Increased Gamma-glutamyl Transferase Research Articles

Phase Ib study of niraparib plus androgen receptor-targeted therapy (ART) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

122 Background: Poly ADP-ribose polymerase (PARP) inhibitor and abiraterone acetate + prednisone (AA+P) has activity in pts with mCRPC regardless of DNA repair gene defects (DRD). Methods: This phase 1b study (Bedivere; NCT02924766) began with a 3+3 dose escalation of niraparib (Part 1), followed by expansion (Part 2) of the recommended phase 2 dose (RP2D) of nira + AA+P. Pts with mCRPC received nira 200 or 300 mg/day with AA+P. Dose-limiting toxicities (DLTs) were evaluated the first 28 days. Serial PK for nira were collected on cycle 1 day 1 (C1D1) over 24 h; PK for nira and abiraterone were collected on C2D1 over 10 h. Results: Nira 200 mg + 1000 mg AA+P was selected as the RP2D dose. 4 pts in 200 mg cohort and 8 pts in 300 mg cohort were enrolled in Part 1. During Part 1, 1 patient in the 300 mg cohort had two DLTs: Gr 3 fatigue and Gr 4 increased gamma glutamyltransferase. Therefore, the 200 mg dose was evaluated in 15 pts in Part 2. In 19 total pts treated with 200 mg niraparib, 12 (63%) pts had Gr 3-4 AEs, 5 (26%) pts had an AE with outcome of drug discontinuation and 1 (5%) patient had an AE with outcome of death (general physical health deterioration; unrelated). AEs of special interest were: 6 pts (32%) thrombocytopenia, 6 pts (32%) hypertension, 5 pts (26%) anemia and 3 pts (16%) neutropenia of any grade. 21% pts in 200 mg cohort had treatment emergent serious AE (TESAE) while 50% treated with 300 mg had TESAE. The exposure (AUC24h) on Day 1 of Cycle 2 for 200 mg niraparib with 1000 mg of AA were 17745±9380 ng.h/mL and 712±140 ng.h/mL, respectively. These exposures are consistent with single agent PK. Summaries of all responses will be provided, including a patient with primarily bone disease and carrying an ATM mutation who had a circulating tumor cell conversion and was on study treatment for 22.1 mo. Conclusions: The safety and PK findings support the choice of nira 200 mg in combination with AA+P in pts with mCRPC. The efficacy of nira + AA+P is being evaluated in an ongoing phase 3 MAGNITUDE study (NCT03748641). Clinical trial information: NCT02924766.

A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial

PurposeThis Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma. MethodsEligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population. Results141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1–8.8) in the eryaspase arm versus 4.9 months (3.1–7.1) in the control arm (HR, 0.63; 95% CI, 0.39–1.01; P = 0.056) and 2.0 months (95% CI, 1.8–3.4) in the eryaspase arm versus 1.8 months (1.4–3.8) in the control arm (HR, 0.67; 95% CI, 0.40–1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37–0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]). ConclusionEryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Tolerability and efficacy of lacosamide and controlled-release carbamazepine monotherapy in patients with newly diagnosed epilepsy and concomitant psychiatric conditions: Post hoc analysis of a prospective, randomized, double-blind trial

