Vitamins E and A increase the passing of the P-gp substrate ivermectin into the brain in mice.

This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8-10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A.

High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial.

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.

Ivermectin treatment in humans for reducing malaria transmission.

BACKGROUND: Malaria is transmitted through the bite of Plasmodium-infected adult female Anopheles mosquitoes. Ivermectin, an anti-parasitic drug, acts by killing mosquitoes that are exposed to the drug while feeding on the blood of people (known as blood feeds) who have ingested the drug. This effect on mosquitoes has been demonstrated by individual randomized trials. This effect has generated interest in using ivermectin as a tool for malaria control. OBJECTIVES: To assess the effect of community administration of ivermectin on malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation index - expanded, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the National Institutes of Health (NIH) RePORTER database to 14 January 2021. We checked the reference lists of included studies for other potentially relevant studies, and contacted researchers working in the field for unpublished and ongoing trials. SELECTION CRITERIA: We included cluster-randomized controlled trials (cRCTs) that compared ivermectin, as single or multiple doses, with a control treatment or placebo given to populations living in malaria-endemic areas, in the context of mass drug administration. Primary outcomes were prevalence of malaria parasite infection and incidence of clinical malaria in the community. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on the number of events and the number of participants in each trial arm at the time of assessment. For rate data, we noted the total time at risk in each trial arm. To assess risk of bias, we used Cochrane's RoB 2 tool for cRCTs. We documented the method of data analysis, any adjustments for clustering or other covariates, and recorded the estimate of the intra-cluster correlation (ICC) coefficient. We re-analysed the trial data provided by the trial authors to adjust for cluster effects. We used a Poisson mixed-effect model with small sample size correction, and a cluster-level analysis using the linear weighted model to adequately adjust for clustering.  MAIN RESULTS: We included one cRCT and identified six ongoing trials.  The included cRCT examined the incidence of malaria in eight villages in Burkina Faso, randomized to two arms. Both trial arms received a single dose of ivermectin 150 µg/kg to 200 µg/kg, together with a dose of albendazole. The villages in the intervention arm received an additional five doses of ivermectin, once every three weeks. Children were enrolled into an active cohort, in which they were repeatedly screened for malaria infection.  The primary outcome was the cumulative incidence of uncomplicated malaria in a cohort of children aged five years and younger, over the 18-week study. We judged the study to be at high risk of bias, as the analysis did not account for clustering or correlation between participants in the same village. The study did not demonstrate an effect of Ivermectin on the cumulative incidence of uncomplicated malaria in the cohort of children over the 18-week study (risk ratio 0.86, 95% confidence interval (CI) 0.62 to 1.17; P = 0.2607; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether community administration of ivermectin has an effect on malaria transmission, based on one trial published to date.

Identification of the metabolites of ivermectin in humans.

Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites.

The effect of breed, sex, and drug concentration on the pharmacokinetic profile of ivermectin in cattle.

Ivermectin (IVM) is one of the most widely used antiparasitic drugs worldwide and has become the drug of choice for anthelmintic and tick treatment in beef cattle production. It is known that pharmacokinetic parameters are fundamental to the rational use of a drug and food safety and these parameters are influenced by different factors. The aim of this study was to evaluate the pharmacokinetic profile of IVM in Bos indicus, Bos taurus, and crossbreed cattle (B. indicus × B. taurus) kept under same field conditions and the possible impacts of sex and IVM formulation (1% and 3.15%). It was observed that IVM concentration was significantly affected by breed. The plasma concentrations of IVM, AUC, Cmax , and t1/2ß were significantly higher in B. indicus compared to B. taurus. Crossbreed animals showed an intermediate profile between European and Indian cattle. No alteration in pharmacokinetics parameters was detected when comparing different gender. Concerning the pharmacokinetic data of IVM formulation, it was verified that Tmax , AUC, and t1/2ß were higher in 3.15% IVM animals than those from 1% IVM formulation. The results clearly indicated that the IVM plasma concentrations in B. indicus were higher than that in B. taurus.

Development and validation of an LC-MS/MS method for the analysis of ivermectin in plasma, whole blood, and dried blood spots using a fully automatic extraction system.

