Drug Safety Research Articles

Role of the Pharmacotherapeutic Monitoring Service (PMS) of the Community Pharmacy in the detection and resolution of adverse reactions to statins linked to possible diagnostic errors in elderly patients

The Medication Review in the Pharmacotherapeutic Follow-up Service (PFS) seems to be an effective method to study long-term drug safety in the outpatient setting. The adverse drug reactions (ADRs) that are not immediately obvious are difficult to identify and sometimes can be confused with a more common condition. Misdiagnosis by not associating the symptoms of AMR to its pharmacological cause causes its masking and hinders its detection. Detect in the SFT service the diagnostic errors related to the non-detection of adverse reactions to statins. The data obtained from the medication review at the Pharmacotherapeutic Follow-up Service (PFS) were pooled for analysis. The patients who received the service were selected with the "DLGM screening" tool, an acronym "Diagnosis load Generated by Medications", that allows us to describe adverse drug reactions (ADRs), when their symptoms are attributed to a pathology, without considering medication as a possible underlying cause.Only the results of patients over 60 years of age, who after a prolonged period of statin use gradually presented musculoskeletal disorders (MSD) and other symptoms theoretically described as possible ADRs, are shown. In 66 % of the cases, corresponding to 14 patients out of a total of 21 studied, the physician modified the treatment and in 92% of these cases there was improvement and a decrease of the consumption of analgesics drug, anti-inflammatory and other drugs used to treat ADR symptoms. DLGM screening identified hidden AMRs in 62 % of patients.

Assessment of pharmacological effects and abuse potential of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 in mice.

The newly emerging synthetic cannabinoids (SCs) 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 have been observed to produce effects by activating cannabinoid type 1 (CB1) receptors. Nevertheless, the pharmacological effects and potential for abuse of these three substances remain to be studied. These substances have yet to be regulated in many countries. We investigated the safety, pharmacological effects, rewarding effects, and cannabinoid withdrawal of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201. This study evaluated the drug safety and the cannabinoid-specific pharmacological effects of the three substances through acute toxicity experiments (in which the LD50 of each substance was obtained) and tetrad experiments (comprising assessments of hypothermia, analgesia, locomotion inhibition, and catalepsy). Furthermore, the conditioned place preference (CPP) experiments and withdrawal experiments were conducted to evaluate the rewarding effect and cannabinoid withdrawal potential of the substances in question. The results demonstrated that all three drugs exhibited certain acute toxic effects and could potentially induce tetrad effects. The data were analyzed using non-linear regression, and the corresponding ED50 values and 95% confidence intervals (CI) were obtained. The rank order of potency was determined to be CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201. In the CPP experiments, it was demonstrated that 5F-EDMB-PICA significantly induced an increase in CPP score at a dose of 0.3mg/kg, while NM-2201 caused an increase in CPP score and a significant aversion effect at a dose of 2 and 3mg/kg, respectively. It is noteworthy that all three types of SCs were observed to produce a significant biphasic effect, indicating that CPP scores were biphasic for all compounds. Following the administration of the CB1 receptor antagonist rimonabant, a notable increase in head twitches and paw tremors was observed, indicating that these three SCs induce cannabinoid withdrawal through the mediation of CB1 receptors. The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances.

Enhancing Herbal Efficacy: Synthesis and Evaluation of Nanosuspension from Withania somnifera Root Extract

