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

scholarly journals Laboratory and field studies to investigate the efficacy of a novel, orally administered combination product containing moxidectin, sarolaner and pyrantel for the prevention of heartworm disease (Dirofilaria immitis) in dogs

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Kristina Kryda ◽  
Robert H. Six ◽  
Kelly F. Walsh ◽  
Susan J. Holzmer ◽  
Sara Chapin ◽  
...  
Keyword(s):  
Field Study ◽  
Mississippi River ◽  
Dirofilaria Immitis ◽  
Field Studies ◽  
Combination Product ◽  
Laboratory Studies ◽  
Chewable Tablet ◽  
Heartworm Disease ◽  
Heartworm Infection ◽  
Lower Mississippi River

Abstract Background Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. Methods In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24–48 µg/kg moxidectin, 2–4 mg/kg sarolaner and 5–10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. Results In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20–44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. Conclusions In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.

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

The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis.

Parasitology ◽  
2015 ◽  
Vol 142 (10) ◽  
pp. 1249-1259 ◽  
Author(s):  
ADRIAN J. WOLSTENHOLME ◽  
CHRISTOPHER C. EVANS ◽  
PABLO D. JIMENEZ ◽  
ANDREW R. MOORHEAD
Keyword(s):  
Dirofilaria Immitis ◽  
Severe Disease ◽  
Mild Disease ◽  
Wild Canids ◽  
Heartworm Disease ◽  
Macrocyclic Lactone Resistance ◽  
The Face ◽  
The Usa ◽  
Clinical Consequences

SUMMARYPrevention of heartworm disease caused by Dirofilaria immitis in domestic dogs and cats relies on a single drug class, the macrocyclic lactones (MLs). Recently, it has been demonstrated that ML-resistant D. immitis are circulating in the Mississippi Delta region of the USA, but the prevalence and impact of these resistant parasites remains unknown. We review published studies that demonstrated resistance in D.immitis, along with our current understanding of its mechanisms. Efforts to develop in vitro tests for resistance have not yet yielded a suitable assay, so testing infected animals for microfilariae that persist in the face of ML treatment may be the best current option. Since the vast majority of D. immitis populations continue to be drug-sensitive, protected dogs are likely to be infected with only a few parasites and experience relatively mild disease. In cats, infection with small numbers of worms can cause severe disease and so the clinical consequences of drug resistance may be more severe. Since melarsomine dihydrochloride, the drug used to remove adult worms, is not an ML, the ML-resistance should have no impact on our ability to treat diseased animals. A large refugium of heartworms that are not exposed to drugs exists in unprotected dogs and in wild canids, which may limit the development and spread of resistance alleles.

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 Comparison of Recreational Fish Consumption Advisories Across the USA

2021 ◽  
Author(s):  
Brittany M. Cleary ◽  
Megan E. Romano ◽  
Celia Y. Chen ◽  
Wendy Heiger-Bernays ◽  
Kathryn A. Crawford
Keyword(s):  
Mississippi River ◽  
Fish Consumption ◽  
Lake Michigan ◽  
Acute Tolerance ◽  
Health Goals ◽  
Fish Consumption Advisories ◽  
Regional Collaboration ◽  
Slope Factor ◽  
The Usa ◽  
Lower Mississippi River

Abstract Purpose of Review Our comparative analysis sought to understand the factors which drive differences in fish consumption advisories across the USA — including exposure scenarios (acute and chronic health risk, non-cancer and cancer health endpoints), toxicity values (reference dose, cancer slope factor, acute tolerance level), and meal size and bodyweight assumptions. Recent Findings Fish consumption provides essential nutrients but also results in exposure to contaminants such as PCBs and methylmercury. To protect consumers from the risks of fish contaminants, fish consumption advisories are established, most often by state jurisdictions, to estimate the amount of a certain fish species a person could consume throughout their lifetime without harm. However, inconsistencies in advisories across the USA confuse consumers and undermine the public health goals of fish advisory programs. To date, no rigorous comparison of state and national fish consumption advisories has been reported. Summary Our work identifies discrepancies in key assumptions used to derive risk-based advisories between US states, reflecting differences in the interpretation of toxicity science. We also address the implications for these differences by reviewing advisories issued by contiguous states bordering two waterbodies: Lake Michigan and the Lower Mississippi River. Our findings highlight the importance of regional collaboration when issuing advisories, so that consumers of self-caught fish are equipped with clear knowledge to make decisions to protect their health.

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

Survival of fish passing downstream at a small hydropower facility

2018 ◽  
Vol 69 (12) ◽  
pp. 1870 ◽  
Author(s):  
Stephen V. Amaral ◽  
Benjamin S. Coleman ◽  
Jenna L. Rackovan ◽  
Kelly Withers ◽  
Benjamin Mater
Keyword(s):  
Mississippi River ◽  
River Flow ◽  
Survival Rates ◽  
Fish Populations ◽  
Negative Effects ◽  
Small Hydropower ◽  
The Usa ◽  
Pass Through ◽  
Hydro Project ◽  
Total Project

Hydropower dams can negatively affect upstream and downstream migratory fish populations in many ways, such as blocking access to upstream habitats and causing injuries or mortality during downstream passage. For downstream passage at projects in the USA, federal regulators and agencies responsible for oversight of hydropower facilities typically require assessment studies and mitigation to address negative effects, with a primary goal of minimising fish impingement and turbine entrainment and mortality. So as to assess the effects of downstream passage of fish populations at a unique, small hydro project on the Mississippi River, impingement and entrainment rates, Oberymeyer gate passage, spillway gate passage, turbine survival, and total downstream passage survival were estimated. It was determined that 85% of fish passing downstream at the project would be small enough to pass through the bar spacing of the trash racks and 15% would be physically excluded. When 55% of river flow enters the turbine intake channel, the total project survival rates were estimated to be 77.3% with an Obermeyer gate bypass rate of 10 and 96.6% with a gate bypass rate of 90%. Therefore, any effects on local fish populations resulting from the operation of the project are expected to be negligible and inconsequential on the basis of expected survival rates for the range and probability of river flows occurring at the project.

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