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1.
Pharmacol Res Perspect ; 5(4)2017 Aug.
Article in English | MEDLINE | ID: mdl-28805970

ABSTRACT

Activation of G protein-coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic ß cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats. Treatment of rat islets with MR1704 increased glucose-dependent insulin secretion. Augmentation of glucose-dependent insulin secretion was abolished by adding a GPR40/FFAR1 antagonist. In mouse, insulinoma MIN6 cells, palmitic acid induced the activity of caspase 3/7 after a 72-h exposure, while pharmacologically active concentrations of MR1704 did not. In an oral glucose tolerance test in normal Sprague-Dawley rats, orally administered MR1704 (1-10 mg·kg-1 ) reduced plasma glucose excursion and enhanced insulin secretion, but MR1704 did not induce hypoglycemia, even at 300 mg·kg-1 , in fasted Sprague-Dawley rats. In addition, orally administered MR1704 reduced plasma glucose excursion and enhanced insulin secretion in diabetic Goto-Kakizaki rats. Oral administration of MR1704 once daily to Goto-Kakizaki rats reduced their blood glucose levels during a 5-week treatment period without reducing pancreatic insulin content; as a result, hemoglobin A1C levels significantly decreased. These results suggest that MR1704 improves glucose homeostasis through glucose-dependent insulin secretion with a low risk of hypoglycemia and pancreatic toxicity. MR1704 shows promise as a new, glucose-lowering drug to treat type 2 diabetes mellitus.

2.
Pharmacol Res Perspect ; 4(4): e00241, 2016 Aug.
Article in English | MEDLINE | ID: mdl-28116094

ABSTRACT

Recently, we identified a novel phosphodiesterase 10A (PDE10A) inhibitor, PDM-042 ((E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine). PDM-042 showed potent inhibitory activities for human and rat PDE10A with IC 50 values of less than 1 nmol/L and more than 1000-fold selectivity against other phosphodiesterases. Tritiated PDM-042, [3H]PDM-042, had high affinity for membranes prepared from rat striatum with a Kd value of 8.5 nmol/L. The specific binding of [3H]PDM-042 was displaced in a concentration-dependent manner by PDM-042 and another structurally unrelated PDE10A inhibitor, MP-10. In rat studies, PDM-042 showed excellent brain penetration (striatum/plasma ratio = 6.3), occupancy rate (86.6% at a dose of 3 mg/kg), and good oral bioavailability (33%). These data indicate that PDM-042 is a potent, selective, orally active, and brain-penetrable PDE10A inhibitor. In behavioral studies using rat models relevant to schizophrenia, PDM-042 significantly antagonized MK-801-induced hyperlocomotion (0.1-0.3 mg/kg) without affecting spontaneous locomotor activity and attenuated the conditioned avoidance response (CAR) (0.3-1 mg/kg). In tests for adverse effects, PDM-042 had a minimal effect on catalepsy, even at a much higher dose (10 mg/kg) than the minimal effective dose (0.3 mg/kg) in the CAR. Furthermore, PDM-042 had no effect on prolactin release or glucose elevation up to 3 mg/kg, while risperidone increased prolactin release and olanzapine enhanced glucose levels at doses near their efficacious ones in the CAR. Our results suggest that PDM-042 is a good pharmacological tool that can be used to investigate the role of PDE10A and may have therapeutic potential for the treatment of schizophrenia.

3.
Biochem Biophys Res Commun ; 424(2): 301-7, 2012 Jul 27.
Article in English | MEDLINE | ID: mdl-22749998

ABSTRACT

We previously reported that eicosapentaenoic acid (EPA) improved statin-induced rhabdomyolysis in rats (Naba et al. [6]). In this study, we report for the first time direct improvement by EPA of statin-induced toxicity in cultured myoblasts and the mechanistic involvement of endoplasmic reticulum (ER) stress. Differentiated rhabdomyosarcoma cells (RD cells) were treated with statins and EPA for 1-4days. Statins induced various toxic changes in RD cells, and EPA attenuated all of these changes. Interestingly, statins increased mRNA expression of ER stress markers (XBP-1 and CHOP) and EPA attenuated both. Further, in a statin-induced rat model of rhabdomyolysis, these markers in skeletal muscle were significantly correlated with plasma CPK activity. In RD cells, statins also increased p-c-Jun protein content and caspase-3/7 activity, while 4-PBA, an ER stress attenuator, PPAR-δ agonist, and EPA attenuated them. These findings suggest that EPA attenuates statin-induced ER stress, JNK activation and toxicity in cultured myoblast cells, and that PPAR-δ may mechanically involved in the effects of EPA.


