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Heliyon May 2024Warfarin, a widely prescribed anticoagulant, is highly effective for various coagulation disorders. However, its efficacy is limited by a narrow therapeutic index and...
Development of a rapid HPLC-fluorescence method for monitoring warfarin metabolites formation: In vitro studies for evaluating the effect of piperine on warfarin metabolism and plasma coagulation.
Warfarin, a widely prescribed anticoagulant, is highly effective for various coagulation disorders. However, its efficacy is limited by a narrow therapeutic index and frequent drug interactions, especially those involving metabolism by Cytochrome P450 (CYP450) enzymes. Piperine, found in black and long pepper, possesses blood-thinning properties and has been observed to inhibit CYP3A and CYP2C enzymes linked to warfarin metabolism. This study investigated the effect of piperine on warfarin metabolism in liver microsomes using a rapid and sensitive HPLC-Fluorescence method. The use of PFP (pentafluorophenyl) column with core shell particles provided the selectivity and resolution to resolve warfarin and its 4-, 6-, 7-, and 10-hydroxy metabolites in addition to the internal standard naproxen in less than 3 min. This is the fastest analytical assay for warfarin and its major metabolites reported to date, making it ideal for metabolic studies. The applicability of the method was demonstrated by monitoring the metabolism of S-warfarin in human and rat liver microsomes, and evaluating the inhibitory effect of piperine on metabolite formation. The results showed that piperine inhibited the formation of the major metabolite, 7-hydroxywarfarin, with half-maximal inhibitory concentration (IC) 14.2 μM and 3.2 μM in human and rat liver microsomes, respectively. Furthermore, coagulation studies using rat plasma showed that piperine does not affect prothrombin time (PT) and activated partial thromboplastin time (aPTT). This study suggested that piperine may present a potential drug interaction with warfarin at the metabolism level, but has no direct effect on the activation of the extrinsic or intrinsic coagulation cascades. Further clinical investigation is therefore required, as piperine may increase the bioavailability of warfarin, thus increasing risk of serious adverse events in patients.
PubMed: 38807873
DOI: 10.1016/j.heliyon.2024.e31266 -
Investigation of the synthesis, gelation potential, and drug-loading capacities of two novel amides.Frontiers in Chemistry 2024This study consists of four steps. In the first, two different biocompatible organogelators were synthesized, starting with the isoleucine amino acid to obtain amide...
This study consists of four steps. In the first, two different biocompatible organogelators were synthesized, starting with the isoleucine amino acid to obtain amide compounds. In the second step, the gelation potential of synthesized organogelators with fatty acid esters and organic solvents was investigated. These esters were chosen as gelation liquids due to their biocompatibility and also their penetration-enhancing properties when the drug is administered via the skin. After the minimum gel concentrations (MGCs) of the organogelators were determined, the melting point of gel was found, and then, Δ gelation enthalpy values were found by means of the Van't Hoff equation. In addition to the gelation abilities and capacities of the organogelators being thus synthesized, their thermal stabilities were also determined. In the third stage of the study, the network which occurred during the formation of the gels was screened by an SEM device, and their characterizations were determined. In the study's fourth stage, the gels were loaded with ibuprofen and naproxen-known for their non-steroidal anti-inflammatory and analgesic effects-and their drug-loading capacities were thus determined.
PubMed: 38800578
DOI: 10.3389/fchem.2024.1369542 -
Polymers May 2024Sodium hyaluronate (HA) is a natural polysaccharide. This biopolymer occurs in many tissues of living organisms. The regenerating, nourishing, and moisturizing...
Sodium hyaluronate (HA) is a natural polysaccharide. This biopolymer occurs in many tissues of living organisms. The regenerating, nourishing, and moisturizing properties as well as the rheological properties of HA enable its application in the pharmaceutical industry as a carrier of medicinal substances. The aim of this work was to assess the release of naproxen sodium (Nap) in the presence of lidocaine hydrochloride (Lid) from the biopolymer-based hydrogels and to determine the respective kinetic parameters of this process. The possible interaction between the HA polysaccharide carrier and the selected drugs was also investigated. Three hydrogels containing Nap and Lid with different concentrations of the biopolymer were prepared. The release of Nap was studied by employing USP apparatus 5. The infrared study and differential scanning calorimetry analysis of physical mixtures and dried formulations were performed. The highest amount of Nap was released from the formulation with the lowest concentration of the biopolymer. The most representative kinetic model that described the dissolution of Nap was obtained through the Korsmeyer-Peppas equation. The release rate constants were in the range of 1.0 ± 0.1 × 10 min-1.7 ± 0.1 × 10 min. Lid did not influence the dissolution of Nap from the formulations tested; however, in the desiccated samples of assessed formulations, the interaction between the polysaccharide and both drugs was observed.
