Effects of ergotamine and ergovaline on the electromyographic activity of smooth muscle of the reticulum and rumen of sheep

OBJECTIVE: To investigate the effects of IV administration of ergotamine and ergovaline and intraruminal administration of ergotamine on electromyographic (EMG) activity of reticuloruminal smooth muscle in conscious sheep. ANIMALS: 3 sheep with indwelling electrodes in the musculature of the reticulum and rumen. PROCEDURE: In a crossover design study, reticuloruminal motility before and after IV administration of ergotamine (5, 10, 20, and 40 nmol/kg) or ergovaline (2.5, 5, and 10 nmol/kg) was evaluated; EMG effects were compared with those of corresponding control treatments (IV administration of saline [0.9% NaCl] solution or acetone, respectively) in sheep. Ergotamine (800 nmol/kg) or water was also administered intraruminally and their effects compared. RESULTS: After IV administration of ergopeptides, vagally dependent cyclical A and B sequences of contraction of the reticulorumen were immediately inhibited, preceding increases in baseline EMG activity (tonus). The return of cyclical contractions was associated with an increase in contraction amplitude. The effects were dose dependent; administration of 40 nmol of ergotamine/kg resulted in responses that continued for 3 to 4 hours. The effects of intraruminal administration of ergotamine were variable; after 8 hours, EMG activity was increased from baseline for < 2 hours in 1 sheep, 10 hours in another, and > 15 hours in the third. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep, the effects of ergotamine and ergovaline on reticuloruminal motility after IV administration and the duration of responses following intraruminal administration suggest that disruption of digestion may occur in animals grazing endophyte-infected pasture that has a high ergopeptide content.     

Tolerance to the Nephrotoxic Component of Narthecium ossifragum in Sheep: The Effects of Repeated Oral Doses of Plant Extracts

Young adult sheep were dosed with extracts of Narthecium ossifragum plants by the oral or parenteral routes and the resulting nephrotoxicity was assessed from the increases in the concentrations of creatinine and urea in the serum. Following single intraruminal or intraperitoneal doses of extracts derived from 30 g N. ossifragum (wet weight) per kg live weight (kg lw), serum creatinine concentrations increased from about 100 mol/L to between 260 and 510 mol/L. The serum urea concentrations increased from about 5–8 mmol/L to between 11 and 66 mmol/L in individual sheep. Daily intraruminal administration of 5–30 g/kg lw to three sheep over a 10- or 15-day period increased creatinine concentrations from 100 mol/L to 300–760 mol/L, and urea concentrations from 5–8 mmol/L to 35 mmol/L. A single intraperitoneal challenge dose of 30 g/kg lw, delivered 7 or 12 days after the final intraruminal dose, did not lead to increased serum creatinine or urea concentrations, indicating that oral treatment had apparently resulted in an increased tolerance to the nephrotoxic principle(s) in N. ossifragum.     

Influence of selenium status in merino weaners on resistance to trichostrongylid infection

Weaned merino lambs, grazing pastures low in selenium, were used to investigate the effect of selenium status on immunity to trichostrongylids. Six weeks following selenium supplementation to 14 of the 27 sheep using intraruminal selenium pellets, 5000 Ostertagia circumcincta and 5000 Trichostrongylus colubriformis larvae were administered orally to all sheep. At four weeks after infection, the mean total worm burden in the selenium supplemented sheep (5537 +/- 343, n = 14) was not significantly different (P greater than 0.05) from that in the unsupplemented sheep (5614 +/- 374, n = 12) and faecal worm egg concentrations were also similar in the two treatment groups. At this time, mean red cell glutathione peroxidase activities in the supplemented and unsupplemented groups were 430 and 11 U g-1 haemoglobin, respectively, and clinical white muscle disease had been observed in the latter group. These results suggest that increasing selenium status of selenium deficient sheep by the use of intraruminal selenium supplementation, has a negligible effect on resistance to an artificial challenge infection of O circumcincta and T colubriformis.     

Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal or intraruminal administration

The pharmacokinetics of ivermectin in plasma following intravenous, intra-abomasal, and intraruminal administration to sheep was determined. When given intravenously, ivermectin was very slowly eliminated with a terminal half-life of 178 h and a volume of distribution at steady state of 5.3 l/kg indicating sequestration in a temporary depot. Intra-abomasal administration resulted in rapid absorption, a peak plasma concentration of 60.6 ng/ml at 4.4 h, and 100% bioavailability. However, intraruminal administration produced a much lower peak concentration (17.6 ng/ml at 23.5 h) and bioavailability (25.1%). A subsequent in vitro study indicated that ivermectin may be rapidly metabolized in the rumen.     

Vitamin E concentrations in blood plasma of sheep and in sheep tissues after a single intraruminal or intraperitoneal administration of DL-alpha-tocopheryl acetate

Twenty-five yearling wethers, weighing 40 to 45 kg were used in a trial designed to compare the effect of the route of administration of vitamin E upon plasma and tissue vitamin E status. Five control sheep without vitamin E administration were killed at the beginning of the trial. Of the remaining 20 sheep, 10 were given DL-alpha-tocopheryl acetate intraruminally and 10 by intraperitoneal injection. Of these, 10 wethers were killed three days after dosing (five from each treatment, IR3 and IP3) and the remaining wethers were killed eight days after dosing (IR8 and IP8). Blood samples were taken throughout the trial from sheep on the IR8 and IP8 treatments. Samples of whole adrenal gland, heart, liver, kidney, brachiocephalicus muscle, lung, pancreas and spleen were taken from all sheep at slaughter and were analysed for their vitamin E content. The blood plasma results showed that the most important index of vitamin E bioavailability, the area under the plasma concentration versus time curve, was greater in the intraperitoneally than intraruminally dosed sheep. There was a higher concentration of vitamin E in the tissues from the intraperitoneal group than the intraruminal group three days after the intraperitoneal injections. The results suggest that the greatest responses in vitamin E concentration in plasma and the tissues were recorded in sheep following intraperitoneal rather than intraruminal dosing with DL-alpha-tocopheryl acetate.     

The effects of ivermectin and moxidectin on egg viability and larval development of ivermectin-resistant Haemonchus contortus

The in vivo effects of ivermectin and moxidectin on egg viability and larval development of ivermectin-resistant Haemonchus contortus were examined over time after anthelmintic treatment of sheep. Twenty merino sheep, (12 months old) were allocated to five treatment groups and infected with ivermectin-resistant H. contortus. Thirty one days later, the sheep were treated with intraruminal ivermectin capsules, oral ivermectin, oral moxidectin or injectable moxidectin at the manufacturer's recommended dosages, or left untreated. At various times up to 112 days after treatment, faecal egg counts (FEC) were determined and development rates of infective larvae (L3) cultured in faeces or on agar were measured. Eggs in faecal cultures from ivermectin capsule treated sheep showed reduced L3 development percentages in comparison to faecal cultures from untreated sheep. Eggs from ivermectin capsule treated sheep, isolated from faeces, and cultured on agar showed similar L3 development to eggs from control sheep. These results demonstrate an inhibitory effect of excreted ivermectin in faeces on larval development of ivermectin-resistant H. contortus. L3 development in faecal culture from animals receiving oral ivermectin were reduced for only 3 days after treatment. Faecal egg counts and development of L3 larvae in both culture systems from moxidectin treated sheep were low, due to the high efficacy of the drug. Egg counts in moxidectin treated sheep were reduced by approximately 90% 24h after treatment, before decreasing to almost 100% at 48h, suggesting that the current quarantine recommendation of holding sheep off pasture for 24h after treatment may still lead to some subsequent pasture contamination with worm eggs.     

Plasma levels following administration of sodium meclofenamate by various routes.

Sodium meclofenamate, an anti-inflammatory and anti-anaphylactic agent, was administered to cattle intravenously, orally and by intraruminal injection. Plasma levels of the free drug were estimated fluorimetrically at intervals after administration by each route. Levels fell rapidly, particularly during the first hour after intravenous injection. Differences between those plasma levels resulting from oral administration and those following intraruminal injection indicated that direct passage into the abomasum was achieved by the former method. Simultaneous intravenous and intrauminal injections achieved immediate high plasma levels and maintained levels adequate for efficacy for 24 h.     

