scholarly journals Comparative Pharmacokinetics of Azithromycin in Serum and White Blood Cells of Healthy Subjects Receiving a Single-Dose Extended-Release Regimen versus a 3-Day Immediate-Release Regimen

2006 ◽  
Vol 51 (1) ◽  
pp. 103-109 ◽  
Author(s):  
Ping Liu ◽  
Hameed Allaudeen ◽  
Richa Chandra ◽  
Kem Phillips ◽  
Arvid Jungnik ◽  
...  
Keyword(s):  
Single Dose ◽  
Blood Cells ◽  
Dose Regimen ◽  
Extended Release ◽  
Drug Exposure ◽  
White Blood Cells ◽  
Area Under The Curve ◽  
Immediate Release ◽  
Mononuclear Leukocytes ◽  
Open Label

ABSTRACT The pharmacokinetic profiles of azithromycin given as a single-dose regimen (2.0-g extended-release microspheres) were characterized in serum and white blood cells (WBC) and compared with those of a 3-day regimen (a 500-mg immediate-release tablet once daily; total dose, 1.5 g) in an open-label, randomized, parallel-group study of 24 healthy adult subjects. Serial blood samples were collected up to 5 days after the start of dosing for both regimens. Safety assessments were conducted throughout the study. A single 2.0-g dose of azithromycin microspheres achieved significantly higher exposures in serum and WBC during the first 24 h after the start of dosing than a 3-day regimen: an approximately threefold higher area under the curve from time zero to 24 h postdose (AUC0-24) and an approximately twofold higher mean peak concentration on day 1. The single-dose regimen provided total azithromycin exposures in serum and WBC similar to those of the 3-day regimen, as evidenced by the similar AUC0-120 and trough azithromycin concentrations in serum and WBC (mononuclear leukocytes [MNL] and polymorphonuclear leukocytes [PMNL]). For both regimens, the average total azithromycin exposures in MNL and PMNL were approximately 300- and 600-fold higher than those in serum. Azithromycin concentrations in MNL and PMNL remained above 10 μg/ml for at least 5 days after the start of dosing for both regimens. This “front-loading” of the dose on day 1 is safely achieved by the extended-release microsphere formulation, which maximizes the drug exposure at the time when the bacterial burden is likely to be highest.

scholarly journals The relative bioavailability of two formulations containing 10 mg Dapagliflozin assessed under fasting conditions in a randomized crossover study in healthy Caucasian subjects

2020 ◽  
Vol 66 (1) ◽  
pp. 30-34
Author(s):  
Monica Oroian ◽  
Diana Ioana Pop ◽  
Ana-Maria Gheldiu ◽  
Sandeep Bhardwaj ◽  
Adriana Marcovici ◽  
...  
Keyword(s):  
Single Dose ◽  
Reference Product ◽  
Area Under The Curve ◽  
Immediate Release ◽  
Relative Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Pharmaceutical Industries

AbstractObjective: The aim of the present study was to evaluate the relative bioavailability of two formulations containing 10 mg dapagliflozin in healthy Caucasian subjects under fasting conditions.Materials and Methods: Forty-eight healthy Caucasian subjects were enrolled in a single-dose, crossover, balanced, open label, randomized clinical trial, with two treatment, two periods and two sequences. The wash-out period was of 7 days and thirty-eight subjects completed both study periods. Each subject received a single dose of 10 mg dapagliflozin as the reference product Farxiga® (AstraZeneca Pharmaceuticals LP, USA) and the test product developed by Sun Pharmaceutical Industries, India. Dapagliflozin plasma levels were determined from blood samples collected in both study periods before and after dosing until 48 hours by using a validated LC-MS/MS method. For pharmacokinetic analysis of data, the non-compartmental method was used (Phoenix® WinNonlin 6.3). The statistical analysis was performed by SAS software 9.1.3 for the logarithmically transformed values of maximum plasma concentration and area under the curve.Results: The 90% confidence intervals for the evaluated pharmacokinetic parameters were found to be in the accepted interval for bioequivalence (80.00-125.00%).Conclusion: The 10 mg dapagliflozin immediate release tablet newly developed by Sun Pharmaceutical Industries, India, is bioequivalent with the reference product Farxiga® under fasted state of the subjects.

scholarly journals 833 A scalable deep learning framework for rapid automated annotation of histologic and morphologic features from large unlabeled pan-cancer H&E datasets

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A874-A874
Author(s):  
David Soong ◽  
David Soong ◽  
David Soong ◽  
Anantharaman Muthuswamy ◽  
Clifton Drew ◽  
...  
Keyword(s):  
Neural Network ◽  
Deep Learning ◽  
Solid Tumor ◽  
Blood Cells ◽  
White Blood Cells ◽  
Digital Pathology ◽  
Area Under The Curve ◽  
Morphological Characteristics ◽  
Learning Framework ◽  
Tumor Types

