In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines.

Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent.

Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6beta-hydroxylation [cytochrome P-450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19), p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1), p-nitrophenol (UGT(pl 6.2)), and valproic acid.

Observation of hepatotoxic effects of 2-n-pentylaminoacetamide (Milacemide) in rat liver by a combined in vivo/in vitro approach.

Milacemide or 2-n-pentylaminoacetamide hydrochloride, a new glycine derivative, was found to cause elevations of plasma transaminases in patients suffering from severe depression and Alzheimer's disease. However, no signs of liver toxicity were observed during the course of earlier conducted subchronic and chronic in vivo studies in rodents and cynomolgus monkeys. In this study an in vivo/in vitro approach has been proposed to detect early alterations in key metabolic and functional liver capacities.

Effect of folate supplementation on clinical chemistry and hematologic changes related to bidisomide administration in the rat.

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide.

A simple method for performing routine histopathological examination of the cardiac conduction tissue in the dog.

In standard toxicity studies, the cardiac conduction tissue is not systematically sampled and examined for histopathological changes. Most methods described use serial sectioning perpendicular to the long axis of the sinoauricular node (SAN) and atrioventricular node (AVN). Dozens of slides are needed to allow examination of a significant portion of the SAN and AVN.

Deoxyuridine suppression test on isolated rat bone marrow cells and the in vitro effect of bidisomide.

The deoxyuridine suppression test was performed on isolated rat bone marrow cells in order to study the effect of bidisomide, a new Class I antiarrhythmic agent, on folate-dependent DNA synthesis. Methotrexate and 5-fluorouracil, two known inhibitors of DNA synthesis, were included in the study to validate the test system. Methotrexate and 5-fluorouracil, at a concentration of 5.

Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonists, in rat and human hepatocyte cultures.

1. The metabolism of SC-42867 and SC-51089, two PGE2 antagonists, was studied in cultured rat and human hepatocytes. Both compounds possess an 8-chlorodibenzoxazepine moiety, but differ from each other by the nature of the side chain connected to the nitrogen atom.

Fasting for 24 h reveals liver microsteatosis after continuous i.v. infusion of milacemide in the rat.

Milacemide (2-n-pentylaminoacetamide) hydrochloride was administered by continuous i.v. infusion for up to 7 days, at 300 and 600 mg/kg per day to male Sprague-Dawley rats.

The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B.

The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.

Arterial reactivity, blood pressure, and plasma levels of atrial natriuretic peptides in normotensive and hypertensive rats: effects of acute and chronic administration of atriopeptin III.

We compared acute and chronic effects of atriopeptin III in normotensive and spontaneously hypertensive rats. Atriopeptin III relaxed isolated aortae and intrarenal microarteries but not coronary and mesenteric microarteries of normotensive rats. Effects on arterial smooth muscle were comparable in hypertensive and normotensive rats and were not affected by long-term treatment of the animals with the peptide.

Smooth muscle relaxing, acute and long-term blood pressure lowering effects of atriopeptins. Structure-activity relationship.

The relationship between the arterial relaxing, acute and long-term blood pressure lowering effects of atriopeptins were analyzed. We therefore evaluated effects of atriopeptin (103-126), i.e.

In vitro vasorelaxing activity of suloctidil.

The vasorelaxing effect of suloctidil was evaluated in isolated rat and rabbit aorta and in isolated rabbit mesenteric and saphenous artery. Suloctidil inhibited contractions induced by increasing extracellular calcium in depolarized arteries, mainly in a competitive way. In the rat aorta, the pA2 value was 7.

Effect of suloctidil on rat liver.

The effect of suloctidil (120 mg/kg body weight PO for 3 weeks) on rat liver was investigated using biochemical and morphological methods: enzymatic activities characteristic of the main cellular compartments were used as biochemical markers of hepatocyte function and morphometry was applied to investigate morphological changes. No sign of hepatotoxicity was evidenced after suloctidil treatment (liver weight; cytochrome c oxidase; glucose 6-phosphatase; NADPH-cytochrome c reductase; D-amino acid oxidase; urate oxidase; fatty acid oxidation; peroxisomal number, volume and size distribution). Suloctidil increased catalase activity by 22% without morphologically detectable changes in the peroxisomes.

