Application of the International Endometrial Tumor Analysis (IETA) in Ultrasound Evaluation of Abnormal Uterine Bleeding.

INTRODUCTION: Abnormal uterine bleeding (AUB) affects a significant proportion of women, particularly around the ages of menarche and menopause. While ultrasonography is a primary diagnostic tool for AUB, techniques like the International Endometrial Tumor Analysis (IETA) scoring system have enhanced diagnostic accuracy for endometrial abnormalities. IETA provides a standardized approach to evaluating endometrial features, which aids in distinguishing benign from malignant lesions. METHODS: This study applied the IETA scoring system to the ultrasound evaluation of 50 women presenting with AUB. The study assessed various endometrial characteristics, including thickness, echogenicity, midline appearance, junction regularity, and vascular patterns. Data were analyzed to correlate IETA scores with histopathological findings and to compare the ultrasound features of benign and malignant lesions. RESULTS: The study found that non-uniform endometrial characteristics and irregular midline appearances were more common in malignant lesions. Specifically, interrupted or irregular endometrial-myometrial junctions, absence of the bright edge, higher color scores, and complex vascular patterns were significantly associated with malignancy. Mean endometrial thickness was notably higher in malignant cases compared to benign ones, with a statistically significant difference. The most frequent IETA scores were 7, 12, and 13. CONCLUSION: Integrating the IETA scoring system into ultrasound evaluation enhances the detection of endometrial abnormalities, improving the differentiation between benign and malignant lesions. This approach provides a reliable framework for diagnosing and managing AUB, potentially reducing the need for invasive procedures and facilitating better clinical decision-making.

A Molecular Dynamic Simulation, Structural Analysis, and Ex Vivo Insights into the P-glycoprotein-Mediated Interactions of Dietary Polyphenols with Cyclin-dependent Kinase Inhibitors: A Potential Strategy to Counteract Drug Efflux.

INTRODUCTION: P-glycoprotein, an ATP-dependent efflux transporter, plays a crucial role in eliminating cellular toxins and affects the intracellular concentration and bioavailability of CDK 4/6 inhibitors. Moreover, dietary flavonoids are natural bio-enhancers that can effectively inhibit the efflux function of these transporters. Therefore, this study aimed to assess the impact of dietary polyphenols on the inhibition of P-glycoprotein and the subsequent efflux of CDK inhibitors palbociclib and ribociclib. METHODS: A molecular docking approach was implemented to evaluate the binding interaction characteristics of CDK4/6 inhibitors in the presence of dietary polyphenols at the ATP binding site. Furthermore, the stability of the complexes was evaluated in two conformations of P-glycoprotein, followed by an ex vivo everted gut sac experiment. RESULTS: The findings demonstrated that the binding of curcumin and quercetin with high affinity (-51.63 and 47.16 Kcal/mol) to ATP binding sites of P-glycoprotein-palbociclib and ribociclib inward conformation complexes resulted in good stability of complex and minimal fluctuation throughout the course of the simulation. It was evident from the everted gut sac ex vivo study that the presence of 100µM of curcumin resulted in an increase of 1.77 and 4.20-fold in the intestinal transit of palbociclib and ribociclib, respectively. CONCLUSION: The study emphasizes the significance of curcumin and quercetin as inhibitors of P-glycoprotein, demonstrating their potential to decrease the efflux of palbociclib and ribociclib, consequently contributing to their bioavailability enhancement.

Strategy to Improve the Oral Pharmacokinetics of Cyclin-Dependent Kinase 4/6 Inhibitors: Enhancing Permeability and CYP450 Inhibition by a Natural Bioenhancer.

Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.

The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

BACKGROUND AND OBJECTIVES: Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of  cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement. METHODS: The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). RESULTS: Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 µM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) Cmax and area under the plasma concentration-time curve (AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. CONCLUSION: The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.

Primary Ewing's Sarcoma of the Kidney Mimicking Renal Cell Carcinoma With Widespread Metastasis: A Case Report and a Brief Review of the Literature.

