Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide.

In the hepatic uptake of organic anions, organic anion transporting polypeptide (OATP) 1B1 is believed to be mainly involved. We have constructed a set of double-transfected cells coexpressing OATP1B1 and hepatic efflux transporters and characterized the transcellular transport of several anions. Recent reports have also suggested the importance of OATP1B3 in the hepatic uptake of some compounds.

Renoprotective effects of telmisartan on renal injury in obese Zucker rats.

The purpose of the present study was to investigate the renoprotective effect of telmisartan, an angiotensin II receptor antagonist, on the early stages of diabetic nephropathy in obese Zucker rats, which is a type 2-related diabetes mellitus model. Telmisartan 1, 3 or 10 mg/kg/day was orally administered to 7-week-old rats that demonstrated glucose tolerance without albuminuria or proteinuria, for 24 consecutive weeks (Experiment A). In another experiment (Experiment B), oral administration of telmisartan 10 mg/kg/day was initiated at the age of 16 weeks after the rats demonstrated marked proteinuria, and continued for 24 weeks.

Renoprotective effects of telmisartan in the 5/6 nephrectomised rats.

The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx). Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium.

Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans.

Telmisartan, a nonpeptide angiotensin II receptor antagonist, is selectively distributed to liver. In the present study, we have characterized the contribution of organic anion transporting polypeptide (OATP) isoforms to the hepatic uptake of telmisartan by isolated rat hepatocytes, human cryopreserved hepatocytes, and human transporter-expressing cells. Because it is difficult to evaluate the transport activity of telmisartan because of its extensive adsorption to cells and culture materials, we performed the uptake study in the presence of human serum albumin.

Pre-Injury magnesium treatment prevents traumatic brain injury-induced hippocampal ERK activation, neuronal loss, and cognitive dysfunction in the radial-arm maze test.

We studied the effect of pre-injury magnesium (Mg(2+)) treatment on hippocampal extracellular signal- regulated kinase (ERK) activation induced by lateral fluid-percussion (FP) brain injury, and on working and reference memory in the radial-arm maze test in rats subjected to such traumatic brain injury (TBI) (n = 56) or to sham injury (n = 12). In the ipsilateral hippocampus, an increase in the phospho-ERK level was detected at 10 min after injury in rats subjected to FP brain injury of moderate severity (1.9-2.

Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients.

Objective: To describe the factors affecting pharmacokinetics of telmisartan, an angiotensin II receptor antagonist, a population pharmacokinetic (PPK) model has been developed based upon the data collected from healthy volunteers and hypertensive patients.

Methods: A total of 1566 plasma samples were collected from 20 healthy volunteers and 129 hypertensive patients, together with the demographic background. The data were analyzed by the NONMEM program using two-compartment model with first-order absorption.

Population pharmacokinetics of epinastine, a histamine H1 receptor antagonist, in adults and children.

Aims: Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H(1) receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children.

Methods: A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption.

Suppression of atopic-like dermatitis by treatment with antibody to lymphocyte function-associated antigen-1 in NC/Nga mouse.

The effect of a blocking-antibody specific for lymphocyte function-associated antigen-1 (LFA-1) was studied in an atopic-like dermatitis model, which was induced by the repeated application of picrylchloride in NC/Nga mice. Prophylactic treatment with anti-LFA-1 monoclonal antibody (mAb), not therapeutic treatment, significantly inhibited the skin severity score and the acanthosis with ulceration and infiltration of mast cells. Furthermore, the serum immunoglobulin E levels and cytokine production (interleukin-4 and interferon-gamma) by splenocytes stimulated with anti-CD3 antibody were also inhibited by treatment with anti-LFA-1 mAb.

Relationship between pharmacokinetic parameters and occurrence of adverse events in clinical trials performed in Europe and United States for an angiotensin II receptor antagonist, telmisartan.

The objective of this study was to clarify the relationship between the pharmacokinetic parameters of telmisartan and the occurrence of adverse events. In order to perform this study, a total of 1500 adverse events was collected from the eight clinical trials performed in Europe and the United States and the pharmacokinetic parameters (C(max) and AUC) were calculated with the parameters obtained from the population pharmacokinetic model which we have built. Using these data, the pharmacokinetic parameters (C(max) and AUC) were compared between subjects with or without the occurrence of adverse events.

