Food And Drug Administration Research Articles

Sotatercept: The First FDA-Approved Activin A Receptor IIA Inhibitor Used in the Management of Pulmonary Arterial Hypertension.

This report illustrates the Food and Drug Administration (FDA) approval of first-in-its-class activin A receptor IIA inhibitor, sotatercept (Winrevair™), for the treatment of pulmonary arterial hypertension (PAH). Sotatercept is used to increase exercise capacity, improve WHO functional class, and decrease the risk of clinical worsening events in adults with PAH. One phase 2 trial, one phase 3 trial, and an ongoing open-label extension study is described in detail within the current text. Sotatercept significantly improved the 6-min walk distance in patients with PAH after 24 weeks with a mean change increase of 40.1 meters in the experimental group versus 1.4 meters decrease in the placebo group. Epistaxis, telangiectasia, increased hemoglobin, hematocrit, red blood cell levels, and dizziness were adverse events more frequently observed in the sotatercept group than in the placebo group. Sotatercept has shown significant benefits in the reduction of pulmonary vascular resistance and N-terminal pro b-type natriuretic peptide in patients with PAH. However, more studies are needed to evaluate the reduction in mortality. Limitations in practice include high cost and unknown long-term effects.

The Rise in Glucagon-Like Peptide-1 Receptor Agonist Related Calls to United States Poison Centers

Abstract Background In 2005, the United States (U.S.) Food and Drug Administration (FDA) approved the first Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) as adjunctive therapy to improve glycemic control in type 2 diabetes. In 2021, the FDA approved semaglutide for chronic weight management. We aim to characterize GLP-1RAs related calls to all U.S poison centers (PCs). Methods We conducted a retrospective review of the U.S. National Poison Data System (NPDS) between 2005 and 2023 for all GLP-1RA exposures. All 55 PCs covering the entire U.S. population submit, in near real-time, de-identified case data to NPDS after providing poison exposure management to callers from the general public and health care providers. Results During the study period, U.S. PCs handled 13,692 GLP-1RAs related calls, of which 12,451 were a GLP-1RA single substance exposures. In 2023, PCs received 4,414 GLP-1RA related calls, compared to 234 in 2014 (a twenty-fold increase over 10 years). Seventy three percent of exposures involved females (n = 10,017). The main reasons for exposure were therapeutic errors (n = 10,213; 75%), adverse drug reactions (n = 1,222; 9%) and suspected suicide (n = 557; 4%). Gastrointestinal symptoms, such as nausea (n = 2,913; 23%), vomiting (n = 2,515; 20%), and abdominal pain (n = 593; 5%), and neurological symptoms, including central nervous system depression (n = 191; 1.5%), dizziness (n = 563; 5%) and headache (n = 495; 4%) were the most commonly reported clinical effects in single substance exposures. Hypoglycemia was reported in 431 cases (3.5%), Most single substance exposures were managed outside a healthcare facility (n = 8.573; 69%), and hospital admission was reported in 5% of exposures (n = 601). Conclusions PCs are well positioned to monitor trends in GLP-1RAs human exposures and associated adverse events and therapeutic errors. Based on available data, PCs can manage specific cases-types without referral to the hospital, preventing unnecessary healthcare utilization. Key messages • Poison centers are well positioned to monitor trends in GLP-1RAs adverse events. • Poison centers can prevent unnecessary healthcare utilization.

Measurement inaccuracy reported via the Manufacturer and User Facility Device Experience database for an implantable pulmonary artery pressure sensor: recalibration direction and magnitude results

