Food And Drug Administration Research Articles

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling.

Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high-fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408-C-1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high-fat breakfast on a 150-mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose-ranging, food effect, and drug-drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high-fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, invivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

An Analysis of Food Recalls in the United States, 2002–2023

This article evaluates and summarizes Food and Beverages (F&B) recalls managed or mandated by the U.S. Food and Drug Administration (FDA) over the past 20 years: the database includes over 35,000 recalls. For recall classification purposes, the causes were separated into 2 overall categories consisting of product contaminants or processing issues. The product contaminants category was further separated into 5 groups: allergens, biological contaminants, chemical contaminants, foreign objects, and undeclared food colors. The processing issues category was separated into 6 groups: cGMP issues, HACCP issues, manufacturing issues, mislabeling or misbranding, refrigeration issues, and under-processing. Product contaminants accounted for 91% of the F&B recalls, while processing issues accounted for the remaining 9%. Two groups accounted for about 76% of the recalls: biological contamination and allergens. The FDA classifies recalls by the potential severity of the health impact. Over half of the F&B recalls were Class I recalls, and biological contamination and allergens accounted for 96% of those recalls. Listeria monocytogenes was the largest cause of all of the recalls accounting for 7,844 recalls: 22% of the total recalls and 45% of the biological contamination recalls. Salmonella serovars were responsible for 6,597 recalls, including 18% of the total recalls and 38% of the biological recalls. Listeria and Salmonella serovars together resulted in 40% of all of the F&B recalls.

Adagrasib in KRYSTAL-12has Broken the KRAS G12C Enigma Code in Non-Small Cell Lung Carcinoma.

Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10-13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

JAK 1-3 inhibitors and TYK-2 inhibitors in dermatology: Practical pearls for the primary care physician

ABSTRACT Guidelines for primary care clinicians on monitoring and safety guidelines regarding Janus kinase and tyrosine kinase 2 inhibitors in the treatment of inflammatory skin conditions are often unclear. This review aims to provide the primary care physician with a review of clinically relevant and updated information regarding the monitoring and overall profile of these medications. To do so, a systematic review was conducted using the PubMed database and relevant Food and Drug Administration (FDA) approved drug inserts from manufacturers. Janus kinase and tyrosine kinase 2 inhibitors have recently gained FDA approval for the treatment of several inflammatory skin conditions including atopic dermatitis, plaque psoriasis, alopecia areata, and vitiligo. There is a known box warning associated with the Janus kinase inhibitors that create the need for monitoring and close follow-up while patients are undergoing these treatments. Although these medications are often prescribed by specialists, as their use becomes more prevalent and therapies continue to gain approval for the treatment of these commonly encountered conditions, it is important for the primary physician to be updated and aware of the current monitoring guidelines and safety profile for this class of medication. Both Janus kinase inhibitors and tyrosine kinase 2 inhibitors display significant efficacy in the treatment of their approved conditions and research continues to move forward with the approval of more medications from these classes.

Use of Hydrochlorothiazide in the United States Following Label Update About Skin Cancer Risk.

On August 20, 2020, the United States (U.S.) Food and Drug Administration (FDA) issued a Drug Safety Communication (DSC) along with labeling updates to inform the public about a small increased risk of non-melanoma skin cancer (NMSC) associated with hydrochlorothiazide (HCTZ) use. This study aims to assess whether the DSC impacted HCTZ use in the U.S. We conducted a trend analysis in the Sentinel Distributed Database using national healthcare administrative data from January 2017 to November 2022. We identified two cohorts each month: An overall cohort of all enrollees and a skin cancer cohort of those with a history of NMSC. For each cohort, we plotted the monthly proportion of patients receiving HCTZ-containing products among those receiving any thiazide diuretics. We performed interrupted time series analyses to quantify the impact of the DSC on these monthly proportions. Secondary analyses were conducted on the proportion of HCTZ users among patients receiving any antihypertensives. In the overall cohort, the DSC was only associated with a statistically significant but clinically negligible trend change of monthly HCTZ proportion within this cohort (0.018%; 95% CI, 0.012%-0.025%). Similar results were observed in the skin cancer cohort. The secondary analysis found no significant level change or trend change in the monthly proportion of HCTZ use among antihypertensive users. We did not observe significant changes in HCTZ use following the DSC about its NMSC risk, among the overall population and those with a history of NMSC. Our findings were in accordance with the DSC recommendation.

Prediction of Pharmacokinetic Drug-Drug Interactions Involving Anlotinib as a Victim by Using Physiologically Based Pharmacokinetic Modeling.

Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug-drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model. The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance. Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUCR and CmaxR values of 0.44 and 0.79, respectively. Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib's interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib's pharmacokinetics.

Impact of Age and Concurrent Antiseizure Medication Use on Lacosamide Dose to Concentration Ratio and Dosing in Pediatric Patients.

To evaluate age, adjunctive antiseizure medication (ASM), and specific ASMs on lacosamide (LCM) weight normalized dose-to-concentration ratio (DCR) and US Food and Drug Administration (FDA) dosing guidelines in pediatric patients. Patients 1 mo to ≤18 years with a LCM serum concentration between October 2009 and June 2017 were considered. Demographics, LCM DCR, and adjunctive ASM were recorded. LCM DCR/hr was used as a surrogate for clearance. Data were stratified by age (1 mo-< 2 yr; ≥ 2-6 yr; ≥ 6-12 yr; and ≥12-≤18 yr), FDA dosing weights, and ASM potential to interaction with LCM. There were 646 sera (380 patients) with median dose 8.36 mg/kg/day (IQR, 5.92-11.16). 50.2% of doses were within FDA-weight guidelines; however, 40.4% exceeded recommendations. Most (81.3%) LCM concentrations were between 2 and 12 mg/L. A difference existed in DCR between ages, with those <2 years having the highest DCR (p < 0.001). Moving across age groups, the DCR decreases by 30.7%, 50.5%, and 63.4%. There was a weak (r2 = 0.073) but significant (p < 0.001) negative correlation between DCR and age. 84.8% received adjunctive ASM consisting of at least one of 31 different ASMs. DCR was higher with adjunctive ASMs compared with monotherapy [0.061 (0.039-0.095) vs 0.043 (0.030-0.062)], respectively (p < 0.001) and was greatest with inducers. Phenobarbital increased DCR by 2.6-fold, topiramate by 72.1%, and clobazam by 32.6%. Inhibitors had no effect. The correlation between age and DCR was weak, accounting for 6% of variability. Strong inducers significantly increased DCR. Synergy may exist when multiple inducers are given. Weak inhibitors did not affect DCR. Those ≥6 to 11 kg, ≥30 to 50 kg, and those given strong inducers may require larger -initial LCM doses. Serum concentrations should be used to individualize dosing, especially in those receiving strong inducers.

INhaled Sedation versus Propofol in REspiratory failure in the Intensive Care Unit (INSPiRE-ICU1): protocol for a randomised, controlled trial

IntroductionSedation in mechanically ventilated adults in the intensive care unit (ICU) is commonly achieved with intravenous infusions of propofol, dexmedetomidine or benzodiazepines. Significant limitations associated with each can impact their...

Individualized medication of venetoclax based on therapeutic drug monitoring in Chinese acute myeloid leukemia patients using an HPLC method.

The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. The analysis required the extraction of a 50 μl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH 2 PO 4 (pH 3.5) (60/40, v/v) on a Diamond C 18 (4.6 mm × 250 mm, 5 μm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). The calibration curve was linear ( R2 = 0.9998) over the range of 75-4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration ( Cmax ) was 1881.19 ± 756.61 ng/ml, while the trough concentration ( Cmin ) was 1212.69 ± 767.92 ng/ml in acute myeloid leukemia patients. Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Diabetic Neuropathy: A Guide to Pain Management.

Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

Online Medication Abortion Direct-to-Patient Fulfillment Before and After the Dobbs v Jackson Decision

