Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training.

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross-sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three-point bending and microcomputer tomography were measured in the femur. Follow-up experiments in human primary muscle cells were used to explore supra-physiological effects of ACE. Data were analyzed using a two-way ANOVA for treatment (ACE or placebo) and condition (exercise or non-exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment-by-condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated-AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho-4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post-exercise.

Discovery of novel diesters incorporating Kojic acid with NSAIDs and Palmitic acid as dual inhibitor of melanogenesis and inflammation.

Our study focuses on creating hybrid compounds and assessing their suitability for use in skincare products. The synergistic combination of Kojic acid, NSAIDs, and Palmitic acid proved to be an effective approach in inhibiting melanin production, making it a promising solution for individuals with hyperpigmentation concerns with Kojic acid (KA) Ibuprofen monoester (IBUM) and Ibuprofen-Kojic acid-Palmitic acid diester (IBUD) exhibiting a potential tyrosinase (38 and 49% inhibition at 200 µM) and anti-melanogenesis activity (77 and 79% inhibition at 100 µM). Furthermore, these compounds exhibited potent anti-inflammatory effects, Kojic acid-Diclofenac monoester (DICM) and Diclofenac-Kojic acid-Palmitic acid diester (DICD) offering potential benefits for inflammation by lowering the paw volume. A stability study under chemical conditions and enzymatic conditions was also performed, wherein DICM and DICD showed a better half-life of 515, 593 h under chemical stability and 6.3, 7.5 h under enzymatic stability studies respectively. The diester hybrids IBUD, DICD, Naproxen-Kojic acid-Palmitic acid diester (NAPD) showed a better permeation and penetration profiles compared to their parent drugs. In-vitro cell line studies were conducted to assess the safety and efficacy of these hybrid esters, with promising results. The dual inhibitor demonstrated minimal cytotoxicity and remarkable anti-melanogenic and anti-inflammatory activities, showing its potential as a versatile agent in addressing both melanogenesis and inflammation.

Navigating Multiple Challenges: Malnutrition and Nephrotoxic Drug Effects in a Non-verbal Child With Autism Spectrum Disorder Requiring Dialysis.

Acute kidney injury (AKI) is a common medication adverse event, particularly in patients with pre-existing medical conditions taking nephrotoxic medications. However, little is known about the differences in the risk of nephrotoxic medication-related complications in children with autism spectrum disorder (ASD) compared to the general pediatric population. A nine-year-old non-verbal boy with ASD was hospitalized for scrotal cellulitis requiring vancomycin and piperacillin/tazobactam due to a lack of clinical response to cephalosporins. His history is significant for being an extremely selective eater, and his appetite decreased over four months prior to presentation. Poorly controlled scrotal pain, despite acetaminophen use, was suspected based on his facial expressions and maternal assessment, especially considering his non-verbal status. Consequently, a non-steroidal anti-inflammatory drug was initiated. The hospital course was complicated by the development of a scrotal abscess, minimal enteral intake, hypoalbuminemia-induced intravascular dehydration, oliguria, and generalized edema. His creatinine increased to 5.11 mg/dL from 0.51 mg/dL despite early discontinuation of nephrotoxic medications and fluid resuscitation, which led to hemodialysis due to worsening AKI. Subsequently, urinary output and edema improved. Creatinine improved to <1 mg/dL with careful creatinine monitoring and concomitant furosemide and albumin infusion in the pediatric intensive care unit. Children with comorbidities, such as malnutrition, who require nephrotoxic medications, need extra attention. Implementing clinical decision support tools or quality improvement programs can promote the prevention of nephrotoxic medication exposure and decrease the incidence of AKI. An alert within an electronic health record system for multiple nephrotoxic drugs and daily multidisciplinary huddles during patient-centered rounds could help reduce and eliminate adverse events. In particular, for non-verbal patients or those with limited communication skills, such as children with ASD, rigorous and close monitoring of vital signs, physical condition, pain, medication intake, and lab results, in addition to a nephrotoxic medication screening and notification system, should be key to optimizing patient care.

A Conservative Management of Perforated Peptic Ulcer: A Case Report.