Ivermectin is deployed in mass drug administration (MDA) campaigns to control parasitic diseases in the tropics, with billions of treatments having been administered in the last three decades. Simple blood sampling tools, like the dried blood spots (DBS) technique, are needed to monitor treatments in such challenging settings. Thus, we developed a fully automated method for the analysis of ivermectin in DBS microsamples, including a bioanalytical and clinical validation. Automated extraction was carried out using a DBS-MS 500 autosampler which was coupled to a LC-MS/MS system. DBS were extracted with 20 µL solvent and eluted on a C8 analytical column. Analysis was performed by multiple reaction monitoring in the positive mode. Automated DBS extraction resulted in consistent recoveries (62.8 ± 4.3%) and matrix effects (68.0 ± 8.1%) between different donors and concentration levels. Intra- and inter-day accuracy and precision deviations were ≤15%, while samples with hematocrits from 20 to 60% could be quantified reliably. The achieved sensitivity of 1 ng/mL in DBS samples is sufficient to analyze ivermectin at the dose given (single oral administration of 12 mg) over a period of at least 72 h post treatment. Importantly, DBS samples are stable after one-month storage at room temperature (accuracy: 88.8-96.2%), thus samples collected in the field must not be shipped on dry ice. Ivermectin concentrations in venous and capillary blood agreed strongly, with a mean difference of -4.8%. Moreover, the drying process of DBS did not alter the analysis and importantly plasma concentrations can be estimated from DBS data using the hematocrit and red blood cell partitioning as correction factor. Our method enables uncomplicated sample collection and shipment as well as automated analysis of large amounts of samples, which is key to surveying MDA campaigns in remote settings.

The pharmacokinetics of moxidectin following intravenous and topical administration to swine.

The pharmacokinetic parameters of moxidectin (MXD) after intravenous and pour-on (topical) administration were studied in sixteen pigs at a single dose of 1.25 and 2.5 mg/kg BW (body weight), respectively. Blood samples were collected at pretreatment time (0 hr) over 40 days. The plasma kinetics were analyzed by WinNonlin 6.3 software through a noncompartmental model. For intravenous administration (n = 8), the elimination half-life (λZ ), the apparent volume of distribution (Vz ), and clearance (Cl) were 10.29 ± 1.90 days, 89.575 ± 29.856 L/kg, and 5.699 ± 2.374 L/kg, respectively. For pour-on administration (n = 8), the maximum plasma drug concentration (Cmax ), time to maximum plasma concentration (Tmax ), and λZ were 7.49 ng/ml, 1.72, and 6.20 days, respectively. MXD had a considerably low absolute pour-on bioavailability of 9.2%, but the mean residence time (MRT) for pour-on administration 10.88 ± 1.75 days was longer than 8.99 ± 2.48 days for intravenous administration. These results showed that MXD was absorbed via skin rapidly and eliminated slowly. The obtained data might contribute to refine the dosage regime for topical MXD administration.

Pharmacokinetics of ivermectin in sheep following pretreatment with Escherichia coli endotoxin.

The comparative pharmacokinetics of ivermectin (IVM), between healthy and in Escherichia coli lipopolysaccharides (LPS) injected sheep, was investigated after an intravenous (IV) administration of a single dose of 0.2 mg/kg. Ten Suffolk Down sheep, 55 ± 3.3 kg, were distributed in two experimental groups: Group 1 (LPS): treated with three doses of 1 µg LPS/kg bw at -24, -16, and -0.75 hr before IVM; group 2 (Control): treated with saline solution (SS). An IV dose of 0.2 mg IVM/kg was administered 45 min after the last injection of LPS or SS. Plasma concentrations of IVM were determined by liquid chromatography. Pharmacokinetic parameters were calculated based on non-compartmental modeling. In healthy sheep, the values of the pharmacokinetic parameters were as follows: elimination half-life (2.85 days), mean residence time (MRT) (2.27 days), area under the plasma concentration curve over time (AUC, 117.4 ng day-1 ml-1 ), volume of distribution (875.6 ml/kg), and clearance (187.1 ml/day). No statistically significant differences were observed when compared with the results obtained from the group of sheep treated with LPS. It is concluded that the acute inflammatory response (AIR) induced by the intravenous administration of E. coli LPS in adult sheep produced no changes in plasma concentrations or in the pharmacokinetic behavior of IVM, when it is administered intravenously at therapeutic doses.