Abstract Introduction Remote monitoring using an implantable pulmonary artery pressure (PAP) sensor (CardioMEMS HF system) in patients with heart failure (HF) has been consistently shown to reduce HF hospitalizations [1]. The success of this approach relies on the accurate measurement of diastolic PAP (dPAP) over time to allow early interventions such as diuretic intensification [2]. However, it remains unclear how the measurement accuracy changes over time after the initial calibration at the time of device implantation. Purpose This study aims to identify measurement inaccuracy events and to quantify the magnitude and direction of required device recalibration for CardioMEMS devices as reported in a large-scale regulatory device database. Methods We used the publicly accessible Manufacturer and User Facility Device Experience (MAUDE) data maintained by the US Food and Drug Administration (FDA). The summary search was performed for the CardioMEMS pulmonary artery pressure sensor for the entire product life cycle from January 2009 to February 2024 [3,4]. The entries related to the measurement accuracy under ‘Device Problems’ categories were obtained. Tested accuracy was reported to have been within ±10mmHg of a reference pressure measurement throughout simulated use for 10 years [5]. Normal range for dPAP is ~8mmHg to 15mmHg [6]. Results A total of 2656 entries were obtained. Following categories were identified for the reported entries: device sensing problem (N=999, 38%); incorrect measurement (N=1349, 52%); incorrect measurement, inappropriate waveform (N=279, 11%), and incorrect, inadequate, or imprecise results or readings (N=29, 1%). After excluding 56 entries for missing information, 2600 entries were included for the analysis. A total of 1676 (64%) entries reported the need for recalibration of the CardioMEMS device. A mean PAP difference (defined as the difference of the mean PAP reference value measured at the time of recalibration minus the CardioMEMS reading obtained during the reference measurement) is shown in Figure 1. Compared to the reference pressure values at the time of recalibration, 488 (29%) of CardioMEMS readings were higher and 1188 (71%) were lower. The absolute recalibration pressure difference was 14.5 ± 9.3 mmHg (mean ± standard deviation, range 0.02-59.3 mmHg). The recalibration by more than 10 mmHg was reported in 1040 (40%) entries. Conclusions Suspected measurement inaccuracy with CardioMEMS device is not uncommon and often necessitate recalibration. Almost one-half (40%) of the recalibrations required more than 10 mmHg correction. These results should inform clinicians to consider recalibration along the course of CardioMEMS monitoring if there is discordance between clinical assessment and the values from the device.Figure 1.Figure 2

Review of the fluoropyrimidine antidote uridine triacetate.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

Exposure to mycotoxins from the consumption of corn-based breakfast cereals in the United Arab Emirates

Corn-based breakfast cereals, known as cornflakes, have become a common breakfast choice worldwide, recognized for their convenience and versatility. However, mycotoxins can contaminate these products, adversely affecting human health. This study assessed the occurrence of major mycotoxins (AFB1, OTA, DON, ZEA, and FUM) in cornflake stock-keeping units (SKUs) marketed in the United Arab Emirates (UAE). It also evaluated the effect of different independent variables (country of origin, temperature on the production day, storage time, presence of chocolate, bran, and nut ingredients) and estimated the exposure levels of the UAE population to these mycotoxins and the associated risk factors. Seventy-six distinct cornflake SKUs were identified through a market screening and tested for mycotoxins using the Enzyme-Linked Immunosorbent Assay (ELISA) technique. AFB1, OTA, ZEA, FUM, and DON were detected in 23.7, 48.7, 27.6, 9.2 and 88.2% of the samples, respectively. The mean concentrations among positive samples were 2.0, 1.0, 10.14, 584.9, and 90.6 μg/kg, respectively. Except for AFB1, the average mycotoxin levels in samples were below the established limits by the European Union (EU). Among positive samples, none exceeded the US FDA limits for all mycotoxins, and only one exceeded the CODEX limit for FUM. On the other hand, four (5.3%), one (1.3%), one (1.3%), and one (1.3%) SKU exceeded EU limits for AFB1, OTA, FUM, and ZEA, respectively. The country of origin (developing vs. developed countries) exhibited a significant effect on AFB1 presence (p < 0.0001). Furthermore, higher temperature on the production day was associated with significantly higher AFB1 occurrence (p = 0.009). Moreover, the presence of chocolate ingredient had a borderline significant effect on AFB1 (p = 0.05) and a significant effect on OTA (p = 0.002), with higher percentages observed in SKUs containing chocolate. However, no significant effects were found for storage time or the presence of bran and nut ingredients in the cornflakes. On the other hand, the HQ values were below 1 for all mycotoxins, indicating low risk. MoE values exceeded 10,000 among regular cornflake consumers, except for FUM, suggesting minimal risk. Liver cancer risk was 0.0032 cases per 100,000 people per year. Weekly OTA exposure was 0.133 ng/kg BW, below PTWI (Provisional Tolerable Weekly Intake).

