Administration of spruce bark (Picea abies) extracts in young lambs exhibits anticoccidial effects but reduces milk intake and body weight gain.

BACKGROUND: Eimeria spp. are widespread apicomplexan parasites known to cause coccidiosis in livestock, resulting in reduced animal welfare and productivity, particularly in sheep. The treatment options are limited, and there is an emerging development of resistance against registered pharmaceuticals. Spruce bark is rich in plant secondary metabolites (PSM), such as condensed tannins, which are bioactive compounds previously shown to have antiparasitic activity. Here, we examined the anticoccidial properties of bark extract of Norway spruce (Picea abies) against a field isolate of ovine Eimeria spp. by treating Eimeria-infected pre-ruminant lambs with water-extracted bark daily for 12 days. We hypothesised that the bark extract would reduce the faecal oocyst excretion and, consequently, the severity of diarrhoea. RESULTS: Oral administration of spruce bark extract significantly reduced the excretion of Eimeria oocysts in milk-fed lambs post treatment till the end of the trial 22 days post infection. This difference in oocyst excretion between the treated and the untreated infected animals increased with time. Compared to the untreated and the sham-infected control group, the group treated with bark extract had softer faeces and reduced milk intake during the treatment period. After discontinuing the treatment, the treated animals got a more solid and formed faeces compared to that of the untreated control group, and the milk intake increased to the level of the sham-infected, untreated control group. The bark extract treated animals had a lower body weight and a lower mean daily body weight gain throughout the whole duration of the experiment. CONCLUSIONS: Bark extract from Norway spruce showed marked anticoccidial properties by reducing the faecal oocyst count and associated diarrhoea in young lambs. Simultaneously we experienced detrimental effects of the treatment, displayed as reduced feed intake and daily body weight gain. Therefore, we suggest conducting similar studies with lower bark extract dosage to explore the possibilities of a better trade-off to reduce the negative impact while maintaining the antiparasitic effect.

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics.

This review is a summary of factors affecting the drug pharmacokinetics (PK) of dogs versus humans. Identifying these interspecies differences can facilitate canine-human PK extrapolations while providing mechanistic insights into species-specific drug in vivo behavior. Such a cross-cutting perspective can be particularly useful when developing therapeutics targeting diseases shared between the two species such as cancer, diabetes, cognitive dysfunction, and inflammatory bowel disease. Furthermore, recognizing these differences also supports a reverse PK extrapolations from humans to dogs. To appreciate the canine-human differences that can affect drug absorption, distribution, metabolism, and elimination, this review provides a comparison of the physiology, drug transporter/enzyme location, abundance, activity, and specificity between dogs and humans. Supplemental material provides an in-depth discussion of certain topics, offering additional critical points to consider. Based upon an assessment of available state-of-the-art information, data gaps were identified. The hope is that this manuscript will encourage the research needed to support an understanding of similarities and differences in human versus canine drug PK.

Repurposing the Veterinary Antiprotozoal Drug Ronidazole for the Treatment of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is a principal cause of hospital-acquired infections and fatalities worldwide. The need for new, more potent anticlostridial agents is far from being met. Drug repurposing can be utilized as a rapid and cost-efficient method of drug development. The current study was conducted to evaluate the activity of ronidazole, a veterinary antiprotozoal drug, as a potential treatment for CDI. Ronidazole inhibited the growth of clinical C. difficile isolates (including NAP1 and toxigenic strains) at a very low concentration (0.125 µg/mL) and showed superior killing kinetics compared with metronidazole, an anticlostridial agent from the same chemical category. In addition, ronidazole did not inhibit growth of several commensal organisms naturally present in the human intestine that play a protective role in preventing CDIs. Furthermore, ronidazole was found to be non-toxic to human gut cells and permeated a monolayer of colonic epithelial cells (Caco-2) at a slower rate than metronidazole. Finally, ronidazole outperformed metronidazole when both were tested at a dose of 1 mg/kg daily in a mouse model of CDI. Overall, ronidazole merits further investigation as a potential treatment for CDIs.

Comparison of veterinary drugs and veterinary homeopathy: part 1.

