Factors Affecting the Pharmacokinetics, Metabolism and Efficacy of Anthelmintic Drugs

The plasma disposition of albendazole, albendazole sulphoxide, and netobimin were investigated in goats following oral administration at the dose rate of 7.5 mg/kg. Netobimin and albendazole were not detectable at any time following drug administration. Plasma levels achieved by the anthelmintically active metabolite, albendazole sulphoxide (ABSO), were not significantly different following administration of albendazole (AUC= 54.40 mug.h/m1; Cmax= 2.38 mug/ml) and albendazole sulphoxide (AUC= 63.04 mug.h/ml; Cmax= 2.77 mug/ml). Following administration of netobimin, the AUC and Cmax for ABSO were 29.76 mug.h/m1 and 1.35 mug/ml, respectively. The effect of the metabolic inhibitor, piperonyl butoxide (administered intramuscularly at 0.5 g/kg bodyweight), on the pharmacokinetics of albendazole (in sheep and goats) and fenbendazole (in goats) was studied. It was found that in sheep, pretreatment with piperonyl butoxide increased the area under the curve (AUC) and the mean residence time (MRT) of albendazole sulphoxide by 77% and 50%, respectively. The AUC and MRT of albendazole sulphone were also significantly increased with piperonyl butoxide pretreatment. In goats, the pharmacokinetic parameters of ABSO were not significantly increased by piperonyl butoxide. Pretreatment of goats with the inhibitor caused more than three-fold increases in the bioavailability of fenbendazole (FBZ) and fenbendazole sulphoxide (FBSO). The plasma disposition of piperonyl butoxide was determined in sheep and goats. Peak plasma concentrations were achieved between 10 and 15 hours. In sheep, the AUC and Cmax were 132.96 mug.h/m1 and 2.92 mug/ml, respectively. In goats, the AUC and Cmax amounted to 82.10 mug.h/ml and 1.17 jag/ml, respectively. A pharmacokinetic dose titration study was carried out with fenbendazole and piperonyl butoxide in sheep. Fenbendazole was given at a fixed dose (5 mg/kg) and piperonyl butoxide was administered orally at 0, 15, 31, 63, 125 and 250 mg/kg. The AUC of fenbendazole (FBZ) and fenbendazole sulphoxide (FBSO) increased significantly with dose rates of piperonyl butoxide equal to or higher than 31 mg/kg. Peak plasma concentrations (Cmax) and mean residence times (MRT) were also significantly increased with the coadministration of fenbendazole and piperonyl butoxide. Piperonyl butoxide given orally to two sheep was well absorbed resulting in an AUC of 761.2 mug.h/m1 (sheep 95) and 538.4 mug.h/ml (sheep96). The efficacy of the combination fenbendazole-piperonyl butoxide (FBZ-PB) was assessed in sheep against benzimidazole-resistant Ostertagia circumcincta and Haemonchus contortus. T h e percentage reduction in the total number of O. circumcincta worms was 7.90% (FBZ alone) and 97.8% (FBZ-PB). For Haemonchus contortus, the percentage reduction was 84.8% (FBZ alone) and 99.0% (FBZ-PB). Reduction in the faecal egg output, 7 days after treatment was 93.7% (FBZ alone) and 99.6 % (FBZ-PB). Piperonyl butoxide, given alone, had no effect against these two nematode species. The in vitro metabolism of fenbendazole, oxfendazole, albendazole preparations and and triclabendazole was studied using microsomal cultured hepatocytes from rat liver. The extent of metabolism was found to be in the order triclabendazole > albendazole > fenbendazole and oxfendazole. Piperonyl butoxide inhibited the S-oxidation of all the benzimidazole drugs studied. 1-aminobenzotriazole inhibited significantly the metabolism of triclabendazole in hepatocyte cultures. The effect of the salicylanilide compound rafoxanide against immature (4 week-old) stages of Fasciola hepatica was investigated in artificially infected sheep. Antipyrine clearance tests together with plasma glutamate dehydrogenase (GLDH) and gamma-glutamyl transferase (mugT) activities were used to follow the evolution of flukicidal therapy with rafoxanide. Glutamate but increased again at 12 weeks post-infection in the infected rafoxanide-treated sheep (group B). In the infected untreated sheep (group A), Antipyrine clearance decreased between 8 and 14 weeks post-infection. In the infected treated sheep (group B), plasma clearance of antipyrine remained unchanged until 10 weeks after rafoxanide treatment when it decreased from the pre-infection value of 5.09 to 3.90 ml/min.kg. Rafoxanide did not alter antipyrine disposition in uninfected sheep (group C)