Ewing's sarcoma family of tumors (ESFTs) are a group of small round cell tumors with common morphological and genetic features, including Ewing's sarcoma of bone, primary extra-skeletal Ewing tumors, extraosseous Ewing sarcoma (EES), and Askin tumors. EES presenting as a primary renal mass is an exceedingly uncommon aggressive tumor with limited reported cases in the literature and often mimics other renal malignancies on imaging. We present a case of a 31-year-old man presenting with left flank pain and abdominal fullness of short duration. Radiological imaging studies showed a large heterogenous mass from the left kidney, confirmed to be Ewing's sarcoma on post-operative histopathological examination (HPE) and immunohistochemistry (IHC) studies. Subsequent follow-up showed extensive metastatic disease. EES of the kidney has a nonspecific presentation and imaging appearance necessitating a multi-disciplinary approach comprising radiological imaging with a high index of suspicion, HPE, IHC, and molecular analysis for the correct diagnosis.

Estimation of CDK inhibitors by RP-HPLC: application for pharmacokinetic interactions studies with PPIs.

Background: The study investigated pharmacokinetic interactions between palbociclib and ribociclib with proton pump inhibitors (PPIs) using the reverse-phase high-performance liquid chromatography (RP-HPLC) method.Methods: Developed RP-HPLC method quantified palbociclib and ribociclib in biological matrices. In vitro metabolic stability assays and in vivo studies in rats evaluated effect of omeprazole and esomeprazole on pharmacokinetics of palbociclib and ribociclib.Results: The RP-HPLC method was sensitive, accurate and linear. Esomeprazole and omeprazole decreased metabolic clearance of palbociclib and ribociclib by several folds. In vivo, esomeprazole elevated Cmax of palbociclib and ribociclib by 90.1% and 86.4%, whereas omeprazole reduced it by 32.0% and 16.8%, respectively.Conclusion: The RP-HPLC method was used to analyze in vitro and in vivo samples. Long-term treatment with PPIs affects pharmacokinetics of palbociclib and ribociclib, necessitating optimal chemotherapy regimen.

[Box: see text].

Healthcare in the Modern Era: Launching a Telemedicine-Based OPD Consultation in Rural Pune (Process, Results, and Challenges).

Introduction Telemedicine serves as a means of overcoming geographical barriers and increasing access to specialist care. This study focuses on the impact of telemedicine on the early diagnosis and treatment of patients, as well as its effect on patient satisfaction. In addition, the study examines the obstacles and facilitators that influence the implementation of telemedicine. Objectives The primary objectives of this study are to assess the effectiveness of telemedicine in facilitating early diagnosis and treatment for patients in need of specialist consultations, to evaluate patient satisfaction with specialist care delivered through telemedicine, and to identify the factors that influence the successful implementation of telemedicine in rural healthcare centers. Methodology An exploratory feasibility study was carried out at two rural health training centers (RHTCs) over a one-year period, enrolling 400 patients requiring specialist consultations. The study involved establishing a telemedicine center, implementing teleconsultations, and collecting data through patient interviews and self-administered questionnaires. Results A majority of teleconsultations, over 79%, were deemed valuable by medical officers, resulting in improved management, better counseling, and earlier diagnoses. More than 76% of patients found telemedicine to be acceptable due to the reduction in travel time and cost. The most common health concerns among patients were diabetes, hypertension, and skin disorders. The study also revealed several challenges, including limited specialist personnel, waiting times, prescription limitations, and connectivity issues. Discussion Telemedicine has proven to be a valuable tool for rural healthcare delivery, providing patients with access to specialist consultations and improving patient outcomes. Both patients and medical officers reported positive experiences with telemedicine. The findings of this study align with existing literature, which highlights the benefits of telemedicine in managing chronic diseases and increasing patient satisfaction. However, it is crucial to address challenges, such as personnel limitations and connectivity issues, to optimize telemedicine's effectiveness. Conclusion Telemedicine offers great potential for enhancing access to specialist care and achieving universal healthcare in rural areas. Despite its limitations, telemedicine demonstrates promising outcomes and warrants further development and optimization to ensure its successful implementation in rural healthcare centers.

A Rare Case of Acute Necrotizing Encephalopathy of Childhood: A Case Report.

Acute necrotizing encephalopathy of childhood (ANEC) is a severe neurological disorder characterized by rapid-onset encephalopathy, often associated with viral infections. Acute necrotizing encephalopathy of childhood is associated with a very high mortality rate, and survivors may face long-term neurological sequelae. Acute necrotizing encephalopathy of childhood needs to be differentiated from its closest differential diagnosis, acute disseminated encephalomyelitis (ADEM). Most of the patients with ADEM recover, with a few of them having residual neurological deficits. We present a case of an eight-year-old boy with an acute history of fever, febrile seizures, and drowsiness. Magnetic resonance imaging revealed a symmetric tricolor appearance of bilateral thalamic lesions, characteristic of ANEC.

Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation.

OBJECTIVES: Cyclin-dependent kinase inhibitors are subject to rapid first-pass metabolism, and their oral absorption is hindered by intestinal CYP3A4 and P-gp. The present study investigates the impact of dietary polyphenols on the oral pharmacokinetics of palbociclib and ribociclib, considering their potential as modulators of CYP3A4 and P-gp. METHODS: Therefore, potential inhibitory effects of dietary polyphenols on drug metabolism and efflux of these drugs were investigated using molecular docking; in vitro preclinical assay using rat liver microsomes and Caco-2 cell monolayers; in vivo, pharmacokinetic parameters were determined in rats pretreated with dietary polyphenols. KEY FINDINGS: Curcumin and quercetin have the highest binding affinities to the PXR's AF-2 region cluster. Curcumin and quercetin significantly inhibited both intestinal efflux and CYP3A4-mediated metabolism of palbociclib and ribociclib (P < .05). In rats pretreated with curcumin, Cmax of palbociclib exhibited a 5.13% increase, while the AUC0-24h of ribociclib showed a significant increase of 18.83% (P < .05). Quercetin administration, notably, impedes the pharmacokinetics of palbociclib. However, the pharmacokinetics of ribociclib remains unaffected by quercetin. CONCLUSIONS: In conclusion, the utilization of curcumin as a bioenhancer can enhance the bioavailability of dual substrates of P-gp and CYP3A4.

Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.

BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein. OBJECTIVE: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib. METHOD: A combined approach of molecular docking and ex vivo everted gut sac model was implemented to predict the potential of proton pump inhibitors i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place. RESULTS: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In ex vivo studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and ex vivo studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib. CONCLUSION: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.

A Cross-Sectional Study to Determine the Association of Corrected QT Interval With Microalbuminuria in Type 2 Diabetes Mellitus.

Introduction Cardiac autonomic neuropathy (CAN) is a frequent and life-threatening complication of type 2 diabetes. Failure to diagnose can lead to high mortality and morbidity. In patients who have diabetes mellitus, microalbuminuria is an independent marker for cardiovascular disease. This study aimed to assess the corrected QT interval with microalbuminuria in type 2 diabetes mellitus. The objective of this study was to estimate the corrected QT interval in subjects with type 2 diabetes mellitus and to determine the association of the corrected QT interval with microalbuminuria type 2 diabetes mellitus. Methodology Ninety-five adult patients (>18 years to 65 years) diagnosed with type 2 diabetes mellitus with microalbuminuria were included in this study. Data were collected on the proforma through history taking and a general physical and systemic examination. An electrocardiograph was taken on the day of admission; the most prolonged QT interval was measured, and the RR interval was calculated. The data were statistically analyzed using IBM SPSS Statistics for Windows, Version 24 (Released 2016; IBM Corp., Armonk, New York, United States). Results There was a significant difference in the corrected QT interval prolongation prevalence between diabetic patients with microalbuminuria and without microalbuminuria (P-value <0.001). The mean corrected QT interval distribution did not differ significantly across various age groups of cases studied with microalbuminuria (P-value 0.98). The distribution of mean corrected QT interval did not differ significantly between the group of male cases and group of female cases studied with microalbuminuria (P-value 0.66). The mean corrected QT interval distribution did not differ significantly across various duration of diabetes groups among the cases studied with microalbuminuria (P-value 0.60). The mean corrected QT interval distribution did not differ significantly across different types of anti-diabetic treatment groups among the cases studied with microalbuminuria (P-value 0.64). Conclusion Type 2 diabetes has been prevalent in Indian and Asian populations. The early management of type 2 diabetes is necessary since the early stages of the disease can reduce the risk of CAN. Therefore, these patients should be diagnosed as early as possible and treated to reduce associated mortality and risk and to improve quality of care.

A novel and sustainable approach for biotransformation of phosphogypsum to calcium carbonate using urease producing Lysinibacillus sphaericus strain GUMP2.