Phase I results of both IV and oral administration for CG-0255: a novel fast-acting antiplatelet drug with a new activation pathway

Abstract Clopidogrel is an extremely widely used antiplatelet drug, but with serious shortcomings. It is a prodrug that depends critically on liver CYP oxidation enzyme CYP2C19 for activation to its active metabolite H4. However, large fractions of world population carry loss of function CYP2C19 alleles, ranging from a low ~21% in Latino to a strikingly high ~59% in east Asian population. Known as clopidogrel resistance, US FDA added a black box warning to clopidogrel label. Despite this issue, routine CYP2C19 screening for clopidogrel patients is not performed, putting many patients at risk. Clopidogrel is also slow to take effect and not amenable for IV formulation, limiting its clinical use in emergency. To overcome these issues, we have invented a novel antiplatelet drug CG-0255, which is the world’s first thioester prodrug with a new activation pathway. CG-0255 has been designed to require only abundantly present and widely distributed carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel active metabolite H4 generated through CYP metabolism. Thus, CG-0255 completely bypasses the CYP metabolism and overcomes clopidogrel resistance. In addition, CG-0255 has a much faster onset of action and high solubility in water and has been formulated for both IV and oral administration. Here we report the results of an open label phase I study of CG-0255 oral tablets to assess safety, tolerability, pharmacodynamics (PK), and pharmacokinetics (PD: inhibition of platelet aggregation, IPA) in healthy volunteers. It was a single dose escalation study, 4 cohorts with 6 participants each given CG-0255 oral tablets at doses ranging from 2 to 10 mg. Clopidogrel was the positive control and given at 300 mg. Blood samples for PK/PD analysis were collected pre-dosing and at various time points post dosing. VerifyNow was used for IPA measurement. CG-0255 is generally safe and well tolerated. PK analysis shows fast and consistent conversion of CG-0255 to active metabolite H4. PD results indicate that CG-0255 IPA is dose-dependent, easily matching or surpassing that of clopidogrel 300 mg for all doses. At the highest 10 mg dose, CG-0255 IPA reaches over 90% in less than 30 minutes, well above that of clopidogrel. In addition, CG-0255 IPA shows minimum individual variations, and the antiplatelet effect is long lasting due to its irreversible binding to the P2Y12 receptor. These results are consistent with our earlier reported Phase I results for CG-0255 IV injection. In conclusion, CG-0255 is a novel, fast-acting and long-lasting antiplatelet drug. It shares identical metabolite H4 with clopidogrel but relies only on carboxylesterases for activation, overcoming the resistance and other issues associated CYP-based oxidation metabolism. As the only antiplatelet drug available for both IV and oral administrations, CG-0255 fills unmet medical needs and will greatly benefit patients and medical community.

Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), alarge number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. Alarge number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from aphaseIstudy on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to areduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as abreakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Hypocalcemia Event Associated with Denosumab: A Real-World Study from FDA Adverse Event Reporting System (FAERS) Database.

Denosumab is widely used for osteoporosis and cancer treatment. However, hypocalcemia induced by denosumab is a frequent adverse event. The objective of this study is to comprehensively investigate the safety signals and the occurrence of hypocalcemia in real-world patient cases reported through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Reports from January 1, 2017 to December 31, 2021 were extracted from the FAERS. Only cases of hypocalcemia suspected to denosumab were eligible in pharmacovigilance study. Denosumab-related hypocalcemia safety signal were identified to characterize their clinical features. A safety signal for hypocalcemia was evaluated using reporting odds ratios (ROR). Among the 102,413 cases related to denosumab, 1042 cases were reported with denosumab-related hypocalcemia. The affected patients were mainly elderly (median age 70years) and male (n = 568, 63.5%). In available data, the median onset time of 23 (range 0-1601) days. Most patients required drug interruption (n = 226, 72.9%) and can achieve a recovered-resolved state (n = 318, 62.1%). For the whole database, denosumab exhibited a safety signal for hypocalcemia (ROR = 14.09, 95% Cl 13.18, 15.06). In the sensitivity analyses, denosumab also showed a safety signal for hypocalcemia in cancer (ROR = 21.28, 95% Cl 18.79, 24.11) and osteoporosis (ROR = 9.29, 95% Cl 6.80, 12.59). Compared with bisphosphonates, denosumab still has safety signal for hypocalcemia (ROR = 1.88, 95% Cl 1.67, 2.11). This pharmacovigilance database analysis indicates a high safety signal for hypocalcemia associated with denosumab, particularly in cancer patients.

Emerging concepts and success stories in type 1 diabetes research: a roadmap for a bright future.

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy.