PubMed: 38794546
DOI: 10.3390/polym16101353 -
Pharmaceuticals (Basel, Switzerland) May 2024Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these drugs exhibit various other pleiotropic effects in several cells, including platelets. Within this article, the multifaceted properties of NSAIDs on platelet functions, activation and viability, as well as their interaction(s) with established antiplatelet medications, by hindering several platelet agonists' pathways and receptors, are thoroughly reviewed. The efficacy and safety of NSAIDs as adjunctive therapies for conditions involving inflammation and platelet activation are also discussed. Emphasis is given to the antiplatelet potential of commonly administered NSAIDs medications, such as ibuprofen, diclofenac, naproxen and ketoprofen, alongside non-opioid analgesic and antipyretic medications like paracetamol. This article delves into their mechanisms of action against different pathways of platelet activation, aggregation and overall platelet functions, highlighting additional health-promoting properties of these anti-inflammatory and analgesic agents, without neglecting the induced by these drugs' side-effects on platelets' functionality and thrombocytopenia. Environmental issues emerging from the ever-increased subscription of these drugs are also discussed, along with the need for novel water treatment methodologies for their appropriate elimination from water and wastewater samples. Despite being efficiently eliminated during wastewater treatment processes on occasion, NSAIDs remain prevalent and are found at significant concentrations in water bodies that receive effluents from wastewater treatment plants (WWTPs), since there is no one-size-fits-all solution for removing all contaminants from wastewater, depending on the specific characteristics of the wastewater. Several novel methods have been studied, with adsorption being proposed as a cost-effective and environmentally friendly method for wastewater purification from such drugs. This article also presents limitations and future prospects regarding the observed antiplatelet effects of NSAIDs, as well as the potential of novel derivatives of these compounds, with benefits in other important platelet functions.
PubMed: 38794197
DOI: 10.3390/ph17050627 -
International Journal of Molecular... May 2024Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated... (Review)
Review
Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways.
Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP's map road as well.
Topics: Humans; Fatty Liver; Chemical and Drug Induced Liver Injury; Adverse Outcome Pathways; Liver; Oxidative Stress
PubMed: 38791241
DOI: 10.3390/ijms25105203 -
Toxics May 2024In small populations and scattered communities, wastewater treatment through vegetation filters (VFs), a nature-based solution, has proved to be feasible, especially for...
In small populations and scattered communities, wastewater treatment through vegetation filters (VFs), a nature-based solution, has proved to be feasible, especially for nutrient and organic matter removal. However, the presence of pharmaceuticals in wastewater and their potential to infiltrate through the vadose zone and reach groundwater is a drawback in the evaluation of VF performances. Soil amended with readily labile carbon sources, such as woodchips, enhances microbial activity and sorption processes, which could improve pharmaceutical attenuation in VFs. The present study aims to assess if woodchip amendments to a VF's soil are able to abate concentrations of selected pharmaceuticals in the infiltrating water by quantitatively describing the occurring processes through reactive transport modelling. Thus, a column experiment using soil collected from an operating VF and poplar woodchips was conducted, alongside a column containing only soil used as reference. The pharmaceuticals acetaminophen, naproxen, atenolol, caffeine, carbamazepine, ketoprofen and sulfamethoxazole were applied daily to the column inlet, mimicking a real irrigation pattern and periodically measured in the effluent. Ketoprofen was the only injected pharmaceutical that reached the column outlet of both systems within the experimental timeframe. The absence of acetaminophen, atenolol, caffeine, carbamazepine, naproxen and sulfamethoxazole in both column outlets indicates that they were attenuated even without woodchips. However, the presence of 10,11-epoxy carbamazepine and atenolol acid as transformation products (TPs) suggests that incomplete degradation also occurs and that the effect of the amendment on the infiltration of TPs is compound-specific. Modelling allowed us to generate breakthrough curves of ketoprofen in both columns and to obtain transport parameters during infiltration. Woodchip-amended columns exhibited K and μ values from one to two orders of magnitude higher compared to soil column. This augmentation of sorption and biodegradation processes significantly enhanced the removal of ketoprofen to over 96%.
PubMed: 38787113
DOI: 10.3390/toxics12050334 -
Chemosphere May 2024This study focuses on the removal and risk assessment of twenty emerging contaminants (ECs) and heavy metals in a REMIX water treatment plant (RWTP) that produces...
This study focuses on the removal and risk assessment of twenty emerging contaminants (ECs) and heavy metals in a REMIX water treatment plant (RWTP) that produces drinking water from combination of wastewater reuse and desalination. The membrane biological reactor (MBR) exhibit removal rates exceeding 95% of pharmaceuticals like acetaminophen, trimethoprim, diclofenac, naproxen, and emtricitabine. The efficiency of brackish reverse osmosis (BWRO) in removing ECs is highlighted, showing substantial efficacy with reduction rates of 99.5%, 75.5%, and 51.2% for sulfamethoxazole, venlafaxine, and benzotriazole, respectively. The advanced oxidation process based on Fenton process reveals removal (>95%) of emtricitabine, efavirenz, and carbamazepine. The study confirms that the combination of treatment units within the RWTP effectively removes heavy metals (>90%), complying with acceptable limits. Risk quotient (RQ) calculations indicate the efficiency of the RWTP in EC removal, serving as benchmarks for public acceptance of reclaimed water. In the context of heavy metals, the study concludes negligible cancer risks associated with reclaimed water consumption over a lifetime. Quantitative structure-activity relationship and occurrence, persistence, bioaccumulation and toxicity (OPBT) models were used to assess EC risk. The study screened and identified potential persistant, bio accumulating and toxic PBT ECs. Critical control points (CCPs) in the RWTP are identified, with brackish and seawater reverse osmosis (BWRO and SWRO) and advanced oxidation process (AOP) recognized as pivotal in hazard management. The study provides valuable insights on the removal of ECs and heavy metals in a wastewater reuse process and demonstrates potential of adopted process configuration in supplying safe drinking water from wastewater recycling.
