Canine digoxin

BACKGROUND: HIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PI-induced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. We also found that HIV PIs significantly increased the intracellular concentrations of BBR in macrophages. However, the underlying mechanisms of HIV PI-induced BBR accumulation are unknown...

Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin...

The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood-brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1...

The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. (3)H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls...

The purpose of this study was to investigate whether changes in the pH of the gastrointestinal tract can directly affect P-glycoprotein (P-gp) function. The effect of changes in extracellular pH on P-gp functionality was examined by testing colchicine (a nonionizable P-gp substrate) in bidirectional Caco-2 and MDR1-Madine Darby canine kidney (MDCK) cell permeability assays, in which the pH of the apical and basolateral chambers was varied. Reduction of the pH from 7.4 to 5.0 and 4.5 markedly increased the apical-to-basolateral flux of colchicine and reduced the basolateral-to-apical flux...

Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 μg/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad...

OBJECTIVE: To review the association between clinical signs and diagnostic findings and the survival time of dogs with dilated cardiomyopathy (DCM), and any influence of treatment prescribed. METHODS: A retrospective observational study of 367 dogs with DCM. Survival times until death or euthanasia for cardiac reasons were analysed using the Kaplan-Meier method plus univariate and multivariate Cox proportional hazards models. Two-tailed P values less than 0.05 were considered statistically significant...

P-glycoprotein (P-gp) plays a crucial role in the multidrug resistance of pathogenic helminths in sheep (Ovis aries) as well as in antiparasitic drug pharmacokinetics in the host. We cloned sheep P-gp cDNA and expressed it stably in Madin-Darby canine kidney (MDCK) cells. The open reading frame consists of 3858 nucleotides coding for a 1285 amino acids containing protein. The sequence shows high homology to the orthologs of other mammalian species, especially cattle. Both ruminant DNA sequences show a 9 bp insertion that is lacking in all other investigated sequences...

Multiple drug resistance protein 1 (MDR1) is composed of two homologous halves separated by an intracellular linker region. The linker has been reported to bind myosin regulatory light chain (RLC), but it is not clear how this can occur in the context of a myosin II complex. We characterized MDR1-RLC interactions and determined that binding occurs via the amino terminal of the RLC, a domain that typically binds myosin heavy chain. MDR1-RLC interactions were sensitive to the phosphorylation state of the light chain in that phosphorylation by myosin light chain kinase (MLCK) resulted in a loss of binding in vitro...

From previous fits of drug transport kinetics across confluent Madin-Darby canine kidney II cell line overexpressing human multidrug resistance 1 cell monolayers, we found that a drug's binding constant to P-glycoprotein (P-gp) was significantly smaller than its IC(50) when that drug was used as an inhibitor against another P-gp substrate. We tested several IC(50) candidate functions, including the standard function, the Kalvass-Pollack function, and the efflux ratio, to determine whether any of them yielded an IC(50) = K(I), as would be expected for water-soluble enzymes...

OBJECTIVE: To test the efficacy and tolerability of long-term administration of the angiotensin converting enzyme inhibitor, benazepril, in dogs with heart failure. METHODS: The study was a prospective, randomized, double-blind, placebo-controlled clinical trial involving 16 centers in France, Italy, Switzerland and UK. A total of 162 dogs with class II and III (ISACHC classification) heart failure caused by chronic valvular disease (CVD) or dilated cardiomyopathy (DCM) were enrolled...

BACKGROUND: The index of myocardial performance has prognostic power in patients with cardiomyopathy and following myocardial infarction. As the index of myocardial performance has been shown to be preload and afterload dependent, the effect of altering contractility on IMP and its components with left ventricular dysfunction has been incompletely delineated. METHODS: Chronic left ventricular dysfunction was induced in 10 canines using coronary microsphere embolization...

Previously, we clarified the species differences in P-glycoprotein (P-gp)-mediated drug transport activity using human MDR1, monkey MDR1, canine MDR1, rat MDR1a, rat MDR1b, mouse mdr1a, and mouse mdr1b transfected LLC-PK(1) cell lines. However, the species differences in the inhibitory effects on P-gp-mediated drug transport have not been clarified yet. The purpose of the present study was to evaluate the species differences in the inhibitory effects of typical P-gp inhibitors, quinidine and verapamil, on P-gp-mediated drug transport using MDR1 transfected cell lines...