Background: Ayurveda emphasizes the balance of mind, body, and spirit, drawing on ancient texts that highlight the medicinal properties of herbs like Withania somnifera, known for its wide range of therapeutic applications and pharmacological benefits. Commonly referred to as Indian ginseng or Ashwagandha, Withania somnifera, demonstrates a variety of therapeutic effect , including anti-inflammatory, antitumor, sedative, hypnotic, deobstruent effects, narcotic, antioxidant, tonic, antistress, diuretic, aphrodisiac, immunomodulatory, and rejuvenating properties. Nanotechnology, particularly through the development of nanosuspensions, offers a significant advancement in medicine, addressing challenges like poor solubility and low bioavailability of lipophilic drugs. Nanosuspensions can enhance drug safety and efficacy by improving solubility and altering pharmacokinetics. Methods: This study focuses on formulating and characterizing a nanosuspension using an ethanolic extract of Withania somnifera roots. The nanosuspension (NSWS) underwent comprehensive characterization, utilizing techniques such as FT-IR spectroscopy, particle size analysis, zeta potential measurement, polydispersity index (PDI) assessment, Field emission scanning electron microscopy (FESEM), X-ray diffraction analysis, pH measurement, and stability testing. This study seeks to explore the potential of nanosuspensions, aiming to integrate nanotechnology with herbal medicine to improve the safety and efficacy of herbal formulations. Results: The nanosuspension (NSWS) shown particle size about 133.09 nm, and its uniform particle distribution was indicated by a Polydispersity Index (PDI) about 0.27. Stability and uniformity were further supported by the zeta potential, particle size, and PDI values. Conclusion: Nanosuspension formulations represents a versatile strategy to improve the therapeutic efficacy of hydrophobic drugs across various routes of administration. Keywords: Withania somnifera, Nanosuspension, Characterization, FT-IR, PDI, FESEM

Safety study on adverse events of zanubrutinib based on WHO-VigiAccess and FAERS databases.

The study endeavors to elucidate AE signals associated with zanubrutinib data from the WHO-VigiAccess and FAERS databases. The aim is to furnish robust scientific evidence to inform clinical practice and regulatory decisions. We meticulously extracted all AE breports tied to zanubrutinib from the both databases, encompassing the period from the drug's market introduction until 30 April 2024. Retrospective quantitative analysis employing ROR, PRR, and BCPNN methodologies were utilized to analysis. The investigation unveiled 1,304 reports from WHO-VigiAccess and 1,141 reports from FAERS related to zanubrutinib. Among the top 30 reported PTs in both databases, those not recorded in the drug label included pyrexia, dizziness, and death. In the FAERS database, signals for zanubrutinib were detected across 19 SOCs. Systems not covered in the drug label included reproductive system and breast disorders, metabolism and nutrition disorders, ear and labyrinth disorders, among others. Unmentioned signals included intestinal perforation, onychoclasis, night sweats, etc. This study confirms common AEs of zanubrutinib and identifies new ones, highlighting the need for careful monitoring and personalized treatment. It also emphasizes the importance of ongoing drug safety surveillance and patient management to maximize therapeutic benefits and minimize risks.

Artificial Intelligence (AI) Applications in Drug Discovery and Drug Delivery: Revolutionizing Personalized Medicine

Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the optimization of treatment regimens, and the improvement of patient outcomes. AI is swiftly transforming the pharmaceutical industry, revolutionizing everything from drug development and discovery to personalized medicine, including target identification and validation, selection of excipients, prediction of the synthetic route, supply chain optimization, monitoring during continuous manufacturing processes, or predictive maintenance, among others. While the integration of AI promises to enhance efficiency, reduce costs, and improve both medicines and patient health, it also raises important questions from a regulatory point of view. In this review article, we will present a comprehensive overview of AI’s applications in the pharmaceutical industry, covering areas such as drug discovery, target optimization, personalized medicine, drug safety, and more. By analyzing current research trends and case studies, we aim to shed light on AI’s transformative impact on the pharmaceutical industry and its broader implications for healthcare.

Trends in Antidiabetic Drug Use and Safety of Metformin in Diabetic Patients with Varying Degrees of Chronic Kidney Disease from 2010 to 2021 in Korea: Retrospective Cohort Study Using the Common Data Model.

