Literatura académica sobre el tema "QT 260.5.F6"

Inflammatory bowel disease (IBD) is an autoimmune disorder caused by uncontrolled immune activation and the subsequent destruction of the colon tissue. Quercetin (Qt) is a natural antioxidant and anti-inflammatory agent proposed as an alternative to mitigate IBD. However, its use is limited by its low oral bioavailability. This study aimed to develop nanoemulsions (NEs) based on a soluble chenopodin/alginate (QPA) complex and Tween 80 (T80), intended for the colonic release of Qt, activated by the pH (5.4) and bacteria present in the human colonic microbiota. NEs with different ratios of QPA/Tw80 (F1-F6) were prepared, where F4Qt (60/40) and F5Qt (70/30) showed sizes smaller than 260 nm, PDI < 0.27, and high encapsulation efficiency (>85%). The stability was evaluated under different conditions (time, temperature, pH, and NaCl). The DSC and FTIR analyses indicated hydrophobic and hydrogen bonding interactions between QPA and Qt. F4Qt and F5Qt showed the greater release of Qt in PBS1X and Krebs buffer at pH 5.4 (diseased condition), compared to the release at pH 7.4 (healthy condition) at 8 h of study. In the presence of E. coli and B. thetaiotaomicron, they triggered the more significant release of Qt (ƒ2 < 50) compared to the control (without bacteria). The NEs (without Qt) did not show cytotoxicity in HT-29 cells (cell viability > 80%) and increased the antioxidant capacity of encapsulated Qt. Therefore, these NEs are promising nanocarriers for the delivery of flavonoids to the colon to treat IBD.

Sugar beet, a potential sugar crop in Bangladesh needs to develop appropriate agronomic package to get maximum yield and quality. Therefore, to study yield and quality of sugar beet as influenced by spacing and fertilization, an experiment was conducted at the Bangladesh Sugarcrop Research Institute (BSRI) farm, Ishurdi, Pabna, during 2019-20 cropping season. To select the most suitable spacing and fertilizer dose, the experiment was carried out in RCBD using two spacing, viz., S1: 50 cm× 20 cm and S2: 60 cm× 20 cm and eight different fertilizer dose viz., F1: Urea, TSP and MoP @ 195, 75 and 169 kgha-1 (2 splits of Urea and MoP), F2: Urea, TSP and MoP @ 195, 75 and 169 kgha-1 (3 splits of Urea and MoP), F3: Urea, TSP, MoP and Cowdung @ 260, 100, 225 kgha-1 and 10 tha-1 (2 splits), F4: Urea, TSP, MoP and Cowdung @ 260, 100, 225 kgha-1 and 10 tha-1 (3 splits), F5: Urea, TSP, MoP and Cowdung @ 260, 100, 225 kgha-1 and 5 tha-1 (2 splits), F6: Urea, TSP, MoP and Cowdung @ 260, 100, 225 kgha-1 and 5 tha-1 (3 splits), F7: Urea, TSP, MoP and Cowdung @ 195, 75, 169 kgha-1 and 10 tha-1 (2 splits), and F8: Urea, TSP, MoP and Cowdung @ 195, 75, 169 kgha-1 and 10 tha-1 (3 splits). The highest leaf number (35.80), shoot length (45.17 cm), root length (38.17 cm), girth (44.33 cm), root dry weight (132.33 g), root yield (86.87 tha-1) and total soluble solid (18.20%) was recorded in the 50cm × 20cm spacing along with application of Urea, TSP, MoP and Cowdung @ 260, 100, 225 kg and 10 tha-1, respectively with 3 splits of Urea & MoP (S1 × F4 combination) followed by 60cm × 20cm spacing along with application of Urea, TSP, MoP and Cowdung @ 260, 100, 225 kg and 10 tha-1, respectively with 3 splits of Urea & MoP (S2 × F4 combination) where leaf number (35.13), shoot length (44.97 cm), root length (38.47 cm), girth (43.90 cm), root dry weight (120.17 g), root yield (88.97 tha-1) and total soluble solid (18.12%) was obtained which were statistically significant and superior as compared to other treatment combinations.