BackgroundRecent advances in machine learning and digital pathology have enabled a variety of applications including predicting tumor grade and genetic subtypes, quantifying the tumor microenvironment (TME), and identifying prognostic morphological features from H&E whole slide images (WSI). These supervised deep learning models require large quantities of images manually annotated with cellular- and tissue-level details by pathologists, which limits scale and generalizability across cancer types and imaging platforms. Here we propose a semi-supervised deep learning framework that automatically annotates biologically relevant image content from hundreds of solid tumor WSI with minimal pathologist intervention, thus improving quality and speed of analytical workflows aimed at deriving clinically relevant features.MethodsThe dataset consisted of >200 H&E images across >10 solid tumor types (e.g. breast, lung, colorectal, cervical, and urothelial cancers) from advanced disease patients. WSI were first partitioned into small tiles of 128μm for feature extraction using a 50-layer convolutional neural network pre-trained on the ImageNet database. Dimensionality reduction and unsupervised clustering were applied to the resultant embeddings and image clusters were identified with enriched histological and morphological characteristics. A random subset of representative tiles (<0.5% of whole slide tissue areas) from these distinct image clusters was manually reviewed by pathologists and assigned to eight histological and morphological categories: tumor, stroma/connective tissue, necrotic cells, lymphocytes, red blood cells, white blood cells, normal tissue and glass/background. This dataset allowed the development of a multi-label deep neural network to segment morphologically distinct regions and detect/quantify histopathological features in WSI.ResultsAs representative image tiles within each image cluster were morphologically similar, expert pathologists were able to assign annotations to multiple images in parallel, effectively at 150 images/hour. Five-fold cross-validation showed average prediction accuracy of 0.93 [0.8–1.0] and area under the curve of 0.90 [0.8–1.0] over the eight image categories. As an extension of this classifier framework, all whole slide H&E images were segmented and composite lymphocyte, stromal, and necrotic content per patient tumor was derived and correlated with estimates by pathologists (p<0.05).ConclusionsA novel and scalable deep learning framework for annotating and learning H&E features from a large unlabeled WSI dataset across tumor types was developed. This automated approach accurately identified distinct histomorphological features, with significantly reduced labeling time and effort required for pathologists. Further, this classifier framework was extended to annotate regions enriched in lymphocytes, stromal, and necrotic cells – important TME contexture with clinical relevance for patient prognosis and treatment decisions.

Efficacy of a Single Dose versus a Multiple Dose Regimen of Mebendazole against Hookworm Infections among School Children: a Randomized Open-label Trial

2020 ◽  
Author(s):  
Tegegne Eshetu ◽  
Mulugeta Aemero ◽  
Ayalew Jejaw
Keyword(s):  
Single Dose ◽  
Dose Regimen ◽  
Multiple Dose ◽  
Open Label ◽  
Preventive Chemotherapy ◽  
Dose Treatment ◽  
School Aged Children ◽  
Multiple Dose Regimen ◽  
Hookworm Infections

Abstract Background: Despite the existence of a population-based control program using single dose albendazole or mebendazole as a preventive chemotherapy, hookworm transmission remains high. It causes a negative impact on the growth and school performance of children. In connection to this preventive chemotherapy, different studies produced conflicting results. This study aimed at evaluating the efficacy of single (500mg) versus multiple doses (100mg twice a day during three consecutive days) of mebendazole against hookworm infections among school-aged children. Methods: This randomized open-label clinical trial took place among school-aged children (6-14 years old) in Burie and Debre Elias towns, Northwest Ethiopia. Using simple randomization, eligible hookworm-positive children were allocated (1:1) to either a single or multiple dose treatment arms. Stool samples were collected and processed using McMaster method at baseline and follow-up period (14-21 days after treatment). Only laboratory technicians were blinded. The cure and egg reduction rates which were assessed after 14-21 days of treatment were the primary and secondary therapeutic outcome measures against hookworm infections, respectively. An independent t-test was used to compare group means, and logistic regression was used to calculate odds ratio (OR). P-value < 0.05 at 95% CI was considered statistically significant. Result: 108 children, 54 in each treatment arm had completed baseline data and received allocated treatment. 103 children had completed follow-up data records and included for the final efficacy analysis. Cure rate against hookworm was significantly higher in the multiple dose (96.1%) than in the single dose (30.8%) with OR=55.125; 95% CI: 11.92-254.9; P < 0.001. The egg reduction rate in the multiple dose treatment arm (99.5%) was also significantly higher than in the single dose arm (68.9%) with difference t (101) =5.38; 95% CI 230.95-505.36; P < 0.001. Conclusion: The single dose regimen of mebendazole for the treatment of hookworm infections showed poor cure and egg reduction rates, while the multiple dose revealed satisfactory. Although multiple dose regimen administration is a bit more complex than the single dose, we strongly encourage replacing it with multiple dose regimen during deworming programs in hookworm endemic areas. Trial registration: This trial is registered in www.pactr.org, # PACTR201911466695052.

Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation

2009 ◽  
Vol 102 (09) ◽  
pp. 538-543 ◽  
Author(s):  
Elena Sabaeva ◽  
Christopher Booze ◽  
Oliver D. Atar ◽  
Christian Eisert ◽  
Dan Hanley ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Blood Cells ◽  
Extended Release ◽  
White Blood Cells ◽  
Background Level ◽  
Blood Components ◽  
Stroke Patients ◽  
Antithrombotic Agent ◽  
Release Formulation ◽  
Post Stroke

SummaryExtended release dipyridamole (ERD) is widely used in patients after ischaemic stroke; however, the ability of this antithrombotic agent to be stored in different blood cells has never been explored in post-stroke patients. We hypothesised that since ERD is known to be highly lipophilic, the drug may be present not only in plasma, but also accumulated in platelets, leukocytes, and erythrocytes. Fifteen patients after documented ischaemic stroke were treated with Aggrenox (ERD and lowdose aspirin combination) BID for 30 days, and 12 of them completed the study. ERD concentrations in blood cells and platelet-poor plasma were measured by spectrofluorimetry at Baseline, Day 14, and Day 30 after the initiation of therapy. The background level of spectrofluorometry readings differs slightly among the blood components (132–211 ng/ml) due to the differences in the preparation of samples and cell isolation techniques. As expected, two weeks of ERD therapy produced steady-state plasma concentration of dipyridamole already at Day 14 (1,680 ±542 ng/ ml), followed by a slight not significant decrease at one month (1,619 ±408 ng/ml). Two weeks of therapy was sufficient to achieve a consistent dipyridamole accumulation in erythrocytes (361 ±43 ng/ml), but not in platelets (244 ±78 ng/ml), or leukocytes (275 ±49 ng/ml).In fact, white blood cells continued dipyridamole intake beyond 14 days period, and this increase (398 ± 66 ng/ml) was significant (p = 0.02) at 30 days. Treatment with ERD in post-stroke patients resulted not only in achievement of therapeutic plasma dipyridamole concentrations, but also deposition of the drug in erythrocytes and leukocytes, but not in platelets. If confirmed, these data will affect our better understanding of dipyridamole pleiotropy, and may explain long-term benefit of ERD formulation.

scholarly journals 81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 216-216
Author(s):  
Steve Caras ◽  
Terrilyn Sharpe
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Peak Concentration ◽  
Immediate Release ◽  
Open Label ◽  
Time Curve ◽  
Time To Peak ◽  
Amphetamine Sulfate ◽  
Quantifiable Concentration ◽  
Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

Pharmacokinetic and Tolerability Comparison of Sustained and Immediate Release Oral Formulations of Nifedipine Tablet Formulations: A Single-Dose, Randomized, Open-Label, Two-Period, Two-Way Crossover Study in Healthy, Fasting Egyptian Male Volunteers

Drug Research ◽  
2019 ◽  
Vol 70 (02/03) ◽  
pp. 91-96
Author(s):  
Soha Mahmoud El-Masry ◽  
Noha Mahmoud El-Khodary
Keyword(s):  
Single Dose ◽  
Plasma Concentrations ◽  
Immediate Release ◽  
Reversed Phase ◽  
Channel Blockers ◽  
Open Label ◽  
Release Formulation ◽  
Chromatography Method ◽  
Significant Difference ◽  
Liquid Chromatography Method

AbstractNifedipine is one of calcium channel blockers that commonly used clinically to treat hypertension and angina in Egyptian patients. A sustained-release (SR) formulation of nifedipine is available in the Egyptian community and administered twice daily. This study aimed to to compare the pharmacokinetics and safety profiles of a 20 mg SR and IR (immediate release) formulation of nifedipine after single-dose administration in healthy Egyptian subjects. Randomized, crossed open-label two- way clinical trial, in 16 healthy adult volunteers, of 24.75±5.20 years, with BMI 23.26±1.756 were assessed. Blood samples were collected at predefined times for 48 h and analyzed for Nifedipine plasma concentrations using validated reversed phase liquid chromatography method with ultraviolet detection. Pharmacokinetics was determined using non- compartmental model pharmacokinetics and analyzed using one-way ANOVA (P≤0.05). Following a single oral administration, SR formulation had a lower Cmax, compared to IR formulation (54.46±17.75 , 107.45±29.85 ng/mL, respectively), and Tmax was significantly longer (2.97 vs. 1.13 h) for the SR and IR formulation, respectively. There was no significant difference between the SR and the IR formulations for AUC0–last and AUC0-∞ (326.7±98.28 vs. 309.27±105.53 ng·h·mL−1 and 380.9 ± 105.24 vs. 334.36±108.1 ng·h·mL−1, respectively). SR formulation of nifedipine showed similar pharmacokinetics to the IR Formulation (F%=1.049), but it additionally allows a less frequent administration. Therefore, The nifedipine SR and IR formulations were well tolerated and displayed comparable safety profiles.

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