Psychiatric comorbidities are common in patients with epilepsy. A double-blind noninferiority monotherapy trial (SP0993; NCT01243177) enrolled newly diagnosed patients (≥16 years) with focal or generalized tonic-clonic seizures. Patients were randomized 1:1 to lacosamide or carbamazepine controlled-release (carbamazepine-CR). Here, we report data from an exploratory post hoc analysis of patients who reported ongoing psychiatric conditions (Medical Dictionary for Regulatory Activities System Organ Class). Of 886 treated patients in the trial, 126 (14.2%; 64 on lacosamide; 62 on carbamazepine-CR) reported at least one ongoing psychiatric condition at screening, most commonly depression (38.1%), insomnia (27.8%), and anxiety (26.2%). In this subgroup, 32/64 (50.0%) patients on lacosamide and 22/62 (35.5%) on carbamazepine-CR completed the trial. The most common reasons for discontinuation in patients on lacosamide and carbamazepine-CR were adverse events (10.9%, 24.2%) and lack of efficacy (18.8%, 11.3%). Treatment-emergent adverse events (TEAEs) were reported in 52 (81.3%) of patients on lacosamide and 56 (90.3%) of patients on carbamazepine-CR, most commonly (≥10% patients in either treatment group; lacosamide, carbamazepine-CR) dizziness (12.5%, 16.1%), headache (12.5%, 14.5%), nasopharyngitis (12.5%, 9.7%), fatigue (7.8%, 14.5%), nausea (7.8%, 11.3%), somnolence (1.6%, 12.9%), and gamma-glutamyltransferase increase (1.6%, 12.9%). Overall, 15 (23.4%) lacosamide-treated and 10 (16.1%) carbamazepine-CR treated patients reported psychiatric TEAEs, most commonly (≥3 patients in either treatment group; lacosamide, carbamazepine-CR) depression (4.7%, 0) and anxiety (3.1%, 6.5%). There were no reports of psychotic disorder, epileptic psychosis, acute psychosis, or serious psychiatric TEAEs. Stratified Kaplan–Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose were similar with lacosamide and carbamazepine-CR (6 months 81.0%, 75.6%; 12 months 62.5%, 66.6%). A higher proportion of patients on lacosamide than carbamazepine-CR completed 6 (67.2%, 45.2%) and 12 months (50.0%, 37.1%) of treatment at the last evaluated dose without a seizure. This exploratory post hoc analysis indicated that lacosamide monotherapy was efficacious and generally well tolerated in patients with newly diagnosed epilepsy and concomitant psychiatric conditions. In this subpopulation, lacosamide showed similar efficacy and numerically better effectiveness than carbamazepine-CR.

The influence of hemodialysis on FibroTest parameters

Abstract Chronic hepatitis C viral infection is an important cause of morbidity and mortality in patients with end-stage renal disease treated with hemodialysis. Liver fibrosis represents a main determinant of liver disease prognosis and clinical management, and its assessment by liver biopsy can decide treatment allocation. Although liver biopsy is the gold standard for staging liver fibrosis, it is an invasive procedure associated with complications that are more prevalent in patients with end-stage renal disease. FibroTest represents a surrogate marker of fibrosis which evaluates the levels of apolipoprotein A1, total bilirubin, haptoglobin, gamma-glutamyltransferase and α2-macroglobulin, generating a score that indicates the level of fibrosis. Discrepancies were observed in clinical practice between FibroTest score and histopathological findings. The aim of this study was to evaluate how hemodialysis influences the level of each FibroTest parameter and the final score. The systematic literature review conducted by us suggests that hemodialysis induces a reduction in apolipoprotein A1, haptoglobin and bilirubin levels, with an increase in gamma-glutamyltransferase and alpha-2-macroglobulin levels. In conclusion, hemodialysis modifies the levels of FibroTest parameters, suggesting that it may also have an impact on the accuracy of liver fibrosis assessment in hemodialysis patients.

Abstract 3891: A phase 1 study to evaluate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer (OC)

Abstract Purposes: To characterize the PK and safety of niraparib as a maintenance therapy in Chinese OC patients. Methods: Eligible patients were randomized 1:1:1 to 100, 200, or 300 mg once daily cohort. Plasma samples were collected following single and multiple dosing and analyzed using a validated LC/MS/MS method. PK parameters were analyzed by standard non-compartmental approach with WinNonlin. A population PK (Pop PK) model was derived from pooled PK data of current study and two previous PK studies in Caucasian: the dose escalation and expansion study (PN001), and the ENGOT-OV16/NOVA sub-study. Non-linear mixed effect modeling was done with NONEM®. Results: 36 patients were randomized and included in the PK and safety analysis set. Niraparib was rapidly absorbed after dosing with tmax~3h. The exposure of niraparib was dose proportional, while other PK parameters such as t1/2, accumulation ratio were dose independent (Table 1). The POP-PK analysis model was established using PK data from 144 Caucasians and 39 Chinese. Chinese patients had a slightly higher Cmax than Caucasian patients but similar total exposure (AUC0-∞) after a single dose. Simulation by final Pop PK model indicated comparable total exposure (AUC0-∞) and Cmax between Chinese and Caucasian patients at the steady-state following multiple daily doses. Treatment emergent AEs (TEAEs) occurred in 97.2% of all patients treated with niraparib. The most frequent (>20%) TEAEs were consistent with the known safety profile of PARP inhibitors. TEAEs of Grade 3/4 reported in ≥ 5% patients included decreased platelet count (13.9%), decreased neutrophil count (11.1%), anemia (8.3%) and increased gamma-glutamyl transferase (5.6%). Conclusions: The PK profile of niraparib in Chinese was consistent with its known profile in Caucasian. Niraparib in Chinese OC patients has a manageable safety profile, similar to that observed in global studies. (NCT03551171) Citation Format: Jian Zhang, Yu Nong Gao, Ge Lou, Ru Tie Yin, Jian Mei Hou, James Yan, Jing Li, Zhi Yi Zhang, Xiao Hua Wu. A phase 1 study to evaluate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer (OC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3891.

