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Allergologie Select 2023Not available.
Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for...
Not available.
PubMed: 37705676
DOI: 10.5414/ALX02422E -
CPT: Pharmacometrics & Systems... Jan 2024Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the...
Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate-glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug-drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically-based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration-time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7-fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non-wild-type variants for both isoforms. This study is a first cornerstone to qualify the PK-Sim platform for use of UGT-mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.
Topics: Humans; Atazanavir Sulfate; Mefenamic Acid; Glucuronosyltransferase; Drug Interactions; Heterocyclic Compounds, 2-Ring; Pyrimidines
PubMed: 37794724
DOI: 10.1002/psp4.13059 -
Toxics Aug 2023Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent...
Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent antioxidant properties and a neuroprotective effect against oxidative stress. However, its impact on the liver is unclear. This study aimed to elucidate the antioxidative effects of MFA and their underlying mechanisms. We observed that MFA treatment upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Treatment with various anthranilic acid derivative-class NSAIDs, including MFA, increased the expression of sequestosome 1 (SQSTM1) in HepG2 cells. MFA disrupted the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, activating the Nrf2 signaling pathway. SQTM1 knockdown experiments revealed that the effect of MFA on the Nrf2 pathway was masked in the absence of SQSTM1. To assess the cytoprotective effect of MFA, we employed tert-Butyl hydroperoxide (tBHP) as a ROS inducer. Notably, MFA exhibited a protective effect against tBHP-induced cytotoxicity in HepG2 cells. This cytoprotective effect was abolished when SQSTM1 was knocked down, suggesting the involvement of SQSTM1 in mediating the protective effect of MFA against tBHP-induced toxicity. In conclusion, this study demonstrated that MFA exhibits cytoprotective effects by upregulating SQSTM1 and activating the Nrf2 pathway. These findings improve our understanding of the pharmacological actions of MFA and highlight its potential as a therapeutic agent for oxidative stress-related conditions.
PubMed: 37755745
DOI: 10.3390/toxics11090735 -
Journal of Cancer Research and Clinical... Dec 2023This work aimed to prepare niosomal formulations of an anticancer agent [mefenamic acid (MEF)] to enhance its cancer targeting. I was utilized as a radiolabeling isotope...
BACKGROUND
This work aimed to prepare niosomal formulations of an anticancer agent [mefenamic acid (MEF)] to enhance its cancer targeting. I was utilized as a radiolabeling isotope to study the radio-kinetics of MEF niosomes.
METHODS
niosomal formulations were prepared by the ether injection method and assessed for entrapment efficiency (EE%), zeta potential (ZP), polydispersity index (PDI) and particle size (PS). MEF was labeled with I by direct electrophilic substitution reaction through optimization of radiolabeling-related parameters. In the radio-kinetic study, the optimal I-MEF niosomal formula was administered intravenously (I.V.) to solid tumor-bearing mice and compared to I.V. I-MEF solution as a control.
RESULTS
the average PS and ZP values of the optimal formulation were 247.23 ± 2.32 nm and - 28.3 ± 1.21, respectively. The highest I-MEF labeling yield was 98.7 ± 0.8%. The biodistribution study revealed that the highest tumor uptake of I-MEF niosomal formula and I-MEF solution at 60 min post-injection were 2.73 and 1.94% ID/g, respectively.
CONCLUSION
MEF-loaded niosomes could be a hopeful candidate in cancer treatment due to their potent tumor uptake. Such high targeting was attributed to passive targeting of the nanosized niosomes and confirmed by radiokinetic evaluation.
Topics: Mice; Animals; Liposomes; Mefenamic Acid; Tissue Distribution; Neoplasms
PubMed: 37982828
DOI: 10.1007/s00432-023-05482-8 -
Journal of Integrative Neuroscience Jul 2023Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA)...
BACKGROUND
Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity.
METHODS
The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted.
RESULTS
Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities.
CONCLUSIONS
The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.
Topics: Mice; Animals; Flumazenil; Mefenamic Acid; Receptors, GABA-A; Catalepsy; Central Nervous System; Seizures; gamma-Aminobutyric Acid; Behavior, Animal
PubMed: 37519168
DOI: 10.31083/j.jin2204104 -
Biomedicine & Pharmacotherapy =... May 2024To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions...
OBJECTIVE
To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS).
METHODS
The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer.
RESULTS
When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS.
CONCLUSIONS
These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.
PubMed: 38703503
DOI: 10.1016/j.biopha.2024.116647 -
Journal of Medicine and Life Dec 2023The inappropriate use of analgesics and antibiotics is a widespread issue among dentists globally, leading to the risk of over-prescription that could negatively affect...
The inappropriate use of analgesics and antibiotics is a widespread issue among dentists globally, leading to the risk of over-prescription that could negatively affect patient health and quality of life. This study aimed to assess the prescribing patterns of analgesics and antibiotics by dentists in Kirkuk City, Iraq, focusing on their attitudes, knowledge levels, and practices regarding these medications. A cross-sectional survey was conducted among 280 dentists in Kirkuk City. The dentists were contacted via their work email addresses, and they responded to a survey. Descriptive statistics, including frequency analysis, were employed to evaluate the appropriateness of analgesic and antibiotic prescriptions for different dental conditions. The first-choice analgesic for 44.6% of dentists was mefenamic acid, followed by paracetamol (31.1%). Regarding antibiotic use, 56.8% of dentists in Kirkuk City reported using antibiotics for empirical and direct therapy. Other dentists (43.2%) revealed that they did not have enough information regarding antibiotic group preference in empirical therapy. 106 of the participants (37.85%) recommended the use of broad-spectrum antibiotics in the treatment of bacterial infections. However, most (45%) were unfamiliar with the group preferences in empirical therapy. Dentists in Kirkuk City showed variations in knowledge and awareness regarding using analgesics and antibiotics. This requires further education and training on proper analgesics and antibiotic stewardship guidelines.