This study aimed to investigate trends in antidiabetic drug use and assess the risk of metformin-associated lactic acidosis (MALA) in patients with chronic kidney disease (CKD). A retrospective observational analysis based on the common data model was conducted using electronic medical records from 2010 to 2021. The patients included were aged ≥18, diagnosed with CKD and type 2 diabetes, and had received antidiabetic medications for ≥30 days. MALA was defined as pH ≤ 7.35 and arterial lactate ≥4 mmol/L. A total of 8318 patients were included, with 6185 in CKD stages 1-2 and 2133 in stages 3a-5. Metformin monotherapy was the most prescribed regimen, except in stage 5 CKD. As CKD progressed, metformin use significantly declined; insulin and meglitinides were most frequently prescribed in end-stage renal disease. Over the study period, the use of SGLT2 inhibitors (13.3%) and DPP-4 inhibitors (24.5%) increased significantly, while sulfonylurea use decreased (p < 0.05). Metformin use remained stable in earlier CKD stages but significantly decreased in stage 3b or worse. The incidence rate (IR) of MALA was 1.22 per 1000 patient-years, with a significantly increased IR in stage 4 or worse CKD (p < 0.001). Metformin was the most prescribed antidiabetic drug in CKD patients in Korea with a low risk of MALA. Antidiabetic drug use patterns varied across CKD stages, with a notable decline in metformin use in advanced CKD and a rise in SGLT2 inhibitor prescriptions, underscoring the need for further optimized therapy.

Evaluation of the Efficacy of Methylene Blue Administration in SARS-CoV-2-Affected Patients: A Proof-of-Concept Phase 2, Randomized, Placebo-Controlled, Single-Blind Clinical Trial

The SARS-CoV-2 pandemic has revolutionized the scientific and medical world in recent years. Methylene blue (MB) is a well-known molecule. The aim of our study was to assess the efficacy of MB against early-phase SARS-CoV-2 infections. All patients with a positive swab for SARS-CoV-2 were eligible for the trial. The intervention was a starting dose of 200 mg MB or placebo in the morning and 100 mg in the evening on the first day and afterwards the standard daily dose of 200 mg. Patients were followed up for safety and efficacy until day 84. We analyzed 21 patients for the safety profile and 19 for the efficacy objective: of these, there were 11 in the MB group and 8 in the placebo one. In both groups, patients had undetectable RNA from day 3 and 10 out of 11 subjects in the MB group were virus free by day 12 vs. 6 out of 8 in the placebo one. None of the patients experienced serious adverse events. MB has proved to be a safe and well-tolerated drug. We did not find superiority of efficacy or viral clearance of MB compared to the placebo. Given the good in vitro efficacy, larger studies are needed to assess MB efficacy against COVID-19 in vivo.

Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs.

Hepatotoxicity can lead to the discontinuation of approved or investigational drugs. The evaluation of the potential hepatoxicity of drugs in development is challenging because current models assessing this adverse effect are not always predictive of the outcome in human beings. Cell lines are routinely used for early hepatotoxicity screening, but to improve the detection of potential hepatotoxicity, in vitro models that better reflect liver morphology and function are needed. One such promising model is human liver microtissues. These are spheroids made of primary human parenchymal and nonparenchymal liver cells, which are amenable to high throughput screening. To test the predictivity of this model, the cytotoxicity of 152 FDA (US Food & Drug Administration)-approved small molecule drugs was measured as per changes in ATP content in human liver microtissues incubated in 384-well microplates. The results were analyzed with respect to drug label information, drug-induced liver injury (DILI) concern class, and drug class. The threshold IC50ATP-to-Cmax ratio of 176 was used to discriminate between safe and hepatotoxic drugs. "vMost-DILI-concern" drugs were detected with a sensitivity of 72% and a specificity of 89%, and "vMost-DILI-concern" drugs affecting the nervous system were detected with a sensitivity of 92% and a specificity of 91%. The robustness and relevance of this evaluation were assessed using a 5-fold cross-validation. The good predictivity, together with the in vivo-like morphology of the liver microtissues and scalability to a 384-well microplate, makes this method a promising and practical in vitro alternative to 2D cell line cultures for the early hepatotoxicity screening of drug candidates.

Ultra-rapid detection of nuclear protein of severe fever with thrombocytopenia syndrome virus by colloidal gold immunochromatography assay.

