Quantitative prediction of CYP3A-mediated drug-drug interactions by correctly estimating fraction metabolized using human liver chimeric mice.

BACKGROUND AND PURPOSE: Fraction metabolized (fm ) and fraction transported (ft ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo fm due to inability to reflect the ft by efflux transporters (ft,efflux ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice. EXPERIMENTAL APPROACH: For estimating human in vitro fm by CYP3A enzyme (fm,CYP3A,in vitro ), six drugs, including CYP3A/P-gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated fm,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo fm,CYP3A (fm,CYP3A,in vivo ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated fm,CYP3A,in vivo using the change of total clearance (CLtotal ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu-PXB and SCID mice with or without ketoconazole. We calculated the change of CLtotal caused by ketoconazole. We compared the CLtotal change in humans with that in Hu-PXB and SCID mice. KEY RESULTS: The fm,CYP3A,in vitro was overestimated compared to the fm,CYP3A,in vivo . Hu-PXB mice showed much better correlation in the change of CLtotal with humans (R2 = 0.95) compared to SCID mice (R2 = 0.0058). CONCLUSIONS AND IMPLICATIONS: CYP3A-mediated DDI can be predicted by correctly estimating human fm,CYP3A,in vivo using Hu-PXB mice. These mice could be useful predicting hepatic fm and ft,efflux .

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Quantitative Prediction of OATP-Mediated Disposition and Biliary Clearance Using Human Liver Chimeric Mice.

Drug biliary clearance (CLbile) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is influenced by metabolic enzymes, transporters, and passive diffusion across hepatocyte membranes. The purpose of this study is to demonstrate the use of Hu-FRG mice [Fah-/-/Rag2-/-/Il2rg-/- (FRG) mice transplanted with human-derived hepatocytes] to quantitatively predict human organic anion transporting polypeptide (OATP)-mediated drug disposition and CLbile To predict OATP-mediated disposition, six OATP substrates (atorvastatin, fexofenadine, glibenclamide, pitavastatin, pravastatin, and rosuvastatin) were administered intravenously to Hu-FRG and Mu-FRG mice (FRG mice transplanted with mouse hepatocytes) with or without rifampicin as an OATP inhibitor. We calculated the hepatic intrinsic clearance (CLh,int) and the change of hepatic clearance (CLh) caused by rifampicin (CLh ratio). We compared the CLh,int of humans with that of Hu-FRG mice and the CLh ratio of humans with that of Hu-FRG and Mu-FRG mice. For predicting CLbile, 20 compounds (two cassette doses of 10 compounds) were administered intravenously to gallbladder-cannulated Hu-FRG and Mu-FRG mice. We evaluated the CLbile and investigated the correlation of human CLbile with that of Hu-FRG and Mu-FRG mice. We found good correlations between humans and Hu-FRG mice in CLh,int (100% within threefold) and CLh ratio (R2 = 0.94). Moreover, we observed a much better relationship between humans and Hu-FRG mice in CLbile (75% within threefold). Our results suggest that OATP-mediated disposition and CLbile can be predicted using Hu-FRG mice, making them a useful in vivo drug discovery tool for quantitatively predicting human liver disposition. SIGNIFICANCE STATEMENT: OATP-mediated disposition and biliary clearance of drugs are likely quantitatively predictable using Hu-FRG mice. The findings can enable the selection of better drug candidates and the development of more effective strategies for managing OATP-mediated DDIs in clinical studies.

QRS and cycle length alternans in a patient with idiopathic left ventricular tachycardia: Postulated mechanism and clinical implications.

Idiopathic left ventricular tachycardia is macro-reentrant tachycardia involving the fascicles in the left ventricle as a part of its reentrant circuit. The detailed circuit mechanisms somewhat remain unclear. We reported QRS and cycle length alternans confirmed after the first application of radiofrequency delivery for the distal site of left posterior fascicle potential (P2) in a patient with idiopathic left ventricular tachycardia.

Quantitative prediction of P-glycoprotein-mediated drug-drug interactions and intestinal absorption using humanized mice.