Peptic ulcer disease (PUD) is a surgical emergency that affects the mucosal lining of the stomach or proximal intestine. Complications of PUD include upper gastrointestinal hemorrhage, perforation, and obstruction. The primary management approach for perforated peptic ulcers is surgery, but conservative management can be conducted in selected cases. A 54-year-old female was referred to the surgical unit with a history of severe upper abdominal pain and repeated vomiting. No other symptoms were reported and there was no significant medical or family history except the history of non-steroidal anti-inflammatory drugs. Examination revealed that the patient had a medical condition. was vitally stable with tenderness in the upper abdomen, in particular the epigastric and right hypochondrial, but no signs of generalized peritonitis. Her white cell count was elevated at 24,000x10^3/UL, and a C-reactive protein of 45.5 mg/dL. An upright CXR revealed the classic gas under the diaphragm. Abdominal CT with oral gastrograffin identified the diagnosis of perforated duodenal ulcer without ulcer leak. The case was treated by conservative management started with resuscitation, nil per os, IV fluid, IV antibiotics, and close observation and the patient was stable with no complications and completed the nonoperative management successfully till discharge after 10 days of hospital stay. The case illustrates that although this condition is uncommon to be treated without surgical intervention, there are some factors and criteria for successful NOM. Peptic ulcer perforation is a life-threatening surgical emergency. Surgery is the standard treatment for PPU and NOM can be conducted safely and successfully in highly selected cases. the surgeon should keep a wide safety window while providing nonstandard management with readiness to operate at any time. We believe that the main factor in successful nonsurgical management of our case is being fasted for a long time before perforation.

Comparing Metabolic Preconditioning and Diabetes As Risk Factors in Knee Arthroplasty Complications.

BACKGROUND AND OBJECTIVES: Advanced osteoarthritis of the knee joint severely affects the patient's mobility, compounded by pre-existing comorbidities such as metabolic preconditioning (such as obesity, dyslipidemia, hyperuricemia, and insulin resistance syndrome) and both type I and type II diabetes. The success of total knee arthroplasty is influenced by knowledge and management of risk factors. The present study aims to evaluate differences in the evolution of risk factors such as obesity, injuries, and sedentary lifestyle, distinguishing those with metabolic preconditions and diabetes. The objectives of our study include (1) investigating the prevalence of obesity among patients, highlighting their proportion in the five categories of body weight; (2) analyzing statistically significant differences between research groups in terms of weight status and physical activity; (3) evaluating postoperative evolution based on the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and without NSAIDs (N-NSAIDs), with an emphasis on overweight patients and those with diabetes; and (4) examining changes in metabolic preconditioning and the incidence of postoperative injury depending on the administration of anti-inflammatory drugs. MATERIALS AND METHODS:  A cohort involving 730 patients diagnosed with gonarthrosis was divided into two groups according to the administration of anti-inflammatory drugs in the first seven postoperative days: N-NSAIDs group (394 patients, 55.3%) and respectively NSAIDs group (319 patients, 44.7%). The prospective, observational study was conducted in terms of risk factors and complications that occurred upon treatment administration in relation to each type of intervention and implant used. The outcomes were assessed in terms of the influence on quality of life, the data being collected and interpreted for the entire cohort, and for each study year individually. RESULTS: The results indicate that almost 69% of them were overweight, while only 31% had a normal weight. Significant differences in weight status were observed between research groups, highlighting the association between obesity and metabolic preconditions or diabetes. Physical activity was absent in a significant proportion, having a notable impact on postoperative evolution, especially in the group without metabolic precondition. Administration of anti-inflammatory drugs influenced postoperative outcomes, with significant differences in overweight and diabetic patients. CONCLUSIONS: The findings suggest the need to manage body weight, promote physical activity, and personalize postoperative treatments, given the complex interactions between obesity, metabolic preconditions, and the administration of NSAIDs.

The contemplation of amylose for the delivery of ulcerogenic nonsteroidal anti-inflammatory drugs.

This manuscript proposes an innovative approach to mitigate the gastrointestinal adversities linked with nonsteroidal anti-inflammatory drugs (NSAIDs) by exploiting amylose as a novel drug delivery carrier. The intrinsic attributes of V-amylose, such as its structural uniqueness, biocompatibility and biodegradability, as well as its capacity to form inclusion complexes with diverse drug molecules, are meticulously explored. Through a comprehensive physicochemical analysis of V-amylose and ulcerogenic NSAIDs, the plausibility of amylose as a protective carrier for ulcerogenic NSAIDs to gastrointestinal regions is elucidated. This review further discusses the potential therapeutic advantages of amylose-based drug delivery systems in the management of gastric ulcers. By providing controlled release kinetics and enhanced bioavailability, these systems offer promising prospects for the development of more effective ulcer therapies.

Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

The transition of medication overuse status by acute medication categories in episodic or chronic migraine patients to non-overuse status after receiving anti-CGRP monoclonal antibodies: a systematic review and meta-analysis of phase 3 randomized control trial.