Subject(s)
Eicosapentaenoic Acid/pharmacology , Endoplasmic Reticulum Stress/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Myoblasts/drug effects , Animals , Butylamines/pharmacology , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Myoblasts/metabolism , PPAR gamma/agonists , Rats
4.
J Pharmacol Sci ; 102(2): 205-12, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17031069

ABSTRACT

We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.


Subject(s)
Analgesics , Behavior, Animal/drug effects , Pain/drug therapy , Piperidines , Sciatic Neuropathy/drug therapy , para-Aminobenzoates , 4-Aminobenzoic Acid/adverse effects , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , Administration, Oral , Analgesics/adverse effects , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Biogenic Monoamines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Motor Activity/drug effects , Pain/metabolism , Pain/physiopathology , Pain Measurement , Piperidines/adverse effects , Piperidines/pharmacology , Piperidines/therapeutic use , Rats , Rats, Wistar , Receptors, GABA/metabolism , Sciatic Neuropathy/metabolism , Sciatic Neuropathy/physiopathology
5.
Biochem Biophys Res Commun ; 340(1): 215-20, 2006 Feb 03.
Article in English | MEDLINE | ID: mdl-16364247

ABSTRACT

The effect of ethyl eicosapentanoate (EPA-E) on statin-induced rhabdomyolysis was investigated by co-administration of EPA-E and pravastatin (PV), as a typical statin, to Eisai hyperbilirubinemic rats (EHBR). It was confirmed that the plasma PV concentration was not affected by simultaneous administration of EPA-E, and there was no cumulative increase of PV during prolonged co-administration of EPA-E and PV. Muscular degeneration was prominent (incidence 5/5; average grade 3.5 (range 2-4)) in EHBR treated with PV alone at 200 mg/kg/day for 14 days, but co-administration of EPA-E at doses of 100, 300, and 1000 mg/kg/day decreased the average grades to 1.4 (range 0.3-3.0), 0.5 (0.2-1.0), and 0.6 (0.0-1.7), respectively. Creatine phosphokinase (CPK) and myoglobin levels in plasma were well correlated with the grade of skeletal muscle degeneration. Thus, EPA-E appears to reduce the severity of statin-induced rhabdomyolysis.


Subject(s)
Disease Models, Animal , Eicosapentaenoic Acid/analogs & derivatives , Hyperbilirubinemia/complications , Hyperbilirubinemia/physiopathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Rhabdomyolysis/prevention & control , Rhabdomyolysis/physiopathology , Animals , Dose-Response Relationship, Drug , Drug Combinations , Eicosapentaenoic Acid/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Pravastatin , Rats , Rhabdomyolysis/chemically induced , Rhabdomyolysis/diagnosis , Severity of Illness Index , Treatment Outcome
6.
Drug Metab Pharmacokinet ; 19(5): 339-51, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15548845

ABSTRACT

The Eisai hyperbilirubinemic rat (EHBR) should be a useful animal model for studies on the toxicity of organic anions which are substrates of multidrug resistance-associated protein 2 (Mrp2), since the systemic exposure to these compounds is expected to be increased in EHBR. In this study, we tested the value of EHBR for this purpose, using pravastatin (PV) and methotrexate (MTX) as model compounds. In the case of a single oral dose of PV (200 mg/kg), C(max) in plasma was 4.0-fold higher and AUC(0-infinity) was 3.6-fold larger than those of normal Sprague-Dawley rats (SDR), respectively. When multiple doses of PV were given to EHBR without co-administration of any other compound, drug-induced skeletal muscle toxicity (myopathy/rhabdomyolysis) and increased creatine phosphokinase (CPK) level were observed, whereas a control experiment using SDR did not show any toxic change. When a single dose of MTX (0.6 mg/kg) was given to EHBR orally, C(max) was 1.7-fold higher and AUC(0-infinity) was 1.6-fold larger than those of SDR, respectively. When multiple doses of MTX were given to EHBR, the changes in bone marrow, spleen and intestines were more severe than those in SDR. These findings support the view that EHBR would be a valuable animal model for toxicity studies on organic anion compounds which are substrates of Mrp2.


