Determination of ivermectin B(1a) in animal plasma by liquid chromatography combined with electrospray ionization mass spectrometry

A novel, sensitive and specific method for the quantitative determination of ivermectin B(1a) in animal plasma using liquid chromatography combined with positive electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) is presented. Abamectin was used as the internal standard. Extraction of the samples was performed with a deproteinization step using acetonitrile. Chromatographic separation was achieved on a Nucleosil ODS 5 microm column, using gradient elution with 0.2% (v/v) acetic acid in water and 0.2% (v/v) acetic acid in acetonitrile. The method was validated according to the requirements defined by the European Community. Calibration curves using plasma fortified between 1 and 100 ng ml(-1) showed a good linear correlation (r > or = 0.9989, goodness-of-fit coefficient < or =8.1%). The trueness at 2 and 25 ng ml(-1) (n = 6) was +4.2 and -17.1%, respectively. The trueness and between-run precision for the analysis of quality control samples at 25 ng ml(-1) was -4.0 and 11.0%, respectively (n = 16). The limit of quantification of the method was 1.0 ng ml(-1), for which the trueness and precision also fell within acceptable limits. Using a signal-to-noise ratio of 3 : 1, the limit of detection was calculated to be 0.2 ng ml(-1). The specificity was demonstrated with respect to ivermectin B(1b).The method was successfully used for the quantitative determination of ivermectin B(1a) in plasma samples from treated bovines, demonstrating the usefulness of the developed method for application in the field of pharmacokinetics.     

A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach.     

Validated capillary electrophoretic method for the analysis of ivermectin in plasma after intragastric administration in pigs and horses

A capillary electrophoretic (CE) method has been developed for the determination of ivermectin (CAS 70288-86-7), a new generation drug with antiparasitic activity, in pig and horse plasma. The method was statistically validated for its linearity, accuracy, precision and selectivity. The linear range was from 1 to 30 ng mL(-1) with correlation coefficients greater than 0.999. The limit of detection was 0.3 ng mL(-1), while the quantitative limit was 1 ng mL(-1), using a 0.5 mL sample size. The validated procedure was used to determination of pharmacokinetic parameters of ivermectin after ingestion of 0.1 mg for pigs and 0.2 mg dose per kg body weight for horses, respectively. Studies were performed on a group of eight pigs and six horses. There were no significant differences between pigs and horses in any of the estimated pharmacokinetic parameters.     

Ivermectin, 'wonder drug' from Japan: the human use perspective

Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin--originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil--has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world's most devastating and disfiguring diseases which have plagued the world's poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin's passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a "wonder" drug.     

Selective Hydrogenation of Avermectin Catalyzed by Iridium-Phosphine Complexes

A series of new iridium complexes, IrCl（COD）（TMOPP） （1） [COD=1,5-cyclooctadiene, TMOPP=tris（4- methoxyphenyl）phosphine], IrCl（COD）（TFMPP） （2） [TFMPP = tris（4-trifluoromethylphenyl）phosphine], IrCl（COD）（BDNA） （3） [BDNA= 1,8-bis（diphenylphosphinomethyl）naphthalene], IrCl（COD）（BISBI） （4） [BISBI= 2,2＇-bis（diphenylphosphinomethyl）biphenyl] and IrCl（COD）（BDPB） （5） [BDPB= 1,2-bis（diphenylphosphinomethyl）benzene], were synthesized and characterized by NMR spectra and elemental analyses. In order to obtain the relationships between complex structures and their catalytic properties, IrCl（COD）（DPPM） （6） [DPPM = bis（diphenylphosphino）methane], IrCl（COD）（DPPE） （7） [DPPE= 1,2-bis（diphenylphosphino）ethane], IrCl（COD）（DPPP） （8） [DPPP=1,3-bis（diphenylphosphino）propane] and IrCl（COD）（TPP） （9） [TPP=triphenylphosphine], were also synthesized according to the reported methods. The hydrogenation results showed that the low electronic density at the central metal was favorable to increase the catalytic activity for the hydrogenation of avermectin, but decrease the selectivity to ivermectin. The complex with a large chelating ring and a bulky chelating backbone would easily cause the cleavage of C-O bond in avermectin to give a byproduct avermectin aglycon.     