Effectiveness of α-tocopherol and selenium supplements in preventing lupinosis-associated myopathy in sheep

Objective To compare the effectiveness of combined selenium and α-tocopherol acetate treatments in preventing lupinosis-associated myopathy in sheep.
Design Measurement of plasma muscle and liver enzymes, and histopathological examination of muscle and liver in the treatment groups.
Procedure The treatments were: subcutaneous injections of selenomethionine and vitamin E (sc(SeM+E)) , an intraruminal selenium pellet and oral doses of vitamin E and intramuscular injections of selenomethionine combined with either oral doses of vitamin E (imSeM+orE) or intramuscular injections of vitamin E in an oily carrier. Another group received no supplements, while a control group was given selenium pellets on day 0 and fortnightly oral doses of vitamin E from day 0 to 72. To produce lupinosis-associated myopathy, the sheep were fed a diet low in vitamin E and given repeated injections of a crude extract of Diaphorthe toxica. Groups sc(SeM+E) and imSeM+orE were stressed by dosing with protected polyunsaturated fatty acids from day 56 onwards.
Results Lupinosis-associated myopathy was induced in all unsupplemented sheep. In these sheep the storage of Se increased and that of vitamin E decreased. The subcutaneous treatment was highly effective in preventing lupinosis-associated myopathy and also produced the highest vitamin E concentrations in plasma and liver. Supplemental vitamin E was more efficacious than supplemental Se. Concentrations of vitamin E in the livers of sheep given intramuscular vitamin E were higher than expected based on plasma concentrations. Oral doses of vitamin E proved the least effective method of increasing concentrations in liver. Lupinosis did not affect Se concentrations in liver or muscle.
Conclusion The sc(SeM+E) treatment is highly effective in preventing lupinosis-associated myopathy but needs to be further assessed when selenium and vitamin E are both limiting in the diet.     

Blockade of satiety factors by central injection of neuropeptide Y in sheep

The ability of neuropeptide Y (NPY) to stimulate feed intake was tested in combination with two treatments known to depress feed intake in sheep. Six ewe and three wether lambs (mean BW = 40 kg) fitted with lateral cerebral ventricular guide cannulas and ruminal cannulas had free access to a nutritionally complete, pelleted diet. Balloons placed into the rumen were filled with either 0, 30 or 60 ml of water/kg BW and left in place for 6 h; intake was measured. Based on the decline in feed intake observed with increasing balloon volume in the rumen, Exp. 2 was designed to test effects of NPY injection (0 or 3.0 nmol) into the lateral cerebral ventricle and ruminal distension (0 or 35 ml/kg BW) for 6 h. During the 6-h test period, feed intake was depressed (P less than .05) by intraruminal balloon distension, but feed intake was increased by NPY injection (P less than .05); no interaction between NPY and distension was detected. Ruminal evacuation revealed that digesta occupied only 43% of the rumen's total volume capacity. Balloons occupied 14% of capacity, whereas meal size in control sheep following a 1.5-h fast equaled 7% of capacity. In Exp. 3, intraruminal infusion of 8 mmol/min of propionate depressed (P = .11) feed intake, whereas NPY injection enhanced (P less than .05) intake. There was no interaction between NPY and propionate infusion. In none of these experiments was cumulative feed consumption at 24 h influenced. We conclude that NPY is a versatile feeding stimulant. It promotes feed intake in feed-satiated, ruminally distended and propionate-infused sheep.     

A review of the use of a controlled-release formulation of ivermectin in the treatment and prophylaxis of Psoroptes ovis infestations in sheep.