In 2009, severe fever with thrombocytopenia syndrome virus (SFTSV), also known as the Dabie bandavirus (DBV), was first discovered in Henan, China. It is a tick-borne zoonotic virus with a fatality rate ranging from 6% to 30%. Currently, we lack safe and effective vaccines or antiviral drugs to treat SFTSV infection. Therefore, the development of a specific, sensitive, and cost-effective detection method is crucial. Using inactivated SFTSV and recombinant SFTSV nucleocapsid protein (SFTSV-NP), we repeatedly immunized mice with different adjuvants and obtained two monoclonal antibodies against SFTSV-NP, which were used to develop a colloidal gold immunochromatographic assay (ICA) rapid test kit for SFTSV. Compared with nucleic acid testing (gold standard), the ICA test strips are 97.67% accurate in testing clinical serum samples (36 cases of clinical serum samples and seven cases of whole blood samples). The test kit was 100% accurate in detecting different SFTSV strains. No false-positive results were generated when detecting other arboviruses. Therefore, our developed SFTSV test kit conveniently, rapidly, and effectively detects SFTSV.

Recent advancement of immunotherapy targeting lung cancer

As one of the leading cause of deaths in all types of cancer, lung cancer has attracted public attention more than decades. Many chemotherapy and physical surgery therapies have been investigated and applied to lung cancer patients to increase the overall survival rate. As a more recently emerging therapy, immunotherapy is keep advancing in recent years and has achieved great success to complement the traditional therapys weak point and even become the first line treatment against certain types of non-small cell lung cancer (NSCLC). The safety and overall survival improvement of immunotherapy drugs has been tested through multiple cycle of clinical trials, validating their potential for lung cancer treatment. Several clinical trials study the application of immunotherapy singly or in combination with chemotherapy has been established to target lung cancer many years ago. Here, this review will introduce the three most common immunotherapies against lung cancer, and both summarize their application and discuss their recent advancement based on multiple ongoing or finished clinical trials.

Efficacy and safety of traditional Chinese medicine in managing bone loss post-endocrine therapy in hormone receptor-positive breast cancer patients.

This study aims to evaluate the efficacy and safety of traditional Chinese medicine (TCM) kidney-tonifying methods in treating bone loss and osteoporosis following endocrine therapy in patients with hormone receptor-positive breast cancer. This research systematically searched 6 major medical electronic databases, initially identifying 986 articles, ultimately including 22 randomized controlled trials. These studies encompassed a total of 1579 patients and investigated the impact of TCM kidney-tonifying methods on lumbar spine bone density, lumbar spine bone density T-values, femoral neck bone density, clinical efficacy, and drug safety. The Cochrane quality scoring system was utilized to assess the quality of the literature, and data were synthesized using meta-analysis techniques. TCM kidney-tonifying methods significantly improved lumbar spine bone density (standardized mean difference [SMD] = 0.70, 95% confidence interval [CI]: 0.43-0.97) and lumbar spine bone density T-values (SMD = 1.012, 95% CI: 0.506-1.517). There was also a positive trend in enhancing femoral neck bone density (SMD = 0.645, 95% CI: 0.321-0.970). Although improvements in clinical efficacy did not reach statistical significance (relative risk [RR] = 1.122, 95% CI: 0.933-1.348), the studies indicated good safety of the treatment, with most studies reporting no significant adverse reactions. TCM kidney-tonifying methods may have a positive therapeutic effect on bone loss and osteoporosis following endocrine therapy in patients with hormone receptor-positive breast cancer, demonstrating good tolerability and safety. Given the current evidence, it is recommended to include TCM kidney-tonifying methods as a complementary therapeutic approach in treatment protocols. Future research should further validate these findings and explore their application in different patient subgroups.

Advancing the role of real-world evidence in comparative effectiveness research.

Aim: Comparative effectiveness research (CER) is essential for making informed decisions about drug access. It provides insights into the effectiveness and safety of new drugs compared with existing treatments, thereby guiding better healthcare decisions and ensuring that new therapies meet the real-world needs of patients and healthcare systems. Objective: To provide a tool that assists analysts and decision-makers in identifying the most suitable analytical approach for answering a CER question, given specific data availability contexts. Methods: A systematic literature review of the scientific literature was performed and existing regulatory and health technology assessment (HTA) guidance were evaluated to identify and compare recommendations and best practices. Based on this review a methods flowchart that synthesizes current practices and requirements was proposed. Results: The review did not find any papers that clearly identified the most appropriate analytical approach for answering CER questions under various conditions. Therefore, a methods flowchart was designed to inform analyst and decision makers choices starting from a well-defined scientific question. Conclusion: The proposed methods flowchart offers clear guidance on CER methodologies across a range of settings and research needs. It begins with a well-defined research question and considers multiple feasibility aspects related to CER. This tool aims to standardize methods, ensure rigorous and consistent research quality and promote a culture of evidence-based decision-making in healthcare.

