Ruthenium–arene complexes with NSAIDs: synthesis, characterization and bioactivity

Ruthenium arene complexes with mono-carbonyl analogues of curcumin as pendant or bridging ligands: Synthesis, anti-cancer activity and interaction with quadruplex DNA

The reciprocal effects on pharmacokinetic parameters after a single oral dose of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and sulindac and repeated oral doses of the H2-receptor antagonists cimetidine and ranitidine were determined in two groups of nine healthy subjects each (indomethacin and sulindac groups). Administration of NSAIDs increased the AUC and decreased the oral clearance and apparent volume of distribution of the H2-receptor antagonists without modifying their t1/2. Urinary data and observed modifications in ranitidine and cimetidine metabolites seem to justify a greater increase of H2-receptor antagonist bioavailability with indomethacin (p less than 0.05) than with sulindac (NS). The administration of ranitidine significantly reduced the sulindac volume of distribution without modifying its clearance, which caused an increase in the maximum concentration and a decrease in the t1/2 (p less than 0.05). The effects of cimetidine on the two NSAIDs were more intense than the effect of ranitidine: the decrease in sulindac volume of distribution (p less than 0.02) was accompanied by a significant reduction in sulindac clearance (p less than 0.05). AUC and urinary amounts of sulindac's sulfone metabolite were decreased. These results show that NSAIDs increased the bioavailability of H2-receptor antagonists, and that the latter drugs decrease the volume of distribution of NSAIDs. Furthermore, cimetidine modifies the oxidation metabolism of sulindac.

A rapid, simple and specific method for estimation of Mefenamic acid in human plasma was validated using Indomethacin as internal standard. The analyte and internal standard were extracted from plasma using simple solid phase extraction. The compound were separated on a reverse-phase column with an isocratic mobile phase consisting of 2 mM Ammonium Acetate in Water and acetonitrile (20:80, v/v) and detected by tandem mass spectrometry in negative ion mode. The ion transition recorded in multiple reaction monitoring mode were m/z 240.1 196.0 for Mefenamic acid and m/z 356.1312.0 for internal standard. Linearity in plasma was observed over the concentration range 35.000 - 7000.000 ng/mL for Mefenamic acid. The cv of the assay was 4.89 % to 5.98 % and accuracy was 99.36 to 102.20 % Intra and Interday respectively at LLOQ level. The validated method was applied to bioequivalence study of 250 mg Mefenamic acid in 28 healthy human volunteers. Total 50 samples from individual volunteers identified as Haemolyzed which were analyze initial and repeat again to cross check the method reproducibity for Haeamolysis effect and compared which found acceptable range. In BA/BE studies Haemolysis effect can be accountable for analysis of drug estimation in plasma. Validation of LC-MS/MS assays includes an assessment of Haemolysis effects though the experiment. Identification of this effect in presence of drug can be helpful tool for estimation of assay in plasma during the course of subject analysis. Validation of the method to evaluate Haemolysis effect can easily prove the impact on drug estimation. Validation of drug estimation can be challenged through the Haemolysis samples which are unknown though Incurred sample reanalysis to compare the method ruggedness with respect to Haemolysis sample which are extracted directly from subjects (volunteers). Methodology can be applied to reduce Haemolysis effect through proper extraction techniques like SPE. We establish method with proper extraction techniques to reduce the Haemolysis effect and then challenge our method in subject analysis specifically for Haemolysis samples along with normal plasma samples. Summarize the assay value for combination drugs for Haemolysis samples and through ISR cross check the techniques used for validation is properly applied. Mefenamic acid is a non-steroidal anti-inflammatory drug used to treat pain, including menstrual pain. It is typically prescribed for oral administration. Mefenamic acid decreases inflammation (swelling) and uterine contractions by a still unknown mechanism. However it is thought to be related to the inhibition of prostaglandin synthesis. There is also evidence that supports the use of Mefenamic acid for perimenstrual migraine headache prophylaxis, with treatment starting 2 days prior to the onset of flow or 1 day prior to the expected onset of the headache and continuing for the duration of menstruation. Since hepatic metabolism plays a significant role in Mefenamic acid elimination, patients with known liver deficiency may be prescribed lower doses. Kidney deficiency may also cause accumulation of the drug and its metabolites in the excretory system. Therefore patients suffering from renal conditions should not be prescribed Mefenamic acid. rapidly absorbed. T max is 2 to 4 h. C max is 20 mcg/mL (single doses). Steady state is reached in 2 days and Apparent Vd is 1.06 L/kg. Protein binding is more than 90%. Excreted in breast milk. Metabolized by CYP-450 enzyme CYP2C9 to 3-hydroxymethyl Mefenamic acid (metabolite I). Further oxidation to a 3-carboxyMefenamic acid (metabolite II) may occur. The metabolites may undergo glucuronidation, and Mefenamic acid is also glucuronidated directly. Approximately 52% of a dose is excreted into the urine primarily as glucuronides of Mefenamic acid (6%), 3-hydroxyMefenamic acid (25%), and 3- carboxyMefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxyMefenamic acid. The half-life is approximately 2 h. MEFENAMIC ACID is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each blue-banded, Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230°-231°C and water solubility of 0.004% at pH 7.1. The chemical name is N-2,3- xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C15H15N02 and the structural formula of Mefenamic acid is