The Association Between Dextromethorphan/Bupropion with Alcohol and Substance Misuse: Reports to the Food and Drug Administration Adverse Event Reporting System (FAERS).

Dextromethorphan/bupropion (DXM/BUP) received Food and Drug Administration (FDA) approval for the treatment of adults with major depressive disorder (MDD) in August 2022. This combination is not known to have abuse liability and is not currently scheduled by the Drug Enforcement Administration (DEA). Notwithstanding, dextromethorphan is a drug of abuse. Herein, we sought to determine whether DXM/BUP has alcohol and/or substance misuse liability. We evaluated spontaneous reports of terms such as "alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse" in the FDA Adverse Event Reporting System (FAERS). The FAERS is a spontaneous reporting database of adverse events submitted to the FDA. We performed a comparative assessment of the alcohol and/or substance misuse liability of DXM/BUP since its market authorization in August 2022, using acetaminophen as the control. Dextromethorphan served as the upper-bound reference point. Our findings showed that, since August 2022, dextromethorphan had a significant reporting odds ratio (ROR) for "drug abuse." In contrast, DXM/BUP did not have a significant ROR for any of the categories of alcohol and/or substance misuse evaluated. Limitations of our findings derive largely from the limitations of the FAERS and its data capture method. The absence of alcohol or substance misuse reported to the FAERS with DXM/BUP accords with the lack of evidence of abuse liability prior to FDA approval and its non-scheduling by the DEA.

PTB-DDI: An Accurate and Simple Framework for Drug-Drug Interaction Prediction Based on Pre-Trained Tokenizer and BiLSTM Model.

The simultaneous use of two or more drugs in clinical treatment may raise the risk of a drug-drug interaction (DDI). DDI prediction is very important to avoid adverse drug events in combination therapy. Recently, deep learning methods have been applied successfully to DDI prediction and improved prediction performance. However, there are still some problems with the present models, such as low accuracy due to information loss during molecular representation or incomplete drug feature mining during the training process. Aiming at these problems, this study proposes an accurate and simple framework named PTB-DDI for drug-drug interaction prediction. The PTB-DDI framework consists of four key modules: (1) ChemBerta tokenizer for molecular representation, (2) Bidirectional Long Short-Term Memory (BiLSTM) to capture the bidirectional context-aware features of drugs, (3) Multilayer Perceptron (MLP) for mining the nonlinear relationship of drug features, and (4) interaction predictor to perform an affine transformation and final prediction. In addition, we investigate the effect of dual-mode on parameter-sharing and parameter-independent within the PTB-DDI framework. Furthermore, we conducted comprehensive experiments on the two real-world datasets (i.e., BIOSNAP and DrugBank) to evaluate PTB-DDI framework performance. The results show that our proposed framework has significant improvements over the baselines based on both datasets. Based on the BIOSNAP dataset, the AUC-ROC, PR-AUC, and F1 scores are 0.997, 0.995, and 0.984, respectively. These metrics are 0.896, 0.873, and 0.826 based on the DrugBank dataset. Then, we conduct the case studies on the three newly approved drugs by the Food and Drug Administration (FDA) in 2024 using the PTB-DDI framework in dual modes. The obtained results indicate that our proposed framework has advantages for predicting drug-drug interactions and that the dual modes of the framework complement each other. Furthermore, a free website is developed to enhance accessibility and user experience.

Mavorixafor: A spotlight on the clinical aspects and prospects of the first USFDA-approved treatment for the primary immunodeficiency WHIM syndrome

WHIM syndrome (WHIMS) is an extremely rare, severe, and potentially fatal genetic condition that affects the immune system, leading to warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM). Effective therapy for WHIMS requires regular monitoring, medical intervention, and a collaborative approach to treatment. Due to the limited therapeutic options, addressing WHIMS is an unmet medical need. The United States Food and Drug Administration (USFDA) recently granted approval for mavorixafor as the first treatment for WHIMS. This review focuses on the pharmacological characteristics, clinical investigations, associated inventions, and prospects of mavorixafor. The literature for this article was searched on PubMed, reputable websites (USFDA and X4 Pharmaceuticals) and free patent databases like Espacenet. WHIMS is distinguished by severe neutropenia and hypogammaglobulinemia, which increases the risk of developing cancer. Mavorixafor enhances the movement of neutrophils and lymphocytes from the bone marrow (BM) to the bloodstream. Hence, it could be beneficial for managing medical illnesses characterized by a decrease in the quantity of neutrophils and lymphocytes in the bloodstream. X4 Pharmaceuticals has submitted patent applications for the utilization of mavorixafor in the treatment of diverse cancer types, inflammatory ailments, B-cell dysfunction, Waldenstrom's macroglobulinemia, and primary immunodeficiency disorders. This suggests that mavorixafor can effectively treat various disorders either alone or when used in conjunction with other medications. It will be intriguing to observe the future approvals of mavorixafor for various disorders.Keywords: Mavorixafor; WHIM syndrome; Cancer; Immunodeficiency; Patent; Prospect