Erdosteine in the treatment of acute and chronic diseases of the respiratory system: resolution of the scientific forum of experts “In the Spotlight”

Airway mucus hypersecretion is a pathophysiologic manifestation of acute and chronic airway inflammatory disease. Mucolytics can reduce mucus viscosity and promote mucus discharge and therefore can be considered pathogenetically based therapy.The purpose of this publication with the resolution of the scientific forum of experts was to discuss pharmacological features, efficacy, and safety of erdosteine.Results. Experts of thescientific forum not only reviewed the results of clinical trials, but also voted on the use of mucoactive drugs according to the principle of Delphi consensus. Comparison of the efficacy and safety of mucoactive drugs (erdosteine, acetylcysteine, carbocysteine, ambroxol) in patients with respiratory diseases by the experts during voting showed that the highest level of agreement among the experts was achieved for the drug Elmucin® (erdosteine) in terms of its mucolytic activity and other pharmacological features, as well as when discussing the safety of the compared drugs in the officially recommended doses. The highest level of agreement was also noted on the erdosteine efficacy in COPD patients in reducing the frequency and duration of disease exacerbations, as well as reducing the risk of hospitalization of COPD patients when used long-term as part of combination therapy. The demonstrated safety profile was the most beneficial among the reviewed mucoactive drugs.Conclusion. Elmucin® is a mucolytic with pleiotropic effects such as complex mucoactive action, potent antioxidant, anti-inflammatory and antibacterial activity with anti-adhesive effect for pathogens that determine its clinical efficacy in the treatment of acute and chronic airway diseases.

Degradation of pathogenic amyloids induced by matrix metalloproteinase-9

Over the past decade, the greatest promise for treating severe and currently incurable systemic and neurodegenerative diseases has turned to agents capable of effectively degrading pathological amyloid deposits without causing side effects. Specifically, amyloid destruction observed in immunotherapy is hypothesized to occur through activation of proteolytic enzymes. This study examines poorly understood effects of an immune enzyme, extracellular matrix metalloproteinase-9 (MMP9), on amyloids associated with Alzheimer's and Parkinson's diseases, lysozyme, insulin, and dialysis-related amyloidoses. The study establishes the universality of MMP9's effect on various amyloids, with its efficacy largely depending on the fibrillar cluster size. Irreversible amyloid degradation by MMP9 is attributed to the destruction of intramolecular interactions rather than intermolecular hydrogen bonds in the fibril backbone. This process results in the loss of ordered fiber structure without reducing aggregate size or increasing cytotoxicity. Thus, MMP9 can mitigate side effects of anti-amyloid therapy associated with the formation of low-molecular-weight degradation products that may accelerate fibrillogenesis and amyloid propagation between tissues and organs. MMP9 shows promise as a component of safe anti-amyloid drugs by enhancing the accessibility of binding sites through “loosening” amyloid clusters, which facilitates subsequent fragmentation and monomerization by other enzymes.

Biopharmaceutical modulatory effects of newly engineered bile acid-Tyloxapol nanogels for attenuation of cytotoxicity in auditory cells

This study presents novel thermoresponsive nanogels composed of chenodeoxycholic acid and Tyloxapol for potential inner ear drug delivery. The nanogels exhibit non-Newtonian, shear-thinning fluid behaviour and rapid gelation at body temperature. Biocompatibility studies were conducted on auditory and macrophage cell lines. Nanogels had a minimal impact on cellular viability, glycolysis, and mitochondrial respiration of auditory cells after 24 h of exposure. However, mitochondrial function analysis in macrophages revealed a significant decrease in oxidative phosphorylation and coupling efficiency after nanogel exposure, accompanied by increased proton leakage. Despite these metabolic disruptions, glycolysis remained unaffected. The Poloxamer matrix appears to be responsible for these effects, independent of the presence of bile acids or Tyloxapol. This study highlights the potential of bile acid-enriched nanogels in drug delivery, particularly their biocompatibility and injectability while acknowledging challenges related to mitochondrial dysfunction in immune cells. These findings suggest that thermoresponsive bile acid and Tyloxapol nanogels have the potential to be safe and effective drug delivery vehicles for inner ear applications.