It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (Tc) of male, C57BL/6J mice (n = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4°C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (Tc,Max)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to Tc,Max, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at Tc,Max, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury.NEW & NOTEWORTHY This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity.

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A novel therapeutic approach targeting rheumatoid arthritis by combined administration of morin, a dietary flavanol and non-steroidal anti-inflammatory drug indomethacin with reference to pro-inflammatory cytokines, inflammatory enzymes, RANKL and transcription factors

The nonsteroid anti-inflammatory drug indomethacin, a potent prostaglandin synthesis inhibitor, may play a role in preventing chemically-induced large bowel cancer development in rats. 250 male Sprague-Dawley rats were given weekly intrarectal doses of 2 mg/kg body weight of acetoxymethyl-methylnitrosamine (AMMN) in the first 10 weeks of the experiment to induce large bowel tumors. Experimental groups received a 0.001% aqueous solution of indomethacin ad libitum as drinking water for different time intervals. At autopsy in week 21, the indomethacin treatment in the first and second 10-week periods, or only in the second 10-week period significantly reduced the number of large bowel tumors compared to non-treatment control groups, while the treatment in the first 10-week period alone did not affect the tumor development. It was observed at autopsy in week 31 that the 10-week cessation of treatment after the effective treatments permitted the growth of tumors, but the treatment in the first and second 10-week periods was effective enough to suppress tumor appearance compared to other groups. It can be concluded that indomethacin has an antiproliferative activity on large bowel carcinogenesis.

Natural honey is well known for its therapeutic value and has been used in traditional medicine of different cultures throughout the world. The aim of this study was to investigate the anti-inflammatory effect of Malaysian Gelam honey in inflammation-induced rats. Paw edema was induced by a subplantar injection of 1% carrageenan into the rat right hind paw. Rats were treated with the nonsteroidal anti-inflammatory drug (NSAID) Indomethacin (10 mg/kg, p.o.) or Gelam honey at different doses (1 or 2 g/kg, p.o.). The increase in footpad thickness was considered to be edema, which was measured using a dial caliper. Plasma and paw tissue were collected to analyze the production of inflammatory mediators, such as NO, PGE2, TNF-α, and IL-6, as well as iNOS and COX-2. The results showed that Gelam honey could reduce edema in a dose-dependent fashion in inflamed rat paws, decrease the production of NO, PGE2, TNF-α, and IL-6 in plasma, and suppress the expression of iNOS, COX-2, TNF-α, and IL-6 in paw tissue. Oral pretreatment of Gelam honey at 2 g/kg of body weight at two time points (1 and 7 days) showed a significantly decreased production of proinflammatory cytokines, which was similar to the effect of the anti-inflammatory drug Indomethacin (NSAID), both in plasma and tissue. Thus, our results suggest that Gelam honey has anti-inflammatory effects by reducing the rat paw edema size and inhibiting the production of proinflammatory mediators. Gelam honey is potentially useful for treating inflammatory conditions.