OBJECTIVE: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. METHODS: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. RESULTS: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. CONCLUSION: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters.

Insight on novel oxindole conjugates adopting different anti-inflammatory investigations and quantitative evaluation.

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 µM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.

Metal-Based Nanomaterials for the Sensing of NSAIDS.

Cadmium sulfide and zinc oxide nanoparticles were prepared, characterized and used as electrode modifiers for the sensing of two non-steroidal anti-inflammatory drugs (NSAIDs): naproxen and mobic. The structural and morphological characterization of the synthesized nanoparticles was carried out by XRD, UV-Vis spectroscopy, FTIR and scanning electron microscopy. The electrode's enhanced surface area facilitated the signal amplification of the selected NSAIDs. The CdS-modified glassy carbon electrode (GCE) enhanced the electro-oxidation signals of naproxen to four times that of the bare GCE, while the ZnO-modified GCE led to a two-fold enhancement in the electro-oxidation signals of mobic. The oxidation of both NSAIDs occurred in a pH-dependent manner, suggesting the involvement of protons in their electron transfer reactions. The experimental conditions for the sensing of naproxen and mobic were optimized and, under optimized conditions, the modified electrode surface demonstrated the qualities of sensitivity and selectivity, and a fast responsiveness to the target NSAIDs.

In vivo effects of a selected thiourea derivative 1-(2-chlorobenzoyl)-3-(2,3-dichlorophenyl) against nociception, inflammation and gastric ulcerogenicity: Biochemical, histopathological and in silico approaches.

The current study was designed to investigate the potential of a synthetic therapeutic agent for better management of pain and inflammation, exhibiting minimal to non-existent ulcerogenic effects. The effect of 1-(2-chlorobenzoyl)-3-(2,3-dichlorophenyl) thiourea was assessed through model systems of nociception and anti-inflammatory activities in mice. In addition, the ulcerogenic potential was evaluated in rats using the NSAID-induced pyloric ligation model, followed by histopathological and biochemical analysis. The test was conducted on eight groups of albino rats, comprising of group I (normal saline), groups II and III (aspirin® at doses of 100 mg/kg and 150 mg/kg, respectively), groups IV and V (indomethacin at doses of 100 mg/kg and 150 mg/kg, respectively), and groups VI, VII, and VIII (lead-compound at 15 mg/kg, 30 mg/kg and 45 mg/kg doses, respectively). Furthermore, molecular docking analyses were performed to predict potential molecular target site interactions. The results showed that the lead-compound, administered at doses of 15, 30, and 45 mg/kg, yielded significant reductions in chemically and thermally induced nociceptive pain, aligning with the levels observed for aspirin® and tramadol. The compound also effectively suppressed inflammatory response in the carrageenan-induced paw edema model. As for the ulcerogenic effects, the compound groups displayed no considerable alterations compared to the aspirin® and indomethacin groups, which displayed substantial increases in ulcer scores, total acidity, free acidity, and gastric juice volume, and a decrease in gastric juice pH. In conclusion, these findings suggest that our test compound exhibits potent antinociceptive, anti-inflammatory properties and is devoid of ulcerogenic effects.

Impact of concurrent medications on the outcome of immunotherapy in non-small cell lung carcinoma.

BACKGROUND: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC. METHODS: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation. RESULTS: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013). CONCLUSIONS: The unnecessary use of NSAIDs along with immunotherapy should be discouraged.

Recent Advancements in Refashioning of NSAIDs and their Derivatives as Anticancer Candidates.

Inflammation is critical to the formation and development of tumors and is closely associated with cancer. Therefore, addressing inflammation and the mediators that contribute to the inflammatory process may be a useful strategy for both cancer prevention and treatment. Tumor predisposition can be attributed to inflammation. It has been demonstrated that NSAIDs can modify the tumor microenvironment by enhancing apoptosis and chemosensitivity and reducing cell migration. There has been a recent rise in interest in drug repositioning or repurposing because the development of innovative medications is expensive, timeconsuming, and presents a considerable obstacle to drug discovery. Repurposing drugs is crucial for the quicker and less expensive development of anticancer medicines, according to an increasing amount of research. This review summarizes the antiproliferative activity of derivatives of NSAIDs such as Diclofenac, Etodolac, Celecoxib, Ibuprofen, Tolmetin, and Sulindac, published between 2017 and 2023. Their mechanism of action and structural activity relationships (SARs) were also discussed to set the path for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer.