Inhibition by suloctidil of [3H] nitrendipine binding to cerebral cortex membranes.

[3H] Nitrendipine binds specifically with high affinity and high capacity (KA congruent to 0.20 +/- 0.01 nM, Bmax = 4.

Antihypertensive activity of tibalosine (CP 804 S) in the rat. Possible involvement of a central alpha 1-adrenergic receptor blockade.

The effect of tibalosine (CP 804 S) on systolic blood pressure and heart rate of unanaesthetized normotensive, spontaneously hypertensive (SHR) and DOCA-salt and Goldblatt hypertensive rats has been examined. After a single oral dose, tibalosine (1.9 to 15 mg/kg) elicited dose-dependent reductions in blood pressure in the four models tested.

Comparison of [3H]nitrendipine binding to heart membranes of normotensive and spontaneously hypertensive rats.

We compared the binding properties of [3H]nitrendipine in heart membranes from 9- and 24-week-old spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). In native membranes of 9-week-old SHR and WKY and of 24-week-old WKY, [3H]nitrendipine binds to a single class of binding sites with high affinity (Kd, approximately equal to 0.20 nM) and high capacity (Bmax, approximately equal to 96 fmol X mg protein-1).

Receptor binding profile of tibalosine, a new antihypertensive.

The ability of 1-(2,3-dihydro-5-benzo[b]thienyl]-2-(4-phenylbutylamino)-1- propanol-(erythro) (tibalosine, CP 804 S), a new antihypertensive agent, to interact with 11 different receptors has been studied by binding assays. Tibalosine interacts specifically with alpha- and beta-adrenergic receptors and calcium channel binding sites. Ki values (nmol/l) for inhibition of specific binding are 26, 1000, 1000 and 770 respectively for the alpha 1-adrenergic, beta 1- and beta 2-adrenergic receptors and calcium channel binding sites.

Anticonvulsant activity of milacemide.

The anticonvulsant activity of a new drug, milacemide (2-(pentylamino)-acetamide), has been studied in animal models of convulsions like those induced by bicuculline, pentylenetetrazol, picrotoxin, strychnine, inhibitors of GABA synthesis as 3-mercaptopropionic acid, allylglycine, isoniazid and thiosemicarbazide and electroshock. Milacemide is particularly effective in inhibiting the convulsions induced by bicuculline. The ED50 is 5.

The adenylate cyclase activity in heart membranes from normotensive and spontaneously hypertensive rats, after chemical sympathectomy, suggests the presence of presynaptic secretin receptors.

Normotensive (WKY) and spontaneously hypertensive (SHR) male adult rats were sacrificed 2 and 3 weeks after 6-hydroxydopamine treatment. Untreated WKY and SHR rats served as controls. In rat heart membranes from WKY rats, 6-hydroxydopamine treatment increased guanosine 5'-O-(2-3-imido)-triphosphate (Gpp(NH)p)-, NaF-, D,L-isoproterenol- and glucagon-stimulated adenylate cyclase activities by 18-38% while secretin stimulation was unaffected.

Effect of milacemide, a glycinamide derivative, on the rat brain gamma-aminobutyric acid system.

Milacemide (CP 1552 S, 2-n-pentylaminoacetamide), a drug with anti-epileptic potency, increases the gamma-aminobutyric acid (GABA) content specifically in the substantia nigra of rat brain. The effect is dose-related from 25 to 100 mg/kg p.o.

Topographical distribution of the secretin- and VIP-stimulated adenylate cyclase system in the heart of five animal species.

Adenylate cyclase stimulation by secretin and VIP was compared to the effect of glucagon, D,L-isoproterenol, Gpp[[NH]p, and NaF in atria and ventricles from rat, guinea pig, rabbit, dog and Cynomolgus monkey. In rat ventricular membranes, secretin was a better stimulant than VIP and was as active as D,L-isoproterenol. In rat auricular membranes both peptides were inactive.