Incidence of respiratory depression between ciprofol and propofol after anesthesia: A systematic review and meta-analysis.

Respiratory depression is a common complication during operative procedures, meanwhile, ciprofol can provide effective sedation for surgical operations. However, there is not enough evidence to prove the advantage of ciprofol in reducing respiratory depression. So, this meta-analysis aimed to assess the efficacy of ciprofol on the incidence of respiratory depression compared with propofol. Two individual researchers conducted searches for randomized controlled trials in PubMed, Embase, and Cochrane Central Register of Controlled Trials. The meta-analysis was performed using Review Manager software. Seven trials with a total of 1408 patients were included in this meta-analysis. The results showed that ciprofol could reduce the incidence of respiratory depression compared with propofol (risk difference [RD] = -0.09, 95% confidence interval [CI]: -0.15 to -0.04). Ciprofol significantly reduced the incidence of respiratory depression when the method of administration was intravenous injection (RD = -0.06, 95% CI: -0.10 to -0.03), or continuous infusion (RD = -0.30, 95% CI: -0.45 to -0.15). Meanwhile, ciprofol significantly reduced the incidence of respiratory depression with the dosage not only greater than or equal to 0.4 mg/kg (RD = -0.11, 95% CI: -0.20 to -0.02), but also <0.4 mg/kg (RD = -0.08, 95% CI: -0.13 to -0.02). And ciprofol significantly reduced the incidence of hypoxemia (risk ratio [RR] = 0.47, 95% CI: 0.28 to 0.80), injection pain (RD = -0.32, 95% CI: -0.46 to -0.17), body movement (RR = 0.60, 95% CI: 0.43 to 0.84), dizziness (RR = 0.75, 95% CI: 0.62 to 0.90). Finally, ciprofol did not increase awakening time (standard mean difference [SMD] = 0.15, 95% CI: -0.02 to 0.31). From this meta-analysis, it is demonstrated that ciprofol might reduce the incidence of respiratory depression and injection pain. These benefits are important in surgery to ensure safe and rapid postoperative recovery. So, ciprofol may be a safe and appropriate drug with fewer adverse effects used in clinical anesthesia.

Sterile Intraocular Inflammation Associated With Faricimab

Randomized clinical trials are conducted to establish both drug safety and efficacy. However, evidence of adverse events associated with these drugs in the clinical practice setting can be of value at generating hypotheses regarding less common safety issues, even if causality cannot be determined. To present and analyze cases of intraocular inflammation associated with faricimab therapy in patients referred to a single European institution. This was a review starting in April of 2024 of an observational case series. Patients were from a single academic-based tertiary referral center in Switzerland. Included in the analysis were patients referred for intraocular inflammation soon after receiving a faricimab intravitreal injection between June 1, 2022, and March 5, 2024. Faricimab, 6 mg (0.05 mL of a 120-mg/mL solution), administrated for neovascular age-related macular degeneration or diabetic macular edema. The systemic and ocular histories and imaging data available were reviewed. The following were evaluated: visual acuity measured with habitual correction using the Early Treatment of Diabetic Retinopathy Study charts before and after the event; intraocular pressure; patient symptoms; anterior, intermediate, or posterior location of the intraocular inflammation; and the presence of retinal vasculitis. Multimodal imaging including color fundus photographs, fluorescein angiograms, indocyanine green angiograms, and optical coherence tomography were reviewed. A total of 12 eyes from 7 patients (mean [SD] age, 73.3 [16.7] years; 4 female [57.1%]) over 22 months were identified as having noninfectious intraocular inflammation after intravitreal faricimab injections. Among these cases, in 2 eyes, retinal vasculitis was present together with anterior and posterior inflammation. One of the 2 eyes had an occlusive form of vasculitis of the arteries and veins, leading to subsequent macular capillary nonperfusion and clinically relevant irreversible vision deterioration from 20/80 to 20/2000. The remaining eyes were characterized by moderate anterior segment inflammation without substantial vision changes. The intraocular inflammation event occurred after a median (IQR) of 3.5 (2.0-4.3) faricimab injections. The median (IQR) interval between the last faricimab injection and the diagnosis of inflammation was 28 (24-38) days. Increased intraocular pressure of 30 mm Hg or higher was found in 3 eyes. This case series highlights the occurrence of rare, but potentially severe, intraocular inflammation associated with faricimab therapy. Although these findings do not prove causality and can only generate hypotheses for future investigations, these results suggest the importance of continuous surveillance and monitoring for patients undergoing faricimab therapy to promptly identify and manage potential adverse events.