For many years after its invention around 1796, homeopathy was widely used in people and later in animals. Over the intervening period (1796-2016) pharmacology emerged as a science from Materia Medica (medicinal materials) to become the mainstay of veterinary therapeutics. There remains today a much smaller, but significant, use of homeopathy by veterinary surgeons. Homeopathic products are sometimes administered when conventional drug therapies have not succeeded, but are also used as alternatives to scientifically based therapies and licensed products. The principles underlying the veterinary use of drug-based and homeopathic products are polar opposites; this provides the basis for comparison between them. This two-part review compares and contrasts the two treatment forms in respect of history, constituents, methods of preparation, known or postulated mechanisms underlying responses, the legal basis for use and scientific credibility in the 21st century. Part 1 begins with a consideration of why therapeutic products actually work or appear to do so.

Comparison of veterinary drugs and veterinary homeopathy: part 2.

Part 2 of this narrative review outlines the theoretical and practical bases for assessing the efficacy and effectiveness of conventional medicines and homeopathic products. Known and postulated mechanisms of action are critically reviewed. The evidence for clinical efficacy of products in both categories, in the form of practitioner experience, meta-analysis and systematic reviews of clinical trial results, is discussed. The review also addresses problems and pitfalls in assessing data, and the ethical and negative aspects of pharmacology and homeopathy in veterinary medicine.

Ethno-veterinary practices in Southern India for captive Asian elephant ailments.

ETHENOPHARMACOLOGICAL RELEVANCE: India has a long tradition of practicing Ayurvedic medicine not only for human ailments, but also for the management of livestock in the form of ethno-veterinary practices. Asian elephant is a significant part of Indian culture, and ethno-veterinary practices have extended to manage and cure various ailments of Asian elephant in captivity. Much of this knowledge has been lost in the light of modern practices. AIM OF THE STUDY: This study is aimed at documenting the existing knowledge on ethno-veterinary medicines practiced by elephant keepers (mahouts) in Tamil Nadu and Puducherry. MATERIALS AND METHODS: The study was carried out between June 2015 and February 2016 employing a questionnaire survey among 50 selected informants (mahouts) with traditional knowledge on plants in veterinary medicine. Information was elicited from the informants on various diseases prevailing among captive elephants and the traditional treatment employed by them. RESULTS: In total, the study documented 53 plant species belonging to 29 families being used as medicine for 23 types of ailments prevailing among captive elephants. Ferula assa-foetida, Zingiber officinale, Piper longum, P. nigrum, Cuminum cyminum, Trachyspermum roxburghianum and Carum bulbocastanum were the most commonly used plants either independently or in combination. Among them, Ferula assa-foetida (12.4%) and Zingiber officinale (10.4%) had the highest usage. Of the 23 diseases reported, constipation was the most common ailment (14.6%) followed by bloating (8.7%) and flatulence (8.7%). CONCLUSION: Documentation of this indigenous knowledge is valuable for the communities concerned, both at present and in future and for scientific consideration for wider use of traditional knowledge in treating captive elephants. The study has identified 53 medicinal plants to treat various ailments among captive elephants in southern India. The most frequently used plants in the captive elephant health care practice are F. assafoetida, Z. officinale, P. longum and P.nigrum. Among the 29 families, Apiaceae and Piperaceae are widely used. The leaves are the most useful part of the plants, while paste is the widely used form of preparation. The present findings show that mahouts have wide knowledge about elephant diseases and their treatment using herbal medicine. A more detailed investigation should be designed on priority to document the dying art of ethno-veterinary practices for the long-term conservation of the Asian elephant.

Assessment of a Flavone-Polysaccharide Based Prescription for Treating Duck Virus Hepatitis.