The options for the treatment and control of sheep scab (psoroptic mange) have been increased in recent years through the introduction of the endectocides ivermectin, doramectin and moxidectin. Whilst therapeutic efficacy is good, the current injectable formulations offer limited protection against re-infestation with Psoroptes ovis. An intraruminal controlled-release formulation of ivermectin has been developed to provide therapeutic and prophylactic activity against a range of sensitive endo- and ecto-parasites of sheep for 100 days after administration. These ivermectin boluses are designed to release ivermectin at 20-40 microg/kg/day over 100 days and were developed for use in sheep of 20-90 kg bodyweight. Several controlled therapeutic and prophylactic trials against sheep scab have been conducted under a variety of protocols with such boluses in Europe and South America. The results of these studies indicate that the bolus provides 100% therapeutic efficacy against established P. ovis infestations and equivalent prophylactic efficacy against challenge infestations administered during the active life of the bolus.     

Efficacy of ivermectin in a controlled-release capsule for the control of breech strike in sheep

Objective To investigate the efficacy of ivermectin in an intraruminal controlled-release capsule (CRC) against blowfly strike.
Design Pen and field trials with controls.
Animals Pen studies: Two breech strike trials involving 60 Romney and 60 Merino sheep. One body strike trial using 100 Merino sheep.
Field trials: Eight trials in New Zealand used 1000 Romney and Romney-cross sheep. Fifty Merino lambs in one trial in Australia.
Procedure Pen studies: Sheep were allocated to two equal groups. One was not treated, the other sheep received a CRC that delivered ivermectin at 20 μg/kg/day for 100 days. In the breech strike trials, each animal was given an oral laxative 2 days before exposure to adult Lucilia cuprina . In the body-strike trial, the sheep sheep were kept wet to increase susceptibility prior to the release of blowflies.
Field trials: Fifty or 200 sheep allocated to equal groups of nontreated or treated with the CRC and grazed at pasture exposed to natural blowfly challenge.
Results Pen studies: Breech strikes developed in 24 of 60 controls but in none of 60 CRC-treated sheep. There was a 35% reduction in the number of CRC-treated sheep struck on the body.
Field trials: The average number of breech strikes in CRC-treated sheep was reduced by 86% (P < 0.001). The number of body strikes in the treated groups was a reduced by 27% (P < 0.05).
Conclusion The ivermectin CRC is a useful aid in controlling breech strike, but provides only moderate reduction in the incidence of body strike.     

Control of gastro-intestinal parasitism in sheep with ivermectin delivered via an intraruminal controlled-release capsule

The efficacy of ivermectin delivered by an intraruminal controlled-release capsule against gastro-intestinal nematodes of sheep was evaluated under controlled conditions. In seven Australian studies involving 170 Merino or Merino x Border Leicester sheep, intraruminal capsules developed for 20-40 kg or 40-80 kg sheep, and delivering 0.8 or 1.6 mg of ivermectin/day respectively for 100 days (minimum dose 20 microg/kg/day), were evaluated. Studies were designed to test the therapeutic efficacy against naturally acquired and induced infections treated at the adult and fourth larval stage, and the prophylactic efficacy against naturally acquired and induced infections with third stage infective larvae. The predominant pathogenic nematodes of sheep were represented. Two studies included known benzimidazole- and levamisole-resistant nematode strains. Sheep were necropsied for total nematode counts 21-8.5 days after treatment. The efficacy of the ivermectin controlled-release capsule was generally >99% against all nematode species tested, including those confirmed to be benzimidazole- and levamisole-resistant. High therapeutic activity was demonstrated against existing adult and fourth larval stage nematode infections at the time of treatment, and high prophylactic efficacy was shown against incoming third stage larvae of all species and strains tested.     

Pharmacokinetics in sheep and cattle of albendazole administered by an intraruminal slow release capsule

Forty sheep and 40 heifers were dosed with an intraruminal slow release capsule (IRSRC) constructed to deliver albendazole (ABZ) at a low daily dosage for three months. Blood samples were collected at standardised intervals for 110 days and analysed by high performance liquid chromatography for the quantification of the two main metabolites sulphoxide (SO.ABZ) and sulphone (SO2ABZ). The plasma profiles show sustained concentrations of the active metabolite SO.ABZ for 105 days in sheep (m = 0.06 +/- 0.032 micrograms ml-1) and 85 days in cattle (m = 0.10 +/- 0.019 micrograms ml-1). In both species, the proportions of the metabolites were inverted compared to that observed after a single dosage. The bioavailability of ABZ after the administration of the IRSRC compared with a drench was reduced in sheep but increased in cattle. The IRSRC exhibited a preventive and therapeutic effect for at least three months.     