PubMed: 38777194
DOI: 10.1016/j.chemosphere.2024.142396 -
Ecotoxicology and Environmental Safety Jun 2024Discharging pharmaceutically active drugs into water and wastewater has become a significant environmental threat. Traditional methods are unable to effectively remove...
Discharging pharmaceutically active drugs into water and wastewater has become a significant environmental threat. Traditional methods are unable to effectively remove these compounds from wastewater, so it is necessary to search for more effective methods. This study investigates the potential of MIL-101(Cr)-NH as a preferable and more effective adsorbent for the adsorption and removal of pharmaceutically active compounds from aqueous solutions. By utilizing its large porosity, high specific surface area, and high stability, the structural and transport properties of three pharmaceutically active compounds naproxen (NAP), diclofenac (DIC) and sulfamethoxazole (SMX)) studied using molecular dynamics simulation. The results indicate that the MIL-101(Cr)-NH adsorbent is suitable for removing drug molecules from aqueous solutions, with maximum adsorption capacities of 697.75 mg/g for naproxen, 704.99 mg/g for diclofenac, and 725.51 mg/g for sulfamethoxazole.
Topics: Water Pollutants, Chemical; Naproxen; Metal-Organic Frameworks; Sulfamethoxazole; Diclofenac; Molecular Dynamics Simulation; Adsorption; Water Purification; Wastewater; Pharmaceutical Preparations
PubMed: 38701652
DOI: 10.1016/j.ecoenv.2024.116333 -
Clinical and Translational Science May 2024Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (C) and area under plasma concentration-time curve over dosing interval at steady state (AUC) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in C, 19% in AUC) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for C and AUC was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.
Topics: Humans; Male; Anti-Inflammatory Agents, Non-Steroidal; Adult; Drug Interactions; Young Adult; Cross-Over Studies; Healthy Volunteers; Area Under Curve; Meloxicam; Naproxen; Celecoxib; Middle Aged
PubMed: 38700290
DOI: 10.1111/cts.13798 -
Addiction Science & Clinical Practice May 2024Zoledronate, a bisphosphonate, is a potent first-line treatment for osteoporosis. It is also a preferred treatment for hypercalcemia especially when unresponsive to...
BACKGROUND
Zoledronate, a bisphosphonate, is a potent first-line treatment for osteoporosis. It is also a preferred treatment for hypercalcemia especially when unresponsive to intravenous fluids. Bisphosphonates can cause acute phase reactions that mimic opioid withdrawal symptoms, which can confound provider decision-making. Our case highlights cognitive bias involving a patient with opioid use disorder who received zoledronate for hypercalcemia secondary to immobilization and significant bone infection.
CASE PRESENTATION
A 41-year-old male is admitted with a past medical history of active intravenous opioid use complicated by group A streptococcal bacteremia with L5-S1 discitis and osteomyelitis, L2-L3 osteomyelitis, and left ankle abscess/septic arthritis status post left ankle washout. His pain was well-controlled by acute pain service with ketamine infusion (discontinued earlier), opioids, acetaminophen, buprenorphine-naloxone, cyclobenzaprine, gabapentin, and naproxen. Intravenous opioids were discontinued, slightly decreasing the opioid regimen. A day later, the patient reported tachycardia, diaphoresis, myalgias, and chills, which the primary team reconsulted acute pain service for opioid withdrawal. However, the patient received a zoledronate infusion for hypercalcemia, on the same day intravenous opioids were discontinued. He had no other medications known to cause withdrawal-like symptoms per chart review. Therefore, it was suspected that an acute phase reaction occurred, commonly seen within a few days of bisphosphonate use.
CONCLUSION
Zoledronate, well known for causing acute phase reactions, was likely the cause of withdrawal-like symptoms. Acute phase reactions with bisphosphonates mostly occur in the first infusion, and the incidence decreases with subsequent infusions. Symptoms typically occur 24-72 h post-infusion, and last at most for 72 h. Cognitive bias led the primary team to be concerned with opioid withdrawal rather than investigating other causes for the patient's presentation. Therefore, providers should thoroughly investigate potential etiologies and rule them out accordingly to provide the best care. Health care providers should also be aware of the implicit biases that potentially impact the quality of care they provide to patients.
Topics: Adult; Humans; Male; Acute-Phase Reaction; Bone Density Conservation Agents; Diagnosis, Differential; Hypercalcemia; Opioid-Related Disorders; Substance Withdrawal Syndrome; Zoledronic Acid
PubMed: 38693547
DOI: 10.1186/s13722-024-00464-8