Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

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.

Synthesis and In-Vivo Evaluation of Benzoxazole Derivatives as Promising Anti-Psoriatic Drugs for Clinical Use.

2-(4-Chlorophenyl)-5-benzoxazoleacetic acid (CBA) and its ester, methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate (MCBA), were synthesized, and their structures were confirmed by 1HNMR, IR, and mass spectrophotometry. The anti-psoriatic activities of CBA and MCBA were tested using an imiquimod (IMQ)-induced psoriatic mouse model, in which mice were treated both topically (1% w/w) and orally (125 mg/kg) for 14 days. The erythema intensity, thickness, and desquamation of psoriasis were scored by calculating the psoriasis area severity index (PASI). The study also included the determination of histopathological alterations in the skin tissues of treated mice. Topical and oral administration of CBA and MCBA led to a reduction in erythema intensity, thickness, and desquamation, which was demonstrated by a significant decrease in the PASI value. In addition, skin tissues of mice treated with CBA and MCBA showed less evidence of psoriatic alterations, such as hyperkeratosis, parakeratosis, scale crust, edema, psoriasiform, and hyperplasia. After administration of either topical or oral dosing, the anti-psoriatic effects were found to be stronger in MCBA-treated than in CBA-treated mice. These effects were comparable to those produced by Clobetasol propionate, the reference drug. This drug discovery could be translated into a potential new drug for future clinical use in psoriasis treatment.

Quantification of Ochratoxin A in 90 spice and herb samples using the ELISA method.

This study addressed the challenge of accurately detecting mycotoxins in herbs and spices, which have gained popularity as alternative medicines but pose health risks due to potential contamination. We used a competitive direct ELISA kit (Art No. 8610), Veratox for Ochratoxin, to quantify Ochratoxin A in the herb and spice samples. The samples were first prepared using solid-liquid extraction with 70% methanol. The resulting filtrate was then subjected to ELISA analysis. The results of the analysis were then further analyzed using principal component analysis (PCA). In this study, PCA was used to classify the concentration levels of Ochratoxin A based on various factors, such as the packaging type, country of origin, shelf life, and sample weight. The limits of detection (LOD) and quantification (LOQ) values indicate the lowest amount of Ochratoxin A that can be detected and quantified, respectively, with high accuracy and precision. The range of the LOD and LOQ values (0.43-0.58 µg/kg and 1.45-1.95 µg/kg, respectively) suggests that the method used was capable of detecting and quantifying Ochratoxin A in the herb and spice samples at different concentrations with a high degree of accuracy and precision. These results suggest that while most of the samples (73.33%) were below the maximum residue limit (MRL) for Ochratoxin A, a significant number of samples (26.67%) had concentrations of Ochratoxin A that were higher than the MRL. This highlights the importance of monitoring Ochratoxin A in herb and spice samples and ensuring the products are safe for consumption.

Prolonged Maternal Separation Reduces Anxiety State and Increases Compulsive Burying Activity in the Offspring of BALB/c Mice.

BACKGROUND: The elevated plus maze (EPM) and the marble burying (MB) tests are common behavioral tests used for behavioral phenotyping in mouse models for neurodevelopmental disorders. However, the behavioral effects of maternal separation (MS), a standard paradigm for early life stress in animals, in both the EPM and MB tests remain incompletely known. OBJECTIVES: This study aimed to investigate the behavioral effects of prolonged MS in the offspring of mice using the EPM and MB tests. METHODS: Male BALB/c mice were isolated from their mothers for 4 h each day during the first 30 days after birth. On day 50 postnatal, groups of separated and non-separated mice (n = 18/each group) were subjected to the EPM and MB tests for comparative behavioral evaluations. In addition, the locomotor activity of mice was evaluated using the actophotometer test. RESULTS: The findings of the EPM test revealed that separated mice exhibited anxiolytic-like behaviors, as evidenced by a significant increase in the latency to closed arms and the time spent in the open arms compared with non-separated mice. Separated mice also showed compulsive burying activity in the MB test, as determined by a significant increase in the number of buried marbles. The results of the actophotometer test did not show any significant change in locomotor activity. CONCLUSIONS: Prolonged MS caused the adult offspring of mice to exhibit a decrease in anxiety state and increased compulsive burying activity, which were not associated with a change in locomotor activity. Further investigations with validated tests are needed to support these findings.

Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors.

BACKGROUND: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy. METHOD: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations. RESULTS: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA. CONCLUSION: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.

Intercostobrachial Nerve (ICBN) Preservation Versus Sacrifice in Axillary Dissection: Randomized Controlled Trial.

OBJECTIVES: Whether to preserve or sacrifice the intercostobrachial nerves (ICBN) is a controversial issue. In this trial, we aim to assess the effects of preservation of the ICBN during axillary dissection for patients with breast cancer in terms of pain score immediately postoperatively and several hours later, need for simple analgesia and narcotics, numbness and arm swelling. MATERIALS AND METHODS: This is a single-institution, single-surgeon randomized controlled trial where a sample of 48 patients with breast cancer, of various age groups, were allocated randomly to any of the 2; preservation or sacrifice categories. Postoperatively, patients were asked by a physician to fill a predesigned questionnaire to assess the studied items during hospitalization and after discharge. RESULTS: Among the 48 included patients, ICBN was sacrificed in 24 patients; of which 18 patients (75%) developed numbness in the inner aspect of the arm. While in the ICBN preservation group (24 patients) only 6 patients suffered numbness (25%) with a significant P-value of 0.001. Estimated duration of surgery with ICBN preservation was 100±22.02 minutes, while it is significantly shorter in the ICBN sacrifice group (83.48±21.55). However, with regard to other variables of pain, seroma formation, need of simple analgesia and narcotics, hospital admission days and arm swelling, there was no significant difference between the 2 groups. CONCLUSION: This study can conclude that preservation of ICBN during axillary dissection in patients with breast CA can save these patients' additional suffering from inner arm numbness. That is at the expense of surgery duration, around 20 minutes longer, for the surgeon to take his/her time in carefully dissecting the axilla properly without injuring these ICBN.

Dexamethasone and diclofenac intramuscular mixture injection and risk of death: A case series study.

Diclofenac and dexamethasone injection mixture could be associated with fatal cardiovascular events, further studies are warrantied to explore the safety of this injection mixture and explore the genetic role of it.

A Statistical Study on the Development of Metronidazole-Chitosan-Alginate Nanocomposite Formulation Using the Full Factorial Design.

The goal of this study was to develop and statistically optimize the metronidazole (MET), chitosan (CS) and alginate (Alg) nanoparticles (NP) nanocomposites (MET-CS-AlgNPs) using a (21 × 31 × 21) × 3 = 36 full factorial design (FFD) to investigate the effect of chitosan and alginate polymer concentrations and calcium chloride (CaCl2) concentration ondrug loading efficiency(LE), particle size and zeta potential. The concentration of CS, Alg and CaCl2 were taken as independent variables, while drug loading, particle size and zeta potential were taken as dependent variables. The study showed that the loading efficiency and particle size depend on the CS, Alg and CaCl2 concentrations, whereas zeta potential depends only on the Alg and CaCl2 concentrations. The MET-CS-AlgNPs nanocomposites were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and in vitro drug release studies. XRD datashowed that the crystalline properties of MET changed to an amorphous-like pattern when the nanocomposites were formed.The XRD pattern of MET-CS-AlgNPs showed reflections at 2θ = 14.2° and 22.1°, indicating that the formation of the nanocompositesprepared at the optimum conditions havea mean diameter of (165±20) nm, with a MET loading of (46.0 ± 2.1)% and a zeta potential of (-9.2 ± 0.5) mV.The FTIR data of MET-CS-AlgNPs showed some bands of MET, such as 3283, 1585 and 1413 cm-1, confirming the presence of the drug in the MET-CS-AlgNPs nanocomposites. The TGA for the optimized sample of MET-CS-AlgNPs showed a 70.2% weight loss compared to 55.3% for CS-AlgNPs, and the difference is due to the incorporation of MET in the CS-AlgNPs for the formation of MET-CS-AlgNPs nanocomposites. The release of MET from the nanocomposite showed sustained-release properties, indicating the presence of an interaction between MET and the polymer. The nanocomposite shows a smooth surface and spherical shape. The release profile of MET from its MET-CS-AlgNPs nanocomposites was found to be governed by the second kinetic model (R2 between 0.956-0.990) with more than 90% release during the first 50 h, which suggests that the release of the MET drug can be extended or prolonged via the nanocomposite formulation.

Bifid appendix: a case report and a review of literature.

Anomalies of the appendix are extremely rare, with a reported incidence of 0.004 to 0.009. Due to the wide range of variations, failing to recognize these anomalies may lead to failure of treatment and complications. We report a case of a 21-year-old female patient who presented to the Emergency Department with a clinical picture of acute appendicitis. After performing the proper laboratory and radiological tests, a decision was made to do a laparoscopic appendectomy which revealed a partially duplicated 'bifid' vermiform appendix with features of acute appendicitis.