scholarly journals Effectiveness of Credelio® Plus, a novel chewable tablet containing milbemycin oxime and lotilaner for the treatment of larval and immature adult stages of Toxocara canis in experimentally infected dogs

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lisa M. Young ◽  
Scott Wiseman ◽  
Elizabeth Crawley ◽  
Dwight D. Bowman ◽  
Craig R. Reinemeyer ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Toxocara Canis ◽  
Time Frame ◽  
Immature Stage ◽  
Chewable Tablet ◽  
Combination Tablet ◽  
Milbemycin Oxime ◽  
Treatment Groups ◽  
Intestinal Nematode ◽  
Respective Treatment

Abstract Background The ascarid, Toxocara canis, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. An effective treatment that kills any pre-patent stages of immature T. canis could additionally reduce or eliminate the development of patent infections that can result in clinical disease in infected dogs and would further reduce environmental contamination of eggs. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to assess the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus) administered orally to dogs that were experimentally infected with immature (L4 or immature adult [L5]) stages of T. canis. Methods The commercial tablet formulation of Credelio Plus® was administered in a time frame relative to inoculation with infective eggs. This allowed for effectiveness to be assessed against each specific immature stage of T. canis. In each study, dogs were randomized and allocated to one of four treatment groups. Each treatment group contained ten dogs that had been experimentally inoculated on Day 0 with infective T. canis eggs and then were dosed once on Day 14 or Day 24 using either placebo tablets or Credelio Plus tablets (IP) to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 or 6 days after their respective treatment. At necropsy, all nematodes recovered from the gastrointestinal tract were counted by species and stage. Results In both dose confirmation studies using geometric mean worm counts, effectiveness of Credelio Plus was ≥ 98.6% and ≥ 96.8% against L4 larval stage T. canis and immature adult [L5] T. canis in both studies, respectively. Conclusions These studies demonstrated that the Credelio Plus combination tablet administered orally to dogs was highly efficacious against experimental infections with L4 and immature adult [L5] stages of T. canis.

scholarly journals Effectiveness of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the treatment of larval and immature adult stages of Ancylostoma caninum in experimentally infected dogs

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel E. Snyder ◽  
Scott Wiseman ◽  
Elizabeth Crawley ◽  
Kim Wallace ◽  
Dwight D. Bowman ◽  
...  
Keyword(s):  
Drug Product ◽  
Geometric Mean ◽  
Time Frame ◽  
Immature Stage ◽  
Combination Drug ◽  
Ancylostoma Caninum ◽  
Combination Tablet ◽  
Milbemycin Oxime ◽  
Infective Larvae ◽  
Intestinal Nematode

Abstract Background The hookworm, Ancylostoma caninum, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. Both the immature and adult stages of A. caninum ingest large volumes of blood during the feeding process and can cause severe anemia and death in young dogs, even before patent infections can be diagnosed using routine faecal examination methods. Thus, effective treatment of any pre-patent stages of immature hookworms can reduce or eliminate the risk of clinical disease in infected dogs and additionally reduce environmental contamination of eggs and infective larvae. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to evaluate the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus®) administered orally to dogs experimentally infected with immature (L4 and immature adult [L5]) stages of A. caninum. Methods Treatments using the intended global commercial tablet formulation of Credelio Plus were administered in a time frame relative to inoculation with infective larvae so that effectiveness could be assessed against each specific immature stage of A. caninum. In each study, dogs were randomized to one of six (study 1) or four (study 2) treatment groups. Each treatment group contained 8 (study 1) or 10 (study 2) dogs that had been experimentally inoculated with infective A. caninum larvae on day 0 and were dosed once on day 7 or day 11. Enrolled subjects were administered placebo tablets, Credelio Plus tablets, or lotilaner mono tablets to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 days after their respective treatment. All nematodes recovered from the gastrointestinal tract at necropsy were counted by species and stage. Results For both dose confirmation studies and based on geometric mean worm counts, efficacy of Credelio Plus was ≥ 97.3% against L4 larval stage of A. caninum and ≥ 98.7% against immature adult (L5) A. caninum. Conclusions These studies demonstrated that the orally administered Credelio Plus combination tablet was highly efficacious in treating immature (L4 and immature adult [L5]) stages of A. caninum in experimentally infected dogs.

