitoring procedures are strong barriers in clozapine prescribing. The aim of the present paper is to discuss the challenges of rapid clozapine titration. The currently approved/recommended titration methods in US, Europe, and Australia are discussed. The rapid clozapine titration was introduced in our hospital in the early 2000's as "last resort" method for aggressive, belligerent or homicidal patients with schizophrenia and bipolar disorder. In our opinion, rapid clozapine titration might shorten the duration of patient and family suffering associated with uncontrolled psychotic symptoms, reduce the need and risks associated with polypharmacy, and reduce the costs of health care services of prolonged hospitalization. As there are no randomized controlled clinical trials to compare the efficacy and safety of standard versus rapid titration of clozapine in schizophrenia or bipolar disorder, future studies are needed.

Trimetazidine Therapy in Coronary Artery Disease: The Impact on Oxidative Stress, Inflammation, Endothelial Dysfunction, and Long-Term Prognosis.

BACKGROUND: In coronary artery disease (CAD), reduction of perfusion in coronary arteries is followed by increases of oxidative stress and decreases of adenosine triphosphate reserve. In this condition, trimetazidine (TMZ), a metabolic anti-ischemic agent, seems to be an ideal therapeutic agent because it increases mitochondrial adenosine triphosphate production. STUDY QUESTION: To evaluate the impact of TMZ on oxidative stress, inflammation, endothelial dysfunction, and long-term prognosis in CAD. STUDY DESIGN: Patients with CAD with symptoms not adequately controlled were enrolled consecutively for a period of 18 months. MEASURES AND OUTCOMES: Five hundred seventy patients with CAD were enrolled in a prospective study and divided into 4 groups in relation with the type of CAD and the addition of TMZ to optimal medical therapy (OMT). The impact of TMZ added to OMT on oxidative stress (total antioxidant status, antioxidized low-density lipoprotein antibodies, and antimyeloperoxidase antibodies), endothelial dysfunction (flow-mediated dilatation and von Willebrand factor activity), and inflammation (C-reactive protein and fibrinogen) at 6 months and on long-term prognosis in CAD in comparison with OMT at 5 years of follow-up was evaluated. RESULTS: At 6 months, TMZ added to OMT significantly decreased the incidence of oxidative stress in CAD (P < 0.03) and reduced endothelial dysfunction and inflammation only in non-ST-elevation acute coronary syndrome (NSTE-ACS, P < 0.04). TMZ added to OMT with or without interventional/surgical vascularization led to decreased readmission for NSTE-ACS and heart failure (P < 0.05) in all patients with CAD and a significantly reduced incidence of cardiovascular death, acute myocardial infarction, and stroke (P < 0.05) in patients with NSTE-ACS at 5 years of follow-up. CONCLUSIONS: In patients with NSTE-ACS, TMZ added to OMT with or without interventional and/or surgical reperfusion reduced oxidative stress, endothelial dysfunction, inflammation, and major acute cardiovascular events, whereas in patients with chronic coronary syndrome, TMZ decreased oxidative stress and readmission for ACS and heart failure.

EurOP2E - the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers.

PURPOSE: Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. METHODS: CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. RESULTS: Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. CONCLUSION: Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system.

Are Bioactive Molecules from Seaweeds a Novel and Challenging Option for the Prevention of HPV Infection and Cervical Cancer Therapy?-A Review.

Cervical cancer represents one of the leading causes of cancer-related death in women all over the world. The infection with human papilloma virus (HPV) is one of the major risk factors for the development of premalignant lesions, which will progress to cervical cancer. Seaweeds are marine organisms with increased contents of bioactive compounds, which are described as potential anti-HPV and anti-cervical cancer agents. Our study aims to bring together all the results of the previous studies, conducted in order to highlight the potency of bioactive molecules from seaweeds, as anti-HPV and anti-cervical agents. This paper is a review of the English literature published between January 2010 and August 2020. We performed a systematic study in the Google Academic and PubMed databases using the key words "HPV infection", "anticancer", "seaweeds", "cervical cancer" and "carcinogenesis process", aiming to evaluate the effects of different bioactive molecules from marine algae on cervical cancer cell lines and on HPV-infected cells. Only original studies were considered for our research. None of the papers was excluded due to language usage or affiliation. Recent discoveries pointed out that sulfated polysaccharides, such as dextran sulfate heparan or cellulose sulfate, blocked the ability of HPV to infect cells, and inhibited the carcinogenesis process. Carrageenans inhibited the virions of HPV from binding the cellular wall. Fucoidan induced the growth inhibition of HeLa cervical cells in vitro. Heterofucans exhibited antiproliferative effects on cancer cell lines. Terpenoids from brown algae are also promising agents with anti-cervical cancer activity. Considering all the results of the previous studies, we observed that great amounts of bioactive molecules from seaweeds could treat both unapparent HPV infection and clinical visible disease. Furthermore, these molecules were very efficient in the treatment of invasive cervical carcinomas. In these conditions, we consider seaweeds extracts as a novel and challenging therapeutic strategy, and we hope that our study paves the way for further clinical trials in the field.

Pharmacological and Therapeutic Properties of Punica granatum Phytochemicals: Possible Roles in Breast Cancer.