Efficacy of PD-1 monoclonal antibody SHR-1210 plus apatinib in patients with advanced nonsquamous NSCLC with wild‐type EGFR and ALK.

9112 Background: Our preclinical study suggested combination of PD-1 monoclonal antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. This was an open-label, multi-center, phase 1/2 study of intravenous SHR-1210 plus oral apatinib in patients with advanced NSCLC. Here, we reported preliminary efficacy and safety outcomes of SHR-1210 plus apatinib in patients with wild‐type EGFR and ALK. Methods: In dose-escalation phase, advanced non-squamous NSCLC patients (pts) previously treated with at least 2nd line chemotherapy were enrolled to explore 2 dose levels of apatinib (250, 375mg/d) + SHR-1210 (200mg, q2w). 250mg/d of apatinib was selected to be combined with SHR-1210 in phase II trial. Pts previously treated with 1st line platinum-based chemotherapy were enrolled. Primary endpoint was ORR per RECIST 1.1. Archived or fresh tumor tissues and blood samples were taken before the treatment, PD-L1 expression and tumor mutation burden (TMB) were tested and correlated with efficacy. TMB was detected by Oseq-pan cancer panel (including 636 genes and 1.95Mb), and then calculated by in-house algorithm developed by BGI Genomics Co., Ltd. Results: 96 pts with advanced non-squamous NSCLC harboring wild‐type EGFR and ALK were recruited . 23 had ≥2 prior lines of systemic treatment, and 73 had 1 prior line of treatment. Median age was 57, male 79.8%, adenocarcinoma 93.9%, ex-smokers 56.7%. ORR and DCR in 91evaluable pts were 29.7% and 81.3%, respectively. Blood TMB (bTMB) test was available in 80/91 evaluable patients and the cut-point was 1.54 muts/Mb as determined by receiver operating characteristic curve. ORR in pts with high bTMB was 50% (19/38). At data cutoff of 20 Jan 2019, 20/27 responders were still on treatment (table). Across all 96pts, 54(56.2%) grade ≥3 TRAEs. AEs of grade ≥3 occurring in 2 or more pts included hypertension, hand-foot syndrome, gamma-glutamyl transferase increase, proteinuria, abnormal hepatic function and alkaline phosphatase increase. Conclusions: SHR-1210 plus apatinib demonstrated promising anti-tumor activity with acceptable safety in patients with non-squamous NSCLC, especially in those with high bTMB. Prospective study is needed to validate the clinical outcome and bTMB as a predictor of efficacy. Clinical trial information: NCT03083041. [Table: see text]

Role of betaine in liver injury induced by the exposure to ionizing radiation.

Oxidative stress, apoptosis, and fibrosis may play a major role in the development of radiation-induced liver damage. Betaine, a native compound widely present in beetroot, was reported to possess hepato-protective properties. The objective of this study was to investigate the influence of betaine on radiation-induced liver damage. Animals were exposed to 9 Gy applied in 3 doses of 3 Gy/wk. Betaine (400 mg/kg/d), was orally supplemented to rats after the first radiation dose, and daily during the irradiation period. Animals were sacrificed 1 day after the last dose of radiation. The results showed that irradiation has induced oxidative stress in the liver denoted by a significant elevation in malondialdehyde, protein carbonyl, and 8-hydroxy-2-deoxyguanosine with a significant reduction in catalase activity and glutathione (GSH) content. The activity of the detoxification enzyme cytochrome P450 (CYP450) increased while GSH transferase (GSH-T) decreased. The activity of the apoptotic marker caspase-3 increased concomitant with increased hyaluronic acid, hydroxyproline, laminin (LN), and collagen IV. These alterations were associated with a significant increase of gamma-glutamyl transferase, alkaline phosphatase and alanine and aspartate aminotransferase markers of liver dysfunction. Betaine treatment has significantly attenuated oxidative stress, decreased the activity of CYP450, enhanced GSH-T, reduced the activity of caspase-3, and the level of fibrotic markers concomitant with a significant improvement of liver function. In conclusion, betaine through its antioxidant activity and by enhancing liver detoxification and reducing apoptosis may alleviate the progression of liver fibrosis and exert a beneficial impact on radiation-induced liver damage.