scholarly journals Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural intestinal nematode infections in dogs presented as veterinary patients in Europe

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brad Hayes ◽  
Scott Wiseman ◽  
Daniel E. Snyder
Keyword(s):  
Field Study ◽  
Drug Product ◽  
Geometric Mean ◽  
Animal Health ◽  
Good Clinical Practice ◽  
Toxocara Canis ◽  
New Combination ◽  
Combination Drug ◽  
Milbemycin Oxime ◽  
Faecal Egg Counts

Abstract Background A randomised, blinded, positive controlled, multicentre, Good Clinical Practice-compliant, pivotal field study was conducted to evaluate the effectiveness and safety of a new combination of lotilaner + milbemycin oxime tablets (Credelio® Plus; Elanco Animal Health) administered orally to client-owned dogs naturally infected with intestinal nematodes. Methods Client-owned dogs presenting to veterinary clinics from households in France, Hungary and Germany were screened for intestinal nematodes. Dogs with an initial positive faecal egg count that was subsequently confirmed with a follow-up faecal examination to demonstrate the presence of naturally occurring mixed or mono-infections with Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum were enrolled on Day 0 into the study. Households were randomised in an approximately 2:1 ratio to receive either an investigational product (IP; Credelio Plus tablets) or control product (CP; Nexgard Spectra® tablets) as treatment. Dogs were administered the IP (n = 278) or CP (n = 117) once on Day 0 at a dose rate of 0.75–1.56 mg/kg bodyweight milbemycin oxime and 20.0–41.5 mg/kg bodyweight lotilaner (IP) or as recommended (CP). Effectiveness of the IP and CP treatments was based on the post-treatment reduction in geometric mean faecal egg counts on Day 8 (range Day 7–10) after treatment as compared to their pre-treatment nematode faecal egg counts. Results Geometric mean (GM) faecal egg counts for T. canis, A caninum and T. vulpis were reduced by ≥ 97.2% in the Credelio Plus group and  by ≥ 95.3% in the afoxolaner + milbemycin oxime group. There were insufficient data to calculate a percentage reduction in GM faecal egg counts between Day 0 and Day 8 for T. leonina due to low prevalence. Credelio Plus was well tolerated in this field study. Of the 355 total doses administered, 82.3% were accepted free choice in the IP group compared to 80.8% in the CP group. Conclusions This study demonstrated effectiveness (≥ 97.2% reduction), safety and tablet acceptance of a combination of milbemycin oxime and lotilaner (Credelio Plus) administered orally to dogs with natural intestinal infections of T. canis, A. caninum and T. vulpis.

scholarly journals Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural flea and tick infestations on dogs presented as veterinary patients in Europe

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sophie Forster ◽  
Scott Wiseman ◽  
Daniel E. Snyder
Keyword(s):  
Field Study ◽  
Treatment Time ◽  
Drug Product ◽  
Clinical Signs ◽  
Rhipicephalus Sanguineus ◽  
Time Frame ◽  
Combination Drug ◽  
Combination Tablet ◽  
Milbemycin Oxime ◽  
Pulex Irritans

Abstract Background A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. Methods In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus® tablets) or the control product (CP: Nexgard Spectra® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0–41.5 mg/kg bodyweight lotilaner and 0.75–1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. Results Flea effectiveness of Credelio Plus® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. Conclusions This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus®) administered orally to dogs naturally infested with fleas and/or ticks. Graphic Abstract

Effect of Color Coding on Visually and Verbally Oriented Tests with Students of Different Field Dependence Levels

1992 ◽  
Vol 20 (4) ◽  
pp. 311-320 ◽  
Author(s):  
Francis M. Dwyer ◽  
David M. Moore
Keyword(s):  
Field Dependence ◽  
Information Acquisition ◽  
Color Coding ◽  
Treatment Groups ◽  
Black And White ◽  
Field Dependent ◽  
Different Types ◽  
Respective Treatment ◽  
The Impact ◽  
Instructional Variable

To assess the impact of instructional color coding on visually and verbally oriented tests and on field-dependent-independent subjects, undergraduate college students (119) were randomly assigned to two treatment groups (color—black and white). These subjects received their respective treatment and received four dependent measures measuring four different types of educational objectives. Results indicated that the subject's level of field dependence is an important instructional variable and that color coding is an effective variable for maximizing information acquisition levels for field dependent over oriented subjects.