Subject(s)
Anions/toxicity , Hyperbilirubinemia/physiopathology , Toxicity Tests , ATP-Binding Cassette Transporters/metabolism , Animals , Anions/pharmacokinetics , Area Under Curve , Blood Proteins/metabolism , Creatine Kinase/metabolism , Disease Models, Animal , Folic Acid Antagonists/toxicity , Half-Life , Hydroxymethylglutaryl-CoA Reductase Inhibitors/toxicity , Hyperbilirubinemia/genetics , Male , Methotrexate/pharmacokinetics , Methotrexate/toxicity , Muscle, Skeletal/enzymology , Pravastatin/pharmacokinetics , Pravastatin/toxicity , Protein Binding , Rats , Rats, Inbred Strains , Weight Gain/drug effects
7.
Biochem Biophys Res Commun ; 322(1): 197-202, 2004 Sep 10.
Article in English | MEDLINE | ID: mdl-15313191

ABSTRACT

Fas (CD95) ligand (FasL) has the ability to induce apoptosis in Fas-expressing glioma cells by binding to Fas. Several molecular species have been designed to be soluble Fas ligands for therapeutic purposes. We successfully constructed a chimeric soluble FasL by fusing an isoleucine zipper motif for self-oligomerization and a FLAG sequence to the extracellular domain of the human Fas ligand (FIZ-shFasL). The cytotoxic effect of FIZ-shFasL on Jurkat cells was equivalent to that of membrane-bound FasL and approximately 10-fold stronger than that of agonistic anti-Fas antibody (CH-11). Flow cytometric analysis demonstrated that the differential Fas expression of human brain tumor cell lines partially correlated with levels of apoptosis through FIZ-shFasL. The upper limit of FIZ-shFasL for safe systemic administration to rat is estimated as below 2 microg/ml in plasma concentration. FIZ-shFasL could be applicable as a therapeutic agent for cancer.


Subject(s)
Apoptosis/drug effects , Isoleucine/administration & dosage , Isoleucine/toxicity , Membrane Glycoproteins/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/toxicity , fas Receptor/metabolism , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Body Weight/drug effects , Cell Line, Tumor/drug effects , Cell Line, Tumor/pathology , Cell Survival/drug effects , Fas Ligand Protein , Female , Humans , Isoleucine/chemistry , Isoleucine/genetics , Jurkat Cells , Leucine Zippers , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/genetics , Membrane Glycoproteins/toxicity , Organ Size/drug effects , Rats , Rats, Wistar , Solubility
8.
Drug Metab Pharmacokinet ; 17(3): 214-20, 2002.
Article in English | MEDLINE | ID: mdl-15618672

ABSTRACT

The pharmacokinetics and pharamacodynamics of M17055, a novel diuretic were studied after a single intravenous administration to rats and dogs, the two species used in the pharmacological and toxicological studies. No gender dependent response to systemic exposure was observed at the high dose level in rats, in agreement with the determined LD(50). A gender difference in urinary excretion of M17055, however, was clearly observed in rats. The slower elimination and the lower total body clearance (CLtot) values of M17055 in dogs reflect the difference of the no-effect level (NOEL) between rats (0.1 mg/kg) and dogs (0.03 mg/kg) well. The diuretic response was well correlated with the urinary M17055 excretion rate by fitting to a sigmoid E(max) model in both rats and dogs. The derived ER(50) value of M17055 in dogs was approximately 10 times less than that reported for furosemide, suggesting that the intrinsic potency of M17055 is equal to or higher than those of other powerful loop diuretics. Although diuretic sensitivity was considered to be lower in dogs than in rats, the higher amount of M17055 reaching the dog kidney is likely to compensate for this. The diuretic response in female rats was predictable by using the pharmacodynamic parameters derived from male rats. These results show that the apparent high diuretic potency and the other pivotal observations for M17055 found in the pharmacological and toxicological studies can be rationalized by the pharmacokinetic and pharmacodynamic properties of the unchanged compound.

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