Aging, independently from the hormonal status, is a major risk factor for cardiovascular morbidity in healthy women. Therefore, we studied the effect of healthy aging on the cardiovascular homeostatic mechanisms in premenopausal and postmenopausal women with similar estrogen levels. Twelve healthy postmenopausal women, confirmed by follicular-stimulating hormone (FSH) and luteal hormone (LH) levels, were compared with 14 normally menstruating women during the early follicular phase (young-EF), to avoid as much as possible the effects of estrogen. Systolic BP was 108 ± 1.5 vs. 123 ± 2.5 ( P < 0.001), supine norepinephrine was 260 ± 30 vs. 216 ± 45 and upright 640 ± 100 vs. 395 ± 50 pg/ml ( P = 0.05) in young-EF vs. postmenopausal, respectively. Plasma renin activity and aldosterone remained unchanged. Vagal cardiac tone indices decreased significantly with aging (young-EF vs. postmenopausal): high-frequency (HF) band, root mean square successive differences (rMSSD) and proportion of R-R intervals >50 ms (PNN50%) were 620 ± 140 vs. 270 ± 70 ( P = 0.04), 53 ± 7 vs. 30 ± 3 ( P = 0.02), and 23 ± 5 vs. 10 ± 3 ( P = 0.04), respectively. LF to HF ratio was 0.85 ± 0.17 in young-EF and became 1.5 ± 0.22 in postmenopausal ( P = 0.03). Both arms of the baroreflex, +BRS (29 ± 5 vs. 13.5 ± 2.5, P = 0.01) and −BRS (26 ± 4 vs. 15 ± 1.5, P = 0.02) decreased with aging. Cardiovascular α1-adrenoreceptor responsiveness significantly increased and β-decreased in postmenopausal compared with young EF ( P < 0.001, both). The corrected QT intervals (QTc) were similar, whereas corrected JT intervals (JTc) and JTc to QTc ratio were prolonged in the postmenopausal group. We conclude that in young women, parasympathetic control is the main regulator of the cardiovascular system and in postmenopausal women, sympathetic tone dominates. The transition from parasympathetic to sympathetic control may contribute to the increased cardiovascular morbidity with aging.

3120 Background: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, permitting mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Debio 0123 has demonstrated significant growth inhibition in vitro in a broad range of cancer cell lines and antitumor activity in vivo in human xenograft tumor models. Methods: Debio 0123-102 (NCT05109975) is a phase 1 dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PKs) and preliminary antitumor activity of Debio 0123 in patients (pts) with advanced solid tumors who have recurred or progressed following prior therapy and/or for whom no standard therapy is available. Debio 0123 is given as monotherapy, once daily, over a 21-day cycle, using a Bayesian Logistic Regression Model-guided dose escalation. The primary objective of this study is to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). Results: As of October 24, 2023, 27 pts were treated with 2 pts ongoing (67% female, mean age 63 years; most common primary tumors: ovarian [33%], colon [18%]). Debio 0123 was escalated from 30 mg to 350 mg. Three pts had dose limiting toxicities (DLTs) [Grade (Gr) 3 fatigue and Gr3 Fridericia-corrected QT (QTcF) prolongation at 350 mg, and Gr3 rash at 260 mg]. The MTD was determined at 260 mg. The most frequent treatment related adverse events (TRAEs) (≥20%) were blood creatinine increased (37%), QTcF prolongation (37%), nausea (33%), vomiting (26%), dysgeusia (22%) and fatigue (22%). The most common TRAEs Gr≥ 3 were QTcF prolongation (n = 3, 11%) and fatigue (n = 2, 7%). Retalted adverse events led to dose interruptions, reductions, or discontinuations in 6 (22%), 4 (15%) and 2 (7%) pts, respectively. Debio 0123 plasma exposure increased proportionally with dose from 150 to 350 mg, with steady state achieved after 15-21 days. Target engagement, assessed by reduction of phosphorylated CDC2 levels in skin biopsies, was observed consistently from a dose of 200 mg. Median duration of treatment was 6 weeks (3-30 weeks). Of the 25 pts with post-baseline tumor assessment, 8 (32%) pts had stable disease as best response of ≥5 weeks duration. Two ovarian pts achieved 17% and 20% reduction in the target lesions as per RECIST 1.1, despite requiring dose reductions from 350mg during the 1st cycle. One of these pts had CA-125 response. Based on cumulative safety, exposure-response data, and additional PK modeling, 260 mg once daily of Debio 0123 was selected as RP2D. Conclusions: Continuous dosing of Debio 0123 as monotherapy has a manageable safety profile and linear pharmacokinetics. A multi cohort expansion, including biomarker-selected and unselected cohorts, will further evaluate the safety and antitumor activity of Debio 0123. Clinical trial information: NCT05109975 .

