The safety-net story about macrocyclic lactone heartworm preventives: a review, an update, and recommendations

A number of safe, effective, and convenient heartworm preventatives are currently available for virtually all canine and feline pets. Yet, a 2001 survey of over 18,000 veterinary clinics in the United States identified more than 240,000 dogs and 3000 cats infected with Dirofilaria immitis. This high level of owner compliance failure is alarming. Prolonged administration of some of the macrocyclic lactone (ML) preventatives kills young larvae, older larvae, "immatures," young adults, and/or old adults. Efficacy of 95% or more requires dosing for 9-30 months, with older worms being more difficult to kill. Of the various MLs, ivermectin (IVM) has the most potent safety-net and adulticidal activity, milbemycin oxime has the least, and selamectin and moxidectin injectable lie somewhere in between. The unique effects of IVM are related to the age of the heartworms at initiation of treatment. The earlier treatment is started, the more stunted and smaller the worms and the shorter their survival time. Conversely, the later treatment is started, the longer the worms live, and the more likely the dog will be antigen- and microfilariae-positive. Drug effects do not appear to be enhanced by increasing the dosage or administering at shorter intervals, and it appears that continuous monthly treatment is needed to produce the full effects of the drug. The American Heartworm Society (AHS) recognizes the safety-net (or reach-back effect) and adulticidal properties of some MLs, particularly IVM. The AHS 2003 (American Heartworm Society, 2004. 2003 Updated guidelines for the diagnosis, prevention, and management of heartworm (Dirofilaria immitis) infection in dogs. In: McCall, et al., (Eds.), Proceedings of the Symposium Session on Recent Advances in Heartworm Disease, The 19th International Conference of the World Association for the Advancement of Veterinary Parasitology, New Orleans, LA, 10-14 August, 2003. Vet. Parasitol. 125, 105-130) canine guidelines state that it is beneficial to administer prophylactic doses of IVM before treatment with melarsomine. Results of laboratory studies suggest that less active dogs are at low risk of severe thromboembolism and death. However, heartworm-positive working dogs might be more at risk. Worsened radiographic and echocardiographic images in a client-owned dog given IVM monthly for 2 years with greatly restricted exercise suggests that such treatment of dogs with clinical, radiographic, and/or echocardiographic evidence of heartworm disease as well as for asymptomatic working dogs is contraindicated. Furthermore, until further data are available, such treatment of even the less active asymptomatic dog should be administered only with much caution and with examination by a veterinarian at least once every 4-6 months. IVM clearly provides potent "safety-net" activity against older larvae, immatures, and young adults in cases of owner compliance failure, even when the owner and veterinarian are not aware that the animal is infected, and offers much promise as a unique "soft-kill" treatment for young, and possibly older adult heartworms, with reduced risks.     

Scintigraphic evaluation of pulmonary perfusion in dogs experimentally infected with Dirofilaria immitis

Pulmonary arterial perfusion was evaluated by perfusion lung scans in ten dogs experimentally infected with heartworm. After larval inoculation, scans were done once a month for 11 months. In 8 of 10 dogs, pulmonary arterial perfusion deficits were detected. The perfusion deficits involved the left cranial, right cranial, and right caudal lung lobes. Generally, there was a poor correlation between vascular abnormalities detected on the survey thoracic radiographs and the perfusion deficits detected by lung scanning. The perfusion deficits did not produce clinical signs or pulmonary infarction.     

Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats

The present study characterizes the safety, pharmacokinetics, and anti-emetic effects of the selective NK-1 receptor antagonist maropitant in the cat. Safety of maropitant was determined following 15 days of subcutaneous (SC) administration at 0.5–5 mg/kg. Maropitant was well tolerated in cats at doses that exceeded the efficacious anti-emetic dose range of the drug by at least a factor of 10 and adverse clinical signs or pathological safety findings were not noted at any dose.The pharmacokinetics of maropitant in cats were determined following single dose oral (PO), intravenous (IV) and SC administration. Maropitant had a terminal half-life of 13–17 h and a bioavailability of 50 and 117% when administered PO and SC, respectively. Efficacy was determined against emesis induced either by xylazine or by motion. A dosage of 1 mg/kg maropitant administered IV, SC or PO prevented emesis elicited by xylazine. The compound had good oral antiemetic activity and a long (24 h) duration of action. Maropitant (1.0 mg/kg) was highly effective in preventing motion-induced emesis in cats. These studies indicate that the NK-1 receptor antagonist maropitant is well tolerated, safe and has excellent anti-emetic properties in cats.     