Dermal pharmacokinetics of pyrazinamide determined by microdialysis sampling in rats.

Studies have demonstrated the efficacy of pyrazinamide (PZA) against stages of the Leishmania parasite that causes cutaneous leishmaniasis. Although PZA is widely distributed in most body fluids and tissues, the amount of drug reaching the skin is unknown. This study aimed to investigate the pharmacokinetics of PZA in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics was assessed by implanting a linear microdialysis probe in the dermis of ten rats. In addition, blood samples were collected to assess plasma pharmacokinetics. Unbound microdialysate (N = 280) and plasma (N = 120) concentrations following single intravenous doses of 25 mg/kg or 50 mg/kg PZA were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. Non-compartmental analysis and non-linear mixed-effects modelling were performed using WinNonlin and NONMEM v.7.3. PZA rapidly permeated into the dermis and reached high levels, with mean maximum concentrations (Cmax) of 22.4 ± 7.1 µg/mL and 48.6 ± 17.3 µg/mL for the two doses studied. PZA showed significant distribution to the skin (fAUCdermal/fAUCplasma = 0.82 ± 0.31 and 0.84 ± 0.25 for 25 mg/kg and 50 mg/kg doses, respectively). Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that free PZA levels in plasma were in equilibrium with tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. This study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.

Formulation Studies of Solid Self-Emulsifying Drug Delivery System of Ivermectin.

BACKGROUND: The suggested dose of ivermectin is 300 µG/kg/day for onchocerciasis but it has low water solubility and poor oral bioavailability. AIM: To prepare and evaluate a solid lipid-based self-emulsifying drug delivery system of ivermectin. MATERIALS AND METHODS: Based on supersaturated solubility study, oil, surfactant, and co-surfactant were selected. On the basis of ternary phase diagrams and simplex-lattice design, self-emulsifying, drug delivery formulations had been developed and optimized. Ivermectin-excipients compatibility studies were performed using differential scanning calorimetry and Fourier transform infrared spectroscopy. Solid self-emulsifying drug delivery formulation was formulated from the optimized batch by surface assimilation method and filled into hard gelatin capsules. In vitro release rate and in vivo pharmacokinetic parameters of ivermectin from the capsules were determined. Two-tailed paired t-test/Dunnett multiple comparison tests were performed for in vivo pharmacokinetic parameter at 95 % of confidence level. RESULTS: Soybeans oil, tween 80, and span 80 were selected as oil, surfactant, and co-surfactant respectively. The ternary diagrams were shown the maximum area for emulsion in 1:2 surfactant/co-surfactant ratio. The optimized batch had found with 30 mg ivermectin, 6.17 g soybeans oil, 0.30 g tween 80, and 3.50 g span 80. All differential scanning calorimetry and Fourier transform infrared characteristic peaks of the optimized formulation were identical with that of pure ivermectin. The area under the curve of ivermectin from the capsule was about two-fold higher than that of ivermectin suspension. CONCLUSIONS: Solid self-emulsifying drug delivery system was an effective oral solid dosage form to improve the oral bioavailability of ivermectin.

Initial evaluations of the effectiveness of spinetoram as a long-acting, oral systemic pulicide for controlling cat flea (Ctenocephalides felis) infestations on dogs.