Pharmacokinetic comparison of an angiotensin II receptor antagonist, telmisartan, in Japanese and western hypertensive patients using population pharmacokinetic method.

The objectives of this study were to develop a population pharmacokinetic (PPK) model for telmisartan based on the pooled data obtained from the different racial populations and then to identify the factors that affect the pharmacokinetics of telmisartan for the comparison between the regions. A PPK model was established based on the data of 1343 subjects in 12 clinical trials. The PK profiles of telmisartan were described with a 2-compartment model with first-order absorption.

Key parameters of sperm motion in relation to male fertility in rats given alpha-chlorohydrin or nitrobenzene.

This study was undertaken to detect key parameters of rat sperm motion in relation to male fertility by comparing the differences in sperm motion induced by treatment with alpha-chlorohydrin (ACH), known to produce spermatotoxicity, and nitrobenzene (NTB), known to produce testicular toxicity. Male rats received ACH (5 or 20 mg/kg/day) or NTB (60 mg/kg/day) for either 3 days or 18 days. Epididymal sperm was assessed for motility using a Hamilton-Thorne Sperm Analyzer (HTM-IVOS).

[Pharmacological and clinical profile of telmisartan, a selective angiotensin II type-1 receptor blocker].

Telmisartan (Micardis) is a potent, long-lasting, nonpeptide angiotensin II type-1 (AT(1)) receptor blocker (ARB) that is indicated for the treatment of essential hypertension. In receptor binding studies, telmisartan showed a high affinity and selectivity for the human AT(1) receptors compared with AT(2) receptors and a slower dissociation rate from the human AT(1) receptor than those of ARBs. In isolated aorta rings, telmisartan was shown to be an insurmountable antagonist of AII-induced contractions.

Involvement of substance P in scratching behaviour in an atopic dermatitis model.

Substance P is speculated to be a key mediator of itching in atopic dermatitis, possibly acting via the tachykinin NK1 receptor. Thus, we examined the effect of a tachykinin NK1 antagonist, BIIF 1149 CL, on scratching behaviour in a picrylchloride-induced dermatitis model in NC/Nga mice. BIIF 1149 CL ((S)-N-[2-[3,5-bis(trifluoromethyl) phenyl]ethyl]-4-(cyclopropylmethyl)-N-methyl-alpha-phenyl-1-piperazineacetamide, monohydrochloride, monohydrate) at a dose of 100 mg/kg, p.

Role of substance P in an NC/Nga mouse model of atopic dermatitis-like disease.

Background: Atopic dermatitis (AD) can be exacerbated or induced in genetically predisposed individuals by psychological stress, which causes the release of substance P (SP). Therefore, SP may play an etiological role in the mechanisms underlying AD.

Methods: Changes in the number of mast cells and SP-containing mast cells in lesional skin, and the serum concentrations of SP and IgE during the development of AD-like disease up to 8 weeks after the start of picryl chloride (PiCl) induction in NC/Nga mice were examined.

Angioarchitecture of tumors induced by two different cloned cell lines established from a transplantable rat malignant fibrous histiocytoma.

Angiogenesis, a biologic process whereby endothelial cells divide and migrate to form new blood vessels, is a key step in tumor growth, invasion, and metastasis. In the present study, we investigated the differences in angioarchitecture between two different tumors induced by cloned cell lines (MT-8 and MT-9), derived from a transplantable rat malignant fibrous histiocytoma, by scanning electron microscopy of vascular corrosion casts. During a 3-week observation period after implantation, the growth of MT-8 tumors appeared to be faster than that of MT-9 tumors.

Stable expression and characterization of human PN1 and PN3 sodium channels.

Nociceptive transduction in inflammatory and neuropathic pain involves peripherally expressed voltage-gated sodium channels, such as tetrodotoxin (TTX)-sensitive PN1 and TTX-resistant PN3. We generated recombinant cell lines stably expressing the human PN1 and PN3 sodium channels in Chinese hamster ovary (CHO) cells using inducible expression vectors. The PN1 and PN3 cDNAs were isolated from human adrenal gland and heart poly(A)+ RNAs, respectively.