BACKGROUND AND PURPOSE: P-glycoprotein (P-gp) exhibits a broad substrate specificity and affects pharmacokinetics, especially intestinal absorption. However, prediction, in vivo, of P-gp-mediated drug-drug interaction (DDI) and non-linear absorption at the preclinical stage, is challenging. Here we evaluate the use of human MDR1 mouse artificial chromosome (hMDR1-MAC) mice carrying human P-gp and lacking their own murine P-gp to quantitatively predict human P-gp-mediated DDI and non-linear absorption. EXPERIMENTAL APPROACH: The P-gp substrates (aliskiren, betrixaban, celiprolol, digoxin, fexofenadine and talinolol) were administered orally to wild-type, Mdr1a/b-knockout (KO) and hMDR1-MAC mice, and their plasma concentrations were measured. We calculated the ratio of area under the curve (AUCR) in mice (AUCMdr1a/b-KO /AUCwild-type or AUCMdr1a/b-KO /AUChMDR1-MAC ) estimated as attributable to complete P-gp inhibition and the human AUCR with and without P-gp inhibitor administration. The correlations of AUCRhuman with AUCRwild-type and AUCRhMDR1-MAC were investigated. For aliskiren, betrixaban and celiprolol, the Km and Vmax values for P-gp in hMDR1-MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of Km and Vmax for P-gp between human and hMDR1-MAC mice were investigated. KEY RESULTS: A better correlation between AUCRhuman and AUCRhMDR1-MAC (R2 = 0.88) was observed. Moreover, good relationships of Km (R2 = 1.00) and Vmax (R2 = 0.98) for P-gp between humans and hMDR1-MAC mice were observed. CONCLUSIONS AND IMPLICATIONS: These results suggest that P-gp-mediated DDI and non-linear absorption can be predicted using hMDR1-MAC mice. These mice are a useful in vivo tool for quantitatively predicting P-gp-mediated disposition in drug discovery and development.

Stress Myocardial Perfusion Imaging Interpretation From the Viewpoint of Fractional Flow Reserve.

BACKGROUND: Myocardial perfusion imaging (MPI) and fractional flow reserve (FFR) are established approaches to the assessment of myocardial ischemia. Recently, various FFR cutoff values were proposed, but the diagnostic accuracy of MPI in identifying positive FFR using various cutoff values is not well established.Methods and Results:We retrospectively studied 273 patients who underwent stress MPI and FFR within a 3-month period. Results for FFR were obtained from 218 left anterior descending artery (LAD) lesions and 207 non-LAD lesions. Stress MPI and FFR demonstrated a good correlation in the detection of myocardial ischemia. However, the positive predictive value (PPV) of FFR for detecting MPI-positive lesions at the optimal FFR thresholds was insufficient (44% for LAD and 65% for non-LAD lesions). This was caused by a sharp drop in PPV at an FFR threshold of 0.7 or more. Notably, 41% of the lesions with normal MPI demonstrated FFRs <0.80. However, MPI-negative lesions had an extremely low lesion rate with FFR <0.65 (6%). Conversely, 78% and 41% of MPI-positive lesions had FFR <0.80 and <0.65, respectively. CONCLUSIONS: The data confirmed that decisions based on MPI are reasonable because MPI-negative patients have an extremely low rate of lesions with a FFR below the cutoff point for a hard event, and MPI-positive lesions include many lesions with FFR <0.65.

Comparisons of Nonhyperemic Pressure Ratios: Predicting Functional Results of Coronary Revascularization Using Longitudinal Vessel Interrogation.

OBJECTIVES: The aim of this study was to investigate the accuracy of pre-percutaneous coronary intervention (PCI) predicted nonhyperemic pressure ratios (NHPRs) with actual post-PCI NHPRs and to assess the efficacy of PCI strategy using pre-PCI NHPR pullback. BACKGROUND: Predicting the functional results of PCI is feasible using pre-PCI longitudinal vessel interrogation with the instantaneous wave-free ratio (iFR), a pressure-based, adenosine-free NHPR. However, the reliability of novel NHPRs (resting full-cycle ratio [RFR] and diastolic pressure ratio [dPR]) for this purpose remains uncertain. METHODS: In this prospective, multicenter, randomized controlled trial, vessels were randomly assigned to receive pre-PCI iFR, RFR, or dPR pullback (50 vessels each). The pre-PCI predicted NHPRs were compared with actual NHPRs after contemporary PCI using intravascular imaging. The number and the total length of treated lesions were compared between NHPR pullback-guided and angiography-guided strategies. RESULTS: The predicted NHPRs were strongly correlated with actual NHPRs: iFR, r = 0.83 (95% confidence interval: 0.72 to 0.90; p < 0.001); RFR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001), and dPR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001). The number and the total length of treated lesions were lower with the NHPR pullback strategy than with the angiography-guided strategy, leading to physiological improvement. CONCLUSIONS: Predicting functional PCI results on the basis of pre-procedural RFR and dPR pullbacks yields similar results to iFR. Compared with an angiography-guided strategy, a pullback-guided PCI strategy with any of the 3 NHPRs reduced the number and the total length of treated lesions. (Study to Examine Correlation Between Predictive Value and Post PCI Value of iFR, RFR and dPR; UMIN000033534).