Utilization of Artificial Intelligence to Improve Equitable Healthcare Access for Breast Implant Patients

Abstract The recently mandated US Food and Drug Administration (FDA) patient decision checklists were developed with the goal of improving the informed decision-making process for patients considering breast implants. Yet, prior research has demonstrated that these checklists are written at reading levels far in excess of that recommended by the National Institutes of Health and the American Medical Association. Patients considering breast implants are required to sign these forms prior to surgery, even if they have little to no comprehension of their contents. This study aims to improve the accessibility, and therefore the utility, of the mandated FDA patient literature using the assistance of artificial intelligence (AI). Patient decision checklists were obtained from the three most utilized breast implant manufacturers in the United States– Allergan, Mentor, and Sientra. AI was then asked to synthesize a novel patient decision checklist, written at the 6th grade reading level, using these checklists as source material. The AI-assisted checklist was edited by plastic surgeons for both formatting and content. Readability analysis of all documents was performed using the Flesch Reading-Ease Score, Flesch-Kincaid Grade Level, Gunning-Fog Index, Coleman-Liau Index, Simplified Measure of Gobbledygook, and Automated Readability Index. Textual analysis included sentence count, word count, number and percentage of complex words, average number of words per sentence, and average number of syllables per word. The overall readability of Allergan, Mentor, and Sientra patient checklists correlated with the college reading level. These documents were of a statistically significantly higher reading level the AI-assisted checklist, which was written at the recommended 6th grade level. Text composition analysis similarly demonstrated substantial differences between the AI-assisted and FDA mandated literature. The currently mandated breast implant patient checklists are written at a college reading level and are inaccessible to the average patient. We propose a new patient decision checklist, generated with the assistance of artificial intelligence, in order to improve healthcare access within plastic surgery. This simplified material can be used as an adjunct to the current checklists in order to improve shared decision making.

Posterior short ciliary arteries ischemia following embolization of anterior ethmoid artery to treat dural arteriovenous fistulas: a case report

BackgroundThe Onyx™ Liquid Embolic System is a non-adhesive liquid embolic agent, which has been proved by the US FDA for embolization of lesions in the peripheral and neurovasculature since 2005. We reported a case of ischemic optic neuropathy after using Onyx-18 to embolize the anterior ethmoid arteries that feeding dural arteriovenous fistulas (DAVF).Case presentationA 57-year-old Asian male presented with anterior cranial fossa DAVF underwent embolotherapy by delivering Onyx-18 through a microcatheter into the anterior ethmoid arteries under angiography guidance. The interventional procedure was successful and no clear evidence was found pointing to untargeted occlusive embolus. But after the surgery the patient experienced delayed painless vision loss in the right eye (RE). The fundoscopy showed unilateral papilledema with pale optic disc in RE, accompanied by significant edema and thickening in the retinal nerve fiber layer (RNFL) of macula. The fundus fluorescence angiography showed that most of the optic disc in RE had postponed or absent fluorescence filling. Visual evoked potential (VEP) confirmed that the amplitude of the P100 component was decreased in RE without significant prolongation of the latency. The patient was diagnosed with anterior ischemic optic neuropathy, but immediate pulse steroid therapy failed to rescue his vision.ConclusionPreoperative evaluation of the patient’s hemodynamic status and fundus examination are essential for assessing the risk of ischemic ocular complications, and the non-adhesive liquid embolic agent Onyx-18 should be used cautiously during endovascular embolization of intracranial artery.

A Retrospective Observational Study of Adverse Drug Reactions (ADR) Reported to ADR Monitoring Centre from 2010 to 2020.

