Pharmacodynamic effects of molidustat on erythropoiesis in healthy cats.

BACKGROUND: Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans. HYPOTHESIS/OBJECTIVE: Determine if molidustat, a novel HIF-PH inhibitor, stimulates erythropoiesis in healthy cats. ANIMALS: Seventeen healthy adult laboratory cats. METHODS: Randomized, placebo-controlled study. Cats were treated PO once daily with suspensions of 0 (Group 1; n = 6), 5 (Group 2; n = 6), or 10 (Group 3; n = 5) mg/kg of molidustat. Effects on red blood cell parameters, reticulocyte indices and plasma erythropoietin (EPO) concentrations were evaluated. Molidustat treatment was stopped when hematocrit (HCT) exceeded 60%. RESULTS: Compared to placebo, a significant increase in mean HCT was evident starting on Day 14 (Group 2:54.4% vs 40.3%, P < .001, 95% confidence interval [CI] for the difference [8.95-19.28]; Group 3:61.2% vs 40.3%, P < .001, 95% CI [15.48-26.43]) and remained significantly higher for the entire treatment period. In molidustat-treated groups, HCT exceeded 60% on Day 21 (Group 2) and Day 14 (Group 3). Mean HCT in molidustat-treated cats returned to within the reference range (29%-45%) after Day 56 and was numerically comparable to placebo from Day 70 onwards. Red blood cell count and hemoglobin concentrations followed a similar pattern as HCT. Mean EPO concentrations significantly increased after molidustat administration on all assessment days. Molidustat treatments were well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: Marked erythropoietic effects were identified after daily administration of molidustat to healthy cats and additional studies are warranted to evaluate the effects in anemic cats.

Plasma pharmacokinetics of tigolaner, emodepside, and praziquantel following topical administration of a combination product (Felpreva®) and of intravenous administration of the individual active ingredients in cats.

Felpreva® for cats contains the new acaricidal/insecticidal active ingredient tigolaner in a fixed combination with the nematocidal and cestocidal compounds emodepside and praziquantel, respectively. The plasma pharmacokinetics of tigolaner, emodepside, and praziquantel were evaluated in clinically healthy cats following topical (spot-on) treatment as fixed combination Felpreva®. For the determination of bioavailability intravenous administration of single active ingredients was also performed. After a single topical administration of Felpreva® using the target dose volume of 0.148 â€‹ml/kg to cats, tigolaner reached mean peak concentrations of 1352 â€‹µg/l with a Tmax of 12 days and a mean half-life of 24 days. Simulation of repetitive topical administration every 91 days indicates only a low risk of accumulation after reaching steady state within two to three administrations. The volume of distribution calculated after intravenous dosing was 4 â€‹l/kg and plasma clearance was low with 0.005 â€‹l/h/kg. Overall plasma exposure was 1566 â€‹mg∗h/l after topical administration, providing an absolute bioavailability of 57%. Tigolaner was mainly cleared via the faeces (54% within 28 days), renal clearance was neglectable (< 0.5% within 28 days). Emodepside and praziquantel showed mean peak concentrations of 44 â€‹µg/l and 48 â€‹µg/l (reached after 1.5 days and 5 â€‹h, respectively). Overall plasma exposures were 20.6 and 3.69 â€‹mg∗h/l, respectively. The elimination half-life was 14.5 days for emodepside and 10 days for praziquantel after topical administration. After topical administration of Felpreva® using 2.5× and 5× dose multiples an almost proportional increase of plasma exposure was observed for all three active ingredients. With the addition of tigolaner, Felpreva® combines the established pharmacokinetic (PK) characteristics of emodepside and praziquantel contained in Profender® spot-on for cats with the favourable PK of tigolaner suitable for a 3-months protection against fleas and ticks.

Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis.

Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness.

Pharmacokinetics of an intravenous and oral dose of enrofloxacin in white rhinoceros (Ceratotherium simum).

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic-pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half-life, area under the curve (AUCtot ), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 µg ml-1  hr-1 , 0.19 ± 0.04 L h-1  kg-1 , and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC24 : MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 µg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.

A toxicokinetic and toxicodynamic modeling approach using Myriophyllum spicatum to predict effects caused by short-term exposure to a sulfonylurea.

Toxicokinetic and toxicodynamic models are a promising tool to address the effects of time-variable chemical exposure. Standard toxicity tests usually rely on static concentrations, but these chemical exposure patterns are unlikely to appear in the field, where time-variable exposure of chemicals is typical. In the present study, toxicodynamic processes were integrated into an existing model that includes the toxicokinetics and growth of the aquatic plant Myriophyllum spicatum, to predict the impact on plant growth of 2 iofensulfuron short-term exposure patterns. To establish a method that can be used with standard data from risk assessments, the toxicodynamics of iofensulfuron were based on effect data from a 14-d standard toxicity test using static concentrations. Modeling showed that the toxicokinetic and toxicodynamic growth model of M. spicatum can be successfully used to predict effects of short-term iofensulfuron exposure by using effect data from a standard toxicity test. A general approach is presented, in which time-variable chemical exposures can be evaluated more realistically without conducting additional toxicity studies.

In vivo efficacy of PF1022A and nicotinic acetylcholine receptor agonists alone and in combination against Nippostrongylus brasiliensis.