Spinetoram is a semi-synthetic, spinosyn class natural product derived from fermentation by the actinomycete, Saccharopolyspora spinosa. Based on LD50 (50% lethal dose) values against adult cat fleas (Ctenocephalides felis) using an in vitro contact assay, spinetoram was approximately 4-fold more potent than spinosad. Subsequently, two parallel-arm, randomized block design laboratory studies were conducted to evaluate the effectiveness of orally administered spinetoram against experimental C. felis infestations on dogs, when administered as a single dose or multiple doses over a 6-12h interval. In the first study, 16 mixed-breed dogs were allocated to two treatment groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; and a single dose of spinetoram at 30mg/kg. In the second study, 32 mixed- and pure-breed dogs were allocated to four treatments groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; a single dose of 60mg/kg; three sequential 20mg/kg oral doses evenly administered over a 6h period; and three sequential 20mg/kg oral doses evenly administered over a 12h period. In both studies, treatments were administered to dogs in a fed state in order to enhance absorption of spinetoram. Therapeutic efficacy was assessed 24h after treatment and persistent efficacy was assessed 48h after each subsequent flea infestation. The duration of effectiveness was assessed at approximate weekly intervals beginning on Day 5 through Day 56 in the first study, or through Day 105 in the second study. In both studies, treatment efficacy was ≥99% (geometric means) through 44 d, with ≥99% efficacy continuing through 72 d for all three treatments in the second study. Efficacy remained ≥90% for at least 8 weeks with a single 30mg/kg dose; through 13 weeks with three sequential 20mg/kg doses; and through 15 weeks with a single 60mg/kg dose. For all time points and in both studies, spinetoram-treated groups had significantly fewer live fleas relative to their respective negative control group (p<0.05). The pharmacokinetic profile in dogs revealed that the mean plasma concentration of spinetoram required for effectiveness against fleas was maintained for at least 3 months regardless of whether the 60mg/kg total body dose was administered as a single bolus or in three sequential 20mg/kg doses administered over a 6-12h period of time. The results of preliminary in vitro and in vivo studies demonstrate that orally administered spinetoram was well tolerated, and provides long lasting effectiveness against C. felis infestations on dogs.

Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent.

Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (Cmax) at day 7 was 0.312 µg/ml and the half-life (t1/2) 35 days, so steady-state blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 µM (auranofin equivalent), or more than 25× the 50% inhibitory concentration (IC50) for E. histolytica and 4× that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 µg/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broad-spectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.).

Simultaneous quantification of tizoxanide and tizoxanide glucuronide in mouse plasma by liquid chromatography-tandem mass spectrometry.

Nitazoxanide (NTZ) is a broad-spectrum antimicrobial agent. Tizoxanide (T) and tizoxanide glucuronide (TG) are the major circulating metabolites after oral administration of NTZ. A rapid and specific LC-MS/MS method for the simultaneous quantification of T and TG in mouse plasma was developed and validated. A simple acetonitrile-induced protein precipitation method was employed to extract two analytes and the internal standard glipizide from 50 µL of mouse plasma. The purified samples were resolved using a C18 column with a mobile phase consisting of acetonitrile and 5 mm ammonium formate buffer (containing 0.05% formic acid) following a gradient elution. An API 3000 triple quadrupole mass spectrometer was operated under multiple reaction-monitoring mode with electrospray ionization. The precursor-to-product ion transitions m/z 264 → m/z 217 for T and m/z 440 → m/z 264 for TG were used for quantification. The developed method was linear in the concentration ranges of 1.0-500.0 ng/mL for T and 5.0-1000.0 ng/mL for TG. The intra- and inter-day precision and accuracy of the quality control samples at low, medium and high concentrations exhibited an RSD of <13.2% and the accuracy values ranged from -9.6 to 9.3%. We used this validated method to study the pharmacokinetics of T and TG in mice following oral administration of NTZ. Copyright © 2016 John Wiley & Sons, Ltd.

DBS-platform for biomonitoring and toxicokinetics of toxicants: proof of concept using LC-MS/MS analysis of fipronil and its metabolites in blood.

A simple, sensitive and high throughput LC-MS/MS method was developed and validated for quantification of fipronil, fipronil sulfone and fipronil desulfinyl in rat and human dried blood spots (DBS). DBS samples were prepared by spiking 10 µl blood on DMPK-C cards followed by drying at room temperature. The whole blood spots were then punched from the card and extracted using acetonitrile. The total chromatographic run time of the method was only 2 min. The lower limit of quantification of the method was 0.1 ng/ml for all the analytes. The method was successfully applied to determine fipronil desulfinyl in DBS samples obtained from its toxicokinetic study in rats following intravenous dose (1 mg/kg). In conclusion, the proposed DBS methodology has significant potential in toxicokinetics and biomonitoring studies of environmental toxicants. This microvolume DBS technique will be an ideal tool for biomonitoring studies, particularly in paediatric population. Small volume requirements, minimally invasive blood sampling method, easier storage and shipping procedure make DBS a suitable technique for such studies. Further, DBS technique contributes towards the principles of 3Rs resulting in significant reduction in the number of rodents used and refinement in sample collection for toxicokinetic studies.