Effects of a water-soluble formulation of tylvalosin on disease caused by porcine reproductive and respiratory syndrome virus alone in sows or in combination with Mycoplasma hyopneumoniae in piglets

BACKGROUND: The effect of a water-soluble formulation of tylvalosin (Aivlosin® 625 mg/g granules) on disease caused by porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae (Mhyop) was investigated in two animal studies. In a PRRSV challenge model in pregnant sows (n = 18), six sows received water medicated at target dose of 5 mg tylvalosin/kg body weight/day from 3 days prior to challenge until the end of gestation. Six sows were left untreated, with a third group remaining untreated and unchallenged. Sows were challenged with PRRSV-2 at approximately 85 days of gestation. Cytokines, viremia, viral shedding, sow reproductive parameters and piglet performance to weaning were evaluated. In a dual infection study (n = 16), piglets were challenged with Mhyop on days 0, 1 and 2, and with PRRSV-1 on day 14 and euthanized on day 24. From day 10 to 20, eight piglets received water medicated at target dose of 20 mg tylvalosin/kg body weight/day and eight piglets were left untreated. Cytokines, viremia, bacteriology and lung lesions were evaluated. RESULTS: In the PRRSV challenge study in pregnant sows, tylvalosin significantly reduced the levels of serum IL-8 (P < 0.001), IL-12 (P = 0.032), TNFα (P < 0.001) and GM-CSF (P = 0.001). IL-8 (P = 0.100) tended to be lower in uterus of tylvalosin sows. All piglets from tylvalosin sows surviving to weaning were PRRSV negative in faecal swabs at weaning compared to 33.3% PRRSV positive piglets from untreated sows (P = 0.08). In the dual challenge study in piglet, tylvalosin reduced serum IL1β, IL-4, IL-6, IL-8, IL-10, IL-12, IL-1α, IL-13, IL-17A, IL-18, GM-CSF, TGFβ1, TNFα, CCL3L1, MIG, PEPCAM-1 (P < 0.001) and increased serum IFNα, IL-1ra and MIP-1b (P < 0.001). In the lungs, tylvalosin reduced IL-8, IL-10 and IL-12 compared to untreated pigs (P < 0.001) and tended to reduce TNFα (P = 0.082). Lung lavage samples from all tylvalosin treated piglets were negative for Mhyop (0 cfu/mL) compared to the untreated piglets which had mean Mhyop counts of 2.68 × 10(4) cfu/mL (P = 0.023). CONCLUSION: Overall, tylvalosin reduced both local and systemic proinflammatory cytokines after challenge with respiratory pathogens in sows and in piglets. Tylvalosin was effective in reducing Mhyop recovery from the lungs and may reduce virus shedding in piglets following transplacental PRRSV infection in sows

An attenuated herpesvirus vectored vaccine candidate induces T-cell responses against highly conserved porcine reproductive and respiratory syndrome virus M and NSP5 proteins that are unable to control infection