Rapid identification of potential nonsteroidal anti-inflammatory drug overdose-induced liver toxicity and prediction of follow-up exposure: Integrating bioanalytical and population pharmacokinetic assay.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs that can cause liver toxicity. The aim of this study was to integrate bioanalytical and population pharmacokinetic (PopPK) assay to rapidly screen and quantify the concentrations of NSAIDs in plasma and monitor clinical safety. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetaminophen (APAP), flurbiprofen (FLB), aspirin (ASP), and ibuprofen (IBP), four commonly used NSAIDs. The PopPK model of the signature toxicant was analyzed based on the published literature. The LC-MS/MS method was successfully validated and applied to determine NSAID concentrations in patient plasma samples. APAP, ASP, and IBP data were best fitted using a one-compartment model, and FLB data were best fitted using a two-compartment model. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. A fast, simple, and sensitive LC-MS/MS method was developed and validated for determining APAP, FLB, ASP, and IBP in human plasma. Combined with the PopPK model, this method was applied to rapidly analyze the concentrations of NSAIDs in clinical samples from patients presenting to the emergency department with acute liver dysfunction and monitored NSAIDs clinical safety.

Understanding treatment of pain during SARS-CoV-2 pandemic in a two-year intercity longitudinal study using wastewater-based epidemiology.

SARS-CoV-2 pandemic had a significant impact on the society, economy, and health of people around the world with consequences that need to be better understood for future pandemic preparedness. This manuscript provides insights into the usage of pharmaceuticals for pain treatment management throughout SARS-CoV-2 pandemic. Four towns and cities with a total population of > 1 million people covering an area of 2000 km2 in South West England were monitored for twenty-four months. Results showed different patterns in pain pharma usage, with small towns having higher population normalised daily loads (PNDLs) than big cities for majority of pain killers studied. This is likely due to demographics of these cities with smaller cities having older population. Per capita consumption of non-steroidal anti-inflammatory drugs (NSAIDs) increased compared to pre-pandemic usage in line with SARS-CoV-2 infections (ibuprofen and acetaminophen), while body pain drugs (diclofenac and naproxen) decreased in line with restrictions and closure of sports facilities. Changes in population normalised daily intake (PNDI) of pain killers were particularly apparent during the 1st and 3rd national lockdown. Comparison of PNDIs with prescriptions highlighted differences related to medication availability (OTC drugs) and patients' nonadherence (prescribed drugs). In addition, several instances of direct disposal events across the catchments were observed which raises an issue of lack of pharma compliance and general understanding of potential environmental impacts from pharma usage.

The Cocktail Effects on the Acute Cytotoxicity of Pesticides and Pharmaceuticals Frequently Detected in the Environment.

Xenobiotics never appear as single, isolated substances in the environment but instead as multi-component mixtures. However, our understanding of the ecotoxicology of mixtures is far from sufficient. In this study, three active pharmaceutical ingredients (carbamazepine, diclofenac, and ibuprofen) and three pesticides (S-metolachlor, terbuthylazine, and tebuconazole) from the most frequently detected emerging micropollutants were examined for their acute cytotoxicity, both individually and in combination, by bioluminescence inhibition in Aliivibrio fischeri (NRRL B-11177). Synergy, additive effects, and antagonism on cytotoxicity were determined using the combination index (CI) method. Additionally, PERMANOVA was performed to reveal the roles of these chemicals in binary, ternary, quaternary, quinary, and senary mixtures influencing the joint effects. Statistical analysis revealed a synergistic effect of diclofenac and carbamazepine, both individually and in combination within the mixtures. Diclofenac also exhibited synergy with S-metolachlor and when mixed with ibuprofen and S-metolachlor. S-metolachlor, whether alone or paired with ibuprofen or diclofenac, increased the toxicity at lower effective concentrations in the mixtures. Non-toxic terbuthylazine showed great toxicity-enhancing ability, especially at low concentrations. Several combinations displayed synergistic effects at environmentally relevant concentrations. The application of PERMANOVA was proven to be unique and successful in determining the roles of compounds in synergistic, additive, and antagonistic effects in mixtures at different effective concentrations.

Nimesulide-Induced Fixed Drug Eruption Followed by Etoricoxib-Induced Fixed Drug Eruption: An Unusual Case Report and Review of the Literature.