SPS-7 - Nintedanib plus pemetrexed/cisplatin in patients with MPM: Phase II findings from the placebo-controlled LUME-Meso trial

Standard 1st-line treatment for patients (pts) with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin (PEM/CIS); median overall survival (OS) is approximately 1 year. Nintedanib (N) is an oral inhibitor of VEGFR, PDGFR and FGFR, and Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has shown efficacy in preclinical models. This study evaluated the efficacy and safety of N+PEM/CIS vs placebo (P)+PEM/CIS in pts with MPM. Pts with unresectable MPM (chemo-naive, ECOG PS 0-1) were stratified by histology (epithelioid/biphasic) and randomised 1:1 to receive up to 6 cycles of PEM (500 mg/m2)/CIS (75 mg/m2) on Day 1 plus N or P (200 mg bid) on Days 2-21. Pts without disease progression received maintenance N or P. The primary endpoint was progression-free survival (PFS). 87 pts were randomised to N+PEM/CIS (n = 44) or P+PEM/CIS (n = 43). Pt characteristics were comparable between the groups; 89% had epithelioid MPM. PFS was significantly improved with N vs P (HR = 0.56 [95% CI 0.34-0.91]; p = 0.0174; median PFS 9.4 vs 5.7 months). PFS benefit was also seen in the epithelioid subgroup (HR = 0.51 [95% CI 0.30-0.86]; p = 0.0101). Preliminary OS data favoured N; objective tumour response was observed in 59% of the N arm vs 44% of the P arm (all partial responses). All pts experienced at least one adverse event (AE; any grade), with 7% of the N arm discontinuing due to AEs vs 15% with P. Serious AEs occurred in 36% vs 42% of pts in the N and P arms, respectively. The most common Grade ≥3 AEs (N vs P) were neutropenia (34% vs 10%), alanine aminotransferase increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). N+PEM/CIS demonstrated clinical efficacy with improved PFS and a tolerable safety profile in pts with unresectable MPM. Based on these promising findings, the study was extended and the Phase III part is recruiting (NCT01907100).

A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout

ObjectivesTo determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach.MethodsA randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at...

Clinical management of parasitic gastroenteritis (PGE) concurrent with moderate pneumonia in a goat: a clinical veterinary case report

Objective: Gastro-enteritis is a parasitic disease caused by the nematode species which is considered as an important parasite in Malaysia. This case report described the management of Parasitic Gastro-enteritis concurrent with pneumonia in goat. Materials and methods: The Jamnapari cross goat aged two years and weighing 40 Kg was presented to the Universiti Veterinary Hospital, Universiti Putra Malaysia with the history of diarrhea and depression. The goat was examined physically. Blood and fecal samples were collected for complete blood count, serum biochemistry analysis and parasitological examination. Standard treatment plan was applied for the correction of the the problem. Results: Physical examination findings revealed the goat was in poor body condition, dull and depressed. Wet and dry fecal traces were observed around the groin region. The temperature was slightly elevated (39.5°C), the heart rate was increased (160 b/min) while other parameters were within normal range. Upon auscultation of the thoracic region, moderate crackle lung sound was determined. Visual observation of the nasal cavity indicated a bilateral mucopurulent nasal discharge. The hemogram result revealed evidence of a normocytic normochromic anemia, leukocytosis, neutrophilia with left shift and monocytosis. Serum biochemistry revealed increases in gamma-glutamyl transferase (GGT), sodium, chloride, creatine kinase (CK), and hyperglobulinemia. Fecal examination revealed increased in Strongyle egg count of about 2,700 eggs per gram of feces using the Modified Mcmaster technique. From the history, physical examination and laboratory findings the goat was diagnosed with clinical parasitic gastroenteritis (PGE) concurrent with moderate pneumonia infection. The therapeutic plan for this case were 45 mL of kaolin-pectin (30 mL/Kg body weight) orally SID for 3 days as anti-diarrhea, 12 mL Levamisole (12 mg/Kg bwt) was administered orally once as anthelminthic, fluid therapy was instituted using 1.5 L of Lactated Ringers’ solution once via intravenously. Trimethoprim-Sulfamethoxazole (1 mL/16 Kg bwt) was administered intramuscularly SID for 3 days. Conclusion: Follow up examination of the goat a week post treatment indicated a good prognosis as the nasal discharges were cleared, diarrhea stopped and the goat was active.