The cyclooctadepsipeptide PF1022A and the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine were tested as examples for drug classes potentially interesting for development as anthelmintics against human helminthiases. These compounds and levamisole were tested alone and in combination to determine their efficacy against the rat hookworm Nippostrongylus brasiliensis. After three oral treatments, intestinal worms were counted. Drug effects on parasite morphology were studied using scanning electron microscopy (SEM). Plasma pharmacokinetics were determined for tribendimidine and dAMD. All drugs reduced worm burden in a dose-dependent manner, however amidantel was significantly less active than the other aminophenylamidines. Combinations of tribendimidine and dAMD with levamisole or PF1022A at suboptimal doses revealed additive effects. While PF1022A caused virtually no changes in morphology, levamisole, dAMD and tribendimidine caused severe contraction, particularly in the hind body region. Worms exposed to combinations of PF1022A and aminophenylamidines were indistinguishable from worms exposed only to aminophenylamidines. After oral treatment with tribendimidine, only the active metabolite dAMD was detectable in plasma and concentrations were not significantly different for oral treatment with dAMD. The results support further evaluation of cyclooctadepsipeptides alone and in combination with cholinergic drugs to improve efficacy. Combining these with registered drugs may help to prevent development of resistance.

Simple and rapid determination of enrofloxacin and ciprofloxacin in edible tissues by turbulent flow chromatography/tandem mass spectrometry (TFC-MS/MS).

A simple and rapid method for the determination of residues of enrofloxacin and its metabolite ciprofloxacin in edible tissues of farm animals using turbulent flow chromatography/tandem mass spectrometry (TFC-MS/MS) is described. The tissue samples were extracted with a mixture of acetonitrile, water and formic acid. After addition of internal standard solution, an aliquot of the extract was injected into the turbulent flow chromatography system. Matrix components contained in the injected sample were separated from the retained analytes on a polymer-based extraction column suited for pretreatment of samples at high flow rates. The analytes were eluted to an analytical column and the quantitative determination was performed using a tandem mass spectrometric detector. The run time for the analysis was 4 min. The limit of quantitation (LOQ) was 25 microgkg(-1) for each analyte and tissue material. Validation was performed in edible tissues of cattle, pig, turkey and rabbit in the range from 25 microgkg(-1) to at least twice the MRL. Mean recovery rates for the tissues of the different species were in the range from 72 to 105% with a coefficient of variation (CV) between 4.3 and 18%.

Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs.

OBJECTIVE: To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation beta1-adrenoceptor-selective blocking agent, with those of carvedilol, a third-generation beta1/beta2 and alpha1-adrenoceptor blocking agent, in dogs. ANIMALS: 12 healthy adult Beagles. PROCEDURES: A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed. RESULTS: After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 microg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 microg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 microg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 microg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol. CONCLUSIONS AND CLINICAL RELEVANCE: After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Studies on a new device for drug delivery to the eye.

Delivery of drugs to the anterior side of the eye is routinely done with eye drops, but this method results in low bioavailability and low patient compliance. Herein, we describe a new device for the delivery of drugs to the eye. The device, called the OphthaCoil, consists of a drug-loaded adherent hydrogel coating on a thin metallic wire, which is coiled. The drug release rates of the dye fluorescein and the antibiotic chloramphenicol have already been evaluated in vitro. In this report the drug release rate of the anti-infective pradofloxacin was evaluated in vitro and in vivo. The data show that the OphthaCoil is capable of sustained drug delivery to the tear film in dogs. Drug levels in the tear fluid of the dogs were well above the MIC-values of relevant bacteria after 16 h, but it should be noted that pradofloxacin has an exceptionally high antimicrobial activity. The study indicates that the OphthaCoil holds promise as a platform for sustained release of drugs to the eye. The device was well tolerated, but the devices were lost when left overnight. Most probably, this is due to the third eyelid pushing the device out of the conjunctival sac during sleep. It should be noted that this complication has no immediate implication for extended wear of the OphthaCoil in humans, as humans do not have third eyelids.

An explorative study to assess the efficacy of toltrazuril-sulfone (ponazuril) in calves experimentally infected with Neospora caninum.

BACKGROUND: Neospora caninum is an important cause of infectious abortion and stillbirth in cattle world-wide. Infection is common and may frequently be passed from mother to calf (vertical transmission) with no signs of disease. Based on our previous observation that N. caninum-infection can be efficiently controlled with toltrazuril-sulfone (ponazuril) in experimentally infected mice, we addressed the question if efficacy could also be obtained in experimentally infected calves. MATERIAL AND METHODS: The study included 19 calves and represents an initial explorative approach to document a basic effectiveness at first. Fifteen animals received each 2 x 10(8) N. caninum trophozoites, half of the dose being injected intravenously and the other half subcutaneously. Efficacy of treatment was assessed using molecular detection of parasite DNA with PCR and pathological alterations by immunohistochemistry in different organs of the animals. Assessment included also clinical, serological and pathophysiological parameters. RESULTS: In those calves medicated with ponazuril (one, or six consecutive days, respectively, starting one day after infection), a complete abrogation of the parasite detectability was obtained in the brain and other organs, while 50% of non-treated calves became PCR-positive in brain and muscles. Clinically, ponazuril chemotherapy of infected calves--in comparison to non-treated infected animals--reduced symptoms (fever), but no differences were observed between treated and non-treated animals with regard to serum enzymes and metabolites. Efficacy of a six-day treatment was also reflected by significantly lower anti-Neospora antibody concentrations developed after infection, when compared to non-treated animals. CONCLUSION: Based on our findings in this initially explorative approach that indicate a basic effectiveness of ponazuril against experimental N. caninum infection in calves, we plan to follow our chemotherapeutical intervention strategy to control bovine neosporosis with a subsequent more extensive field study with naturally infected calves.