Systemic Hypersensitivity

Pieters, Raymond

doi:10.1002/9780470386385.ch19

Cited by 3 publications

(3 citation statements)

References 73 publications

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“…The increased size was decided as follows. From pharmacovigilance reporting of PH 6, a closely related product, between 2008–2016, the estimated incidence of hypersensitivity-related reactions was approximately two dogs per 10,000 doses distributed [26], which is in line with estimates for many marketed human pharmaceuticals [27]. Mathematical simulations based on that estimate showed that in a prospective study, group sizes capable of providing statistically significant estimates of incidence (e.g.…”

Section: Discussionmentioning

confidence: 69%

“…Regarding the origin of hypersensitivity related responses, none of the findings in literature or any of the in vivo , in vitro or chemical approaches were helpful. A pharmacovigilance-based estimated incidence of around two hypersensitivity-related cases (combined anaphylaxis and anaphylactoid, the latter much more common) per 10,000 doses distributed is in line with other marketed products in human medicine [27]. In the study of McTier et al [1] where PH 12 was compared with an orally administered ivermectin-pyrantel control, there were three mild to moderate anaphylactoid responses observed; one in the positive control product and two in the PH 12 group.…”

Section: Discussionmentioning

confidence: 78%

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Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs

et al. 2019

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Background The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. Methods Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. Results Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045–37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. Conclusions PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 78%

Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs

et al. 2019

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“…Although several hypotheses, such as the hapten hypothesis (7), the p-i hypothesis (8), and the danger hypothesis (9), have been proposed to explain how LMW drugs can mechanistically induce a drug-specific T cell response, predicting these reactions has proven difficult because of the knowledge gaps in understanding the risk factors. Further complicating matters, these mechanistic hypotheses are not mutually exclusive, and some drugs can induce drug-specific T cell responses by more than one mechanism (10).…”

Section: Allergic Reactionsmentioning

confidence: 99%

Nonclinical Tools to Assess Risk of Drug Hypersensitivity Reactions

Whritenour

Casinghino

Collinge

et al. 2016

Annu. Rev. Pharmacol. Toxicol.

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The term drug hypersensitivity refers to a category of adverse drug reactions mediated by various immunological and nonimmunological mechanisms. Small-molecule drugs and biotherapeutics have been associated with drug hypersensitivity reactions (DHRs), and the mechanisms driving the responses vary. Depending on the mechanism, some DHRs may be detected in nonclinical toxicology studies, and there may be tools and models in place that can be used as part of a risk assessment strategy. In contrast, for other mechanisms, particularly those that are not readily detected during nonclinical development, predictive tools and strategies for risk assessment are not well defined. This chapter provides an overview of the nonclinical tools currently available to assess the risk for developing DHRs.

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Immunotoxicology

Burns‐Naas¹,

Pallardy²

2013

Nonclinical Safety Assessment

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Systemic Hypersensitivity

Cited by 3 publications

References 73 publications

Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs

Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs

Nonclinical Tools to Assess Risk of Drug Hypersensitivity Reactions

Immunotoxicology

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