Adverse Drug Reactions (ADR) are one of the essential causes of hospital admissions and pose a significant clinical and economic burden on the healthcare system. The Adverse Drug Reaction Monitoring Centre (AMC) in JIPMER functioning under the Pharmacovigilance Programme of India (PvPI) plays a vital role in ensuring medication safety by routinely detecting and monitoring ADRs. Hence, this study aimed to assess the characteristics of ADR reported from 2010 to 2020 in AMC JIPMER and to detect signals, if any. To study the characteristics of Adverse Drug Reactions (ADR) reported to a regional ADR monitoring center from 2010 to 2020 and to detect signals of disproportionate reporting (SDRs) if any from the reported ADRs. A total of 6007 ADR reports with a single suspect drug were included for analysis from 2010 to 2020. The characteristics of these reports, including patient's age and gender, Number and percentage of ADRs, the causality of ADR using WHO UMC (World Health Organization-Uppsala Monitoring Scale), the seriousness of the ADR, and outcome were collected from the ADR reports. MedDRA (Medical Dictionary for Regulatory Activities) Preferred Terms (PT) were used to classify adverse drug reactions. Causality analysis using the Naranjo Algorithm and Preventability using Modified Schumock and Thornton criteria were performed for the ADRs. The number and percentage of severe ADRs were analyzed. The System Organ class of all the ADRs was enumerated. ADRs not mentioned in the US FDA (United States Food and Drug Administration) product label (unlabelled reactions) were documented. Unlabeled reactions with ≥3 ADR reports were included for signal detection by disproportionality analysis. Antineoplastic drugs, followed by antimicrobials, anticonvulsants, Anti snake venom, and NSAID were the most common drugs implicated in ADRs. Skin and subcutaneous tissue disorders were the most common System Organ Class (SOC) involved in the ADRs. Among the 6007 reports, 19.2% were serious ADRs. Most of the ADR reports were of possible causality followed by probable and certain as per WHO UMC and Naranjo causality scales. Only ten ADRs were preventable and one reaction (Tamoxifen-induced neuropathy) was eligible for signal detection. Disproportionality analysis using a 2x2 contingency table showed insignificant signal detection using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Analysis of ADRs from an ADR Monitoring center functioning in a tertiary care hospital shows antineoplastic drugs to be the most common drugs associated with adverse drug reactions, with rash being the most common adverse effect. The majority of the ADRs were not preventable. No Signals of Disproportionate Reporting (SDR) were detected in our study.

Lactoferrin: a secret weapon in the war against pathogenic bacteria

The excessive use of antibiotics to treat bacterial infectious diseases in all living beings has caused a global epidemic of bacterial resistance to antibiotics, leading to the emergence of multidrug-resistant and pandrug-resistant strains. In 2019, the World Health Organization (WHO) reported that antimicrobial resistance causes at least 700,000 deaths per year worldwide. Therefore, in this global war against microorganisms, a therapeutic alternative is necessary to help us win this battle. A key in this race against the clock could be lactoferrin (Lf), a cationic glycoprotein of the mammalian innate immune system that is highly conserved among mammals. Lf is a multifunctional glycoprotein with immunomodulatory, anticarcinogenic, wound-healing, antioxidant, antimicrobial, and bone regeneration properties, in addition to improving the gut microbiota. Lf limits the growth of microorganisms through the sequestration of iron but can also interact directly with some components of the outer membrane of Gram-negative bacteria or bind to teichoic acids in Gram-positive bacteria, destabilizing the membrane and resulting in lysis. Moreover, cleavage of the Lf molecule could promote the production of lactoferricins (Lfcins) and lactoferrampin (Lfampin) from the N-terminal end, which are known to often have stronger antimicrobial effects than the native molecule, as well as analogous peptides, such as HLopt2, which have also shown enhanced antimicrobial activity. Bovine Lf (bLf) has been approved by the US Food and Drug Administration (FDA), and the European Food Safety Authority for its use as a dietary supplement in food products. Because of its effectiveness, accessibility, low cost, and nontoxicity, Lf could be a promising alternative for preventing or treating infections in animals and humans.