Topics: Humans; Anti-Bacterial Agents; Cross-Sectional Studies; Iraq; Quality of Life; Practice Patterns, Dentists'; Analgesics; Prescriptions; Dentists
PubMed: 38585523
DOI: 10.25122/jml-2023-0405 -
European Journal of Pharmaceutics and... Dec 2023Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in...
Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in vitro is limited and multiple simulated intestinal fluid recipes have been developed but with no consensus which is optimal. This study has utilised nine bioequivalent simulated fed intestinal media recipes that cover over 90% of the compositional variability of sampled fed human intestinal fluid. The solubility of 24 drugs (Acidic; furosemide, ibuprofen, indomethacin, mefenamic acid, naproxen, phenytoin, piroxicam, valsartan, zafirlukast: Basic; aprepitant, atazanavir, bromocriptine, carvedilol, dipyridamole, posaconazole, tadalafil: Neutral; acyclovir, carbamazepine, felodipine, fenofibrate, griseofulvin, itraconazole, paracetamol, probucol) has been assessed to determine if structured solubility behaviour is present. The measured solubility behaviour can be split into four categories and is consistent with drug physicochemical properties and previous solubility studies. For acidic drugs (category 1) solubility is controlled by media pH and the lowest and highest pH media identify the lowest and highest solubility in 90% of cases. For weakly acidic, basic and neutral drugs (category 2) solubility is controlled by media pH and total amphiphile concentration (TAC), a consistent solubility pattern is evident with variation related to individual drug media component interactions. The lowest and highest pH × TAC media identify the lowest and highest solubility in 70% and 90% of cases respectively. Four drugs, which are non-ionised in the media systems (category 3), have been identified with a very narrow solubility range, indicating minimal impact of the simulated media on solubility. Three drugs exhibit solubility behaviour that is not consistent with the remainder (category 4). The results indicate that the use of two bioequivalent fed intestinal media from the original nine will identify in vitro the maximum and minimum solubility values for the majority of drugs and due to the media derivation this is probably applicable in vivo. When combined with a previous fasted study, this introduces interesting possibilities to measure a solubility range in vitro that can provide Quality by Design based decisions to rationalise drug and formulation development. Overall this indicates that the multi-dimensional media system is worthy of further investigation as in vitro tool to assess fed intestinal solubility.
Topics: Humans; Solubility; Hydrogen-Ion Concentration; Intestines; Pharmaceutical Preparations; Indomethacin; Intestinal Absorption
PubMed: 37890541
DOI: 10.1016/j.ejpb.2023.10.017 -
Therapeutic Advances in Vaccines and... 2023Needle pain due to routine vaccination is an important factor contributing to low vaccine adherence and immunization coverage. Prophylactic oral analgesics can address...
Efficacy of oral mefenamic acid paracetamol as a prophylactic analgesic for needle pain in children receiving vaccination: a three-arm, parallel, triple-blind, placebo-controlled MAP VaC randomized controlled trial.
BACKGROUND
Needle pain due to routine vaccination is an important factor contributing to low vaccine adherence and immunization coverage. Prophylactic oral analgesics can address this important issue of needle pain related to vaccination. Paracetamol and mefenamic acid are commonly used nonsteroidal anti-inflammatory drugs for pain relief, but there is little published literature on whether the same can be used for needle pain related to vaccination.
OBJECTIVES
This study was planned to compare the efficacy of oral mefenamic acid and paracetamol over placebo as a prophylactic analgesic during vaccination and prophylactic antipyretic during the post-vaccination period.
DESIGNS
Three-arm, triple-blind, randomized controlled trial.
METHODS
This study was conducted at the outpatient department of a tertiary-level medical college in South India from January 2021 to June 2022. In this three-arm interventional trial, each arm had either a single dose of placebo or mefenamic acid (4 mg/kg/dose) or paracetamol (10 mg/kg/dose). These medicines were administered orally 30 min before vaccination to reduce needle pain.
MAIN OUTCOME AND MEASURES
Outcome was measured with the change of FLACC (Face, Leg, Activity, Cry, Consolability) scoring at the time of vaccination, subsequently at 15 and 30 min of vaccination in all three groups. Appearance of fever, grade of fever, and need for antipyretics 24 h after vaccination were also noted.
RESULTS
There was a significant difference in FLACC scores at the time of administration ( = 0.010) and at 15 min ( = 0.014) with mefenamic acid compared to placebo. Although the paracetamol group showed a difference when compared to the placebo, it was not significant at the time of administration ( = 0.401), at 15 min ( = 0.451), or 30 min ( = 0.892) post-vaccination. The appearance of fever, grade of fever, and use of antipyretic up to 24 h post-vaccination had no significant difference among any of the three groups.
CONCLUSION
Mefenamic acid was more potent than placebo for pre-vaccination pain prophylaxis in children. There was no difference in the appearance of fever and its grade among the three groups. The promising results from this trial warrant further large-scale studies to recommend a single oral dose of mefenamic acid to tackle needle pain related to vaccination in children to improve vaccine adherence and coverage.
TRIAL REGISTRATION
CTRI (Clinical trials registry-India) (CTRI/2021/01/030239). [Date of Commencement: 13 Jan 2021, Date of last recruitment: 30 June 2022 (now closed for new participants)].
PubMed: 38077267
DOI: 10.1177/25151355231216122