Comparative pharmacokinetic disposition of closantel in sheep and goats

The pharmacokinetic disposition of closantel was examined following intraruminal (i.r.) or intramuscular (i.m.) administration to adult Merino sheep and to adult and 3-month-old, suckling Angora goats. In adult goats the maximum concentration (C_max) and area under the plasma concentration with time curve ( AUC ) following 3.75, 7.5 and 15.0 mg closantel/kg given i.r. increased with dose however the time of C_max (r_max= 2.6d) in plasma was unaffected by dose rate. The elimination phase (K₁₀) of closantel was monoexponential with a half-life ( t _½) of 4.7d again unaffected by dose rate. Apart from a more rapid absorption phase and earlier T_max following 3.75 mg closantel/kg i.m., pharmacokinetic behaviour was similar to that following i.r. administration at 3.75 or 7.5 mg/kg. Although absorption rate was more rapid in kids after i.r. administration at 7.5 mg/kg, pharmacokinetic disposition of closantel was otherwise similar to that in adult goats. No closantel was detected in milk of treated does or in the plasma of their kids. I.R. closantel at 7.5 mg/kg was more slowly absorbed in goats than in sheep but C_max was similar in both species. However, K₁₀ t _½ was significantly shorter in goats (4d) than in sheep (14d). Faster elimination resulted in an almost three-fold lowering of AUC in goats and could dramatically reduce the sustained action of closantel in this species compared with sheep.     

The metabolic response to norepinephrine in carbon tetrachloride poisoned sheep

The intraruminal administration of carbon tetrachloride to healthy sheep caused a sharp rise in the serum OCT levels. The plasma concentration of non-esterified fatty acids (NEFA) increased, while blood glucose remained unaffected. The glucose response to the intravenous injection of norepinephrine was greatly reduced after carbon tetrachloride administration, indicating a depletion of the liver glycogen. The NEFA response was not altered. As the increase in NEFA caused by carbon tetrachloride was only moderate, a block in lipoproteinsynthesis is discussed as the main factor in the development of the fatty liver.     

Fibrinogen-degrading proteins from Haemonchus contortus used to vaccinate sheep.

Sixteen nonsibling sheep, approximately 12 months old, that were raised in a helminth-free environment, were used for 2 protection studies 6 months apart. Sheep were vaccinated weekly for 5 weeks by IM injection of fibrinogen-degrading proteins derived from the intestinal tract of adult Haemonchus contortus. Ten days after the last vaccination, sheep were given 2,500 infective H contortus larvae by intraruminal injection. Vaccinated sheep produced specific antibodies, and were protected from the worm challenge. Significant differences in mean fecal worm egg counts for 56 days after worm challenge, in mean numbers of H contortus worms, and female fecundity ratios at necropsy were detected in vaccinated sheep, compared with those in control sheep. These data suggest that the fibrinogen-degrading proteins have a protective role in vaccination of sheep against H contortus.     

Relative bioavailability of rafoxanide following intraruminal and intra-abomasal administration in sheep

The bioavailability of rafoxanide was compared after intraruminal and intra-abomasal administration in healthy adult sheep (n = 6) in a single dose, 2 parallel group study at 7.5 mg/kg. Rafoxanide concentrations in plasma were measured by means of HPLC analysis. Primary pharmacokinetic parameters for bioavailability and disposition of rafoxanide in plasma for both routes of administration were determined by non-compartmental and non-linear, 1-compartmental pharmacokinetic analysis, respectively. Significantly (P < or = 0.05) higher peak plasma concentrations (c(max)) of rafoxanide and a more rapid rate of absorption (c. 3.5 times) was observed in sheep after intra-abomasal (i-a) administration compared to intraruminal (i.r.) administration. A significantly (P < or = 0.05) longer lag period (t(lag)) before absorption (6.8 +/- 2.9 h) occurred after i.r. than after i-a treatment (1.9 +/- 0.6 h). There was no significant difference (P > 0.05) in AUC, MRT and in the rates of elimination (k10-HL and t(1/2beta)) between the i.r. and i-a routes of administration. The results of the study demonstrated the important influence of the rumino-reticulum on absorption of rafoxanide in sheep.     