Comparative plasma and milk dispositions, faecal excretion and efficacy of per os ivermectin and pour-on eprinomectin in horses.

The horse milk gains increasing interest as a food product for sensitive consumers, such as children with food allergies or elderly people. We investigated the plasma and milk disposition, faecal excretion and efficacy of per os ivermectin (IVM) and pour-on eprinomectin (EPM) in horses. Ten mares were divided into two groups. The equine paste formulation of IVM and bovine pour-on formulation of EPM were administered orally and topically at dosage of 0.2 and 0.5 mg/kg bodyweight. Blood, milk and faecal samples were analysed using high-performance liquid chromatography. The plasma concentration and persistence of IVM were significantly greater and longer compared with those of EPM. Surprisingly, EPM displayed a much higher disposition rate into milk (AUCmilk/plasma : 0.48) than IVM (AUCmilk/plasma : 0.19). IVM exhibited significantly higher faecal excretion (AUCfaeces : 7148.54 ng·d/g) but shorter faecal persistence (MRTfaeces : 1.17 days) compared with EPM (AUCfaeces : 42.43 ng·d/g and MRTfaeces : 3.29 days). Faecal strongyle egg counts (EPG) were performed before and at weekly intervals after treatment. IVM reduced the EPG by 96-100% for up to 8 weeks, whereas the reduction in the EPM group varied from 78 to 99%. In conclusion, due to the relatively low excretion in milk, EPM and IVM may be used safely in lactating mares if their milk is used for human consumption. Nevertheless, much lower plasma and faecal availabilities of EPM could result in subtherapeutic concentrations, which may increase the risk of drug resistance in nematodes after pour-on EPM administration compared with per os IVM.

Mechanism for transport of ivermectin to the stratum corneum in rats.

Ivermectin (IVM) is used as an oral medication for scabies, a skin infection caused by a mite, sarcoptes scabiei, which parasitizes in the stratum corneum. After oral administration IVM is absorbed from the intestine, and finally distributed to the stratum corneum to eliminate the mites. However its transport mechanism remains unclear. A pharmacokinetic study was performed using hairless Wistar Yagi (HWY) rats, which have no or atrophied sebaceous glands, and Wistar rats as a reference. After oral administration of IVM to both groups, the area under the concentration-time curve of IVM in the dermis and epidermis (dermis-epidermis) of HWY rats were about 60% lower than that of Wistar rats, even though the plasma concentration profiles were comparable in both groups. In addition at 12 h after the administration, IVM concentration in the outer stratum corneum, the shallower layer of the dermis-epidermis, was higher compared to that in the deeper layer. In the dermis-epidermis of the skin from various locations, the concentrations of IVM and squalene, the latter of which is secreted to the skin surface via the sebaceous gland, were positively well correlated. Those results suggest that IVM is transported to the stratum corneum via the sebaceous glands.

A comparison of the efficacy and pharmacokinetics of ivermectin after spring and autumn treatments against Cyathostominae in horses.