Effects of Interferon‐Tau and Steroids on Cytochrome P450 Activity in Bovine Endometrial Epithelial Cells

The objective of the current study was to examine cyclooxygenase (COX), cytochrome P450 1A (CYP1A) and 2C (CYP2C) activity in bovine endometrial cell cultures following exposure to oxytocin (OT), interferon‐τ (IFN), estradiol (E2) and/or progesterone (P4). Bovine endometrial epithelial cells were treated with OT, IFN, a combination of OT+IFN or control (CON) media for 24 h. For the second experiment, cells were treated with E2, P4, a combination of E2 + P4 or CON media for 24 h. Treatments were performed in triplicate, and the experiment was repeated four times (n = 12 per treatment). Treatment with OT alone increased (p < 0.01) activity of COX compared with CON; however, OT alone did not alter activity of CYP1A (p = 0.55) or CYP2C (p = 0.46) compared with CON. Activity of CYP1A and CYP2C was decreased in cells exposed to IFN (p < 0.01) or OT+IFN (p < 0.01) compared with CON. Treatment with E2 alone did not alter activity of CYP1A (p = 0.64) or CYP2C (p = 0.06) compared with CON. Activity of CYP1A and CYP2C was decreased (p < 0.01) in P4 vs CON. In summary, IFN exposure, irrespective of OT treatment, decreased the activity of CYP1A and CYP2C. Activity of CYP1A was decreased following P4 treatment alone, while that of CYP2C was decreased following both P4 and E2 + P4 treatment. The mixed function monooxygenase enzymes, CYP1A and CYP2C, have been implicated in synthesizing embryotoxic compounds; therefore, downregulation in the endometrium may be necessary during maternal recognition of pregnancy.     

Nutrient disorders of Dianthus ‘Bouquet Purple’

‘Bouquet Purple’ pinks (Dianthus sp.) were grown in silica-sand culture to induce and photograph symptoms of nutritional disorders. Plants received a complete modified Hoagland's all-nitrate (NO₃) solution. Nutrient-deficient treatments were induced with a complete nutrient formula minus one of the nutrients, and a boron (B)-toxicity treatment was induced by increasing B 10-fold in the complete nutrient formula. Plants were monitored daily to document sequential series of symptoms as they developed. Typical symptomology of nutrient disorders and corresponding tissue concentrations were determined. All treatments exhibited deficiency symptomology. Disorders for nitrogen (N), iron (Fe), calcium (Ca), and sulfur (S) were the first to manifest in pinks. Unique symptomology was observed for plants grown under potassium- (K), B-, copper- (Cu), and molybdenum- (Mo) deficient conditions, which supported the need for a species-specific approach when characterizing nutrient disorders of floriculture crops.     

Comparison of major and trace element concentrations in Danish greenhouse tomatoes (Lycopersicon esculentum Cv. Aromata F1) cultivated in different substrates

The concentration of major and trace elements was determined for tomato (Lycopersicon esculentumcv. Aromata F1) fruits grown in three different substrate systems. The systems were soil and rockwool irrigated with a normal nutrient solution and rockwool irrigated with a nutrient solution with elevated electrical conductivity (EC). At three harvest times, tomato fruits were analyzed for Ca, Cu, Fe, K, Mg, Mn, Na, P, S, Sr, and Zn by ICP-AES and for Cd, Cr, Mo, Ni, Pb, Sn, and V by HR-ICPMS. The concentrations of Ca, Cd, Fe, Mn, Mo, Na, Ni, Sr, and Zn were significantly different (p < 0.05) for tomato fruits grown on the different substrates. Between the harvest times different levels (p < 0.05) were shown for Ca, Cd, Fe, Mn Na, Ni, Sr, Zn Cu, K, Mg, P, Sn, and V. The concentration of Cd was >15 times higher and the concentration of Ca was 50-115% higher in soil-grown fruits than in rockwool-grown fruits. Principal component analysis applied on each harvest split the data into two groups. One group includes soil-grown fruits, and the other group includes rockwool-grown fruits with the two different nutrient solutions.     