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures due to abnormal electrical activity in the brain. Despite advancements in treatment, approximately 30% of patients remain unresponsive to current antiepileptic drugs (AEDs), highlighting the need for alternative therapies. Mefenamic acid (MFA), a nonsteroidal anti-inflammatory drug (NSAID), has shown potential anticonvulsant properties, possibly through modulation of GABAA receptors and adenosine signaling. Objective: This study aimed to evaluate the anticonvulsant effects of MFA in a pentylenetetrazol (PTZ)-induced seizure model in mice, focusing on its possible mechanisms of action. Methods: Male NMRI mice were administered MFA at doses of 5, 10, and 15 mg/kg i.p40 minutes before PTZ (80 mg/kg i.p.) to induce seizures. Diazepam served as a standard drug, and caffeine was used to investigate adenosine receptor modulation. Seizure onset, duration, and severity were recorded. Data were analyzed using one-way ANOVA followed by Tukey’s post-hoc test. Results: MFA at 5 mg/kg significantly delayed seizure onset and provided complete protection against PTZ-induced seizures, with results comparable to diazepam. Higher doses (10 and 15 mg/kg) delayed seizure latency but were less effective in reducing seizure duration. The addition of caffeine nullified MFA's protective effects, suggesting adenosine A1 receptor involvement. Conclusion: MFA, particularly at 5 mg/kg, exhibits significant anticonvulsant effects in a PTZ-induced seizure model, likely through GABAergic modulation and adenosine A1 receptor interaction. These findings suggest MFA as a potential adjunctive therapy for epilepsy, warranting further investigation.

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.

Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It is most often used for treating pain of dysmenorrhoea in the short term (seven days or less), as well as mild to moderate pain including headache, dental pain, postoperative and postpartum pain. It is widely available in many countries worldwide. To assess the efficacy of single dose oral mefenamic acid in acute postoperative pain, and any associated adverse events. We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. Single oral dose, randomised, double-blind, placebo-controlled trials of mefenamic acid for relief of established moderate to severe postoperative pain in adults. Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Four studies with 842 participants met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197 with placebo, and 452 with lignocaine, aspirin, zomepirac or nimesulide. Participants had pain following third molar extraction, episiotomy and orthopaedic surgery. The NNT for at least 50% pain relief over 6 hours with a single dose of mefenamic acid 500 mg compared to placebo was 4.0 (2.7 to 7.1), and the NNT to prevent use of rescue medication over 6 hours was 6.5 (3.6 to 29). There were insufficient data to analyse other doses or active comparators, or numbers of participants experiencing any adverse events. No serious adverse events or adverse event withdrawals were reported in these studies. Oral mefenamic acid 500 mg was effective at treating moderate to severe acute postoperative pain, based on limited data. Efficacy of other doses, and safety and tolerability could not be assessed.

Introduction: Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, and antipyretic effects. This medication is used for mild to moderate pain, including headaches, toothaches, postoperative and postpartum pain, dysmenorrhea, and osteoarthritis. This study aims to provide an overview of public knowledge about mefenamic acid pain relievers. Method: This study uses quantitative descriptive research, which conducts direct research on respondents (the community) who are taken as research subjects. This study describes the level of public knowledge about mefenamic acid anti-pain. Results: The most users of mefenamic acid are women, which is 49 people (62.12%), with the most vulnerable age, namely 17-25 years old, as many as 26 people (35.62%), with the most work, which is not working as many as 37 people (50.68%), with the last education of each respondent in high school, which is 35 people (47.95%). Patient knowledge about the use of mefenamic acid reached 75.02%, which was obtained from the processing of data from community research on mefenamic acid, including quite good knowledge. Conclusion: Mefenamic acid is more commonly found in women, especially in young age groups. Most users are unemployed and have a high school-level education background. The level of public knowledge about the use of mefenamic acid is quite good, but further educational efforts are still needed to increase a more comprehensive understanding of the use of the drug. It is recommended that regular counseling be carried out on the appropriate and rational use of drugs, especially for young age groups and people who do not have a background in health education.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.

Two new ruthenium(II) arene complexes, 2a (C(24)H(34)B(10)FeRuS(2)) and 2b (C(15)H(26)B(10)O(2)RuS(2)), bearing a carborane unit and other different functional groups were synthesized, and their cytostatic effects on cancerous cells were evaluated. Our observations illustrate that a structural change from a ferrocene unit to a carboxyl group could lead to high selectivity toward cancer cells and facilitate the efficient inhibition of the proliferation of target cells, indicating that the tuning of the overall properties of the ruthenium(II) arene complex by appropriate ligand tagging is critical to creating a selective antineoplastic agent.

NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-α and Fas ligation: the role of reactive oxygen species