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 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 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

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) for the prevention of heartworm disease (Dirofilaria immitis) in client-owned dogs in the USA

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lisa M. Young ◽  
Scott Wiseman ◽  
Elizabeth Crawley ◽  
Kim Wallace ◽  
Daniel E. Snyder
Keyword(s):  
Field Study ◽  
Mississippi River ◽  
Dirofilaria Immitis ◽  
Drug Product ◽  
Clinical Effectiveness ◽  
Combination Product ◽  
Combination Drug ◽  
Milbemycin Oxime ◽  
Heartworm Disease ◽  
The Usa

Abstract Background Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months. Methods In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75–1.53 mg/kg milbemycin oxime and 20–41.5 mg/kg lotilaner (n = 159) or the CP (Sentinel® Flavor Tabs®; milbemycin oxime/lufenuron) at the label-recommended dose rate (n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott’s) testing to assess the establishment of any patent adult heartworm infections. Results All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs. Conclusions This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis. Graphic Abstract

Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects

2018 ◽  
Vol 40 (4) ◽  
pp. 550-561.e3 ◽  
Author(s):  
Yunona Khomitskaya ◽  
Nadezhda Tikhonova ◽  
Konstantin Gudkov ◽  
Svetlana Erofeeva ◽  
Victoria Holmes ◽  
...  
Keyword(s):  
Extended Release ◽  
Fixed Combination ◽  
Drug Product ◽  
Single Component ◽  
Combination Drug

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.

The behaviour of infective Ancylostoma caninum larvae in serum gradients

1981 ◽  
Vol 55 (3) ◽  
pp. 203-208 ◽  
Author(s):  
M. A. Zietse ◽  
J. C. M. Klaver-Wesseling ◽  
J. C. M. Vetter
Keyword(s):  
Animal Species ◽  
Ancylostoma Caninum ◽  
Infective Larvae

ABSTRACTExperiments were carried out to investigate if sera of animal species other than dog are chemotactically active for infective larvae of Ancyclostoma caninum. Those sera were also found to contain such a factor(s), although the larvae were attracted significantly better by dog serum. How this chemotaxis might be applied to the in vivo situation, when infective A. caninum larvae penetrate the skin of dogs, is discussed.

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