Fixed drug eruption (FDE) is a well-recognized, non-immediate, drug hypersensitivity reaction, often attributed to the use of various medications, most commonly non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Cross-reactivity between related NSAIDs in FDE has been reported, but among chemically unrelated NSAIDs, is rare. Herein, we present a rare well-documented case where a patient initially displayed tolerance to etoricoxib after experiencing a nimesulide-induced FDE. Subsequently, the patient developed an etoricoxib-induced FDE, accompanied by the development of bullous lesions. This case report and the literature review on comparable FDE occurrences shed light on the intricate nature of FDEs, suggesting the possibility of cross-reactivity between chemically related and unrelated NSAIDs or the emergence of new drug-specific T cells without cross-reactivity after multiple exposures to a drug in a susceptible patient. Our case underscores the importance of increased awareness and vigilance among both physicians and patients in the realm of personalized medicine. Further research is needed to unravel the intricate mechanisms behind these drug eruptions, improve diagnostic approaches, and enhance patient care.

Metformin-Mediated Improvement in Solubility, Stability, and Permeability of Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs and to improve the bioavailability of orally administered drugs, according to the literature research and preliminary studies. We synthesized two drug-drug molecular salts (ketoprofen-metformin and phenylbutazone-metformin) with NSAIDs and thoroughly characterized them using SCXRD, PXRD, DSC, and IR analysis to improve the poor solubility of NSAIDs. In vitro evaluation studies revealed that the thermal stability and solubility of NSAIDs-MET were substantially enhanced compared with those of NSAIDs alone. Unexpectedly, an additional increase in permeability was observed. Since the structure determines the properties, the structure was analyzed using theoretical calculations to reveal the intermolecular interactions and to explain the reason for the change in properties. The salt formation of NSAIDs with MET could substantially increase the bio-absorption rate of NSAIDs, according to the in vivo pharmacokinetic findings, which provides an experimental basis for developing new antipyretic and analgesic drugs with rapid onset of action.

Designing Powerful Biindole-Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements.

Among inherently chiral selectors of axial stereogenicity, usually resulting in very good enantiodiscrimination performances, the biindole-based family has the additional advantage of very easy functionalization of the two nitrogen atoms with a variety of substituents with desirable properties. Aiming to evaluate the possibility of exploiting such feature to enhance the enantiodiscrimination ability of the archetype structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2'-biindole atropisomeric core conjugated to bithiophene wings enabling fast and regular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl substituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the selector series was comparatively evaluated in proof-of-concept chiral voltammetry experiments with a "benchmark" chiral ferrocenyl probe as well as with chiral non-steroidal anti-inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl ≪ hydroxyethyl sequence of selector substituents, supporting our assumption on the beneficial role of an additional coordination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.

Analysis of Cutaneous Adverse Drug Reactions (ADR) Reported at an ADR Monitoring Center of a Tertiary Care Teaching Institute in Central India.

Background Cutaneous adverse drug reactions (ADRs) are among the most frequent ADRs. Knowledge of the pattern of cutaneous ADRs (CADRs) and causal drugs helps prevent and reduce the incidence of CADR, which in turn reduces the incidence of hospitalization and expenses for the patient. Objectives To analyze CADR according to demographic profile, morphological pattern, causative drugs, severity, and outcome in patients suffering from CADRs. Materials and methods Retrospective data analysis was conducted in the Adverse Drug Reaction Monitoring Centre (AMC) of the tertiary care teaching institute between February 2020 and September 2023 under the Pharmacovigilance Program of India (PvPI). All ADRs reported were analyzed based on the following parameters: total number of ADRs reported, number of CADRs, information related to demographic parameters, the clinical presentation of CADRs, and suspected medication. Causality assessment was done using the World Health Organisation-Uppsala Monitoring Centre (WHO-UMC) scale. Severity was assessed using a modified Hartwig and Seigel scale. Results A total of 125 CADRs were analyzed. Considering the gender-wise distribution, 65 females and 60 males suffered from CADR. The most common drug category responsible for CADRs was antimicrobials (63.2%), followed by topical agents (12.8%). Maculopapular rash (33.6%) was the most common presenting symptom, followed by itching (27.2%). Few patients suffered from serious CADRs such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).  Conclusion A wide clinical spectrum of CADRs ranging from maculopapular rash to fixed-drug eruption to serious SJS was observed in our study. The most common causative agents for CADRs were antimicrobials, followed by topical agents and NSAIDs. For early diagnosis and management of CADRs, it is critical to have data on the potential cutaneous adverse effects of commonly used drugs, to educate the patients regarding common early symptoms of drug reactions (e.g., erythematous rash, edema, urticaria, mucosal erosions, itching, burning of skin, etc.), and to monitor the patient, especially during the start of therapy. To ease the burden of CADRs, a therapeutic plan of anticipating, avoiding, recognizing, and responding to ADRs should be implemented.