PURPOSE: Stable transformants expressing human multidrug resistance 1 (MDR1), monkey MDR1, canine MDR1, rat MDR1a, rat MDR1b, mouse mdr1a, and mouse mdr1b in LLC-PK1 were established to investigate species differences in P-glycoprotein (P-gp, ABCB1) mediated efflux activity. METHODS: The seven cDNAs of MDR1 from five animals were cloned, and their transformants stably expressing the series of MDR1 in LLC-PK1 were established. Transport studies of clarithromycin, daunorubicin, digoxin, erythromycin, etoposide, paclitaxel, propranolol, quinidine, ritonavir, saquinavir, verapamil, and vinblastine were performed by using these cells, and efflux activity was compared among the species...

Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, or biliary efflux, it is anticipated that information regarding the potential interaction of drug candidates with Pgp will be a future regulatory expectation. Therefore, to be able to utilize in vitro Pgp inhibition findings to guide clinical drug interaction studies, the utility of five probe substrates (calcein-AM, colchicine, digoxin, prazosin, and vinblastine) was evaluated by inhibiting their Pgp-mediated transport across multidrug resistance-1-transfected Madin-Darby canine kidney cell type II monolayers with 20 diverse drugs having various degrees of Pgp interaction (e...

Compounds known to modulate P-glycoprotein (P-gp) activity were evaluated in cell monolayers expressing P-gp for their effects on the secretory transport of P-gp substrates paclitaxel, vinblastine, and digoxin. Paclitaxel has been proposed to selectively interact with a binding site on P-gp that is distinct from the vinblastine and digoxin-binding site. Using Madin-Darby canine kidney (MDCK)-multidrug resistance-1 (MDR1), MDCK-wild-type (WT), and Caco-2 cell monolayers, the basal-to-apical (BL-AP) apparent permeability (Papp) of [3H]paclitaxel, [3H]vinblastine, and [3H]digoxin in the presence of various concentrations of a series of structurally diverse P-gp substrates and modulators of P-gp function were determined...

The effect of verapamil on ventricular dysrhythmias was evaluated using two canine models. In one model, ventricular dysrhythmias were induced by 1% halothane-epinephrine (1.5 approximately 30 micro g/kg/min.) in 20 dogs (Group I). In the other model, ventricular dysrhythmias were induced by digoxin (0.1 approximately 0.2 mg/kg) in 27 dogs (Group II). Verapamil (0.2 approximately 0.5 mg/kg) was given to treat these ventricular dysrhythmias. When verapamil was ineffective, lidocaine (1 approximately 2 mg/kg) was given following the administration of verapamil...

Multidrug resistance in cancer chemotherapy frequently correlates with overexpression of the P-glycoprotein drug transporter. Attempts to reverse P-glycoprotein-mediated multidrug resistance with racemic verapamil or its less toxic (R)-enantiomer have been complicated by cardiotoxicity. The objective of this study was to investigate the effects of the major verapamil metabolite, norverapamil, as well as the PR-22 and D-620 metabolites, on P-glycoprotein-mediated drug transport. We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes...

Caco-2 epithelial layers were used as a model to re-evaluate the mechanism(s) by which intestinal digoxin absorption is limited by its active secretion back into the lumen. It is widely recognised that intestinal secretion of digoxin is mediated by the ATP-binding cassette (ABC) transporter Multidrug Resistance 1, MDR1. In MDR1-transfected Madin-Darby canine kidney, MDCKII, cell monolayers, digoxin secretion was reduced by the MDR1 inhibitor cyclosporin A, whereas no inhibition was seen in the presence of MK-571, 3-([(3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl]-[(3-dimethylamino-3-oxoprphyl)-thio)-methyl]-thio) propanoic acid, a Multidrug Related Protein (MRP) inhibitor...

Potential risks of cyclohexanol (CH) and cyclohexanediol (CHD) isomers, which are the metabolites derived from cilexetil ester side-chain of several prodrugs such as antibiotics (e.g. cefotiam hexetil) and an antihypertensive agent (candesartan cilexetil), were examined in beagles that were made congestive heart failure (CHF) by rapid ventricular pacing. The following three experiments tested the cardiac effects of i.v. doses of: (1) the metabolites alone, (2) the metabolites under the digoxin-induced bradycardia, and (3) the metabolites given concomitantly with digoxin (0...