Myocardial repolarization time, J-point to T-peak and T-peak to T-end intervals, have different heart rate dependency and autonomic nerve interference in healthy prepubertal children.

OBJECTIVE: The JT interval of the myocardial repolarization time can be divided into Jpoint to T-peak interval (JTp) and T-peak to T-end interval (Tpe). It is well known that the JT interval is dependent on the heart rate, but little is known regarding heart rate dependence for JTp and Tpe. The aim of the present study was to clarify the heart rate dependence of JTp and Tpe and to elucidate the interference of autonomic nervous activity with these parameters. METHODS: We evaluated 50 prepubertal children (mean age: 6.4 ± 0.5 years; male:female, 22:28) without heart disease. JTp, Tpe, and the preceding RR intervals were measured using 120 consecutive beats (lead CM5). First, the relationships between the RR interval and JTp and Tpe were evaluated by Pearson's correlation coefficient. Second, to evaluate autonomic interference with JTp and Tpe, the degree of coherence between RR interval variability and JTp or Tpe variability was calculated using spectral analysis. RESULTS: Significant positive correlations were observed between the RR interval and JTp (y = 0.116x + 105.5; r = 0.594, p < 0.001) and between the RR interval and Tpe (y = 0.037x + 44.7; r = 0.432, p < 0.001). Tpe variability had a lower degree of coherence with RR interval variability (range: 0.039-0.5 Hz) than with JTp variability (0.401 [interquartile range, 0.352-0.460] vs. 0.593 [0.503-0.664], respectively; p < 0.001). CONCLUSIONS: Tpe had lower heart rate dependence and a lower degree of autonomic nervous interference than did JTp.

Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs.

INTRODUCTION: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. METHODS: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. RESULTS: Covariate adjusted QT (slope -12.57 ms/°C) and JTpca (-14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. CONCLUSION: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.

A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium.

INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.

Automated JTpeak analysis by BRAVO.

Using BRAVO algorithm (AMPS-LLC, NY, v4.4.0), 5223 ECGs from a publicly available annotated dataset from a randomized clinical trial on four different compounds and placebo were analyzed. ECGs were automatically processed and JTp interval was computed on: 12 standard ECG leads, Vector Magnitude (VM), and root mean square (RMS) leads. On VM and RMS, JTp intervals were nearly identical (228 ± 29 vs. 227 ± 30 ms respectively, with correlation of 0.99, p < 0.0001). On lead II, JTp interval was about 10 ms longer, but highly correlated with that measured on VM (0.94, p < 0.0001). Similarly, on lead V5, JTp was about 8 ms longer than on VM, with a correlation of 0.95, p < 0.0001. When compared to the public available annotations, JTp by BRAVO generated longer (about 8 ms) measurement and evidenced outliers conducible to both the T-wave peak (in few ECGs presenting notched shapes) and, to a lesser degree, to the J point, due to variability of the two algorithms. Differences on the drug-induced effect from the four compounds were negligible.

The algorithmic performance of J-Tpeak for drug safety clinical trial.

INTRODUCTION: The interval from J-point to T-wave peak (JTp) in ECG is a new biomarker able to identify drugs that prolong the QT interval but have different ion channel effects. If JTp is not prolonged, the prolonged QT may be associated with multi ion channel block that may have low torsade de pointes risk. From the automatic ECG measurement perspective, accurate and repeatable measurement of JTp involves different challenges than QT. We evaluated algorithm performance and JTp challenges using the Philips DXL diagnostic 12/16/18-lead algorithm. Measurement of JTp represents a different use model. Standard use of corrected QT interval is clinical risk assessment on patients with cardiac disease or suspicion of heart disease. Drug safety trials involve a very different population - young healthy subjects - who commonly have J-waves, notches and slurs. Drug effects include difficult and unusual morphology such as flat T-waves, gentle notches, and multiple T-wave peaks. METHODS: The JTp initiative study provided ECGs collected from 22 young subjects (11 males and females) in randomized testing of dofetilide, quinidine, ranolazine, verapamil and placebo. We compare the JTp intervals between DXL algorithm and the FDA published measurements. The lead wise, vector-magnitude (VM), root-mean-square (RMS) and principal-component-analysis (PCA) representative beats were used to measure JTp and QT intervals. We also implemented four different methods for T peak detection for comparison. RESULTS: We found that JTp measurements were closer to the reference for combined leads RMS and PCA than individual leads. Differences in J-point location led to part of the JTp measurement difference because of the high prevalence of J-waves, notches and slurs. Larger differences were noted for drug effect causing multiple distinct T-wave peaks (Tp). The automated algorithm chooses the later peak while the reference was the earlier peak. Choosing among different algorithmic strategies in T peak measurement results in the tradeoff between stability and the accurate detection of calcium or sodium channel block. CONCLUSION: Measurement of JTp has different challenges than QT measurement. JTp measurement accuracy improved with combined leads RMS and PCA over lead II or V5.

JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis.

AIM: Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. RESULTS: JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. CONCLUSION: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.

INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single­lead ECGs collected from freely moving dogs and monkeys.

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effect while maintaining bone mineral density in mice.

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.

Detection of T Wave Peak for Serial Comparisons of JTp Interval.

Electrocardiogram (ECG) studies of drug-induced prolongation of the interval between the J point and the peak of the T wave (JTp interval) distinguished QT prolonging drugs that predominantly block the delayed potassium rectifier current from those affecting multiple cardiac repolarisation ion channel currents. Since the peak of the T wave depends on ECG lead, a "global" T peak requires to combine ECG leads into one-dimensional signal in which the T wave peak can be measured. This study aimed at finding the optimum one-dimensional representation of 12-lead ECGs for the most stable JTp measurements. Seven different one-dimensional representations were investigated including the vector magnitude of the orthogonal XYZ transformation, root mean square of all 12 ECG leads, and the vector magnitude of the 3 dominant orthogonal leads derived by singular value decomposition. All representations were applied to the median waveforms of 660,657 separate 10-s 12-lead ECGs taken from repeated day-time Holter recordings in 523 healthy subjects aged 33.5 ± 8.4 years (254 women). The JTp measurements were compared with the QT intervals and with the intervals between the J point and the median point of the area under the T wave one-dimensional representation (JT50 intervals) by means of calculating the residuals of the subject-specific curvilinear regression models relating the measured interval to the hysteresis-corrected RR interval of the underlying heart rate. The residuals of the regression models (equal to the intra-subject standard deviations of individually heart rate corrected intervals) expressed intra-subject stability of interval measurements. For both the JTp intervals and the JT50 intervals, the curvilinear regression residuals of measurements derived from the orthogonal XYZ representation were marginally but statistically significantly lower compared to the other representations. Using the XYZ representation, the residuals of the QT/RR, JTp/RR and JT50/RR regressions were 5.6 ± 1.1 ms, 7.2 ± 2.2 ms, and 4.9 ± 1.2 ms, respectively (all statistically significantly different; p < 0.0001). The study concludes that the orthogonal XYZ ECG representation might be proposed for future investigations of JTp and JT50 intervals. If the ability of classifying QT prolonging drugs is further confirmed for the JT50 interval, it might be appropriate to replace the JTp interval since with JT50 it appears more stable.

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation.

Classic glucocorticoids that have outstanding anti-inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti-inflammatory effects while reducing the occurrence of side effects, is one of the most anticipated drugs. However, there have been no SGRMs marketed to date. The assumption is that there are two major mechanisms of action of glucocorticoids via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, the anti-inflammatory effects of glucocorticoids are mostly mediated through TR, while the side effects associated with glucocorticoids are largely caused by TA. We started to evaluate novel orally available SGRMs that maintain anti-inflammatory effects while minimizing adverse effects by favoring TR over TA. Based on this evaluation, we discovered JTP-117968, (4b'S,7'R,8a'S)-4b'-benzyl-7'-hydroxy-N-(2-methylpyridin-3-yl)-7'-(trifluoromethyl)-4b',6',7',8',8a',10'-hexahydro-5'H-spiro[cyclopropane-1,9'-phenanthrene]-2'-carboxamide, a non-steroidal SGRM. JTP-117968 has partial TR activity, but exhibits extremely low TA activity. The maximum TR efficacy of JTP-117968 was comparable to its structural analogue, PF-802, (4bS,7R,8aR)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide, which is the active form of Fosdagrocorat that has been developed clinically as a first-in-class orally available SGRM. Remarkably, the TA activity of JTP-117968 was much weaker than PF-802 not only in in vitro assays, but also in in vivo mice experiments. These findings indicate that JTP-117968 exhibits improved TR/TA dissociation because the compound has significantly lower TA activity compared with an already reported SGRM. Therefore, JTP-117968 is expected to be a useful compound for evaluating ideal SGRMs in the future.

JTP-103237, a novel monoacylglycerol acyltransferase inhibitor, modulates fat absorption and prevents diet-induced obesity.

