Effects of a single 10mg dose of empagliflozin on postprandial insulin kinetics in patients with postbariatric hypoglycaemia

Introduction: Postbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics. Materials and methods: Insulin secretion, hepatic insulin extraction and total insulin clearance were evaluated after a single of empagliflozin 10mg vs. placebo followed by a standardized liquid mixed meal were evaluated in 11 subjects with confirmed PBH after GB over 3h. Parameters of interest were calculated using established mathematical models. Indices were compared between the groups using the Wilcoxon signed-rank test. Results Total beta-cell responsiveness tends to be lower with empagliflozin vs. placebo (24.83±11.00 vs. 27.15±9.68 [10-9 min-1], p=0.150). Total first-pass hepatic insulin extraction increased after empagliflozin compared to placebo (49.6±14.2 vs. 39.7±12.1 %, p=0.006), while no significant effect of empaglizflozin on basal first-pass hepatic insulin extraction was observed (79.7±7.1 vs. 81.1±6.6 %, p=0.521). Total insulin clearance resulted to be significantly lower after empagliflozin compared to placebo (3.91±1.58 vs. 3.00±1.27 l/min, p=0.002). Conclusion The present analysis suggests that the hypoglycaemia-attenuating effect of SGLT2-inhibition in patients with PBH is mainly mediated by an increment in insulin clearance, with also a tendency to a reduction in insulin secretion.

A phase Ib study of anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma.

4075 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract adenocarcinoma. Several clinical trials are exploring the combination treatment of anti-angiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral small molecule inhibitor of receptor tyrosine kinases, with inhibitory effects on tumor angiogenesis and growth. Anlotinib plus TQB2450,an anti-PD-L1 mAb, have shown anti-tumor activity in preclinical study and here we investigate the efficacy and safety of different dosage of this regimen as second-line treatment for advanced biliary tract adenocarcinoma. Methods: Patients with advanced biliary tract adenocarcinoma who had progressed after first-line treatment received anlotinib (once daily for 2 weeks on/1 week off) plus TQB2450 (1200mg once) every three weeks. The planned anlotinib dose levels to be explored were 10mg (starting) and 12mg daily. Dose expansion was performed after the determination of the maximum tolerable dose. Response to treatment was evaluated using the RECIST 1.1 criteria, supplemented by iRECIST. The primary endpoints were MTD, ORR, and the secondary endpoints were PFS, OS and safety. Results: Both 10mg and 12mg of anlotinib were tolerable after the initial safety observation of different doses from May 2019 to April 2020. 34 patients (8 cases of gallbladder cancer [GBC], 22 of intrahepatic cholangiocarcinoma [ICC] and 4 of extrahepatic cholangiocarcinoma [ECC]) were enrolled, 22 patients in the 10mg dose group and 12 in the 12mg dose group. The median age was 57 (37-72) years and 55.9% (19) of the patients were female. At the analysis cut-off date of 31 December 2020, the median follow-up duration was 14.9 months. Of the 34 patients, 4 patients had partial response (PR, 2 cases in the 10mg group and 2 in the 12mg group), including 2 cases with GBC and 2 with ICC, 17 had stable disease (SD, shrinkage, 12 in the 10mg group and 5 in the 12mg group) and 5 SD (enlargement, 4 in the 10mg group and 1 in the 12mg group), 7 had progression disease (PD, 5 in the 10mg group and 2 in the 12mg group) and 1 patient of ECC could not be evaluated. In the overall population, the median PFS (mPFS) was 5.95 (95%CI: 3.78-11.50) months. The mPFS was 5.29 (95%CI: 3.45-10.32) months in 10mg group and 12.98 (95%CI: 1.38-NR) in 12mg group. The median OS was not reached and the 12-month OS rate was 64.71% (60.87% in the 10mg group and 72.73% in the 12mg group). Grade 3 or higher toxicities were observed in 8 patients, with elevated transaminase (n = 4, 11.8%), elevated bilirubin (n = 3, 8.8%), fatigue (n = 1, 2.9%), hypertension (n = 1, 2.9%) and prolonged QTc (n = 1, 2.9%). Conclusions: Anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma was well tolerated and showed promising efficacy. No unexpected adverse events were observed in both drugs. This regimen is worthy of further exploration. Clinical trial information: NCT03825705.