The aim of the present study was to determine the efficacy of ivermectin against Cyathostominae infections and to describe the drug's pharmacokinetic parameters during two seasonal deworming treatments in horses. The study was performed on warm-blooded mares aged 3-12 years weighing 450-550 kg. A single bolus of an oral paste formulation of ivermectin was administered at a dose of 0.2 mg/kg BW in spring and autumn. Fecal samples were tested before treatment and 1, 2, 3, 4, 6, 10, 20, 30, 40, 50, 60, 75 days after treatment. Ivermectin concentrations in blood samples collected before treatment, 0.5, 1, 2, 3, 4, 6, 12, 24, 36 and 48 hours after treatment, and 3, 4, 6, 8, 10, 15, 20, 25, 30, 40, 50, 60 and 75 days after drug administration were determined by high pressure liquid chromatography. Drug absorption was significantly (p<0.05) slower (tmax: 21.89±11.43 h) in autumn than in spring (tmax: 9.78±8.97 h). Maximum concentrations (Cmax) of ivermectin in the blood plasma of individual horses (8.40-43.08 ng/ml) were observed 2-24 h after drug administration during the spring treatment and 2-36 h (6.43-24.86 ng/ml) after administration during the autumn treatment. Significantly higher (p<0.05) ivermectin concentrations were found during the first 4 hours after administration in spring in comparison with those determined after the autumn treatment. The administration of the recommended dose of ivermectin resulted in 100% elimination of parasitic eggs from feces in spring and autumn treatment.

Failure of ivermectin per rectum to achieve clinically meaningful serum levels in two cases of Strongyloides hyperinfection.

Two cases of Strongyloides hyperinfection are presented. Ivermectin was initially administered orally and per rectum pending the availability of subcutaneous (SC) preparations. In neither case did rectal suppositories of ivermectin achieve clinically meaningful serum values. Clinicians should use SC preparations of ivermectin as early as possible in Strongyloides hyperinfection and dissemination.

Effect of high fat intake on the pharmacokinetic profile of ivermectin in rabbits.

Ivermectin (IVM) is used as an oral drug for treatment of scabies. It was reported that the area under the plasma concentration-time curve (AUC) of IVM was higher in healthy volunteers after a high-fat meal than in those who were fasting, but the mechanism has not been clarified yet. In fasted rabbits, the AUC after oral administration of IVM as a solution was higher than that of a suspension, indicating that the absorption of IVM depends on how much is dissolved in the gastrointestinal tract. On the other hand, the AUC was higher in rabbits pre-treated with a high-fat solution (HF; fat and cholesterol) than in those that had fasted, when IVM was administered orally not only in suspension but also in solution, and even when it was administered intravenously. In addition, the increase in total cholesterol level in the HF condition was correlated with the increase in IVM level. These results suggest that enhancement of solubility may not be the only reason for the increase of AUC in rabbits. It is also suggested that the increase of cholesterol concentration might change the distribution profile of IVM in plasma, and accordingly its concentration could be increased.

Ivermectin exposure leads to up-regulation of detoxification genes in vitro and in vivo in mice.

The biodisposition of the antiparasitic drug ivermectin in host and parasite is decisive for its efficacy and strongly depends on the efflux by ATP-Binding Cassette (ABC) transporters and on its biotransformation by cytochromes P450. The purpose of this study was to evaluate, in vitro and in vivo, the ivermectin ability in modulating the expression of the most important genes involved in drug detoxification. Gene expression of ABC transporters and cytochromes was evaluated by RT-qPCR in murine hepatic and intestinal cell lines exposed to increasing ivermectin doses, and in liver and intestine of mice orally administered with single or repeated therapeutic doses of ivermectin (0.2 mg/kg). Plasma, brain, liver and intestinal concentrations of ivermectin and its main metabolite were measured by HPLC in ivermectin-treated mice. In hepatocyte cell line, ivermectin up-regulated expression of Abcb1a, Abcb1b, Abcc2, Cyp1a1, Cyp1a2, Cyp2b10; while Abcb1a, Abcb1b, Abcg2, Cyp1a1, Cyp1a2, Cyp2b10 and Cyp3a11 levels were induced in intestinal cell line. In mice, repeated administration of ivermectin induced the expression of Abcb1a, Abcc2, Cyp1a1 and Cyp2b10 in intestine while only Cyp3a11 was induced in liver. Compared with single administration, repeated ivermectin administration lowered plasma, liver and intestine drug concentration, while increasing main metabolite content in plasma and intestine. These findings can be regarded as a warning that repeated ivermectin exposure is able to induce detoxification systems in mammals that may lead to subtherapeutic drug concentration. This may also be an important consideration in the assessment of drug-drug interaction and toxicity for other ABC transporters and CYP450s substrates.