Abstract Chronic iron overload associated with hereditary hemochromatosis or repeated red cell transfusions is known to cause cardiac failure. Cardiac arrhythmias have been incidentally noted in patients with iron overload, but often times dismissed as being caused by other co-morbid conditions. Studies with iron-loaded gerbils suggest a role for iron in the development of cardiac arrhythmias, however these studies utilized short duration recordings of anesthetized gerbils. Furthermore, we were unable to reproduce these loading protocols without significant morbidity and mortality. Our goal was to characterize iron-induced arrhythmias in the chronically instrumented, untethered, telemetered gerbil. Monitored gerbils were divided into 2 groups: iron-loaded (n=23) and control (n=8). Iron loaded gerbils received iron dextran intraperitoneally at a dose of 1.7 (n=4), 3.0 (n=5) or 6.2 (n=14) g/kg; control gerbils received dextran. Gerbils were weighed and given a physical exam weekly. Electrocardiograms were recorded for 10 seconds every 30 minutes for approximately 6 months (DSI Ponehma) and reviewed daily. Quantitative analysis was completed on 6 iron loaded (6.2g/kg) and 3 control gerbils. Heart rate and intervals were calculated and arrhythmias were characterized and counted. Cardiac and hepatic histology and tissue iron concentration were assessed. All gerbils showed evidence of frequent sinus arrhythmia (more than one episode per hour). However, except for two control gerbils that showed frequent unifocal PVCs, no significant arrhythmias were noted in daily review. There was no difference in heart rate, P duration, PR interval, QRS duration or QT interval between groups. Neither total number of arrhythmias nor arrhythmias per minute were different between groups. One iron-loaded gerbil had a single episode (11 beats) of supraventricular tachycardia. Two iron-loaded gerbils had PVCs, one had only a single beat and the other had 9 unifocal PVCs over the duration of the study. Iron-loaded gerbils rarely showed other arrhythmias One control gerbil had 260 unifocal PVCs over the duration of the study. Other arrhythmias were noted rarely. Body weight and heart weight was not different between groups, while liver weight increased with increasing iron dose. Cardiac and hepatic iron were significantly increased in iron loaded gerbils when compared to control. Liver weight increased as iron dose increased. Seven of 14 gerbils loaded to 6.2 g/kg developed ascites as assessed both by physical examination and necropsy. We conclude that an iron load sufficient to cause clinical liver disease does not, in the absence of co-morbid conditions, cause cardiac arrhythmias in the gerbil model of iron overload. This suggests that iron alone is insufficient to cause cardiac arrhythmias.

Abundant hydrocarbon resources were discovered in the Xiazijie fan-delta in the Triassic Baikouquan Formation in Mahu sag, Junggar basin. However, the maximum depositional age of Baikouquan Formation and provenance of this fan-delta are still unclear, which would be unfavourable for further hydrocarbon exploration. In this study, we used detrital zircon U-Pb dating and composition statistics of conglomerate clast and sandstone grain from Baikouquan Formation to constrain the maximum depositional age and provenance of the Xiazijie fan-delta. The results showed that (1) the conglomerate clast compositions of Xiazijie fan-delta mainly consisted of tuff and intermediate-felsic magmatic rocks, and sandstone samples could be classified as litharenite type with the lithic fragments were almost entirely volcanic lithic fragments; (2) the average Qt:F:L values of sandstone samples (M152-S1 and M152-S2) were 26:7:67 and 21:8:71, respectively, and they plotted in the magmatic arc domain in the Qt-F-L ternary diagram, indicating the tectonic setting of source area of Xiazijie fan-delta was magmatic arc; (3) M152-S1 yielded U-Pb ages ranging from 417 Ma to 253 Ma, with a dominant age peak at 313 Ma and two secondary age peaks at 411 Ma and 268 Ma, respectively, while M152-S2 yielded U-Pb ages ranging from 467 Ma to 256 Ma, with a dominant age peak at 307 Ma and two secondary date peaks at 405 Ma and 262 Ma; (4) the mean age of youngest two zircon grains of M152-S1 was 254.8 ± 4.7 Ma, while that of M152-S2 was 257.6 ± 3.8 Ma, suggesting the Baikouquan Formation might be deposited after the Changhsingian to Olenekian; (5) the magmatic rock ages of central West Junggar were distributed mostly between 450–260 Ma, with a dominant age peak at 307 Ma. The ages distribution between magmatic rock of central WJ and detrital zircons of M152-S1 and M152-S2 were similar, indicating the central WJ domain should be the major source area of the Xiazijie fan-delta; (6) the magmatic rock of Hakedun–Hongguleleng area in the Central WJ was characterized by a peak age at 305Ma, which was consistent with the peak ages of M152-S1 and M152-S2, indicating the Hakedun-Hongguleleng area was likely to be their major source area; and (7) one minor peak age at 411 Ma and another at 405 Ma were obtained from M152-S1 and M152-S2, respectively, and a zircon grain with Middle Ordovician age at 467 Ma was obtained from M152-S2, indicating Late Silurian–Early Devonian Chagankule pluton in the Saier Mountain and Ordovician Honggleleng ophiolite mélange in the Sharburt mountain were the minor source areas. This research has significant implications for stratigraphic correlation in Junggar basin and hydrocarbon exploration in the Xiazijie fan-delta conglomerate reservoir.