Because polysaccharide and flavone ingredients display good antiviral activity, we developed a flavone/polysaccharide-containing prescription that would be effective against duck viral hepatitis (DVH) and investigated its hepatoprotective effects. Flavones were derived from Hypericum japonicum (HJF) (entire herb of Hypericum japonicum Thunb) and Salvia plebeia (SPF) (entire herb of Salvia plebeia R. Br.), and polysaccharides were derived from Radix Rehmanniae Recens (RRRP) (dried root of Rehmannia glutinosa Libosch). This prescription combination was based on the theory of syndrome differentiation and treatment in traditional Chinese veterinary medicine. In vitro and in vivo experiments were conducted using the three single ingredients compared to the combined HRS prescription to determine their anti-duck hepatitis A viral (anti-DHAV) activity. The results showed that all experimental conditions displayed anti-DHAV activity, but the HRS prescription presented the best effect. To further investigate the hepatoprotective effect of the HRS prescription on DHAV-induced hepatic injury, we tested the mortality rate, the hepatic pathological severity score, plasma biochemical indexes of hepatic function, blood DHAV gene expression levels and peroxidation damage evaluation indexes and then analyzed correlations among these indexes. The results demonstrated that the HRS prescription significantly decreased the mortality rate, reduced the severity of hepatic injury, decreased the hepatic pathological severity score, depressed blood DHAV gene expression levels, and returned the indexes of hepatic function and peroxidation almost to a normal level. These results indicate that the HRS prescription confers an outstanding hepatoprotective effect, and we expect that it will be developed into a new candidate anti-DHAV drug.

Ethno veterinary uses of medicinal plants of district Karak, Pakistan.

ETHNOPHARMACOLOGICAL RELEVANCE: In the study area, the traditional knowledge regarding the uses of local wild medicinal plants for treating diseases of domestic animals and birds is totally in the custody of elders of the existing community. The young ones are not much aware about such important practices. AIM OF THE STUDY: The main aim of the study was to document and to release this knowledge from the custody of elders and share with the community. MATERIALS AND METHODS: Total 115 people between 20 and 80 years of age were interviewed and information was collected through semi-structured questionnaires. The data obtained were quantitatively analyzed using the use value (UV) formula. The collected specimens were pressed, dried, preserved, mounted on Herbarium sheets, identified properly and were submitted in the Herbarium, Department of Botany, Hazara University, Mansehra, Pakistan. RESULTS: With the co-ordination and cooperation of the local people, 46 plant species of 42 genera belonging to 31 families were collected, 3 were monocotyledons while 43 plant species belonged to dicotyledonae class. Considering taxonomic characteristics, it was confirmed that 12 trees, 10 shrubs and 22 herbs were commonly used by the local people in ethno veterinary practices. Two plants like Cistanche tubulosa and Cuscuta reflexa from family Orobanchaceae and family Cuscutaceae respectively lack chlorophyll and are parasites on host plants like Doedonia, Ziziphus, Calligonum and Calotropis. The powder of both plants showed great ethno veterinary value. The parts of 46 plant species commonly used for ethno veterinary practices were whole plants (32.60%), leaves (26.08%), fruits (17.39%), stems (13.04%) and roots (10.86%). Medicinal plants were administered through various routes i.e. oral (78.26%), skin (17.21%) and smoke (4.34%). CONCLUSION: The traditional knowledge of local plants of ethno veterinary values is mainly possessed by elders and transmitted from generation to generation with chances of elimination of such traditional knowledge due to less awareness. The present study was designed to document this ethno veterinary related knowledge and to share it with community members for use in future.

An evidence-based approach to the evaluation of ethnoveterinary medicines against strongyle nematodes of equids.