Estimating Efflux Transporter-Mediated Disposition of Molecules beyond the Rule of Five (bRo5) Using Transporter Gene Knockout Rats.

Transporter gene knockout models are a practical and widely used tool for pharmacokinetic studies in drug discovery. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are major efflux transporters that control absorption and bioavailability, and are important when determining oral drug disposition. To the best of our knowledge, beyond the rule of five (bRo5) molecules launched on the market to date tend to be substrates for efflux transporters. The purpose of this study is to evaluate in vivo the impact of efflux transporters on the oral absorption process and systemic clearance using rats which lack P-gp and/or Bcrp expression. We administered five bRo5 substrates (asunaprevir, cyclosporine, danoprevir, ledipasvir, and simeprevir) intravenously or orally to wild-type and Mdr1a, Bcrp, and Mdr1a/Bcrp knockout rats, calculated the clearance, oral bioavailability, and absorption rate profile of each substrate, and compared the results. Systemic clearance of the substrates in knockout rats changed within approximately ±40% compared to wild-types, suggesting the efflux transporters do not have a significant influence on clearance in rats. On the other hand, the oral absorption of substrates in the knockout rats, especially those lacking Mdr1a, increased greatly-between 2- and 5-fold more than in wild-types. This suggests that rat efflux transporters, especially P-gp, greatly reduce the oral exposure of these substrates. Moreover, results on the absorption rate-time profile suggest that efflux transporters are constantly active during the absorption period in rats. Transporter knockout rats are a useful in vivo tool for estimating the transporter-mediated disposition of bRo5 molecules in drug discovery.

Polymorphism and expression level of CYP51 (cytochrome P450) and sensitivity to ipconazole in Fusarium fujikuroi isolates.

The relationship between the nucleotide sequences of CYP51, its expression level and its sensitivity to ipconazole of Fusarium fujikuroi isolates were investigated. Single nucleotide polymorphisms (SNPs) were observed in the CYP51 of isolates with different sensitivities to ipconazole, but no amino acid substitution was detected in the putative amino acid sequence of the CYP51 protein. On the other hand, the expression of CYP51 was enhanced by the presence of ipconazole, and it tended to be higher in isolates with lower sensitivities and no gibberellin productivity. In the presumed promoter region, the upstream nucleotide sequence of CYP51, several common SNPs and insertions of nucleotides were detected in the lower sensitivity isolates. These results suggest that F. fujikuroi isolates consist of 2 different groups in sensitivity and gibberellin productivity, and no amino acid substitution in CYP51 protein may contribute to the stably high efficacy of ipconazole against rice Bakanae disease for more than 25 years.

Feasibility and safety of jailed-pressure wire technique using durable optical fiber pressure wire for intervention of coronary bifurcation lesions.

OBJECTIVES: The objective was to evaluate the safety, feasibility, and accuracy of the jailed-pressure wire technique using a durable optical fiber-based pressure wire with high-pressure dilatation using a non-compliant balloon after main vessel stenting. BACKGROUND: Fractional flow reserve (FFR) information can help interventionists determine whether they should treat a jailed-side branch (SB). However, re-crossing a pressure wire into a jailed-SB is sometimes technically difficult. METHODS: Fifty-one consecutive lesions from 48 patients who underwent the jailed-pressure wire technique were retrospectively investigated. The primary endpoint was complication rate and secondary endpoints included success rate of FFR measurement, incidence of wire disruption, and final drift rate. The usability of FFR for percutaneous coronary intervention of coronary bifurcation lesion was also evaluated. RESULTS: Median age of the patients was 69 years and 80.4% were men. The most frequent underlying disease was stable angina (70.6%) and 68.6% were type B2 lesions. Our main findings were: the procedure was performed successfully in all cases without any complications or wire disruption, FFR could be measured without significant final drift in 95.9% of cases, and FFR measurements helped interventionists determine whether to perform a final kissing balloon dilatation in 49.0% cases. CONCLUSIONS: The jailed-pressure wire technique using a durable optical fiber-based pressure wire with high-pressure post-dilatation maneuver was safe, feasible, and accurate.