Efficacy of Melatonin against Oxidative Stress, DNA Damage and Histopathological Changes Induced by Nicotine in Liver and Kidneys of Male Rats

The present study was carried out to investigate and compare the effect of nicotine alone and in combination with melatonin on some oxidants and antioxidant parameters, histopathological changes and DNA integrity in the liver and kidneys of male rats. For this purpose 75 mature male rats weighing 120-140g were randomly divided into five groups; control group (1% ethanol in saline), nicotine group (rats administrated nicotine at a dose of 0.6mg/kg body weight; BW) and nicotine and melatonin groups (rats administrated the same dose of nicotine plus 1, 5 or 10mg/kg BW melatonin, respectively). Nicotine and ‏ melatonin were injected intraperitoneally daily for 21days. Fasting blood samples were collected from each rat one day after the end of last injection (at 22nd day) and sera were collected for determination of total antioxidant capacity (TAC). Five rats were sacrificed from each group; Liver and kidneys were collected for estimation of oxidative stress parameters (MDA, SOD and GSH), histopathological examination and for estimation of DNA damage. The results revealed that nicotine increased MDA, decreased TAC, SOD and GSH, induced histopathological changes and increased the percentage of DNA damage in the liver and kidneys Melatonin administration with nicotine counteracted the effect of nicotine on previous parameters. The effect of melatonin was dose dependent and the 10mg dose produced the highest protective effect. It is concluded that melatonin can ameliorate the harmful effect of nicotine on the liver and kidneys of male rats.

Efficacy and safety of oral nifedipine with or without vaginal progesterone in the management of threatened preterm labor

Background: Preterm labor (PTL) is a serious emergency wherein robust management is imperative for achieving improved outcome. Objective: To evaluate the efficacy and safety of nifedipine alone vs nifedipine with vaginal progesterone in managing threatened PTL. Materials and Methods: This comparative study was carried out at the Pakistan Institute of Medical Sciences, Islamabad over a 2-year’ period, from September, 2013 to August, 2015. The study included 276 patients with threatened PTL. Half of them were allocated to nifedipine alone group whereas the remainder half to the additional progesterone group. In nifedipine alone group (group A), all the patients were given 20mg of rapid release nifedipine orally. If uterine contraction continued, a 10mg dose was repeated every 20 min with a maximum of 40mg within the first hour. After completing the first hour, 20mg was given every 4–6 hr for 72 hr. In the additional vaginal progesterone group (group B), following successful tocolysis with nifedipine, additional - maintenance tocolysis was ensured with vaginal progesterone 200mg daily. Results: Successful acute tocolysis was achieved with nifedipine among 86.23% patients. Mean pregnancy prolongation was 11.13 ± 5.08 days in group A while 29.73 ± 3.10 days in group B. (p0.001). Conclusion: Acute tocolytic therapy with nifedipine was successful in the majority of our patients. The additional daily use of vaginal progesterone suppositories resulted in significant prolongation of pregnancy as well as reduction in the rate of low birth weight and neonatal ICU admissions. Key words: Preterm labor, Tocolytics, Nifedipine, Progesterone.

Evaluation of antidepressant activity of tramadol in albino mice using forced swim model

Background: The fact that tramadol can be used as an antidepressant, has been already proved by some animal studies. The objective of the present study was to evaluate antidepressant activity of tramadol in albino mice using forced swim model.Methods: Forced swimming test (FST) model was used to evaluate the antidepressant effect. Mice in the group "I" were given normal saline. Mice in the group II were given imipramine. Mice in the group III were given tramadol 10mg/kg. Mice in the group IV were given tramadol 20mg/kg. Mice in the group V were given tramadol 40mg/kg. All doses in all groups were given by intra peritoneum route.Results: The average values of immobility in group I were higher significantly compared to group III, IV and V. The values of group I and group II were found to be comparable. It was found that the baseline mean value was 196.33 which reduced to 5.16 with the effect of imipramine where imipramine was given to those mice. But in tramadol 10mg group, it was highest, and it came down to 40.66 and as the dose of tramadol was increased, the immobility time reduced from 40.66 at 10mg dose to 31.33 at 20mg dose and finally to 13.33mg at 40mg dose.Conclusions: Considering the results of two different animal models of depression it can be concluded that Tramadol has antidepressant activity at 10mg, 20mg, 40mg which was almost similar to Imipramine.