[Meloxicam (Mobic): a review of its pharmacological and clinical profile].

Meloxicam (Mobic) is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid, exhibiting selectivity for cyclooxygenase (COX)-2 over COX-1. Meloxicam has shown potent anti-inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models. It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat, but also of bone and cartilage destruction.

Three-dimensional angioarchitecture in transplantable rat fibrosarcomas.

Three-dimensional angioarchitecture in a transplantable fibrosarcoma (SS) in F344 rats was investigated by scanning electron microscopy (SEM) of vascular corrosion casts. Tumours were produced in syngeneic rats by implantation of a tumour fragment from another SS tumour. Viable SS tumours, observed up to post-implantation (PI) week 5, showed a high degree of vascularization, consisting of arterioles and veins, and intertwining capillaries branching from such vessels.

Influence of the CYP2D6*10 allele on the metabolism of mexiletine by human liver microsomes.

Aims: To study the influence of CYP2D6*10 on the formation of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM) using microsomes from human liver of known genotypes.

Methods: Microsomes from human livers of genotype CYP2D6*1/*1 (n = 5), *1/*10 (n = 6) and *10/*10 (n = 6) were used in this study. The formation of PHM and HMM was determined by high-performance liquid chromatography.

Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 10). Testicular toxicity of adriamycin observed 2 and 4 weeks after a single intravenous administration.

The present study was performed to clarify whether toxic effects of the antitumor drug, adriamycin (ADR) on the male genital organ can be adequately detected 2 and 4 weeks after a single intravenous administration in the rat. ADR was intravenously administered once to 10 Crj:CD (SD) male rats/group aged 6 weeks (4-week group) and 8 weeks (2-week group) at doses of 0, 2 and 6 mg/kg. The rats were sacrificed at the age of 10 weeks.

Meloxicam inhibits prostaglandin E(2) generation via cyclooxygenase 2 in the inflammatory site but not that via cyclooxygenase 1 in the stomach.

We studied the effects of meloxicam on prostanoid levels, both in the inflammatory site in rat carrageenin-induced pleurisy and in the rat stomach injected with 1 mol/l NaCl solution, to clarify the relationship between its low gastric toxicity and its relative cyclooxygenase (COX) 2 selectivity. NS-398 (3 mg/kg), a highly selective COX-2 inhibitor, and meloxicam (3 mg/kg) exhibited anti-inflammatory effects in the pleurisy model. Prostaglandin (PG) E(2) thromboxane (TX) B(2) and 6-keto-PGF(1alpha) were detectable in the inflammatory site.

The lethal expression of the GluR2flip/GluR4flip AMPA receptor in HEK293 cells.

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) -type glutamate receptors play a critical role in excitotoxicity associated with cerebral hypoxia, ischaemia and other acute brain insults. AMPA receptors are composed of GluR1-GluR4 subunits in homomeric and heteromeric assemblies, forming nonselective cation channels. In addition, each subunit has alternative splice variants, flip and flop forms.

Quantitative prediction of in vivo drug interactions between nevirapine and antifungal agents from in vitro data in rats.

We investigated the effects of ketoconazole (KCZ) and fluconazole (FCZ) on rat liver microsomal nevirapine (NVP) metabolism in vitro and on NVP plasma profiles in vivo in order to determine whether the in vivo drug interactions could be predicted quantitatively from the in vitro data. The Ki values of KCZ and FCZ for NVP 12-hydroxylation were 1.59 microm and 11.

Stable expression of human homomeric and heteromeric AMPA receptor subunits in HEK293 cells.

Human homomeric and heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors (GluRs) were stably expressed in HEK293 cells with cDNAs encoding the flip splice variant of GluR1, GluR2, GluR3, GluR4 subunit, and the GluR1/GluR2, GluR3/GluR2, and GluR4/GluR2 combination. The lethal combination of GluR2 and GluR4 subunits was found in high expression levels of both receptors. The AMPA-evoked current voltage relationships demonstrated the functional channel properties, such as a double rectification in GluR1, GluR3, and GluR4 receptors, and a linear relation in receptors assembled from GluR2 alone and coexpression of GluR2 with the other subunits.