Review of alternative medicine (AM) treatments for diabetes

In the US, diabetes is a signification public health issue. It is one of the leading causes of death and number one cause of kidney failure. Even with increased awareness and medical advances, the diabetic trends with the US adult population are not very encouraging. The number of diabetes cases in the US the last twenty years has more than doubled and out of the 37.3 million adults in the US with diabetes, 20% of them don’t even know that they have it.1 Diabetes is a chronic disease with no available cure, medical practitioners and researchers have focused on controlling it with through medicine and lifestyle changes. Diet, exercise and healthy lifestyle are the most important factors on managing diabetes. There are several Alternative Medicine (AM) treatments that are available to manage diabetes today. Diet, exercise, herbs and supplements, yoga and meditation are some of the available AM treatments for diabetes. Herbs and supplements do not come under the purview of the U.S. Food and Drug Administration (FDA) because they are not classified as medicines. Moreover, there are not enough definitive research that proves the efficiency and efficacy of AM treatments. In this paper, I have described AM treatments available today and their impact on diabetes management.

Adverse events after chemodenervation with onabotulinum neurotoxin A in children with hypertonia and sialorrhea.

To identify the incidence and type of adverse events reported after chemodenervation with onabotulinum neurotoxin A (BoNT-A) in children with hypertonia and sialorrhea and compare adverse events in the on-label or off-label use of BoNT-A with regard to dose, patient's age, and location of the injection. Using a retrospective chart review, we studied BoNT-A injections occurring from January 2017 to December 2020 in patients at a pediatric hospital. The electronic health record was examined to identify adverse events reported within 2 months of the injection. Data included the patient's age, sex, race, and ethnicity, as well as the type of toxin injected, the dose, the location of injection, and the patient's weight. We analyzed 1733 procedures. Adverse events were infrequent (2.5%) and not serious, most commonly reported as pain or discomfort. All adverse events were temporary and there were no deaths. We did not observe a meaningful difference in the frequency of adverse events for injections that exceeded the 2022 US Food and Drug Administration (FDA)-approved maximum dose compared to injections that were within the FDA-approved dose range. The likelihood of adverse events did not increase with higher doses of BoNT-A. More adverse events were reported for injection into the salivary glands (4.37%) than into the extremities (2.26%). Higher doses of injected BoNT-A in a pediatric population may be safe. Further work is needed to investigate the relationship between dose and efficacy.

Restrictions on pharmacist dispensing of mifepristone remain a hard pill to swallow

AbstractThis analysis explores the basis for the US Food and Drug Administration (FDA) requiring a Risk Evaluation and Mitigation Strategy (REMS) for mifepristone for the termination of intrauterine pregnancy. Controversies surround mifepristone and its REMS. The safety and efficacy of mifepristone are briefly reviewed with respect to FDA's actions. It is difficult to justify the continued requirement for a REMS for mifepristone by applying the regulatory framework and considering mifepristone's safety record. Drugs with higher risks are on the US market without an FDA‐mandated REMS. Canada removed all restrictions on the use of mifepristone for abortion, which has not resulted in patient safety concerns. All pharmacists should be permitted to dispense mifepristone. The continued requirement for a mifepristone REMS in the US appears to be based more on politics rather than evidence.

In Vitro Sonodynamic Therapy Using a High Throughput 3D Glioblastoma Spheroid Model with 5-ALA and TMZ Sonosensitizers.

Sonodynamic therapy (SDT) administered using low-intensity pulsed ultrasound and sonosensitizers is an emerging, minimally invasive, targeted deep-tissue therapy for solid tumors such as glioblastoma multiforme (GBM). Initial clinical trials show promising outcomes for SDT treatments of GBM. A crucial aspect of SDT is the sonosensitizer that interacts with ultrasound, facilitating energy transfer to the tumor, thus inducing therapeutic efficacy. Current in vitro methods for determining the therapeutic efficacies of sonosensitizers are time-consuming and expensive. A novel high-throughput magnetically printed 3D GBM model is used to overcome this challenge. The hypothesis is that the use of two sonosensitizers, one a chemotherapeutic drug, enhances SDT efficacy through their additive chemical interactions. The GBM model is used to evaluate the effectiveness of two sonosensitizer molecules, 5-aminolevulinic acid (5-ALA) and theU.S. Food and Drug Administration (FDA)-approved chemotherapeutic drug Temozolomide (TMZ). It is confirmed that implement high-throughput GBM models to evaluate sonosensitizer combinations and their efficacies is feasible and, for the first time, show that the combined effect of both sensitizers, 5-ALA and TMZ, is superior for preventing spheroid growth than employing each molecule separately. This finding is relevant for future clinical trials of GBM treatment with SDT.