A Single Dose Monoclonal Antibody (mAb) Immunoprophylaxis Strategy to Prevent RSV Disease in All Infants: Results of the First in Infant Study with MEDI8897

Background RSV is the most common cause of lower respiratory tract infection (LRTI) among infants making prevention of RSV disease a public health priority. A significant unmet need exists for RSV prevention in healthy infants. Our goal is to develop a mAb with an extended half-life (t½) capable of protecting infants for an entire RSV season by using a single intramuscular (IM) dose. This study was conducted to evaluate the safety profile, pharmacokinetics (PK), RSV neutralizing antibody titers, and anti-drug antibody (ADA) responses for MEDI8897 in healthy preterm infants born between 32 and 35 weeks gestational age. Methods Infants were randomized 4:1 to receive a single IM injection of MEDI8897 10mg (n = 8), 25mg (n = 31), 50mg (n = 32) or placebo (n = 18) and followed for 360 days. Enrollment occurred during the 2,015 RSV seasons in the US, South Africa, and Chile. Blood was collected at multiple timepoints. Infants who met criteria for a medically-attended (MA) LRTI had nasal swabs obtained for RSV testing by RT-PCR. Results A total of 85/89 (95.5%) infants completed the study. Adverse events (AEs) were reported in 17/18 (94.4%) placebo and 66/71 (93.0%) MEDI8897 recipients. Five serious AEs (three LRTIs, two febrile seizures) were reported in three MEDI8897 recipients. No events were consistent with hypersensitivity reactions. The estimated MEDI8897 serum t½ ranged from 62.5 to 72.9 days. On day 151, 87% of the infants who received the 50mg dose of MEDI8897 had serum concentrations above the target EC90 level of 6.8 µg/ml, and 93.3% showed a ≥3-fold rise from baseline in serum anti-RSV neutralizing antibody titers. ADA was detected in 28.2% of MEDI8897 recipients, but when present was not associated with any safety findings. ADA was detected at day 361 only in 26.5% of subjects. MA-LRTI was reported in 5 (7%) MEDI8897 recipients through 150 days after dosing. The one subject with an MA-LRTI caused by RSV had received a 10mg dose of MEDI8897. Conclusion In healthy preterm infants, the safety profile of MEDI8897 was favorable. The extended t½ of MEDI8897 with the corresponding increase in RSV neutralizing antibody levels was confirmed and supports protection from RSV disease during a typical 5-month season with a single 50mg IM dose. This study was sponsored by MedImmune. Disclosures J. B. Domachowske, Medimmune: Investigator, Research grant; Regeneron: Investigator, Research grant; Pfizer: Investigator, Research grant; Glaxo Smith Kline: Investigator, Research grant; Novavax: Investigator, Research grant; Janssen: Investigator, Research grant; A. Khan, MedImmune: Employee and Shareholder, Salary and stock; M. T. Esser, MedImmune: Employee and Shareholder, Salary and stock; K. M. Jensen, MedImmune: Employee and Shareholder, Salary and stock; T. Takas, MedImmune: Employee and Shareholder, Salary and stock; T. Villafana, MedImmune: Employee and Shareholder, Salary and stock; F. Dubovsky, MedImmune: Employee and Shareholder, Salary and stock; M. P. Griffin, MedImmune: Employee and Shareholder, Salary and stock

Abstract 2790: Aggressive Atorvastatin Decreases Wall Shear Stress In The Carotid Artery