Diagnostic Performance of the Simultaneous Acquisition Rest 99 mTc-Tetrofosmin/Stress 201Tl Dual-Isotope Protocol With a Semiconductor Camera　- Comparison With the Rest-Stress 99 mTc-Tetrofosmin Protocol.

BACKGROUND: This study compared the diagnostic value of myocardial perfusion imaging (MPI) between the rest-stress 99 mTc-tetrofosmin protocol (Tc/Tc protocol) and simultaneous acquisition rest 99 mTc-tetrofosmin/stress 201Tl dual-isotope protocol (SDI protocol) with a semiconductor camera.Methods and Results: We retrospectively studied 147 patients who underwent stress MPI using a cadmium-zinc-telluride camera and invasive coronary angiography within a 3-month interval. The Tc/Tc and SDI protocols were used in 59 and 88 patients, respectively. The sensitivity, specificity, and accuracy of the summed difference score in per-patient analysis were 56%, 85%, and 69%, respectively, for the Tc/Tc protocol and 89%, 82%, and 85%, respectively, for the SDI protocol. The area under the receiver operating characteristic curve was significantly better for the SDI than Tc/Tc protocol for the left anterior descending artery (0.836 vs. 0.674; P=0.0380), the left circumflex artery (0.754 vs. 0.599; P=0.0441), and in per-patient analysis (0.875 vs. 0.707; P=0.0135). There was no significant difference in the diagnostic accuracy of the summed stress score for any vessel or in per-patient analysis between the 2 protocols. CONCLUSIONS: The SDI protocol had a higher diagnostic accuracy for the detection of coronary ischemia than the Tc/Tc protocol.

Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism.

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1-PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.

Estimated pulmonary capillary wedge pressure assessed by speckle tracking echocardiography predicts successful ablation in paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with left atrial (LA) remodeling caused by pressure and/or volume (LAV) overload. Increased pulmonary capillary wedge pressure (PCWP) represents LA pressure overload. We recently reported that pulmonary capillary wedge pressure (ePCWP) can be estimated by the kinetics-tracking (KT) index that combines LA function and volume using speckle tracking echocardiography (STE), and has a strong correlation with PCWP measured by right heart catheterization (r = 0.92). Therefore, we hypothesized that ePCWP is the best echocardiographic predictor of successful AF ablation. METHODS: We enrolled 137 patients with paroxysmal AF (age: 61 ± 10 years) who underwent pulmonary vein isolation. We measured LAV index, LA emptying function (EF) and LA stiffness during sinus rhythm before ablation using STE. PCWP was noninvasively estimated by STE as we previously reported. Parameters were compared between a group with AF recurrence (n = 30, age: 59 ± 11 years) and a group with successful ablation (sinus rhythm maintained for >1 year) (n = 107, age 61 ± 11 years). RESULTS: The ePCWP was correlated with PCWP measured by right heart catheterization (r = 0.76, p < 0.01). Compared with the non-recurrence group (n = 107, age: 61 ± 11), the AF recurrence group had significantly increased ePCWP (10.6 ± 3.5 vs 14.6 ± 2.9 mmHg, p < 0.01), minimum LAV index (29 ± 12 ml/m(2) vs 37 ± 14 ml/m(2), p < 0.01) and LA stiffness (0.47 ± 0.33 vs 0.83 ± 0.59, p < 0.01), but lower total LA EF (44 ± 11% vs 39 ± 13%, p < 0.01) before ablation. In multivariate logistic regression analysis, ePCWP was the most significant independent predictor of successful ablation. Using 13 mmHg of PCWP as the optimal cutoff value, the sensitivity and specificity for successful ablation were 73 and 77% (area under the curve = 0.81), respectively. CONCLUSION: The ePCWP that is measured by the combination of LA function and volume before ablation was a better predictor of the successful ablation compared with LA function and volume separately. The ePCWP estimated by STE is useful to predict the successful ablation in paroxysmal AF, and could be useful to improve candidate selection for AF ablation.

Noninvasive estimation of pulmonary capillary wedge pressure in patients with mitral regurgitation: A speckle tracking echocardiography study.