121 EXPRESSION OF STEROID RECEPTORS IN THE CUMULUS - OOCYTE COMPLEX AROUND OVULATION IN THE BITCH

2014 ◽  
Vol 26 (1) ◽  
pp. 174 ◽  
Author(s):  
M. Z. Tahir ◽  
K. Reynaud ◽  
S. Thoumire ◽  
S. Chastant-Maillard ◽  
M. Saint-Dizier
Keyword(s):  
Oocyte Maturation ◽  
Steroid Receptors ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Cumulus Cells ◽  
Immature Stage ◽  
Mean Value ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Relative Standard

In the bitch, oocytes are ovulated at an immature stage (prophase I) and resume meiosis in the oviduct, 3 to 4 days after ovulation while they are still surrounded by 2 to 3 layers of cumulus cells. Canine cumulus-oocyte complexes (COC) are exposed to high and changing plasma concentrations of 17β-oestradiol (E2) and progesterone (P4) during the periovulatory period. In order to explore whether oocyte maturation may be regulated by steroids in this species, the expression of E2 (ERα, ERβ) and P4 (nuclear: PR; membrane: PGRMC1, PGRMC2, mPRα, mPRβ, mPRγ) receptors was studied in COC at precise times around ovulation. Ovaries were collected from Beagle bitches during anestrus (n = 4), after the beginning of proestrus, and before the LH peak (Pre-LH, n = 7), after the LH peak and before ovulation (Pre-ov, n = 8), and at Day 1 (n = 11) and Day 4 (n = 8) post-ovulation. Anoestrus COC were recovered from follicles smaller than 1 mm in diameter. The COC at the Pre-LH and Pre-ov stages were aspirated from preovulatory follicles (4.5–6 mm in diameter). Such follicular COC were partially denuded to leave the 2 to 3 innermost cumulus layers firmly attached to the zona pellucida. Post-ovulatory COC, naturally surrounded by 2 to 3 cumulus layers, were recovered by oviductal flushing. Total RNA was extracted from 3 batches of 10 COC per stage, then reverse transcribed. The expression of steroid receptors was assessed in duplicate by qPCR (LightCycler® 480, Roche Diagnostics) using the relative standard curve method and normalized by the geometric mean value of the two most stable reference genes (BGLR and RPS5; NormFinder software) chosen among four genes previously tested. Relative amounts of mRNA levels were compared between stages by ANOVA followed, when necessary, by a Tukey test. The ERα and ERβ expression did not vary significantly with the stage. In contrast, a significant variation between stages in nuclear and 4 membrane P4 receptor expression was observed (P < 0.0001 for PR; P < 0.001 for PGRMC1 and mPRβ; P < 0.05 for PGRMC2 and mPRγ). The PR mRNA levels were significantly higher at Pre-ov than at any other stage. PGRMC1 expression was significantly higher at Pre-ov and Day 4 compared with anestrus and Pre-LH, and was at an intermediate level at Day 1. The expression of PGRMC2, mPRβ, and mPRγ remained low from anestrus to Day 1 and increased significantly at Day 4. Lastly, mRNA levels of mPRα were below the detection limit at all stages. This is the first report of steroid receptor expression in canine COC at precise times around ovulation. The stage-specific variation in expression of nuclear and of several membrane P4 receptors around ovulation suggests a role for P4 in canine oocyte maturation. The exact localisation of these receptors in cumulus cells, oocytes, or both remains to be determined.