Cyathostomins are the most important gastrointestinal nematode infecting equids. Their effective control is currently under threat due to widespread resistance to the broad spectrum anthelmintics licenced for use in equids. In response to similar resistance issues in other helminths, there has been increasing interest in alternative control strategies, such as bioactive plant compounds derived from traditional ethnoveterinary treatments. This study used an evidence-based approach to evaluate the potential use of plant extracts from the UK and Ethiopia to treat cyathostomins. Plants were shortlisted based on findings from a literature review and additionally, in Ethiopia, the results of a participatory rural appraisal (PRA) in the Oromia region of the country. Systematic selection criteria were applied to both groups to identify five Ethiopian and four UK plants for in vitro screening. These included Acacia nilotica (L.) Delile, Cucumis prophetarum L., Rumex abyssinicus Jacq., Vernonia amygdalina Delile. and Withania somnifera (L.) Dunal from Ethiopia and Allium sativum L. (garlic), Artemisia absinthium L., Chenopodium album L. and Zingiber officinale Roscoe. (ginger) from the UK. Plant material was collected, dried and milled prior to hydro-alcoholic extraction. Crude extracts were dissolved in distilled water (dH2O) and dimethyl sulfoxide (DMSO), serially diluted and screened for anthelmintic activity in the larval migration inhibition test (LMIT) and the egg hatch test (EHT). Repeated measures ANOVA was used to identify extracts that had a significant effect on larval migration and/or egg hatch, compared to non-treated controls. The median effective concentration (EC-50) for each extract was calculated using PROBIT analysis. Of the Ethiopian extracts A. nilotica, R. abyssinicus and C. prophetarum showed significant anthelmintic activity. Their lowest EC-50 values were 0.18 (confidence interval (CI): 0.1-0.3), 1.1 (CI 0.2-2.2) and 1.1 (CI 0.9-1.4)mg/ml, respectively. All four UK extracts, A. sativum, C. album, Z. officinale and A. absinthium, showed significant anthelmintic activity. Their lowest EC-50 values were 1.1 (CI 0.9-1.3), 2.3 (CI 1.9-2.7) and 0.3 (CI 0.2-0.4)mg/ml, respectively. Extract of A. absinthium had a relatively low efficacy and the data did not accurately fit a PROBIT model for the dose response relationship, thus an EC-50 value was not calculated. Differences in efficacy for each extract were noted, dependent on the assay and solvent used, highlighting the need for a systematic approach to the evaluation of bioactive plant compounds. This study has identified bioactive plant extracts from the UK and Ethiopia which have potential as anthelmintic forages or feed supplements in equids.

Ethnoveterinary plants for the treatment of camels in Shiwalik regions of Kathua district of Jammu & Kashmir, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Camel is an important mode of transportation in the hot and hilly tracts of Shiwaliks of Kathua districts. The camel owners of the region lack the modern veterinary facilities and therefore depend heavily upon local treatments for the animal. This ethnoveterinary knowledge of plants is acquired by them from their forefathers and generally moves from one generation to another orally. The oral mode of transferring this valuable knowledge is vulnerable to erosion with the passage of time and generations. MATERIAL AND METHODS: Ethnoveterinary information was collected by interviewing 38 camel keepers and traditional healers as per the questionnaire. The data collected was analysed quantitatively using three indices viz. use-value (UV), informant consensus factor (ICF), and fidelity level (Fl %). RESULTS: A total of 41 plants were found to be of ethnoveterinary importance in the present study. Herbs and trees (41.5% each) were the most used life forms. The most used plant part was fruit (27.9%). Rhizome, root and whole plant parts collectively contributed to 18.6%. Most of the ethnoveterinary practices (65.9%) used oral mode of medication. The values of UV and Fl (%) shows that the most important species for curing the ailing camels were Curcuma longa, Trachyspermum ammi, Brassica campestris, Tamarindus indica, Phyllanthus emblica, Cassia fistula, Eruca sativa, Plumbago zeylanica etc. The high values of ICF (0.91-0.99) show that the informants share the knowledge for the treatment of camels amongst themselves on regular basis. CONCLUSION: A good number of plants are utilised by the informants to cure camels. Most of the preparations used fruits and leaves. Only 18.6% of the practices required destructive collection and such species need sustainable use and conservation. Some of the species like Tamarindus indica, Cassia fistula, Eruca sativa, Albizia lebbeck and Citrus medica require further phytochemical and pharmacological studies.

Preliminary study of plants used in ethnoveterinary medicine in Tunisia and in Italy.

BACKGROUND: A survey relative to the use of plants for the cure of animals in Tunisia was conducted in order to make a comparison with the same species (or similar ones) in central and southern Italy. MATERIALS AND METHODS: available bibliographical data both for Italy and for Tunisia were consulted. RESULTS: Thirty-nine plants, representing 22 families, used in Tunisia in ethnoveterinary medicine were reported, and comparisons made with close species used in Central and Southern Italy. Seven of the 39 species (about the 18% of the total) are not present in Italian flora. Fourteen of the 39 species (35% of the total) are also used in Italy. Camelidae (dromedaries and camels) are the most valuable types of domestic animals cured in Tunisia, but ovines, horses, bulls, dogs are also treated. Some uses coincide with those existing in different Italian regions. The plants used are the most common and most easily found in these areas. CONCLUSION: The present study confirms the convergence in ethnoveterinary medicine between Tunisia and Italy, even if it appears less significant than in human ethnobotany. Further studies are required in areas of Tunisia that have not yet been studied, in order to get the possibility of an evaluation of active compounds.