OA22.02 Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial

Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ∼1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM. Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS). 87 patients were randomized to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favor nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

Potential role of raltegravir-based therapy to induce rapid viral decay in highly viraemic HIV-infected neonates

We report safety and tolerability of raltegravir (RAL) as a forth HIV agent in two highly viraemic newborns. Raltegravir (6 mg/kg) was given orally twice daily. The other antiretrovirals were assumed according to standard dose for newborns. The first baby was born at week 36. An antiretroviral therapy consisting of zidovudine, lamivudine, and lopinavir/ritonavir was started 96 hour after delivery. Raltegravir was added at hour 120, being plasma HIV-1 RNA above 10×106 copies/ml. HIV RNA declined to 5·000 copies/ml at day 30. The second baby was born at week 40. He was started on zidovudine, lamivudine, and nevirapine at day 0, while RAL was added at day 3. Plasma HIV-1 RNA declined from 6·6×106 at birth to 52 copies/ml at day 28. RAL tolerability was good in both patients, one with gamma-glutamyltransferase increase, which normalized after RAL discontinuation. Raltegravir-based four drug regimen may be effective and well tolerated in highly viraemic HIV neonates up to 4 weeks.

Effects of mycotoxin adsorbents in aflatoxin B 1 - and fumonisin B 1 -contaminated broiler diet on performance and blood metabolite

The present study examined the effect of aflatoxin (AFB1) and fumonisin (FB1) at the levels of 2 mg kg−1 AFB1 and 100 mg kg−1 FB1 and the efficiency of use of different levels of adsorbent based on sodium and calcium aluminosilicate on growth performance, hematological parameters, and biochemical parameters of broilers. A total of 1,440 Cobb broilers were distributed into the following treatments: positive control (PC) - no mycotoxin and adsorbent (AD); PC+3AD - no mycotoxin, with 3 g kg−1 adsorbent in feed; negative control (NC) - only mycotoxin; NC+1AD - with mycotoxin and 1 g kg−1 adsorbent in feed; NC+2AD - with mycotoxin and 2 g kg−1 adsorbent in feed; and NC+3AD - with mycotoxin and 3 g kg−1 adsorbent in feed. The amounts of AFB1 and FB1 added to NC reduced weight gain (35%) and feed intake (50%) compared with PC; however, inclusion of 2 or 3 g kg−1 adsorbent to NC alleviated such losses. Birds fed NC showed anemia, immunosuppression, and impaired liver function, observed by reduced cholesterol and increased gamma glutamyl-transferase activity compared with PC; values returned to normal levels when 2 or 3 g kg−1 of the adsorbent (as fed) were used. Mycotoxins cause adverse effects on most of the parameters studied, and the use of adsorbent at the levels of 2 and 3 g kg−1 of the adsorbent as fed partially negates the adverse effect of mycotoxicosis.

Gamma-glutamyl transferase is an indicator of gestational diabetes mellitus

Increased gamma-glutamyl transferase (GGT) is associated with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus in pregnant women. This cross sectional study was conducted in the Department of Clinical Pathology in collaboration with Department of Obstetrics and Gynecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from March 2014 to February 2015 to assess the GGT as an indicator of GDM. Total 66 pregnant women were enrolled in this study in the Department of Obstetrics and Gynecology, BSMMU. Total 33 cases were considered as Group I (GDM) and 33 controls were Group II (normal healthy pregnant women). Two ml of blood was collected in plain test tube from each patient. Gestational diabetes mellitus were diagnosed by FBS and 2hr after 75g glucose in this study as cases. Normal healthy pregnant women was included in this study as control. GGT was higher in GDM group compared to normal healthy pregnant women (30.60±7.78 vs. 16.45±4.97, p<0.001). So, with the help of GGT we can take preventive measure and precaution to reduce the risk of GDM in pregnant women.Bangladesh Med J. 2015 Sep; 44 (3): 152-156

Effect of Oral Contraceptive Pills on the Blood Serum Enzymes and DNA Damage in Lymphocytes Among Users.