scholarly journals Efficient model-based bioequivalence testing

Biostatistics ◽  
2020 ◽  
Author(s):  
Kathrin Möllenhoff ◽  
Florence Loingeville ◽  
Julie Bertrand ◽  
Thu Thuy Nguyen ◽  
Satish Sharan ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Area Under The Curve ◽  
European Medicines Agency ◽  
Type I ◽  
Nonlinear Mixed Effects Models ◽  
Type I Errors ◽  
Significance Level ◽  
Treatment Groups ◽  
Model Based ◽  
Bioequivalence Testing

Summary The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable.

scholarly journals Candidate stress biomarkers for queen failure diagnostics

2020 ◽  
Author(s):  
Alison McAfee ◽  
Joseph Milone ◽  
Abigail Chapman ◽  
Leonard J Foster ◽  
Jeffery S Pettis ◽  
...  
Keyword(s):  
Heat Shock ◽  
Pesticide Exposure ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Protein Markers ◽  
Persistent Problem ◽  
Treatment Groups ◽  
Root Cause ◽  
Respective Treatment ◽  
Candidate Protein

AbstractBackgroundQueen failure is a persistent problem in beekeeping operations, but in the absence of overt symptoms it is often difficult, if not impossible, to ascertain the root cause. Stressors like heat-shock, cold-shock, and sublethal pesticide exposure can reduce stored sperm viability and lead to cryptic queen failure. Previously, we suggested candidate protein markers indicating heat-shock in queens, which we investigate further here, and tested new stressors to identify additional candidate protein markers.ResultsWe found that heat-shocking queens for upwards of one hour at 40 °C was necessary to induce significant changes in the two strongest candidate heat-shock markers, and that relative humidity significantly influenced the degree of activation. In blind heat-shock experiments, we tested the efficiency of these markers at assigning queens to their respective treatment groups and found that one marker was sufficient to correctly assign queens 75% of the time. Finally, we compared cold-shocked queens at 4 °C and pesticide-exposed queens to controls to identify candidate markers for these additional stressors, and compared relative abundances of all markers to queens designated as ‘healthy’ and ‘failing’ by beekeepers.ConclusionsThis work offers some of the first steps towards developing molecular diagnostic tools to aid in determining cryptic causes of queen failure. Further work will be necessary to determine how long after the stress event a marker’s expression remains changed and how accurate these could be in the field.

Sexual Behaviour in Male Healthy Rats: A Comparison Between Indian Tribulus terrestris Linn. Extracts with Protodioscin Standardized Bulgarian Extract

2019 ◽  
Vol 9 (1) ◽  
pp. 32-38
Author(s):  
Mohammed Azeemuddin Mukhram ◽  
Mohamed Rafiq ◽  
Neeraj Kumar ◽  
Atul Namdeorao Jadhav ◽  
Suryakanth Dattatray Anturlikar ◽  
...  
Keyword(s):  
Serum Testosterone ◽  
Male Rats ◽  
Tribulus Terrestris ◽  
Mean Values ◽  
Treatment Groups ◽  
Group I ◽  
Significant Difference ◽  
Respective Treatment ◽  
Sex Stimulant ◽  
Ranking Analysis

Background: Tribulus terrestris Linn. (TT) is reported for its ability to improve male sexual performance, and protodioscin is responsible for the activity. This study was designed to correlate and compare various extracts of Indian TT with Bulgarian TT, and also the effect of protodioscin content on the activity. Methods: Bulgarian TT extract (BT) and prepared solvent extracts [aqueous (WIT), supercritical fluid (SIT) and methanol (MIT)] of Indian TT were standardized and compared using UV spectrophotometric method. Forty male rats were randomized into 5 groups of 8 each. Group I served as untreated control and group II to V were treated with 100 mg/Kg b.wt. of MIT, WIT, BT and SIT, respectively. The groups received the respective treatment for fourteen days. Sexual behavior of the rats was observed on Day-1&14. Serum testosterone was estimated after the last observation. Results: It was found that there was a statistically significant difference between the treatment groups. However, based on the mean values/ranking analysis of all the parameters, the order of potency was WIT > SIT &#8805; BT > MIT. Conclusion: These findings indicate that the aqueous extract of Indian TT which contains lesser protodioscin showed comparatively better sex stimulant activity in comparison to the other tested extracts.

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