Metabolite concentrations in plasma following treatment of cattle with five anthelmintics

Plasma concentrations of anthelmintics and their metabolites were determined after cattle were treated at recommended dose rates and routes of administration. Fenbendazole, oxfendazole, febantel, albendazole and thiabendazole were given orally and oxfendazole was also administered with an intraruminal injector. After fenbendazole, oxfendazole and febantel were administered, fenbendazole, oxfendazole and fenbendazole sulphone were all detected in plasma in each case. However, there were marked differences between the three anthelmintics in the peak concentrations and areas under the plasma concentration/time curve (AUC) of these three metabolites. Intraruminal administration of oxfendazole produced higher AUC for fenbendazole and fenbendazole sulphone than did oral administration. Albendazole sulphoxide and sulphone were detected in cattle plasma after albendazole administration but no parent drug was present. These metabolites disappeared more rapidly in cattle than has been reported for sheep. Only 5(6)hydroxythiabendazole was detected in cattle plasma after thiabendazole treatment.     

Excretion of A Single Dose of Selenium in Sheep

The excretion of Se⁷⁵ via the feces and urine was studied in 30 sheep. Se⁷⁵-sodium selenite was injected subcutaneously, using three different doses ranging from a tracer dose to a therapeutic dose. By the intraruminal route the substance was given in a tracer dose and a therapeutic dose. Se⁷⁵-selenomethionine was injected subcutaneously and intraruminally in a tracer dose. Se⁷⁵-selenocystine was given intravenously in a dose higher than that regarded as a therapeutic dose.After intraruminal injection a higher percentage of the dose was excreted via the feces than via the urine. After the two highest subcutaneous doses the urinary excretion was significantly higher than the fecal excretion. After a high selenium dose the percentage eliminated via the urine was greater than after a low dose, whether the subcutaneous or the intraruminal route was used.The fecal and urinary excretion of Se⁷⁵ was of approximately the same order after injection of Se⁷⁵-selenomethionine and Se⁷⁵-selenocystine as after injection of the tracer dose of Se⁷⁵-sodium selenite.In 2 sheep, 1.4 per cent and 3.7 per cent, respectively, of a therapeutic dose were excreted via the bile in 48 hours.Less than 3 per cent of a subcutaneous dose was eliminated with the expired air in 24 hours.Exactly how much of a therapeutic dose is excreted within, for instance, 2 weeks is difficult to establish, as the treated animal’s selenium supply with the feed is not known. In the experiments reported here, however, approximately 64 per cent of a subcutaneous and 75 per cent of an intraruminal therapeutic dose were excreted over a two-week period.     

Intraruminal controlled release of cyromazine for the prevention of Lucilia cuprina myiasis in sheep

The efficacy of cyromazine, continuously released from intraruminal capsules at dose rates from 0.5 to 2 mg kg-1 d-1, was evaluated against implants of eggs and first instar larvae of Lucilia cuprina on Merino sheep. Estimates from the non-linear relationship between the success of implants and plasma concentrations showed that 95 per cent protection of sheep could be achieved at a mean release rate of 1.39 mg kg-1 d-1 cyromazine which gave rise to a mean plasma concentration of 0.26 mg litre-1. Present formulations allowed protection for about 90 days in a 40 kg sheep. The 'square wave' type of release profile provided negligible suboptimal dosing thus limiting the potential for selection of resistance. Systemic application of cyromazine provides control of covert and overt strike among sheep and could be used in ecologically based strategies for the control of L. cuprina populations.