BACKGROUND: Echocardiographic parameters to predict pulmonary capillary wedge pressure (PCWP) in mitral regurgitation (MR) are not yet elucidated. We reported that PCWP could be accurately estimated by novel KT index which is defined as log10[left atrial (LA) emptying function (EF)/LA volume]. We examined the usefulness of the KT index as a predictor of PCWP in primary and secondary MR with sinus rhythm and also MR with atrial fibrillation. METHODS: LA dimension, strain, volume, EF, and E/e' were measured in moderate to severe MR with sinus rhythm (n=58, age: 67±8 years) and MR with atrial fibrillation (n=24, age: 69±11 years) just before catheterization and in normal subjects (n=26, age: 67±11 years) using speckle tracking echocardiography. MR with sinus rhythm was divided into primary MR (n=27) and secondary MR (n=31). The estimated PCWP (ePCWP) was calculated as 10.8-12.4×KT index. RESULTS: There was a correlation between PCWP and LA dimension, E/e', minimum LA volume index, active LAEF, total LAEF, or LA strain (r=0.32, r=0.31, r=0.55, r=-0.61, r=-0.51, and r=-0.50, respectively, p<0.05). The better correlation was found between PCWP and ePCWP in MR including both primary and secondary MR and also MR with atrial fibrillation (r=0.70, r=0.67, and r=0.58, respectively, p<0.01). Multiple regression analysis revealed that ePCWP was an independent predictor of PCWP in MR. The ePCWP demonstrated good diagnostic accuracy (area under the curve of 0.86) and sensitivity (81%) and specificity (71%) to predict elevated PCWP >15mmHg using a cut-off of 16mmHg. CONCLUSION: The ePCWP was the reliable echocardiographic parameter to predict PCWP in primary and secondary MR and might also be useful in MR with atrial fibrillation. The ePCWP may have an incremental value in a clinical setting.

A useful model capable of predicting the clearance of cytochrome 3A4 (CYP3A4) substrates in humans: validity of CYP3A4 transgenic mice lacking their own Cyp3a enzymes.

The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R(2) = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates.

Neointimal calcification after stenting and chronic kidney disease.

The timing and incidence of neointimal calcification after stenting (NIC) is largely unknown. The purpose of our study was to elucidate the characteristics of NIC. The presence of NIC in patients who underwent intravascular ultrasound between June 30, 2009 and June 30, 2012 was analyzed. The patients were divided into two groups based on the follow-up period: < 365 days or ≥ 365 days. A total of 181 images were analyzed. Those with NIC had a lower estimated glomerular filtration rate [51 (6-60) versus 61 (52-72) mL/minute/1.73 m²; P < 0.01] and longer time after stenting [3198 (1710-3684) versus 211 (180-516) days; P < 0.01] compared to those without NIC. NIC during short-term follow-up was observed only in patients who were on hemodialysis. On the other hand, NIC in the long-term follow-up was observed only in patients with bare metal stents. The development of NIC was related to renal function and time after stenting. NIC in the short-term and the long-term follow-up was observed only in patients who were on hemodialysis and who were implanted with a bare metal stent, respectively.

A case report of acute myocardial infarction induced by coronary spasm. Intravascular findings.

A 53-year-old male complaining of chest pain was admitted to our hospital with suspected acute myocardial infarction (AMI). Emergent coronary angiography (CAG) determined a totally occluded middle right coronary artery (RCA). Thrombus aspiration was conducted, followed by intravascular ultrasound (IVUS) imaging. Diffuse intima plus media thickness was identified at the obstruction site and a thrombus was observed proximally to the occlusion site on IVUS. Following isosorbide dinitrate (ISDN) administration, dilatation of the RCA was confirmed. IVUS study indicated the luminal dilatation was achieved by the release of the diffuse intima plus media thickening. Of note, plaque volume showed no significant difference after administration of ISDN at any vessel site. These results clearly show that luminal dilatation and vessel dilatation were achieved from the redistribution of plaque volume (intima plus media). A follow-up CAG showed no significant stenosis in the RCA. After a provocation test using methylergometrine maleate, the RCA was totally occluded at the very site of the initial event. The involvement of vasospasm as a cause of AMI in the present case was doubly confirmed with characteristic IVUS images of vasospasm in the acute phase and with a provocation test at follow-up.

Structural features of phenoxycarbonylimino neonicotinoids acting at the insect nicotinic receptor.

Substituted-phenoxycarbonylimino neonicotinoid ligands with an electron-donating group showed significantly higher affinity to the insect nicotinic receptor relative to that of the analogue with an electron-withdrawing substituent, thereby establishing in silico binding site interaction model featuring that the phenoxy ring of neonicotinoids and the receptor loop D tryptophan indole plane form a face-to-edge aromatic interaction.