Chemotherapy Options in New Patients with Drug Susceptible Tuberculosis and Concurrent HIV Infection

The objective: to compare effectiveness and safety of isonicotinoylhydrazine-O,N' iron (II) sulfate dihydrate with the drug of isonicotinic acid hydrazide group in the complex therapy of patients with drug susceptible tuberculosis and HIV infection.Subjects and Methods. In 2020-2021, 40 patients with HIV infection and drug susceptible respiratory tuberculosis with a positive sputum test were examined in Moscow Regional Clinical TB Dispensary as a part of the post-registration observational study. The subjects were randomized into two groups – Main Group (MG) and Comparison Group (CG). Isonicotinoylhydrazine-O,N' iron (II) sulfate dihydrate was administered to the patients from MG as a part of regimen 1 of chemotherapy (instead of isoniazid). The effectiveness and safety of the investigational drug and comparator were evaluated. The primary effectiveness criteria included resolution of clinical symptoms of intoxication and sputum conversion. The secondary effectiveness criterion was positive X-ray changes. The safety criterion was the absence of adverse reactions.Results. During the study period, no adverse reactions were registered when isonicotinoylhydrazine-O,N' iron (II) sulfate dehydrate was used, as well as isoniazid. Good tolerability was noted as well as high compliance to treatment by patients. Thus, both in terms of effectiveness and safety, isonicotinoylhydrazine-O,N' iron (II) sulfate dihydrate is comparable to isoniazid as part of anti-tuberculosis chemotherapy for patients with drug susceptible tuberculosis and concurrent HIV infection.

Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases.

Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays pivotal roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutics across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs and discusses the major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.

Preparation and evaluation of novel oral tacrolimus nanocochleates for organ transplantation to reduce individual differences and improve drug safety

After organ transplantation, patients require treatment with immunosuppressive drugs to prevent immune rejection and transplantation failure. Tacrolimus (FK506) is a widely used immunosuppressant known for its potent immunosuppressive effect and narrow therapeutic range. Monitoring of FK506 blood concentrations is essential to avoid nephrotoxicity. In this study, a novel FK506 nanomedicine (FK506 cochleates) was developed using a microfluidic method to reduce variability among individuals and improve drug safety. The particle size of FK506 cochleates was (183.3 ± 1.4) nm, the zeta potential was −(39.28 ± 2.12) mV, and the encapsulation efficiency was more than 85 %. Particle size of FK506 cochleates could be maintained for up to 12 weeks in freeze-dried powder form. Small-angle X-ray scattering (SAXS) experiment confirmed the formation of cochleates by adding calcium solution. In vitro release studies demonstrated a sustained-release profile of FK506 from the cochleates carrier. Furthermore, the cochleates carrier could protect FK506 from the influence of stomach acid and slowly release the drug in the intestine. After oral administration, FK506 cochleates exhibited sustained-release properties in rats, accumulating in the spleen and lymph nodes − key anatomical sites for FK506’s pharmacological action. Importantly, FK506 cochleates significantly prolonged the survival time in the rabbit heart transplantation model while maintaining good safety profiles. In conclusion, the FK506 cochleates showed promising potential for enhancing drug safety in therapeutic organ transplantation.