The Bridging Research Accelerating Network Program of the Japan Agency for Medical Research and Development has increased academic research on nonclinical studies to acquire proof of concept for pharmaceuticals, and recently some universities with special technological knowledge have started collaborative research with pharmaceutical companies. In such joint research, companies often repeat studies conducted by academic institutions to ensure that the study data meet the reliability requirements for new drug applications (NDAs). Conducting repeated studies is costly and time consuming and delays the R&D process prior to filing NDAs. If reliable study data could be generated by academia, it would enhance the speed of drug development and promote the early launch of new drugs. This review explains aspects of research reliability which must be noted by academia, particularly with regard to studies cited in papers submitted to scientific journals or for NDAs. It also explains methods for maintaining records in experimental notebooks and how to correct records. The standards for "attributable, legible, contemporaneous, original, accurate" data, commonly referred to as the ALCOA standards, which ensure the integrity of raw data, are also introduced. In addition, the research reliability of facilities is discussed, such as how measurement equipment should be maintained and how experimental records should be stored. Ensuring the reliability of the study implementation process and the facility/equipment support process makes it possible to reconstitute studies and improve the reproducibility of the results, which is a fundamental principle of science. This review will be useful for pharmacy education in universities.

Recent clinical studies on chronic kidney disease (CKD) reported that renal dysfunction was a critical risk factor for cardiovascular events (CVE), which lead us to reconsider the effect of cardioprotective agents on the kidney. Glomerulonephritis, which is the major cause of CKD, is characterized by mesangial cell proliferation and extracellular matrix deposition. Nicorandil, a therapeutic drug for angina and acute heart failure, have been reported to show antiproliferative activity in mesangial cells. In this study, we first investigated the in vivo effects of nicorandil in anti-Thy1 nephritis rats. In male F344 rats, anti-Thy1 nephritis was induced by the injection of an anti-Thy1 antibody. From three days before induction, nicorandil (10, 30 mg/kg per day) was administered in the drinking water for 12 consecutive days. Anti-Thy1 nephritis resulted in a significant increase in proteinuria and glomerular mesangial cell proliferation. In nephritis rats, nicorandil (30 mg/kg per day) significantly suppressed increase in proteinuria, mesangial cell proliferation (the number of glomerular cell and glomerular area), and renal hypertrophy without affecting blood pressure. Nicorandil significantly prevented the overexpression of type I collagen, fibronectin, transforming growth factor (TGF)-beta, and platelet-derived growth factor (PDGF) mRNA. These results suggest that nicorandil may have renoprotective effects in mesangioproliferative glomerulonephritis.

The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 microg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1-10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 microg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating motilin.

OBJECTIVE It was studied to determine if nicorandil can improve frequent urination in rats with partial bladder outlet obstruction (BOO) without changing the blood pressure. MATERIALS AND METHODS Voiding behavior was observed 6 to 8 d after obstruction in female rats with BOO that loaded 30 ml/kg of water. A drug was administered orally. Changes in systemic blood pressure and heart rate were studied in conscious BOO rats using the tail cuff method. RESULTS The voiding frequency was increased and the average voided volume was decreased in BOO rats compared with normal rats. Nicorandil (1 mg/kg), cromakalim (0.1 mg/kg) and isosorbide dinitrate (ISDN; 1000 mg/kg) decreased voiding frequency significantly in BOO rats. Nicorandil also increased the average voided volume significantly. Although cromakalim and ISDN at doses effective at decreasing voiding frequency caused blood pressure to drop, nicorandil at an effective dose did not affect blood pressure and heart rate. CONCLUSION Nicorandil improved frequent urination without changing the blood pressure. These results suggested that a hybrid of a K(ATP) channel opener and nitric oxide donor, nicorandil was bladder-selective compared with vasculature in BOO rats.

The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a motilin receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via motilin receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.

The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.

myeloperoxidase 36 -, carvedilol cytotoxicity 88 -, catalase activity 173 -, endothelin-1 13 -, enzyme-linked immunosorbent 155 -, gastric mucosal histamine 78 -, --lipid peroxides 78 -, --nitric oxide 78 -, --PGE 2 78 -, gastrointestinal contractility 224 -, hippocampal kindled rat 252 -, inositol phosphates 52 -, lipid peroxidation 35, 173 -, liver enzymes 164 -, luciferase 115 -, mammalian heart QT changes 253 -, MAP kinase 59 -, mechanical strength 130 -, melanoma cell apoptosis 208 -, --growth in vitro 208 -, --proliferation 208 -, monocyte adhesion 155 -, motilin receptor binding 141 -, mRNA stability 58 -