Introduction: Both wall shear stress (WSS) and inflammation play an important role in atherosclerotic plaque initiation and progression. Lipid-lowering therapy has been shown to be effective in stabilizing them by reducing plaque inflammation. However, its effect on WSS remains unknown. Therefore, the role of high- and low-dose lipid-lowering therapy using an HMG Co A reductase inhibitor - atorvastatin on WSS in carotid artery was investigated. Methods: Twenty-six patients included in the ATHEROMA study were assessed using phase-contrast magnetic resonance imaging (MRI). All patients demonstrated plaque inflammation by intraplaque accumulation of ultrasmall super paramagnetic particles of iron oxide (USPIO) on at baseline. They were randomized in a double-blinded manner to either 10mg or 80mg atorvastatin daily for 12 weeks. WSS at common carotid artery (CCA), maximum (MS) stenosis and internal carotid artery (ICA) were assessed from in vivo phase contrast MRI at both 0 and 12 weeks. Results: There were no significant differences in WSS in CCA, MS and ICA between the two groups at baseline. At 12 weeks, WSS in CCA and MS at end diastole were significantly lower in the 80mg group than those in the 10mg group (p=0.03 and 0.04 respectively). Significant reductions of WSS in all the three locations were observed in the 80mg group at 12 weeks (p= 0.01, 0.04 and 0.04 respectively) whereas no significant change was seen in the 10mg dose group. Conclusions: Aggressive lipid-lowering therapy is associated with a significant reduction in WSS. This suggests that reduction in WSS may be associated with reduction in plaque inflammatory burden and vice-versa. Lipid-lowering therapy may not only reduce inflammation but also improve the hemodynamics.

Generation, Functional Characterization and Clinical Application of a Novel Fc-Optimized Anti-FLT3 Antibody for the Treatment of Acute Myeloid Leukemia

Abstract 2187 For more than a decade, chimeric/humanized second generation monoclonal antibodies (mAb) are used in cancer therapy. While their success e.g. in lymphoma therapy is undisputed, mAb are not established as treatment for acute myeloid leukemia (AML). Moreover, the therapeutic activity of available mAb leaves ample room for improvement. In the recent years, modifications of the human IgG1 Fc-part have enabled the development of third generation mAb with markedly improved capability to recruit Fc-receptor bearing immune effector cells. We here report on the development and evaluation of an Fc-optimized mAb directed to FLT3, an antigen expressed on leukemic cells of the majority of AML patients. In vitro, this antibody termed 4G8-SDIEM effectively induced antibody-dependent cellular cytotoxicity (ADCC) against FLT3-expressing AML cells at concentrations as low as 10ng/ml. Compared to the parental humanized antibody, the ADCC activity of 4G8-SDIEM was increased by a factor of 100. FLT3 expression on primary AML cells (range, 500–5000 molecules) was considerably higher as compared to healthy hematopoietic cells (several hundred molecules). 4G8-SDIEM did not induce relevant ADCC against healthy cells and did not decrease the CFU-forming capacity of bone marrow (BM) cells in vitro. The mAb was then produced in pharmaceutical quality and quantity at a university-owned production unit and used for compassionate need treatment of a 30 year old AML patient (FAB M0, complex kariotype with 45, XY, inv(3)(q21q26), -7, 9q-) with relapse after haploidentical and unrelated donor stem cell transplantation (SCT). Preclinical testing revealed that 4G8-SDIEM effectively induced ADCC of the patients peripheral blood (PB) mononuclear cells (PBMC) against NALM16 leukemia cells and autologous leukemic blasts. Directly before initiation of treatment, the percentage of leukemic blasts among the patients PBMC was 11% and 38% in PB and BM, respectively, and his AML cells displayed homogeneous FLT3 expression. The percentage of NK cells (CD56+CD3-) was 7% and 5% in PB and BM, respectively, with less than 2% displaying an activated phenotype (CD69+). 4G8-SDIEM was applied in escalating doses (d1: 10μg; d2: 100μg; d3: 1mg; d4: 2mg; d5, 7, 10: 10mg). Several hours after the first 10 mg-dose 5×108 CD3/CD19-depleted donor lymphocytes were infused. Besides elevated temperature (max. 38.2°C), no relevant side effects of treatment were observed. After the first first 10mg dose, BM blasts were nearly saturated with mAb as judged by crosscompetition assays. Serum concentration of 4G8-SDIEM reached 1.0μg/ml 1h after the first 10mg dose declining to 0.4 μg/ml 24h later. Upon treatment, serum levels of the index cytokines TNF and IL-6 (peak d4, 60 and 27pg/ml, respectively) and the percentage of activated NK cells (peak d6, 42%) in PB increased rapidly. Already at day 4, leukemic blasts were nearly completely cleared from the PB (<2%), while effects in BM were less pronounced (down to 15%) indicating that lower effector to target cell ratios in the BM limit the therapeutic activity of the mAb. In any case, the anti-leukemic effects of 4G8-SDIEM remained transient, as 10 days after initiation of therapy blast counts in PB and BM reached and later exceeded pre-treatment levels. Thus we conclude that although 4G8-SDIEM clearly exerts anti-leukemic effects in vivo, it may not be capable of inducing long-lasting responses of AML in proliferative phase. Rather, we envisage application of the mAb in settings with suitably high effector to target cell ratios such as minimal residual disease in morphological complete remission, possibly in combination with adoptive NK cell transfer. As of now, development of 4G8-SDIEM cost |CE2 million and required 2.5 years from bench to bedside. Thus, development and early clinical evaluation of novel mAb can be achieved at academic institutions at reasonable costs and time before initiation of larger clinical Phase II/III studies by the pharmaceutical industry. Such an approach may not only accelerate the developmental process for anti-tumor mAb, but rather for innovative biological drugs in general. Disclosures: Hofmann: University of Tuebingen, Germany: Patents & Royalties. Grosse-Hovest: University of Tuebingen, Germany: Patents & Royalties. Aulwurm: University of Tuebingen, Germany: Patents & Royalties. Buehring: University of Tuebingen, Germany: Patents & Royalties. Jung: University of Tuebingen, Germany: Patents & Royalties.