Introduction HMPL-689 is a potent and highly selective small molecule inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ). Despite available agents targeting the B-cell receptor (BCR) pathway, there remains a need for alternative therapies in the relapsed/refractory (R/R) setting due to agent-specific toxicities and suboptimal efficacy among lymphoma subtypes. This study (NCT03128164) is a phase 1, open-label, dose escalation and expansion study in China to assess the safety, pharmacokinetics (PK), and preliminary efficacy of HMPL-689 as a monotherapy in patients with R/R lymphomas. Here we present the preliminary results of the dose-escalation phase of the study. Methods In this dose escalation phase, patients with R/R lymphoma failed of standard therapy, at least 1 prior therapy, were eligible. The dose-escalation study consisted of cohort A (BID) and cohort B (QD), in which HMPL-689 was orally administered continuously on a 28-day cycle. The modified toxicity probability interval scheme-2 (mTPI-2) design was applied for the dose escalation and maximum tolerated dose (MTD) determination. Blood samples for PK and pharmacodynamics (PD) analyses were collected during Cycle 1 and Day 1 of each subsequent cycle. Results A total of 56 patients were enrolled, with 5 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 23 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL), 9 mantle cell lymphoma (MCL), 9 diffuse large B cell lymphoma (DLBCL), and 3 Hodgkin's lymphoma (HL) patients (Table 1). The median age was 56 years (range 26-73). The median number of prior therapies was 3 (range 1-8), of which 39 patients had prior exposure to rituximab. 29 patients received HMPL-689 in cohort A (BID): 2.5 mg (n=3), 5 mg (n=9), 7.5 mg (n=8), and 10 mg (n=9), while 27 patients were in cohort B (QD): 5 mg (n=3), 10 mg (n=3), 20 mg (n=9), 30 mg (n=9), and 40 mg (n=3). Median duration of HMPL-689 therapy was 7.6 months (range 0.4 -Not reached [NR]). The most common Grade ≥3 non-hematologic treatment emergent adverse events (TEAEs) were pneumonia and hypertension. Grade ≥3 hematologic TEAEs were neutropenia (Table 2). No Grade 5 TEAE was reported. In cohort A, 4 dose limited toxicities (DLTs) were observed, including Grade 3 asymptomatic amylase (2 pts, 5 mg), Grade 4 hypercalcemia (1 pt, 10 mg), Grade 3 lipase increased (1 pt, 10 mg). In cohort B, 5 DLTs including Grade 3 skin maculopapular (1 pt, 20 mg), hypertriglyceridemia (1 pt, 30 mg), QT interval prolongation (1 pt, 30 mg) and rash (2 pts, 40 mg) were reported. Plasma PK data for the 5-30 mg QD and 2.5-10 mg BID multiple-dose regimens were determined. HMPL-689 drug exposures increased in a dose proportional fashion up to 30mg QD, as reflected in AUC and Cmax. The geometric mean AUCtau and Cmax at 30 mg QD in patients were approximately 2150 h•ng/mL and 260 ng/mL, respectively at steady state. The median Tmax was around 2 h and the arithmetic mean t1/2 was within the range of 5-10 hours, consistent across all dose levels. 51 out of the 56 patients had post-baseline tumor assessment, with 6 complete response (CR) (2 CLL/SLL, 4 FL), 21 partial responses (PR) (2 CLL/SLL, 5 MZL, 7 FL, 4 MCL, 3 DLBCL) and 18 stable disease (SD) (2 MZL, 9 FL, 4 MCL, 1 DLBCL, 2 HL). This resulted in 52.9% (27/51) objective response rate (ORR) in efficacy evaluable patients. The median time to response (TTR) and duration of response (DOR) were 3.5 months (1.8-8.4) and 6.4 months (0.7-NR), respectively (Table 3). One patient with FL who achieved CR (per post hoc independent radiologic review) was on treatment &gt; 586 days. Final data quality control/verification is ongoing. As a result, 30 mg QD of HMPL-689 has been selected as recommended phase 2 dose (RP2D) based on overall safety and tolerability, PK/PD and preliminary efficacy data. Conclusions: HMPL-689 was well tolerated and the RP2D was determined to be 30 mg QD orally. It exhibited dose-proportional pharmacokinetics, a manageable toxicity profile, and promising single-agent clinical activity in R/R B-cell lymphoma patients. The dose expansion study is ongoing, evaluating the safety and efficacy of HMPL-689 in patients with R/R B-cell lymphoma. Acknowledgement 1. We would like to thank all patients and their families who participated in this trial; 2. We would like to thank all investigators, study coordinators and the entire project team. Disclosures Duan: Hutchison MediPharma Limitied: Current Employment. Yu:Hutchison MediPharma Limitied: Current Employment. Cai:Hutchison MediPharma Limitied: Current Employment. Su:Hutchison MediPharma Limited: Current Employment.