Phosphogypsum (CaSO4) is produced as a waste by-product during phosphoric acid production in the fertilizer industry. Only 15% of worldwide phosphogypsum production is recycled, while 85% is stored in the vicinity of factories as huge piles resulting in environmental and health hazards. An extensively studied biotransformation of phosphogypsum to calcium carbonate or calcite (CaCO3) using sulfate reducing bacteria (SRBs) is a prolonged process and results in the formation of extremely hazardous H2S gas. Here we report for the first time a novel approach for biotransformation of phosphogypsum to CaCO3 using urease producing Lysinibacillus sphaericus strain GUMP2. The strain could effectively transform phosphogypsum to crystalline, bead-shaped CaCO3 precipitates. In a batch reactor with the PG loading rate of 60 g/L, 100% biotransformation was observed within seven days. After calcite recovery, the ammonium sulfate formed in the supernatant was recovered by precipitation. Urease-producing L. sphaericus strain GUMP2 could be used to remove the hazardous phosphogypsum from the environment by converting it to the industrially useful CaCO3 and ammonium sulfate, a valuable agricultural fertilizer. This novel and sustainable approach could be a promising solution for the hazardous phosphogypsum in the phosphoric acid industries.

Study of helminth eggs ( Ascaris suum) inactivation by anaerobic digestion and electrochemical treatment.

Background: The use of insufficiently treated wastewater or Faecal sludge in agriculture raises concerns because of the pathogen content. Helminth eggs (HE) are one of the most crucial pathogens for ensuring public health and safety. Widely used disinfection treatment methods do not guarantee the complete inactivation of helminth eggs. The current study evaluated the effectiveness of anaerobic digestion and electrochemical process on helminth ( Ascaris suum) egg inactivation. Methods: Lab-scale biochemical methane potential (BMP) assay was conducted by spiking A. suum eggs in a serum bottle. Total solid (TS), volatile solid (VS), pH, biogas production and its composition, and volatile fatty acids (VFA) were analyzed along with A. suum inactivation every third day for the initial 15 days and fifth day for 45 days. In the second set of experiments, a hypochlorite (4700 ppm) solution was generated by electrolysis of aqueous NaCl solution in a membrane-less electrochemical cell. The hypochlorite was diluted (940, 470, 235, and 156ppm) in wastewater, spiked with A. suum eggs and then examined for inactivation at regular intervals. Results: The results of the anaerobic digestion treatment documented 98% inactivation of A. suum eggs (0.15 eggs/mL) in 35 days and remained at 0.14 eggs/mL until day 45. Correlation analysis revealed a positive relationship between non-viable eggs and pH and a negative relationship with all the other parameters. Electrochemical treatment achieved 10% inactivation at 940 ppm concentration in 24h. Conclusions: This study revealed that the inactivation of A. suum eggs by anaerobic digestion or electrochemical treatment is a combined effect of more than one parameter.

Fracture resistance to treated teeth using known endodontics techniques in Indian patients.

Teeth with crown structure less than 50% can be restored. Therefore, it is of interest to evaluate an in vitro efficacy of Zirconia post, Glass fiber post, polyethylene-woven fiber posts, and Quartz posts. Forty eight recently extracted mandibular first premolar teeth were randomly grouped in to 4 different groups with 12 samples in each group. After endodontic treatment samples in all groups underwent post preparation followed by restoration with respective posts. The mean fracture resistance (Newton) were 463.5 ± 14.3 (Group I) 425.2± 23.5 (group II), 410.4± 18.6 (Group 3) and 385.2 ± 14.2 (group 4). Data shows that Zirconia post had highest fracture resistance compared to other tested groups.

Should the Use of Acid Reducing Agents in Conjunction with Ribociclib be Avoided? An Integrated QbD Approach for Assessment of pH-Mediated Interaction.

The objective of the study was to evaluate the possible pH-dependent interaction of ribociclib succinate with acid-reducing agents, which are concomitantly administered as supportive care medicines in cancer. Quality by Design-based analytical method development for a weakly basic drug ribociclib succinate supposedly having the characteristic ability of pH-dependent solubility was carried out for analyzing micro-dissolution experiment samples in biorelevant media to study pH-dependent interaction. An accurate and robust analytical method was developed using a three-level three-factorial box-behnken design for quantification of ribociclib succinate in micro-dissolution samples by the implementation of the Analytical Quality by Design approach. Here, pH of aqueous mobile phase and flow rate proved to be critical process parameters. The gastric compartment solubility was found to be 814.05 µg/mL, which dropped down to 494.71 µg/mL after a pH shift from pH 1.2-6.5. In the intestinal compartment, initial solubility was 717.58 µg/mL, which reduced to 463.20 µg/mL after a pH shift from 6.5 to 6.8. Concluded results state that pH shift does not impact the solubility or the absorption of the drug to a significant extent in the presence of acid-reducing agents. However, the study would prove to be a practical approach for examination of the behavior of the drugs at the initial stages.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 µM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

Expression of IL-6, TNF-α, and hs-CRP in the serum of patients undergoing single-sitting and multiple-sitting root canal treatment: A comparative study.

Background: In recent times, single-sitting root canal therapy has gained momentum over multiple-sitting root canal therapy due to its superior clinical outcome and less time required for treating the patient. Aim: Thus, the aim of current study was to compare the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) in the serum of patients undergoing single-sitting and multiple-sitting root canal treatment. Materials and Methods: This cross-sectional experimental study was conducted on 300 subjects who were indicated for root canal treatment. Subjects were categorized into Group I (single visit) and Group II (multiple visits).Clinical data was obtained and serum samples were collected both before and after 1 week of treatment completion. Inclusion criteria were those patients (a) over 18 years of age, (b) without any disease of inflammatory etiology, and (c) who had not previously received endodontic treatment or any related therapeutic treatment. Exclusion criteria were those (a) without a complete clinical history, (b) with greater than one indicated tooth, (c) who did not complete their treatment, and (d) with any periodontal disease. Chi-square and Student's t-test were applied. Results: It was found that in single-sitting root canal treatment, there was a statistically significant reduction in these inflammatory biomarkers, although no difference in clinical efficacy was observed. Conclusion: Single-visit root canal treatment is a better option for treatment of pulpitis compared to multiple-sitting treatment.

Inhibition of Cytochrome P450 Enzyme and Drug-Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK Inhibitors for Breast Cancer Chemotherapy.

BACKGROUND AND OBJECTIVE: Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential. METHODS: The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between proton pump inhibitors and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4. RESULTS: Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1'-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86µM and 9.71µM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30µM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib, whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism. CONCLUSION: Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals.

A Comparative Evaluation of Anesthetic Effectiveness of 4% Articaine vs 0.5% Bupivacaine for Lower Molar Tooth Extraction.

BACKGROUND: Safe and efficient pain control is essential for today's dental practice. This randomized controlled study was conducted to evaluate the effectiveness of 0.5% bupivacaine with 4% articaine in lower molar tooth extraction. METHODS: One hundred subjects were classified into two groups, with 50 samples for each. Group A participants were managed with 0.5% bupivacaine with 1:200,000 epinephrine and group B participants with 4% articaine with 1:100,000 epinephrine for mandibular first and second molar extraction. Criteria such as onset and duration of anesthesia, pain throughout the procedure, pain during injection, and pain after the procedure were evaluated. Systolic and diastolic blood pressure (mmHg) and heart rate (per minute)were evaluated for all participants. RESULTS: There was a faster onset (53.2 vs 83.1 s) and lesser duration of action (216.6 vs 298.4 min) with articaine (group B) compared to bupivacaine (group A). Thirty-eight (76.0%) participants in group A and 44 (88.0%) participants in group B did not require re-anesthesia, whereas 12 (24%) participants in group A and six (12%) participants in group B required one-time re-anesthesia and it was insignificant. CONCLUSION: Articaine has a faster onset but a relatively lower duration of action and requires statistically insignificant but lower re-anesthesia. As a result, articaine anesthesia can be efficiently recommended in oral surgical techniques.

An overview of regulations for bioequivalence assessment of locally acting orally inhaled drug products for the United States, Europe, Canada, and India.

INTRODUCTION: Bioequivalence is established by comparing the bioequivalence study results of generic drugs with the reference listed drug. Several global regulatory agencies have published the guidance for locally acting orally inhaled drug products (OIDPs) for bioequivalence approaches. AREAS COVERED: The prime intent of the present article is to compare the regulatory guidance for bioequivalence assessment of locally acting OIDPs published by global regulatory authorities. Regulatory recommendations on bioequivalence were based on assessment for different parameters such as inhaler device, formulation, reference product selection, in-vitro, and in-vivo studies. The United States Food and Drug Administration and Health Canada suggest an aggregated weight of evidence approach and the European Medicines Agency promotes a stepwise approach, whereas though the Indian authorities have not published guidance specifically on OIDPs but provided guidelines for bioavailability and bioequivalence studies. EXPERT OPINION: For OIDPs, currently, there is no universally adopted methodology, and regulatory guidance has not been globally harmonized. By understanding and comparing bioequivalence recommendations for different regions, we can create more sensitive, and economic evaluation methods for OIDPs. This could open more alternatives of safe, effective generic OIDPs to the public.