An ethnopharmacological assessment of the use of plants against parasitic diseases in humans and animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical surveys are detecting an increasing frequency of exotic plant species in pharmacopeias, which has led researchers to investigate the role of such species in traditional medical systems. According to the diversification hypothesis, exotic species are included to complete pharmacopeias, i.e., to treat diseases for which no native species are known, thus broadening the scope of the plant repertoire. MATERIALS AND METHODS: The present study was conducted at two rural communities in northeastern Brazil aiming at a survey of the plants known or used by the population to treat endo- and ectoparasitic diseases in humans and animals. In addition, plant extracts exhibiting acaricide activity were assessed using the engorged female immersion and larval packet tests (LPT). RESULTS: The results of the present study showed a tendency for native species to be used against ectoparasites and exhibit a broader scope of use compared to exotic species. In turn, exotic species were predominantly indicated to treat diseases caused by endoparasites, although there was an overlap of native and exotic species relative to some therapeutic purpose, e.g., ticks. Only two of the plant species tested exhibited acaricide activity (Nicotiana glauca Graham and Croton blanchetianus Baill.), and in both cases, the activity was weak. CONCLUSION: The ethnobotanical data do not fully support the suggested hypothesis. Overall, the wide versatility of exotic species was not exclusively used to treat parasitic diseases in humans and animals. In addition, the selection of acaricide plants based on the ethnopharmacological study generated uninteresting results.

New claims in folk veterinary medicines from Uttar Pradesh, India.

BACKGROUND: In remote areas, folk medicines play a significant role in livestock health care management. The aims of this study were to document folk veterinary medicines of the Uttar Pradesh region and identify promising species for pharmacological studies. METHODS: Fieldwork was conducted over a period of two years in Uttar Pradesh, utilizing the "transect walk" method of participatory rural appraisal (PRA). The data were analyzed through the following techniques: use-value, relative frequency of citation and informant consensus factor (Fic). RESULTS: This research details the use of 83 medicinal plants used to treat 36 livestock ailments. A total of 91 new medicinal claims were discovered. The ailments are categorized into 11 ailment categories based on certain group of ailments (symptoms/similarities, etc). The Fic values indicate that there was a high degree of consensus among informants regarding how to treat burns, coughs, colds and fevers. The most useful medicinal species, ranked according to their perceived usefulness were: Linum usitatissimum, Saccharum officinarum, Brassica napus, Acacia nilotica, Alocasia macrorrhizos, and Calotropis gigantea. For certain medicinal uses, Ferula asafoetida, Linum usitatissimum, Pandanus tectorius, Brassica juncea, Brassica napus, Madhuca longifolia, Alocasia macrorrhizos and Tagetes erecta were also frequently cited for cures with a Fic value of over 3.00. In remedy preparations, the leaves were the most frequently used plant part (22 instances) and most of the preparations were in the form of crushed plant parts, leaves or otherwise. Herbs were the most frequently used source of medicine (43), followed by trees (21) and shrubs (17%). CONCLUSIONS: Those plants which received high relative frequency citation (Fic) values may prove useful for pharmacological studies in new drug development projects, especially Ferula asafoetida (used for flatulence), Linum usitatissimum (a galactagogue), Pandanus tectorius (used for estrus regulation/preparation for breeding), Brassica juncea (to cure infections of the tail), Brassica napus (also to cure infections of the tail), Madhuca longifolia (to cure maggots in the hoof), Alocasia macrorrhizos (for estrus regulation) and Tagetes erecta (for otitis).

[Comments on the Guidelines for the Prudent Use of Antibacterial Veterinary Pharmaceuticals (Guidelines for Antibiotics)]. / Anmerkungen zu den "Leitlinien für den sorgfältigen Umgang mit antimikrobiell wirksamen Tierarzneimitteln" (Antibiotika-Leitlinien).