A survey of veterinarians’ knowledge,attitudes and practices regarding an emerging disease: Coccidioidomycosis in Washington State

Coccidioides immitis is an emerging fungal pathogen in Washington State (WA). While the geographical boundaries of C. immitis in WA have not been well characterized, human infections have resulted from exposure in the south‐central region of the state. Since 2010, only one dog has been identified as a probable locally acquired animal case, despite pilot canine serological surveys from south‐central WA revealing a 9.8% seroprevalence. On the suspicion that clinical animal cases may be underdiagnosed and/or underreported, we assessed WA veterinarians’ knowledge, attitudes and practices regarding coccidioidomycosis. All veterinarians with active licenses in WA were invited to complete a self‐administered, web‐based survey from November 2018 to January 2019. Four hundred and twenty‐five of 2,211 (19.2%) veterinarians returned the survey and were eligible for inclusion in the final analysis. Nearly, all respondents (98.8%) had heard of coccidioidomycosis, but only 31.5% and 25.6% knew that locally acquired animal and human cases, respectively, had been reported in WA. Only half (52.6%) of participants knew that the disease was reportable. Fewer than 20% of respondents reported confidence that their knowledge of coccidioidomycosis was up to date, and 76.9% “never” or “rarely” considered the risk of disease in their patients. A statistically significant predictor of a high knowledge score (≥70%), however, included practicing in endemic counties where the Washington State Department of Health had previously delivered outreach and education services. While the results suggest some success with these activities, it is clear that information on the emergence of coccidioidomycosis is not adequately reaching veterinary practitioners in WA. The data support that more frequent CE opportunities, and dissemination of public health communications through veterinary‐specific modalities, would help fill the knowledge gap. In turn, improved diagnosis and reporting of animal cases would assist in our overall understanding the epidemiology of coccidioidomycosis in WA.     

The ability of a topical novel combination of fipronil, amitraz and (S)-methoprene to protect dogs from Borrelia burgdorferi and Anaplasma phagocytophilum infections transmitted by Ixodes scapularis

Healthy, purpose-bred laboratory beagle dogs that had not been exposed to ticks and were seronegative for Borrelia burgdorferi and Anaplasma phagocytophilum were randomly assigned to four groups of eight dogs each. Control group 1 was not treated. Groups 2, 3 and 4 were treated with a single topical application of a new formulation of fipronil, amitraz and (S)-methoprene (CERTIFECT?, Merial Limited, GA, USA) at 28, 21 or 14 days prior to tick infestation, respectively. Each dog was infested with 25 female and 25 male field-collected adult Ixodes scapularis ticks that had infection rates of 66% for B. burgdorferi sensu stricto and 23% for A. phagocytophilum, as determined by polymerase chain reaction. Two and five days after tick infestation, control dogs had an average of 9.5 and 13.9 attached adult female ticks, respectively, whilst the 24 treated dogs remained tick-free aside from a single tick on the 2nd day after infestation. Serial serological tests demonstrated that the ticks successfully infected 8/8 control dogs with B. burgdorferi and co-infected 6/8 with A. phagocytophilum. B. burgdorferi infection also was confirmed in most control dogs by culture (6/8) and PCR (7/8) of skin biopsies. In contrast, CERTIFECT protected all 24 treated dogs against infection by both B. burgdorferi and A. phagocytophilum, as demonstrated by their negative serological tests throughout the study and the absence of any positive skin biopsy culture or PCR in these dogs.