Results from a phase I safety lead-in study investigating the combination of erlotinib and the histone deacetylase inhibitor entinostat in patients with advanced NSCLC

e14545 Background: Preclinical studies showed the synergistic effect of entinostat with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in NSCLC cell lines. Entinostat (SNDX-275, Syndax Pharmaceuticals) is an oral, class 1 isoform selective HDACi that restores the expression of e-cadherin and sensitivity to EGFR-TKI in NSCLC cell lines. The aim of this study was to determine the safety and feasibility of combining entinostat with erlotinib in advanced NSCLC patients in order to determine the recommended Phase 2 dose. Methods: Patients with recurrent or metastatic NSCLC whose tumors progressed on prior chemotherapy were treated with either 5 or 10mg orally of entinostat once every two weeks and erlotinib 150mg daily. Results: A total of 9 patients were enrolled (3 at entinostat 5mg; 6 at 10mg). Characteristics: Sex: M/F: 6/3; Age range: 46–84 yrs; ECOG PS: 0–1; Smoking status: 1/8 (never/current or prior smokers); Number of prior treatments: 1–2. There was one DLT of grade 3 asthenia. This occurred in one of the six patients in the 10mg dose cohort. The most common adverse events were anorexia, and asthenia. This was more often noted in elderly patients. Of the 9 evaluable patients, one patient had a confirmed partial response and remains on study (>5 cycles) and another patient had stable disease for 8 months. Pharmacokinetic analysis has been completed with both drugs exhibiting levels comparable to historical data. No drug:drug interaction was observed. EGFR FISH, EGFR mutation, and epithelial-to-mesenchymal marker analysis is in progress. Conclusions: This study has established the safety and a recommended phase 2 dose of 10 mg of entinostat once every other week in combination with 150 mg daily of erlotinib in a 28-day cycle in advanced NSCLC patients. A randomized, double blinded phase 2 study has been initiated with 43 patients enrolled to date. [Table: see text]