In 2010 the German Bundestierärztekammer (Federal Chamber of Veterinarians) and the AGTAM (Working Group "Veterinary Pharmaceuticals") published the Guidelines for the prudent use of antibacterial veterinary pharmaceuticals in an updated version. Within the limits of therapeutic freedom, veterinarians are committed to take into account the latest scientific findings in veterinary medicine. These findings may, however, include conflicting interpretations if such an approach is expressed by an accredited university or anywhere else in the field of science. Hence, the state of science in veterinary medicine is not only defined by the Guidelines for Antibiotics, rather, the complete recognized scientific literature has to be considered. The Guidelines for Antibiotics are not legally-binding rules. They define the best approach and not the minimum standard for the use of antibiotics. The clinical examination provides the basis for medical treatment in each specific case. Further laboratory diagnostics represent an additional supportive instrument that is used by the veterinarian at his discretion depending on the necessity. Laboratory tests of bacterial sensitivity (identification of pathogens and antibiogram) may become necessary within the framework of diagnostics. As examples demonstrate, laboratory tests of bacterial sensitivity cannot be performed in every clinical case. It appears to be desirable to further discuss the use of antibacterial veterinary pharmaceuticals in the species-specific attachments in more concrete and specific terms, taking into consideration the standards of evidence-based medicine.

Pain: mechanisms and management in horses.

Pain is a multidimensional sensory phenomenon that has evolved as a protective method for maintaining homeostasis and facilitating tissue repair. Both excitatory and inhibitory physiologic and pathologic mechanisms are involved in its generation and maintenance. Untreated pain and nervous system changes (plasticity) that occur during chronic pain make pain much more difficult or impossible to effectively treat. Therapies directed toward the treatment of pain should be mechanism based and preventative whenever possible. Prospective, randomized clinical trials conducted in horses that suffer from naturally occurring pain will help to determine the current best approaches to effective pain therapy.

Interpreting culture and susceptibility data in critical care: perks and pitfalls.

PROBLEM: The need for immediate, effective antimicrobial therapy in the critical care patient must be tempered by approaches which simultaneously minimize emergence of antimicrobial resistance. Ideally, therapy will successfully resolve clinical signs of infection, while eradicating infecting pathogens such that the risk of resistance is avoided. Increasing limitations associated with empirical antimicrobial choices direct the need for culture and susceptibility data as a basis of therapy. Even so, such in vitro data should be utilized within its limitations. OBJECTIVES: To demonstrate the attributes and limitations of patient and population culture and susceptibility (pharmacodynamic) data in the selection of antimicrobial drugs and to demonstrate the design of individualized dosing regimens based on integration of pharmacodynamic (PD) and pharmacokinetic (PK) data. DIAGNOSIS: Limitations in culture and susceptibility testing begin with sample collection and continue through drug selection and dose design. Among the challenges in interpretation is discrimination between pathogens and commensals. Properly collected samples are critical for generation of data relevant to the patient's infection. Data are presented as minimum inhibitory concentrations (MICs). The MIC facilitate selection of the most appropriate drug, particularly when considered in the context of antimicrobial concentrations achieved in the patient at a chosen dose. Integration of MIC data with key PK data yields the C(max):MIC important to efficacy of concentration-dependent drugs and T>MIC, which guides use of time-dependent drugs. These indices are then used to design dosing regimens that are more likely to kill all infecting pathogens. In the absence of patient MIC data, population data (eg, MIC(90)) may serve as a reasonable surrogate. CONCLUSIONS: Properly collected, performed, and interpreted culture and susceptibility data are increasingly important in the selection of and design of dosing regimens for antimicrobial drugs. Integration of PK and PD data as modified by host and microbial factors supports a hit hard, exit fast approach to therapy that will facilitate efficacy while minimizing resistance.

Characteristics of drug use on sheep farms in Ontario, Canada.

This study examined characteristics of the use of drugs, especially antimicrobials, on Ontario sheep farms. Forty-nine sheep farms participated in a 12-month prospective study. Producers documented treatment events during the study period and drug use data from the records were summarized. The most frequently used drugs of the 15 drug categories used by producers belonged to the following categories: antimicrobial (40.7%, n=2710), vitamin/mineral (12.0%), and biological (11.1%). Short-acting penicillin (27.2%, n=1103), long-acting oxytetracycline (22.9%), and long-acting penicillin (21.9%) were the most frequently used antimicrobials. The drugs that were used most frequently on sheep farms were antimicrobials, of which 93% of treatments were extra-label. Extensive extra-label drug use may be the result of the limited number of drugs that are approved in Canada for use in sheep.