Porcine reproductive and respiratory syndrome virus (PRRSV) remains a leading cause of economic loss in pig farming worldwide. Existing commercial vaccines, all based on modified live or inactivated PRRSV, fail to provide effective immunity against the highly diverse circulating strains of both PRRSV-1 and PRRSV-2. Therefore, there is an urgent need to develop more effective and broadly active PRRSV vaccines. In the absence of neutralizing antibodies, T cells are thought to play a central role in controlling PRRSV infection. Herpesvirus-based vectors are novel vaccine platforms capable of inducing high levels of T cells against encoded heterologous antigens. Therefore, the aim of this study was to assess the immunogenicity and efficacy of an attenuated herpesvirus-based vector (bovine herpesvirus-4; BoHV-4) expressing a fusion protein comprising two well-characterized PRRSV-1 T-cell antigens (M and NSP5). Prime-boost immunization of pigs with BoHV-4 expressing the M and NSP5 fusion protein (vector designated BoHV-4-M-NSP5) induced strong IFN-γ responses, as assessed by ELISpot assays of peripheral blood mononuclear cells (PBMC) stimulated with a pool of peptides representing PRRSV-1 M and NSP5. The responses were closely mirrored by spontaneous IFN-γ release from unstimulated cells, albeit at lower levels. A lower frequency of M and NSP5 specific IFN-γ responding cells was induced following a single dose of BoHV-4-M-NSP5 vector. Restimulation using M and NSP5 peptides from PRRSV-2 demonstrated a high level of cross-reactivity. Vaccination with BoHV-4-M-NSP5 did not affect viral loads in either the blood or lungs following challenge with the two heterologous PRRSV-1 strains. However, the BoHV-4-M-NSP5 prime-boost vaccination showed a marked trend toward reduced lung pathology following PRRSV-1 challenge. The limited effect of T cells on PRRSV-1 viral load was further examined by analyzing local and circulating T-cell responses using intracellular cytokine staining and proliferation assays. The results from this study suggest that vaccine-primed T-cell responses may have helped in the control of PRRSV-1 associated tissue damage, but had a minimal, if any, effect on controlling PRRSV-1 viral loads. Together, these results indicate that future efforts to develop effective PRRSV vaccines should focus on achieving a balanced T-cell and antibody response

Effects of a water-soluble formulation of tylvalosin on disease caused by porcine reproductive and respiratory syndrome virus alone in sows or in combination with Mycoplasma hyopneumoniae in piglets

Abstract Background The effect of a water-soluble formulation of tylvalosin (Aivlosin® 625 mg/g granules) on disease caused by porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae (Mhyop) was investigated in two animal studies. In a PRRSV challenge model in pregnant sows (n = 18), six sows received water medicated at target dose of 5 mg tylvalosin/kg body weight/day from 3 days prior to challenge until the end of gestation. Six sows were left untreated, with a third group remaining untreated and unchallenged. Sows were challenged with PRRSV-2 at approximately 85 days of gestation. Cytokines, viremia, viral shedding, sow reproductive parameters and piglet performance to weaning were evaluated. In a dual infection study (n = 16), piglets were challenged with Mhyop on days 0, 1 and 2, and with PRRSV-1 on day 14 and euthanized on day 24. From day 10 to 20, eight piglets received water medicated at target dose of 20 mg tylvalosin/kg body weight/day and eight piglets were left untreated. Cytokines, viremia, bacteriology and lung lesions were evaluated. Results In the PRRSV challenge study in pregnant sows, tylvalosin significantly reduced the levels of serum IL-8 (P < 0.001), IL-12 (P = 0.032), TNFα (P < 0.001) and GM-CSF (P = 0.001). IL-8 (P = 0.100) tended to be lower in uterus of tylvalosin sows. All piglets from tylvalosin sows surviving to weaning were PRRSV negative in faecal swabs at weaning compared to 33.3% PRRSV positive piglets from untreated sows (P = 0.08). In the dual challenge study in piglet, tylvalosin reduced serum IL1β, IL-4, IL-6, IL-8, IL-10, IL-12, IL-1α, IL-13, IL-17A, IL-18, GM-CSF, TGFβ1, TNFα, CCL3L1, MIG, PEPCAM-1 (P < 0.001) and increased serum IFNα, IL-1ra and MIP-1b (P < 0.001). In the lungs, tylvalosin reduced IL-8, IL-10 and IL-12 compared to untreated pigs (P < 0.001) and tended to reduce TNFα (P = 0.082). Lung lavage samples from all tylvalosin treated piglets were negative for Mhyop (0 cfu/mL) compared to the untreated piglets which had mean Mhyop counts of 2.68 × 104 cfu/mL (P = 0.023). Conclusion Overall, tylvalosin reduced both local and systemic proinflammatory cytokines after challenge with respiratory pathogens in sows and in piglets. Tylvalosin was effective in reducing Mhyop recovery from the lungs and may reduce virus shedding in piglets following transplacental PRRSV infection in sows