Monoacylglycerol acyltransferase 2 (MGAT2) plays an important role in intestinal fat absorption. We discovered the novel MGAT2 inhibitor, JTP-103237, and evaluated its pharmacological profile. JTP-103237 selectively inhibited MGAT2 without remarkable species differences and reduced absorbed lipids in circulation. After lipid administration, JTP-103237 slightly but significantly decreased triglyceride content in proximal small intestine and significantly increased the lipids content in the distal small intestine. In addition, JTP-103237 significantly increased MGAT substrate (monoacylglycerol and fatty acid) content in the small intestine. JTP-103237 increased plasma peptide YY levels after lipid loading and reduced food intake in a dietary fat-dependent manner. After chronic treatment, JTP-103237 significantly decreased body weight and increased O2 consumption in the early dark phase in high fat diet induced obese (DIO) mice. Moreover, JTP-103237 improved glucose tolerance and decreased fat weight and hepatic triglyceride content in DIO mice. Our findings indicate that JTP-103237 prevents diet-induced obesity by inhibiting intestinal MGAT2 and has unique properties as a drug for the treatment of obesity.

Prolyl oligopeptidase inhibition decreases extracellular acetylcholine levels in rat hippocampus and prefrontal cortex.

Several investigative prolyl oligopeptidase (PREP) inhibitors have been shown to improve learning and memory in various preclinical trials but the mechanism of action behind these effects remains unclear. Since hippocampal and cortical acetylcholine (ACh) is known to play an important role in cognitive processes, the effects of two potent PREP inhibitors, JTP-4819 and KYP-2047, on extracellular ACh levels in hippocampus and medial prefrontal cortex were assessed using in vivo microdialysis. Conscious rats were treated with a single dose (15 or 50µmol/kg i.p.) of JTP-4819, KYP-2047 or vehicle, and extracellular ACh levels were monitored for 5h after treatment. In hippocampus, KYP-2047 had no significant effect on the ACh levels, although a trend towards decreased levels was observed at the higher dose. JTP-4819 had no significant effect on the hippocampal ACh levels at the lower dose (15µmol/kg), but the higher dose (50µmol/kg) significantly decreased ACh levels in hippocampus by about 25%. In cortex, the smaller dose (15µmol/kg) of KYP-2047 decreased ACh levels maximally by 25%, and a similar (ns) effect was also observed after the higher dose. JTP-4819 had no effect at the lower dose, but the higher dose decreased ACh levels maximally by about 30%. In conclusion, the present results suggest that the cognition-enhancing effects of investigative PREP inhibitors are not due to enhanced cholinergic transmission in hippocampus or cortex.

Jugulotympanic paragangliomas treated with Gamma Knife radiosurgery: a single-center review of 58 cases.

OBJECT: Jugulotympanic paragangliomas (JTPs) are rare benign tumors whose surgical treatment is usually associated with partial resection of the lesion, high morbidity, and even death. Gamma Knife radiosurgery (GKRS) has been reported as a useful treatment option. The goal of this retrospective study is to analyze the role of GKRS in tumor volume control and clinical outcomes of these patients. METHODS: A total of 75 patients with JTPs were treated with GKRS at the authors' center from 1995 to 2012. The authors analyzed those treated during this period to allow for a minimal observation time of 2 years. The MR images and clinical reports of these patients were reviewed to assess clinical and volumetric outcomes of the tumors. The radiological and clinical assessments, along with a group of prognostic factors measured, were analyzed using descriptive methods. The time to volumetric and clinical progression was analyzed using the Kaplan-Meier method. Prognostic factors were identified using log-rank statistics and multivariate Cox regression models. RESULTS: The mean follow-up was 86.4 months. The authors observed volumetric tumor control in 94.8% of cases. In 67.2% of cases, tumor volume decreased by a mean of 40.1% from the original size. Of patients with previous tinnitus, 54% reported complete recovery. Improvement of other symptoms was observed in 34.5% of cases. Overall, clinical control was achieved in 91.4% of cases. Previous embolization and familial history of paraganglioma were selected as significant prognostic factors for volumetric response to GKRS treatment in the univariate analysis. In multivariate analysis, no factors were significantly correlated with progression-free survival. No patient died of side effects related to GKRS treatment or tumor progression. CONCLUSIONS: Gamma Knife radiosurgery is an effective, safe, and efficient therapeutic option for the treatment of these tumors as a first-line treatment or in conjunction with traditional surgery, endovascular treatment, or conventional fractionated radiotherapy.

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate).

Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.