The continuous use of synthetic hormones as contraceptive pill or hormonal replacement therapy among women is increasing day by day. The widespread use of different formulations as oral contraceptives by women throughout their reproductive cycle has given rise to a serious concern for studying the effects of oral contraceptives on enzymatic profile and DNA damage in peripheral blood lymphocytes among users. The present study was carried out on women taking oral contraceptives. The study was based on the questionnaire having the information of reproductive history, fasting, age, health, nature of menstrual cycle, bleeding and other disease. The profile of the blood serum enzymes i.e. alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), aminotransferases (SGOT and SGPT), serum proteins (albumin and globulin) and DNA damage in lymphocytes was studied among users and non-users. The results of the present study suggest that OCs not only effects enzymatic activity but also results in DNA damage that may vary with the duration of using oral contraceptives. A significant increase in LDH, GGT, SGPT, SGOT, globulin and decrease in ALP as well as albumin was found among users as compared to non-users. The observed DNA damage was more in users as compared to non-users. Hormonal contraceptives seem to exert DNA damage and also have significant effects on blood serum enzymes.

Chemical Composition of Golden Berry Leaves Against Hepato-renal Fibrosis

ABSTRACTThe role of Physalis peruviana (golden berry) as functional food against hepato-renal fibrosis induced by carbon tetrachloride (CCl4) was evaluated. The chemical composition of leaves referred the presence of withanolides and flavonoids. Two compounds, ursolic acid and lupeol, were isolated and their structures were elucidated by different spectral analysis techniques. The biological evaluation was conducted on different animal groups; control rats, control orally treated with plant extract (500 mg/kg body weight twice a week for six consecutive weeks), CCl4 (0.5 ml/kg body weight diluted to 1:9 (v/v) in olive oil and injected intraperitoneally) group, CCl4 treated with plant extract and CCl4 treated with silymarin as a reference herbal drug. The evaluation was done through measuring oxidative stress markers; malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO). Liver function indices; aspartate and alanine aminotransferases (AST & ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin and total hepatic protein were also estimated. Kidney disorder biomarkers; creatinine, urea and serum protein were also evaluated. The results revealed plant safety and decrease in NO, MDA, IgG, ALP, tissue protein, bilirubin, creatinine and urea levels. Increase in SOD, AST, ALT, GGT and serum protein levels were observed. Improvement in liver and kidney histopathological architectures were also seen. In conclusion, Physalis peruviana recorded a significant protective role in liver and kidney against fibrosis. Further studies are needed to evaluate its isolated compounds and its use in pharmacological applications and clinical uses.

Abstract B179: Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations

Abstract Background: Cabo inhibits tyrosine kinases including MET, VEGF receptors, AXL, and RET. The primary objective of this phase 1 study was to establish the recommended phase 2 dose (RP2D) of Cabo in Japanese pts; secondary objectives included assessment of safety, pharmacokinetics, and preliminary evidence of anti-tumor activity. Results from the dose escalation (DE) portion of the study have been previously reported. The final results of the study are presented, including data from expansion cohorts (ECs) in NSCLC with defined molecular alterations involving known driver oncogenes. Methods: Pts with advanced solid malignancies were enrolled in successive cohorts to receive escalating doses of Cabo orally once daily in a 3+3 design using capsule or tablet formulations. The RP2D was previously determined to be 60 mg qd tablet. Based on responses observed in pts with NSCLC, 3 molecularly defined NSCLC ECs were planned at the RP2D: EC1) pts with mutant EGFR and previous treatment with an EGFR inhibitor, EC2) pts with KRAS mutations, and EC3) pts with rearranged ALK (and previous treatment with an ALK inhibitor), RET, or ROS1. Tumor assessments per RECIST were performed on study day 29, and every 8 weeks thereafter until discontinuation of study treatment. Results: Forty three total pts were enrolled. Twenty three pts were enrolled in the DE cohorts, including 9 pts with NSCLC. