Single Dose Of Drug Research Articles

Bioequivalence study of ticagrelor in normal, healthy Indian subjects under fasting conditions: A randomized, blinded, crossover study

Objectives: The objectives of this study were to evaluate the bioequivalence and safety profiles of the test drug and reference drug of 90 mg ticagrelor tablets under fasting conditions. Methods: This was a randomized, blinded, balanced, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study in normal, healthy adults. Subjects were randomized to receive a single dose of test or reference drug (ticagrelor 90 mg oral) under fasting conditions with a 16-day washout period. The primary pharmacokinetic variables were peak plasma concentration (Cmax), area under the plasma concentration (AUC) time curve measured to the last quantifiable concentration (AUCT), and time to maximum drug concentration (Tmax). Bioequivalence was concluded if 90% confidence intervals (CIs) of the geometric mean ratio of the test/reference drugs AUCT and Cmax are within the predefined range of 80%–125%. Adverse events (AEs) were also assessed. Results: Forty-two healthy adult males were enrolled, but 4 withdrew and 38 subjects successfully completed the study. There was no difference between the test and reference drugs regarding pharmacokinetic parameters. The median (range) Tmax was 1.67 h (1–4 h) and 2 h (1–4.5 h) for the test and reference products, respectively. The estimated 90% CIs of the geometric mean ratio for AUCT and Cmax satisfied the predefined bioequivalence criteria of 80%–125%. On analysis of variance, no significant “sequence” and “period” effects were observed for the pharmacokinetic parameters. No AEs were reported in the study. Conclusion: Our findings indicate that the test product is bioequivalent to the reference product and safe and well-tolerated in healthy Indian adults.

Drug synergy model for malignant diseases using deep learning.

Drug synergy has emerged as a viable treatment option for malignancy. Drug synergy reduces toxicity, improves therapeutic efficacy, and overcomes drug resistance when compared to single-drug doses. Thus, it has attained significant interest from academics and pharmaceutical organizations. Due to the enormous combinatorial search space, it is impossible to experimentally validate every conceivable combination for synergistic interaction. Due to advancement in artificial intelligence, the computational techniques are being utilized to identify synergistic drug combinations, whereas prior literature has focused on treating certain malignancies. As a result, high-order drug combinations have been given little consideration. Here, DrugSymby, a novel deep-learning model is proposed for predicting drug combinations. To achieve this objective, the data is collected from datasets that include information on anti-cancer drugs, gene expression profiles of malignant cell lines, and screening data against a wide range of malignant cell lines. The proposed model was developed using this data and achieved high performance with f1-score of 0.98, recall of 0.99, and precision of 0.98. The evaluation results of DrugSymby model utilizing drug combination screening data from the NCI-ALMANAC screening dataset indicate drug combination prediction is effective. The proposed model will be used to determine the most successful synergistic drug combinations, and also increase the possibilities of exploring new drug combinations.

Clinical and pharmacological effectiveness of Fit-O-Metrin drug in the scheme of treatment of bovine postpartum metritis

The article presents data on the approval of the new Fit-O-Metrin drug for accelerating the recovery of cows from postpartum metritis. The experiment was focused on monitoring the excretion of exudate; restoration and strengthening of the contractile function and regenerative processes in the uterus after the use of the drug. Favorable conditions for uterine disease are often created during calving. However, the reproductive function of animals is mostly determined by the ability to restore the physiological state of the uterus in the postpartum period. Thus, in the experimental farm AgroTsvit 2012 (Zhytomyr region), clinical and laboratory examination of cows in the postpartum period determined that the prevalence of metritis covers up to 42% of the herd. The largest percentage of sick cows had purulent form (53.1 %), catarrhal-purulent metritis was registered in 30.4 %, catarrhal – in 16.5 %. Through our own research, we determined the effectiveness of the experimental drug Fit-O-Metrin, made on the basis of plant materials (extract of thyme, motherwort, and common barberry) for intrauterine administration as part of the treatment regimen for bovine metritis. In the clinical test, 13 sick cows were involved, to which Fit-O-Metrin was applied according to three different schemes. Another 5 animals with metritis were included in the control group, which were treated according to the standard protocol for the farm. However, regardless of the chosen scheme, the complete cessation of the release of inflammatory exudate from the vagina of the entire cow's herd was recorded already on the 6–7 day (in the control group – on the 9 day). Normalization of tone and anatomical position of the uterus, complete closure of the cervical canal was noted on the 8th day (in the control group – on the 12 day). The most optimal scheme of using the herbal preparation against postpartum purulent metritis is 2 days injections, 2 days break, 2 days injections, 2 days break, final injection. A single dose of the FitO-Metrin drug is 30 ml. Key words: postpartum metritis, Fit-O-Methrin, cattle, treatment scheme, effectiveness, exudate, sexual cycle.

Breeze 2.0: an interactive web-tool for visual analysis and comparison of drug response data.

Functional precision medicine (fPM) offers an exciting, simplified approach to finding the right applications for existing molecules and enhancing therapeutic potential. Integrative and robust tools ensuring high accuracy and reliability of the results are critical. In response to this need, we previously developed Breeze, a drug screening data analysis pipeline, designed to facilitate quality control, dose-response curve fitting, and data visualization in a user-friendly manner. Here, we describe the latest version of Breeze (release 2.0), which implements an array of advanced data exploration capabilities, providing users with comprehensive post-analysis and interactive visualization options that are essential for minimizing false positive/negative outcomes and ensuring accurate interpretation of drug sensitivity and resistance data. The Breeze 2.0 web-tool also enables integrative analysis and cross-comparison of user-uploaded data with publicly available drug response datasets. The updated version incorporates new drug quantification metrics, supports analysis of both multi-dose and single-dose drug screening data and introduces a redesigned, intuitive user interface. With these enhancements, Breeze 2.0 is anticipated to substantially broaden its potential applications in diverse domains of fPM.

Predicting anti-cancer drug combination responses with a temporal cell state network model.

Cancer chemotherapy combines multiple drugs, but predicting the effects of drug combinations on cancer cell proliferation remains challenging, even for simple in vitro systems. We hypothesized that by combining knowledge of single drug dose responses and cell state transition network dynamics, we could predict how a population of cancer cells will respond to drug combinations. We tested this hypothesis here using three targeted inhibitors of different cell cycle states in two different cell lines in vitro. We formulated a Markov model to capture temporal cell state transitions between different cell cycle phases, with single drug data constraining how drug doses affect transition rates. This model was able to predict the landscape of all three different pairwise drug combinations across all dose ranges for both cell lines with no additional data. While further application to different cell lines, more drugs, additional cell state networks, and more complex co-culture or in vivo systems remain, this work demonstrates how currently available or attainable information could be sufficient for prediction of drug combination response for single cell lines in vitro.

Pharmacokinetic Interactions Between Bazedoxifene and Cholecalciferol: An Open-Label, Randomized, Crossover Study in Healthy Male Volunteers.

The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects. Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs). For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263-1.1765) for Cmax and 1.1329 (1.0232-1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005-0.9117) for Cmax and 0.8056 (0.7445-0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases. A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.

BIOEQUIVALENCE STUDY OF GENERIC MOLNUPIRAVIR IN HEALTHY VOLUNTEERS

Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease.The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers.Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 – 125.00%.Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0–16) and Cmax were 96.31% – 113.64% and 91.37% – 114.8%, respectively. These intervals fit within the established limits of 80.00–125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs.Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.

New Fractional Cancer Mathematical Model via IL-10 Cytokine and Anti-PD-L1 Inhibitor

In this study, we explore a recent biological model created to analyze the behavior of cancer cells by administering a dose of a drug containing anti-PD-L1 and IL-10 with the Caputo and Atangana–Baleanu derivative in the Caputo sense (ABC). Using the Caputo derivative in order to examine the stability of the non-linear system, we are able to demonstrate that it is existent and unique, and to introduce several numeric data obtained for the fractional values in MATLAB by using the Adams–Bashforth–Moulton (ABM) method. Additionally, by using the predictor–corrector approach, the numerical results from the system with ABC derivative will be produced. As a result, it has been observed that immune system cells that are exposed to single-dose drug with fractional order effectively combat cancer cells. The tumor cells decrease by 70.44% and 80.16% for the system generalized by the Caputo and ABC derivative, respectively, for the order α=0.42.

Bioequivalence Study Comparing a Generic and Innovator Drug of Rosuvastatin 20 mg

The bioequivalence study was conducted to compare the bioavailability of two rosuvastatin 20 mg film-coated tablet formulations (test and reference formulation). This study was an open-label, randomized, single-dose, two-periods, twotreatments, and crossover study which included 32 healthy adult male and female subjects under fasting conditions. Each of the two study periods was separated by a 7 days washout period. A single oral dose of test or reference drug was administered to the subject in each period based on the randomization scheme. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were the area under the plasma concentration-time curve from time zero to 72 h (AUC0-72h), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (Tmax), and the elimination half-life (T1/2). The geometric mean ratio (GMR) and 90% Confidence Interval (90% CI) for AUC0-72h and Cmax of test/reference drug for rosuvastatin were 97.05 % (89.07%– 105.74%) and 101.15% (89.53%– 114.26%). Since the 90% CI with α 0.05% for AUC0-72h and Cmax of rosuvastatin were within the standard bioequivalence range (80.00– 125.00%), it was concluded that the two rosuvastatin film-coated tablets (test and reference drug) were bioequivalence in terms of the rate and extent of absorption.

Clinical Profile of Patients on Antiepileptic Drugs Experiencing Ataxia as an Adverse Drug Reaction: A Longitudinal Observational Study

Introduction: Ataxia is one the common adverse drug effect caused by Antiepileptic Drugs (AEDs). It can result from either single therapeutic dose of a particular drug, prolonged use of same drug or acute poisoning. Aim: To determine the disease burden and clinical profile of patients who are on AEDs and develop ataxia. Materials and Methods: This was a longitudinal observational study, carried out at Mahatma Gandhi Medical College and Research Institute, Puducherry, from January 2016 to March 2022. The clinical characteristics of patients who presented with ataxia on AEDs and with no previous history of ataxia were documented. Based on the time of onset of ataxia patients were divided into 3 groups: Group A- Ataxia developed within 24 hours of onset of drug intake; Group B- Ataxia developed within 24 to 72 hours from prescription of drug; Group C- Ataxia developed after 72 hours from the time of drug administration. Patients were further classified into those having sensory ataxia and cerebellar ataxia. Based on the time of clinical resolution patients were classified into 3 sub-groups: Group 1- Clinical resolution within 72 hours; Group 2- Clinical resolution in 72 to 144 hours; and Group 3- Clinical resolution after 144 hours. Data was collected systematically and results were statistically analysed using Microsoft Excel spreadsheet software program. Results: Out of the total number of epileptic patients (1600) on AEDs, 34 patients developed ataxia. Of these 34 patients, 15 (44.11%) were on Phenytoin, 12 (35.29%) were on Carbamazepine, 3 (8.82%) were on Gabapentin, 2 (5.88%) were on Zonisamide, and 2 (5.88%) were on Lamotrigine. Dose of these drugs were modified within 1 day, after 1 and 3 weeks and after 1 month in 9 (26.47%), 7 (20.58%), 12 (35.29%), and 4 (11.76%) patients, respectively. Two patients had presented with acute poisoning. Half the 50% (n=17) patients had symptoms of sensory ataxia and remaining half had symptoms of cerebellar ataxia. Conclusion: Ataxia secondary to AEDs is seen with both the older and newer drugs. Awareness of the possibility of AEDs induced ataxia can help in early diagnosis and its management.

Comprehensive Perspectives for Erectile Dysfunction Pharmacotherapy: From Mechanism to Application

In recent years, the incidence of erectile dysfunction (ED) has continued to rise worldwide. Since pharmacotherapy is still the most common and effective method for the treatment of ED at present, many methods and drugs have been designed or developed for the treatment of ED. Oral phosphodiesterase-5 inhibitors and androgen supplement therapy are currently the common therapeutics for ED; however, some patients have poor responses to these drugs because of the multiple pathogenic mechanisms of ED. Researchers are trying to find other treatment ways. On the one hand, many new strategies and concepts, such as targeted therapy, are also integrated into clinical or preclinical research; on the other hand, some combined therapies that have synergistic effects with a reduced dose of a single drug and less adverse effects are also developed. This review article summarized the efficacy of the latest first-line, second-line drugs and adjuvant therapies for the treatment of ED, as well as the application of comprehensive treatments, which will help doctors not only deeply understand the mechanism of ED but select the suitable therapeutics for those patients.

Evaluation of the Bactericidal Activity of Gramicidin S Against <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i> Clinical Isolates with Single and Multiple Exposure

Background . Sore throat of infectious and inflammatory origin is one of the most common reasons for the prescription of antimicrobial drugs. The use of antimicrobial peptides (AMPs) for topical therapy may be a promising solution, due to the peculiarities of AMPs’ mechanism of action, taking into account the high importance of microbial resistance spread problem in relation to systemic etiotropic drugs. The aim of the study was to assess the formation of resistance to AMP Gramicidin S (GS) of clinical isolates of Streptococcus pneumoniae and Staphylococcus aureus , including strains resistant to antimicrobial drugs during repeated exposure, in the setting close to their actual use in clinical practice. Materials and methods . The object under study is AMP GS. The test microorganisms are reference strains of S.pneumoniae (ATCC 6303), S.aureus (ATCC 6538–P), and 10 strains of clinical isolates of each type of microorganisms, types with antimicrobial resistance (including MRSA). At the first stage, the antimicrobial activity of GS was evaluated by the method of microdilutions in plates by estimating the value of the minimum inhibitory and the minimum bactericidal concentrations (MIC and MBC, respectively). At the second stage, using reference strains and 4 clinical isolates of each microorganism, including types with antimicrobial resistance, resistance was formed in two ways simultaneously (with liquid and solid media) for 7 consecutive passages over 7 days with GS at concentrations equal to 0.5 and 1.0 MIC. The number of surviving microorganisms was estimated and the MIC and MBC were determined at each passage. Results . At the first stage, the MIC of GS in relation to S.pneumoniae was 8 µg/ml for 5 strains, 16 µg/ml for 5 strains, and 4 µg/ml for one. For 10 out of 11 strains of S.aureus , including MRSA, the MIC of GS was 4 µg/ml (for 1 strain — 8 µg/ml). For 4 strains of S.pneumoniae , MBC of GS was equal to MIC (16 µg/ml), for 7 strains MBC was 4–8 times higher than MIC, and mostly amounted to 32 µg/ml (for 1 strain — 64 µg/ml). MBC for 6 strains of S.aureus was equal to MIC (4 µg/ml), for the 5 remaining strains MBC was 2–8 times higher than MIC, but did not exceed 64 µg/ml. At the second stage, it was found that the estimated values of GS MIC and MBC with repeated exposure to GS remained at the same level for 7 passages in all strains, including those resistant to antibiotics in liquid and solid media. Conclusions . Gramicidin S demonstrated high bactericidal activity against reference strains and clinical isolates of leading pathogenic microorganisms S.pneumoniae and S.aureus , including strains resistant to systemic antimicrobial drugs, while MIC and MBC did not exceed concentrations contained in single doses of drugs used in clinical practice. During repeated exposure (7 passages in 7 days), there were no signs of the formation of resistance of test strains of pathogens, including those resistant to systemic antimicrobial medicines from the groups of beta-lactams, macrolides, fluoroquinolones, tetracyclines, aminoglycosides, etc.

Safety, Tolerability, and Pharmacokinetic Profile of Single and Multiple Ascending Doses of GB5121, a CNS-Penetrant BTK Inhibitor, in Healthy Subjects

Background: GB5121 is an oral, brain-penetrant, potent, highly selective, irreversible, small molecule Bruton's tyrosine kinase inhibitor (BTKi) in development for hematologic malignancies with CNS involvement. Preclinical studies demonstrated that GB5121 exhibited several characteristics differentiating it from other BTKis, including rapid equilibrium into the brain, increased brain target occupancy, and fast inactivation rate. These characteristics combined with GB5121's kinase selectivity and activity in in vitro and in vivo DLBCL models support its clinical investigation in BTK-driven CNS lymphomas. This first-in-human study was designed to evaluate the single- and multiple-dose safety, tolerability, pharmacokinetics (PK; including CNS penetrance) and pharmacodynamics (PD), the effect of food, drug interactions, and cardiac safety of GB5121 to inform dosing and concomitant medications in clinical studies. Methods: This is an ongoing Phase 1, double-blind, randomized, placebo-controlled, single ascending and multiple ascending dose (SAD, MAD) study in healthy subjects, with staggered dose escalations and adaptive dose selection. Safety is assessed throughout the study and PK and PD are characterized using serial blood samples collected up to 48 hours post-dose for GB5121 plasma concentrations, BTK target occupancy (TO), and target engagement (TE). Cerebrospinal fluid (CSF) samples are collected at 2 hours post-dose to characterize the relationship between GB5121 plasma concentrations and CNS penetrance. GB5121 PK parameters (e.g., AUClast, AUCinf, Cmax, Tmax, t1/2) are estimated by standard noncompartmental methods. Results: Preliminary PK results from 3 completed SAD cohorts are presented, including 23 subjects (7 receiving 5 mg, 8 receiving 15 mg, and 8 receiving 45 mg: randomized in a 3:1 ratio to receive GB5121 or placebo) in a fed state (moderate-fat meal). A review of blinded safety data thus far indicated that the study drug was generally well tolerated with no serious adverse events or early study discontinuations reported. PK parameters are presented in Table 1. GB5121 was rapidly absorbed following oral administration with mean plasma Tmax ranging from 1-2 hours and exhibited a terminal half-life of approximately 3 hours. Single-dose GB5121 exposure (AUCinf) increased in a greater than dose-proportional manner from 5 to 15 mg and near dose-proportional from 15 to 45 mg. Mean GB5121 CSF:unbound plasma concentration ratios approximated 1, indicating unimpeded access of unbound drug in plasma into the CNS. The observed GB5121 plasma exposure, CNS penetrance, and preliminary TO and TE PD data were consistent with that of a translational PK/PD model. Conclusions: Data from the first 3 SAD cohorts in healthy subjects indicated that low doses of GB5121 provided plasma exposure and CSF penetrance adequate to drive desired BTK inhibition in the CNS. Blinded safety data indicated that single-dose study drug administration was well tolerated across the dose range. PD analysis and additional evaluations are ongoing and final results will be presented. The safety and PK profiles of GB5121 support its continued evaluation in the ongoing Phase 1b/2 open-label, international study in adult subjects with relapsed/refractory primary/secondary CNS lymphoma, or primary vitreoretinal lymphoma (STAR CNS; NCT05242146). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Efficiency Multi-Drug Functional Profiling in a Microfluidic Device Towards Personalized Predictions in Pediatric Leukemia

Treatment of pediatric acute lymphoblastic leukemia (ALL) has seen dramatic improvements over the last several decades, leading to overall survival rates of over 85%. However, for patients with relapsed/refractory disease, achieving complete remission remains extremely challenging. Improving treatment outcomes for these patients will require increasingly personalized treatment strategies that make use of functional screens in addition to molecular profiling technologies for treatment selection. Given the past success of combination chemotherapy in cancer treatment and recent promise for newly developed targeted agents, functional assays that are able to evaluate patient response to combinations of therapies will likely be most effective in identifying clinically actionable treatment protocols. Moreover, assays that can achieve this with minimal patient sample and reduced experimental workload will have the greatest potential for clinical translation and integration into clinical workflows. To that end, this work aims to develop a microfluidic assay to directly test candidate combinations of therapeutics in patient derived ALL cells. We aim for this to serve as a more effective way to screen for drug combination response and higher order interactions relative to standard wellplate formats. Once validated, this assay can be used to identify biomarkers of response to standard and experimental combination regimens in pediatric ALL, and ultimately, could be used to prospectively guide therapy in newly diagnosed patients. The developed device achieves this by enabling simultaneous exposure to 3 superimposed small molecule drug gradients across a 3D culture of leukemia cells such that each location in the device comprises a unique combination of all 3 drugs within a simplex (Fig 1A). Single cell drug concentration exposure is determined from experimentally validated steady state computational fluid dynamics (CFD) model predictions, and single cell viability is analyzed via Calcein (live), PI (dead) and Hoechst (nuclear) staining following 48 hours of treatment. Using this system, we then develop a novel experimental and computational framework for evaluating drug combination efficacy and synergy across the full range of combination ratios captured in our device. Specifically, we evaluate response across multiple devices at optimally spaced dose levels, increasing coverage of the 3-drug combination space and allowing for custom implementation of established synergy models. This enables synergy assessment in a continuous gradient of drug combination ratios, as opposed to the discrete combination ratios commonly evaluated in standard assays, and may further improve detection of drug synergy and identification of the most potent and efficacious combination ratios. To demonstrate this, we analyze response to a combination of daunorubicin, vincristine, and nelarabine in Jurkats, a T-ALL cell line, across 7 different devices at 7 different dose levels (Fig 1B). We quantify viability as a function of concentration across each device and each dose level, and generate dose response curves at distinct zones within the device. Specifically, we generate dose response curves in zones dominated by daunorubicin, vincristine, and nelarabine alone and find half maximal effective concentration values (EC50 values) similar to those reported in literature. We further evaluate response at varying ratios of each 2-drug combination, and generate dose response curves as shown in Fig 1B. Analyzing the 2-drug combination dose responses relative to single-drug dose responses allows for quantification of 2-drug combination synergy based on Loewe and DiaMOND synergy models, and future work will extend our developed method to analyze emergent 3-drug combination synergy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial

PurposeDry eye disease is a multifactorial disorder that affects the ocular surface, with symptoms including ocular irritation, impaired vision, and pain. Nicotinic acetylcholine receptor (nAChR) agonists are novel treatments for dry eye disease; this study investigates the nAChR agonist OC-02 (simpinicline solution) as an aqueous nasal spray. MethodsPEARL (Clinical Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms of Dry Eye Disease) was a Phase II study that evaluated the efficacy and safety of OC-02 (simpinicline solution) nasal spray (OC-02 SNS) in adult patients with dry eye disease. Patients ≥22 years of age were eligible if they had an Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in >1 region or ≥4 for all regions, or Schirmer test score (STS) ≤10 mm; there were no restrictions on eye dryness score (EDS). Patients (N = 165) were randomly assigned 1:1:1:1 to vehicle (control; n = 42) or OC-02 SNS (0.11 mg, 0.55 mg, or 1.1 mg; n = 41 per group) and received a single dose of study drug (100 µL using a nasal spray atomizer) at visit 1 and visit 2 (15–19 days after visit 1). Primary efficacy outcomes were change in the STS from baseline to immediately after treatment administration (visit 1) and change in the EDS from before to 5 minutes after treatment during controlled adverse environment exposure (visit 2). FindingsBaseline demographic and ocular clinical characteristics were similar across all groups. Single-dose OC-02 SNS improved the signs and symptoms of dry eye disease. For the STS, statistically significant and dose-dependent improvements were found from before to after treatment with OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, 3.0 mm; 0.11 mg OC-02 SNS, 9.0 mm; 0.55 mg, 17.5 mm; and 1.1 mg, 19.6 mm). For EDS, statistically significant and dose-dependent improvements were found from before to 5 minutes after treatment with higher doses of OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, –6.5; 0.11 mg OC-02 SNS, –9.4; 0.55 mg, –17.4; and 1.1 mg, –20.7). OC-02 SNS was well tolerated: only 2 ocular adverse events were reported (eye pruritis and keratitis), and the most common nonocular events were cough and throat irritation. ImplicationsSingle-dose OC-02 SNS over a range of doses immediately and significantly increased tear production and improved eye dryness. Together with previous studies of OC-01 (varenicline solution) nasal spray, our findings suggest that agonist stimulation of nAChRs in the nasal cavity is a valid and effective mechanism to elicit natural tear production in patients with dry eye disease. ClinicalTrials.gov identifier: NCT03452397.

Bioequivalence Study of Etoricoxib 120 mg in Healthy Subjects

Etoricoxib is an oral selective cyclo-oxygenase-2 (COX-2) inhibitor with anti-inflammatory and antirheumatic properties belonging to the group of NSAIDs. Study Objective: The objective of this study was to investigate the bioequivalence study of Etoricoxib, Tricox® 120 mg film coated caplet manufactured by PT Guardian Pharmatama for PT Nulab Pharmaceutical Indonesia in comparison with Etoricoxib 120 mg, Arcoxia® film coated tablet manufactured by Frosst Iberica, S.A., Spain, registered and packed by PT Merck Sharp Dohme Pharma Tbk Pasuruan, East Java. Indonesia. Methods: The study was conducted using an open-label, randomized, single-dose, two-periods, two-treatment, crossover study under fasting for 10 hours with 7 (seven) days washed-out period between each period. A single oral dose of the test drug or reference drug was administered to 16 healthy male subjects. The number of subjects who finished the study was fourteen (14) healthy male subjects. Serial plasma samples were obtained over a 72 hours period. Plasma concentrations of the drug were determined by LC-MS/MS method. From the Etoricoxib concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUC0-72h, AUC0-∞, and Cmax, while the statistical interval proposed was 80.00 - 125.00% for AUC0-72h and Cmax with 90% Confidence Interval (CI) with α = 5.00%. The estimation of Tmax and T1/2 in the bioequivalence study was based on a nonparametric statistical procedure on the original data using Wilcoxon Sign Test. Results: The main pharmacokinetic parameters of the test drug Tricox® (BN: T200909) compared to reference drug, Arcoxia® (BN: T015857) were calculated based on geometric mean ratio and 90% confidence interval (CI). The results for AUC0-72h and Cmax were 91.97% (87.50% – 96.66%) and 96.98% (88.41% – 106.36%) respectively, with intra-subject variability (%CV) were 13.56% for AUC0-72h and 7.28% for Cmax. Hence, the number of 14 (fourteen) subjects has adequate number for required power of study. Conclusion: The study demonstrated that the test drug Tricox® (BN: T200909) manufactured by PT Guardian Pharmatama for PT Nulab Pharmaceutical Indonesia bioequivalence in term of both rate and extent of absorption to the reference drug Arcoxia® (BN: T015857) manufactured by Frosst Iberica, S.A., Spain, registered and packed by PT Merck Sharp Dohme Pharma Tbk Pasuruan, East Java. Indonesia.

Bioequivalence Study of Two Etoricoxib 90 mg Film-Coated Tablet Formulations

The present study was conducted to compare the bioavailability of two etoricoxib 90 mg film-coated tablet formulations (test formulation and reference formulation). This study was an open-label, randomized, single-dose, two-periods, twotreatments, and crossover study which included 24 healthy adult male and female subjects under fasting conditions. Each of the two study periods was separated by a 7 days washout. A single dose of test or reference drug was administered to the subject in each period based on the randomization scheme. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were the area under the plasma concentration-time curve from time zero to 96 h (AUC0-96h), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (Tmax), and the elimination half-life (T1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for etoricoxib were 102.39% (97.63% – 107.38%) for AUC0-96h and 93.23% (86.54% – 100.43%) for Cmax. The 90% Confidence Intervals (CI) calculated for AUC0-96h and Cmax of etoricoxib were within the standard bioequivalence range (80.00– 125.00% for AUC0-t and Cmax). It was concluded that the two etoricoxib film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption

Bioequivalence Study of Two Formulations of Cefixime

Cefixime is a broad-spectrum oral antibiotic used for treating a wide variety of bacterial infections. Study Objective: The objective of this study was to find out whether bioequivalence study of Cefixime 200 mg, Profim® capsule manufactured by PT Promedrahardjo Farmasi Industri in comparison with Cefixime 100 mg, Cefspan® capsule manufactured by PT Dankos Farma, For PT Kalbe Farma Tbk, under license by Astellas Pharma Inc., Osaka – Japan. Methods: The study was conducted using an open-label, randomized, single-dose, two-periods, two-treatments, crossover study under fasting conditions with 8 (eight) days washed-out period between each period. According to the random design, a single oral dose of the test drug or reference drug was administered to 30 healthy male subjects after overnight fasting. The number of subjects who finished the study was twenty-eight (28) healthy male subjects. Serial plasma samples were obtained over a 32 hours period. Plasma concentrations of the drug were determined by LC-MS/MS method. From the Cefixime concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUC0-32h, AUC0-∞, and Cmax, while the statistical interval proposed was 80.00 - 125.00% for AUC0-32h and Cmax with 90% Confidence Interval (CI) with α = 5.00%. The estimation of Tmax and T1/2 in the bioequivalence study was based on a nonparametric statistical procedure on the original data using Wilcoxon Sign Test. Results: The main pharmacokinetic parameters of the test drug Profim® (BN: B051A21P-1)/ reference drug, Cefspan® (BN: KCEFB00038) ratio were as follows: AUC0-32h: 105.86 (95.41 - 117.44) with CV Intra Subjects was 22.72% and Cmax: 105.63 (95.33 - 117.03) with CV Intra Subjects was 22.43 %. Whilst TMAX of the test drug Profim® (BN: B051A21P-1)/ reference drug, Cefspan® (BN: KCEFB00038) were respectively 4.50 (3.50 – 6.00) h and 4.50 (3.00 – 6.00) h; mean T1/2 were respectively 4.18 ± 0.78 h and 4.14 ± 0.56 h; and mean Slope were respectively (-0.17) ± 0.03 h and (-0.17) ± 0.02 h. There is no adverse event that occurred during this study. Conclusion: The present study demonstrated that the evaluated test drug Profim® (BN: B051A21P-1) were bioequivalence in term of both rate and extent of absorption to the reference drug Cefspan® (BN: KCEFB00038).

Dynamics of synovitis activity after intraarticular administration of xefocam in patients with rheumatoid arthritis

The aim of the study was to assess the efficacy of intra-articular injection of lornoxicam (xefocam, Nycomed) in patients with rheumatoid arthritis. Xefocam was injected into knee joints of 15 patients with rheumatoid arthritis, 8 mg once a week for the period of 3 weeks. The following parameters were assessed: pronouncement of arthralgia, joint tenderness at palpation, circumference of knee joint on the level of the upper patellar margin. Prior and post treatment ultrasonography and thermography were used. Significant clinical improvement was observed in 11 patients. In 3 cases the dynamics was less positive and in 1 patients the effect of single dose drug injection was preserved for less than one week. Arthralgia manifestation (p0.01), joint tenderness at palpation (p0.01) and joint circumference (p0.05) showed reliable decrease. Ultrasonography showed reliable decrease the synovial membrane thickness. Xefocam injection could be successfully used to suppress moderate inflammatory joint changes in patients with rheumatoid arthritis when there are no strict indications to local steroid therapy.

Single-dose antibiotic therapy for urinary infections during pregnancy: A systematic review and meta-analysis of randomized clinical trials.

During pregnancy, urinary infections are an important cause of maternofetal morbidity and mortality and may lead to several complications. To verify whether the use of antibiotic therapy in a single dose when compared with multiple doses in lower tract urinary infections during pregnancy is effective to obtain microbiologic cure. Online databases were searched. Keywords used were "single-drug dose", "antibiotic", "fosfomycin", "amoxicillin", "trimethoprim", "pregnancy", and "urinary tract infection". Studies were included if they were randomized controlled trials, the population was pregnant woman, microbiologic cure was attained, and one of the treatment groups received single-dose antibiotic therapy. Preselected studies have been independently read by pairs, and data were extracted according to a predetermined sheet. The Cochrane tool was used for the risk of bias. A total of 1063 women from nine studies were included. The primary outcome was the microbiologic cure attested by urine culture. When compared with the multiple-day use of antibiotics, the single-dose treatment has shown statistically similar results in reaching culture cure (odds ratio 1.02, 95% confidence interval 0.73-1.44). The current study has shown that the use of single-dose treatment for lower tract urinary infections during pregnancy can be recommended, especially using fosfomycin. This review has not been registered.