Background: Pomgranate (Punica granatum) represents a high source of polyphenols with great bioavailability. The role of this fruit in the prevention and treatment of various malignant pathologies has been long time cited in both scientific and non-scientific literature, making thus important to identify its involvement in the pathophysiological processes. The treatment for breast cancer had focused on the inhibition of the mechanisms that governs the estrogen activity. These mechanisms are covered either by the antagonism of the estrogen receptor (ER) or by the inhibition of the estrogen synthesis. Our interest in identifying a bioactive compound rich in polyphenols, which induces both the antagonism of the estrogen receptor, and the inhibition of the estrogen synthesis, revealed us the pomegranate fruit and its derivatives: peel and seeds. Pomegranates' chemical composition include many biological active substances such as flavonols, flavanols, anthocyanins, proanthocyanidins, ellagitannins and gallotannins. Materials and Methods: We performed a review of the scientific literature by using the following keywords: "pomegranate", "breast cancer", "Punica granatum", "pomegranate polyphenols". Our search was performed in the PubMed and Google Scholar databases, and it included only original research written in English from the last 20 years. None of the articles were excluded due to affiliation. A total number of 28 original papers, which mentioned the beneficial activity of pomegranate against breast cancer, were selected. Both clinical and preclinical studies were considered for this review. Results: Recent discoveries pointed out that polyphenols from Punica granatum possess strong anti-cancer activity, exhibited by a variety of mechanisms, such as anti-estrogenic, anti-proliferative, anti-angiogenetic, anti-inflammatory, and anti-metastatic. Pomegranate extracts induced cell cycle arrest in the G0/G1 phase, and induced cytotoxicity in a dose- and time-dependent manner. Moreover, several polyphenols extracted from pomegranate inhibited the invasion potential, migration and viability of breast cancer cells. The effects of pomegranate juice on serum estrogens and other sexual hormones levels were also investigated on two human cohorts. Conclusions: Punica granatum represents a promising area in oncology. The large availability and low cost, associated with the lack of side effects, made from this natural product a great strategy for the management of breast cancer. There are several mechanistic studies in mouse models and in breast cancer cell lines, suggesting the possible pathways through which polyphenols from pomegranate extracts act, but larger and better-controlled studies are necessary in the future. Only two small clinical trials were conducted on humans until now, but their results are contradictory and should be considered preliminary.

Hydroxychloroquine and COVID-19: Lack of Efficacy and the Social Construction of Plausibility.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 SARS- Cov2 has taken the world by surprise. Among the first promising repurposing agents proposed for treatment and prophylaxis, 2 antimalarial agents came into limelight: chloroquine and its less toxic derivative, hydroxychloroquine (HCQ). Intense research and public debates have followed. AREAS OF UNCERTAINTY: As HCQ is still used and studied, future research may bring novel evidence, modifying the state-of-the-art. Despite the lack of a single randomized control trial (RCT) with positive results, there are currently (as for the search on 30th of August 2020) more than 250 RCT registered on ClinicalTrials.gov with HCQ in COVID patients, and more than 150 of them are "still recruiting" or "not yet recruiting" patients. DATA SOURCES: Our study combines a therapeutic evaluation of RCT data with a sociological analysis of related controversies, examining scientific and public arena discourses. RESULTS: Although any hope of a positive effect was brought exclusively by some and not all of the observational studies, none of the 7 RCT published until now have found any benefit. From a sociological perspective, the HCQ controversy is a useful case study for understanding the construction of plausibility in a cultural context polarized into competing versions of reality, with different epistemologies and ideologies. CONCLUSIONS: The results of the first RCTs have been published, and they are disappointing; beneficial effects of HCQ could not be proven either for negative conversion on polymerase chain reactions of COVID patients or for postexposure prophylaxis. The question to be asked is: how many studies do we need until HCQ is abandoned? Argumentative time work, appealing to temporal properties of HCQ including its historical use, accumulation of evidence, alternative therapeutic scenarios, and sensationalist tempo for rhetorical purpose, plays a significant role in its continuing legitimation.

A Systematic Review of Clinical Studies on the Effect of Psychoactive Cannabinoids in Psychiatric Conditions in Alzheimer Dementia.

BACKGROUND: The systematic reviews and meta-analyses performed until now did not provide the adequate picture of actual knowledge in the field of neuropsychiatric symptoms treatment using psychotropic cannabinoids in patients with Alzheimer disease (AD). THE STUDY QUESTION: Which is the level of evidence, from quantitative and qualitative point of view, concerning the efficacy and safety of the treatment with psychotropic cannabinoids of neuropsychiatric symptoms in AD? STUDY DESIGN: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Google Scholar Data, and Clinicaltrials.gov were searched for randomized clinical trials with cannabinoids in Alzheimer dementia agitation and aggression. MEASURES AND OUTCOMES: The rationale, the objectives, and the methods used for searching the trials have been established according to PRISMA Criteria 2009. RESULTS: The total number of patients in the 9 publications evaluated in this study, which included data from 6 clinical trials, was 422 patients-treatments, where treatment was a psychoactive cannabinoid or placebo, some of them obtained by multiplying selected patients with the number of cannabinoid treatments in the crossover studies. There are multiple sources of bias in the analyzed studies; 2 elements have prevented conclusive results. One element was polypragmazia, a major role being played by the use of psychotropic drugs other than cannabinoids, in an effort to reduce agitation and aggressive behavior. The second one was the large number of concomitant symptoms, for example, pain (commonly causing anxiety and agitation). CONCLUSIONS: No clear conclusion can be drawn on the effectiveness of psychoactive cannabinoids in the treatment of psychiatric manifestations, in particular agitation and aggression, in AD. In the future, large randomized controlled trial with adequate designs, without crossover and for longer duration, adapted to cannabinoid pharmacokinetics, is required to establish the real efficacy and safety of these drugs in aggressive and/or agitated patients with AD.