Online pharmacies have emerged as stakeholders in abortion care since the US Food and Drug Administration (FDA) relaxed in-person dispensing requirements in 2020. The role of online pharmacies in dispensing abortion medications following the Dobbs v Jackson Women's Health Organization decision on June 24, 2022, is understudied. To describe medication abortion prescription fulfillment patterns for 1 online pharmacy 1 year before and after the Dobbs v Jackson decision, considering patient, prescriber, and state policy characteristics. This cross-sectional study assesses deidentified medication abortion prescription fulfilment data from 1 online pharmacy. Prescribers sent prescription requests to the online pharmacy, which dispensed abortion medications to patients by mail. The study sample included prescription requests fulfilled by the online pharmacy between June 20, 2021, and June 24, 2023, for patients aged at least 18 years who received the combined medication abortion regimen. Data were analyzed from July 2023 to July 2024. The US Supreme Court Dobbs v Jackson decision on June 24, 2022. Patient and prescriber characteristics are described, including patient age, state to which the prescription was sent, medications prescribed, and prescribing prescriber's clinic care modality (in-person only, hybrid [in-person and virtual], and virtual only). States were grouped according to the Guttmacher Institute classification of policy support for abortion (most or very supportive, somewhat supportive, and somewhat restrictive). Fulfillment trends were disaggregated by prescriber modality and state policy environment; 2 states with similar telehealth but differing coverage policies (Illinois and Colorado) were compared. The dataset included 87 942 observations. Most prescriptions were sent to individuals younger than 30 years (57.1%), with a mean (SD) age of 28.7 (6.4) years. Throughout the study period, the greatest volume of prescription requests came from states with most or very supportive policies and from prescribers at virtual-only platforms. More prescriptions were sent in the year after Dobbs v Jackson (daily mean [SD], 88.5 [47.2] prescriptions in March 2022 vs 201.5 [97.5] prescriptions in March 2023) with fulfillment spikes following the Dobbs v Jackson leak on May 2, 2022, and decision on June 24, 2022. State policy contexts mirrored the overall trends, while prescriber modality trends were unique, with a big spike in fulfillment at 12 weeks after the Dobbs v Jackson decision for hybrid clinics compared with in-person-only clinics and telehealth-only platforms, which saw their largest spikes in mean daily prescription fulfillment the week immediately after Dobbs v Jackson. Illinois and Colorado had similar fulfillment trends, with spikes immediately following the Dobbs v Jackson decision and overall higher fulfillment after Dobbs v Jackson, with a daily mean (SD) of 10.5 (7.0) prescriptions in Illinois and 8.8 (5.7) prescriptions in Colorado in March 2022 versus 26.6 (13.6) prescriptions in Illinois and 16.7 (10.1) prescriptions in Colorado in March 2023. These findings illustrate the increasingly critical role online pharmacies play in direct-to-patient abortion care provision in the US and the strong linkages between virtual-only prescribers and online pharmacies. These findings suggest that barriers to accessing online pharmacies for abortion care should be removed.

Oral Administration of Taurodeoxycholate, A GPCR19 Agonist, Effectively Ameliorates Atopic Dermatitis in A Mouse Model.

Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disorder, characterised by intense pruritus and recurrent eczematous lesions. Recently, the US FDA has approved Janus kinase (JAK) inhibitors for oral treatment in AD patients. However, oral immunomodulatory agents have demonstrated adverse effects. In previous studies, we demonstrated the efficacy of topical taurodeoxycholate (TDCA), a G protein-coupled receptor 19 (GPCR19) agonist, on AD. In this study, we further evaluated the efficacy of orally administered TDCA on MC903- and dinitrochlorobenzene (DNCB)-induced AD mouse models. Oral administration of TDCA significantly ameliorated AD symptoms and reduced both epidermal and dermal thickness. Additionally, oral TDCA treatment inhibited the infiltration of myeloid and lymphoid cells into AD lesions. TDCA also suppressed the expression of thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-13, IL-33, IL-1β, tumour necrosis factor-alpha (TNF-α) and chemokine (C-C motif) ligand 17 in the skin and blood. Given the previously demonstrated safety profiles of TDCA, oral TDCA may offer a beneficial and safer alternative for AD patients.

Real-world (rw) treatment (tx) patterns and overall survival (OS) in patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) treated with avelumab first-line maintenance (1LM): Updated results from the SPEAR Bladder II study.

393 Background: Avelumab 1LM tx is approved in the US for pts with la/mUC who do not have disease progression after platinum-based chemotherapy (PBC). The tx landscape is evolving due to the recent approvals of newer therapies for pts with la/mUC. This study examines rw tx patterns, tx sequencing post avelumab 1LM, and OS in pts with la/mUC who initiated 1L tx in the US community oncology setting. Methods: This retrospective cohort study used the US Oncology Network (iKnowMed) EHR database. The study included adult pts (≥18 years) with la/mUC initiating 1L tx (index date) between Dec 1, 2019, and Nov 30, 2023. Pts were censored for OS at their last contact date or the end of study period, Feb 28, 2024. Descriptive statistics were used to describe tx patterns. Kaplan-Meier analysis was used to evaluate OS from the start of 1LM or second-line (2L) enfortumab vedotin (EV) treatment post avelumab 1LM. Results: A total of 1,658 pts with la/mUC initiated 1L tx with a median (range) follow-up of 9.0 months (0.1-50.4). The median (range) age at diagnosis was 73 years (31-90+), 74.7% were male and 47.1% had ECOG performance status ≤1. The 1L therapies included: IO monotherapy (41.2%), PBC only (32.4%), PBC followed by avelumab 1LM (11.2%), and other tx (15.1%). Since the US FDA approval (June 30, 2020), the utilization of avelumab 1LM among 1L PBC users ranged from 25.0% to 32.9% in 2023. Median (range) follow-up from the start of avelumab 1LM was 9.1 months (0.5-42.2). During the study observation period, 44 pts (23.7%) remained on avelumab 1LM. Median (95% CI) OS from start of avelumab 1LM was 18.5 months (13.8-23.8). Among the overall study cohort, 598 (36.1%) and 196 pts (11.8%) received 2L and third-line tx, respectively. The most common 2L therapies were IO monotherapy (44.1%) and EV monotherapy (23.9%). After discontinuation of avelumab 1LM, 81 pts (43.5%) received 2L tx, 48 (59.3%) of those received EV; median OS from start of 2L EV was 12.7 months (7.2-16.5). Conclusions: These rw study findings demonstrate avelumab 1LM effectiveness for pts whose disease has not progressed on 1L PBC and provides evidence of the use of 2L EV after avelumab 1LM. There was an increased uptake of avelumab 1LM since its FDA approval. Survival outcomes are consistent with the JAVELIN Bladder 100 clinical trial and other rw studies that had shorter follow-up. We observed high IO monotherapy use despite the platinum-ineligible population typically making up 11% of pts with la/mUC. 1 Some of these pts treated with IO monotherapy may benefit from alternative 1L regimens. Future rw studies are needed to further characterize contemporary tx patterns, optimal tx sequencing, and survival in pts with la/mUC amidst the evolving tx landscape. 1 Gupta S, et al. JNCI 2024;116(4):547–554.

Trofinetide treatment for Rett syndrome: Lessons to learn

The US FDA approval of trofinetide as the first pharmacological treatment to improve Rett syndrome's symptomatology marks a significant milestone with broad implications for various disorders. The LILAC trials demonstrate long-term safety and efficacy of trofinetide.1,2 While further research is needed to fully resolve the condition, insights from trofinetide trials can inform strategies for future treatments and trials.

Geographic differences in susceptibility profiles of potential non-class B carbapenemase-producing Enterobacterales isolates against ceftazidime-avibactam, meropenem-vaborbactam, colistin, amikacin, gentamicin, and tigecycline: Data from the Antimicrobial Testing Leadership and Surveillance, 2018–2022

To evaluate the susceptibility profiles of regional meropenem-resistant (MEM-R) potential non-class B carbapenemase-producing Enterobacterales (CPE) isolates (without confirmation by phenotypic tests) against important antibiotics, we extracted data from the 2018-2022 Antimicrobial Testing Leadership and Surveillance. This data included susceptibility information of MEM-R potential non-class B CPE isolates against indicated antibiotics - amikacin [AMK], gentamicin [GM], ceftazidime-avibactam [CZA], colistin [CST], meropenem-vaborbactam [MVB], and tigecycline [TGC] - from sepsis patients hospitalized in ICUs across six major regions. Carbapenemase-encoding genes of the tested CPE isolates, determined by multiplex PCR and Sanger sequencing, were also analyzed. Susceptibility breakpoints recommended by CLSI 2024 and US FDA criteria (for TGC only) against Enterobacterales were employed. A total of 1,500 potential non-class B CPE isolates (89% of which were Klebsiella pneumoniae) were tested globally. Resistance rates to AMK and GM against the evaluated isolates were statistically higher in Africa/the Middle East, Europe, and India compared to other regions. A similar pattern was observed in the susceptibility of these potential CPE isolates to CZA and MVB. High CST resistance rates were noted in Asia, Latin America, and Europe (29%-35%). Furthermore, the proportions of potential CPE isolates carrying genes encoding blaOXA variants were notably higher among the tested CPE isolates in India, Europe, and Africa/the Middle East regions (99.2%, 53.3%, and 96.7%, respectively) compared to other regions. Trends in resistance to important antibiotics among potential non-class B CPE isolates warrant close monitoring.

Energy-Based Medical Devices in Plastic Surgery: A Comparison of FDA-Approved Indications to Advertised Claims.

Lasers and energy-based devices are commonly employed in aesthetic medicine. In the United States, the FDA regulates lasers as medical devices, restricting marketing to approved indications and making off-label claims illegal. Despite this, no comprehensive analysis of off-label marketing prevalence exists. The authors of this study aim to compare the FDA-approved indications for 2 popular aesthetic lasers to their online advertising claims. Additionally, they seek to educate aesthetic providers on the current regulatory restrictions surrounding off-label advertising. FDA-approved indications for 2 lasers-helium plasma dermal resurfacing and 2940 nm fractional erbium-doped yttrium aluminum garnet-were obtained from the publicly available Establishment Registration & Device Listings Database. Online advertisements regarding the capabilities of each laser were collected from practice websites in the United States. Our analysis of 100 online claims for each laser revealed that more than half of the websites advertising helium plasma (n = 59) and 44 websites advertising fractional lasers made at least 1 off-label claim. Both plastic surgeons and nonplastic surgeons made at least 1 off-label claim, with no statistically significant difference between the groups. Despite FDA regulation of medical devices, online advertising regarding the indications and capabilities of popular medical lasers varies widely. Patients who seek information regarding aesthetic laser treatments may encounter inaccurate and differing claims for these treatments, potentially leading to false expectations and poor patient outcomes.

Isolation and Preliminary Characterization of Probiotic Isolates from Healthy Thai Adult Feces

Probiotics are known for health-promoting microorganisms, for examples, assisting gastrointestinal digestion and short chain fatty acid producers. Several current oral human probiotics were derived from human samples; yet, of various ethnic (genetics) and dietary patterns. As probiotics from similar ethnic (genetics) and dietary pattern might confer certain advantages (e.g., more compatibility with hosts), this study isolated and characterized probiotics from healthy Thai adults. To screen for potential probiotic isolates from healthy Thai adult feces, and preliminary characterize these probiotic isolates by biochemical tests and 16S rRNA gene sequencing, following the established Thailand’s Food and Drug Administration (FDA) and National Center for Genetic Engineering and Biotechnology (BIOTEC) guidelines. Twenty fecal samples with clinically verified healthy Thai males and females aged 22-42 years were cultivated on MRS (or M17) media along the broad probiotic screenings (pH 4.0 and 0.1% oxgall) for bacterial probiotic propagation. All derived colonies of different morphologies were continued colony PCR using universal probiotic primers (specific for genera Bifidobacterium, Enterococcus, Lactobacillus, Pediococcus and Streptococcus thermophilus), and only PCR-positive colonies from any of these probiotic primer pair were further cultivation for isolates. Then, these isolates were screened and characterized general probiotic properties that included acid tolerance (pH 2.0), bile salt tolerance (0.3% bile salt), hydrophobicity, antibiotic (ampicillin, ciprofloxacin, erythromycin and vancomycin) susceptibility, no hemolysis activity, catalase, and potassium hydroxide (KOH). The final passing isolates represented potential probiotic isolates that could perhaps maintain in gastrointestinal tract with safety, and were full-length 16S rRNA gene sequenced to identify the genus and species by BLASTN against non-redundant GenBank database. A total of 295 bacterial isolates were obtained from the cultivated on MRS (or M17) media along the broad probiotic screenings from 20 fecal samples. Then, following the general probiotic property characterizations and the full-length 16S rRNA gene sequence analysis, 7 potential isolates were finally derived: 2 Bifidobacterium animalis subsp. lactis, 1 Lactobacillus (new genus name as Limosilactobacillus) reuteri, 1 L. reuteri or L. vaginalis, and 3 Pediococcus pentosaceus. These isolates exhibited strong acid and bile salt tolerances, and relatively high cell surface hydrophobicity. These isolates were susceptible to ampicillin and erythromycin, similar to a reference probiotic control Lactobacillus casei strain Shirota; and the CU13-450 and CU13-451 were also susceptible to vancomycin, similar to a reference control Bifidobacterium breve. Catalase-negative consistent with these bacteria in intestinal tract as anaerobes or facultative anaerobes, and KOH-negative result inferred the Gram-positive bacteria consistent with the full-length 16S rRNA gene sequence identification (Bifidobacterium, Lactobacillus, and Pediococcus are Gram-positive bacteria). No hemolysis activity was observed for these isolates. These 7 probiotic isolates had general probiotic properties and with confirmed the 16S rRNA gene sequences, that follow the Thailand’s FDA and BIOTEC guidelines. However, additional beneficial function investigations, such as in vitro epithelial cell adhesion and in vivo animal model, and whole genome sequencing, should be performed to better validate their possible human health benefits and safety.

True Benefits of Immune Checkpoint Inhibitors in the Treatment of Malignant Pleural Mesothelioma in Japan.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

Telomerase in Cancer Therapeutics.

While silent in normal differentiated human tissues, telomerase is reactivated in most human cancers. Thus, telomerase is an almost universal oncology target. This update describes preclinical and clinical advancements using a variety of approaches to target telomerase. These include direct telomerase inhibitors, G-quadruplex DNA-interacting ligands, telomerase-based vaccine platforms, telomerase promoter-driven attenuated viruses, and telomerase-mediated telomere targeting approaches. While imetelstat has been recently approved by the Food and Drug Administration (FDA), several other approaches are in late-stage clinical development. The pros and cons of the major approaches will be reviewed.