ESI+ MS/MS confirmation of canine ivermectin toxicity

Ivermectin is a semisynthetic macrocyclic lactone anthelmintic of the avermectin family derived from Streptomyces fermentation products. Avermectins are used as antiparasitic agents in domestic animals; although considered relatively safe, one must consider animal species, breed, weight, and age in dosage determinations.In January 2006, two canines were presented to the UK Livestock Disease Diagnostic Center after dying from suspected ivermectin overdoses [30-50 mg/kg body weight]. To confirm this clinical diagnosis we developed a rapid, sensitive semiquantitative ElectroSpray Ionization-Mass Spectrometry (ESI/MS) method for ivermectin in canine tissue samples. Pharmaceutical ivermectin contains two ivermectins differing by a single methyl group, and each compound forms interpretation-confounding adducts with tissue Na(+) and K(+) ions. We now report that ivermectin administration was clearly confirmed by comparison with standard and dosage forms of ivermectin, and simple proportionalities based on mass spectral intensity of respective molecular ions allowed semiquantitative estimates of injection site tissue concentrations of 20 and 40 microg/g tissue (wet weight) in these animals, consistent with the history of ivermectin administration and the clinical signs observed.There is a distinct need for both rapid detection and confirmation of toxic exposures in veterinary diagnostics, whether for interpretation of clinical cases antemortem or for forensic reasons postmortem. It is vital that interpreters of analytical results have appropriate guidance in the scientific literature and elsewhere so as to enable clear-cut answers. The method presented here is suitable for routine diagnostic work in that it allows rapid extraction of ivermectin from tissue samples, avoids the need for high-performance liquid chromatography and allows ready interpretation of the multiple ivermectin species seen by ESI(+) MS/MS in samples originating from veterinary dosage forms.     

Simultaneous analysis of three avermectins in soils by high-performance liquid chromatography with fluorescence detection

A simple and sensitive method has been developed and validated for the determination of abamectin B_1a (ABA B_1a), emamectin B_1a (EMA B_1a) benzoate and ivermectin H₂B_1a (IVM H₂B_1a) in soils. The avermectins (AVMs) residues were extracted from soils with acetonitrile/water (9?:?1, v/v) and then were purified on C₁₈ solid-phase extraction (SPE) cartridge. After being derivatised by N-methylimidazole (N-MIM) and trifluoroacetic anhydride (TFAA), the residues of three AVMs were analysed by high-performance liquid chromatography with fluorescence detection (HPLC-FLD). The method was validated in terms of system suitability, linearity, selectivity, precision, recovery, specificity and stability. There was a good linear relationship (R ^2?>?0.99) for three AVMs ranged from 0.01 to 5?µg?mL^?1. The LOD and LOQs of ABA B_1a, EMA B_1a benzoate and IVM H₂B_1a for standard solutions were 1.1–1.7 and 3.6–5.7?µg?L^?1 respectively. The accuracy of AVMs in soils was from 83.7 to 115.5% with precision less than or equal to 12.4%. Using the developed method, 9 soil samples with 9.3–12806.3?µg?kg^?1 of AVMs residues had been detected.     

In situ DRIFT study of nonoxidative methane reaction on Mo/SnO2 catalyst

A kinetic study of the homogeneous catalytic hydrogenation of avermectins is reported for a series of isosteric p-substituted arylphosphines as ligands. The activity of the rhodium complexes formed in situ from [RhCl(COD)]₂ increased with increasing the electron-donor capacity of the P(p-XC₆H₄)₃: P(p-ClC₆H₄)₃ < P(C₆H₅)₃ < P(p-CH₃C₆H₄)₃ < P(p-OCH₃C₆H₄)₃. As expected, this trend was also observed when using preformed complexes thereof. Linear correlations based on Hammett and Kabachnik treatments are provided as useful tools to guide the exploration work towards improved [RhCl(COD)]₂/P(p-XC₆H₄)₃ catalytic systems.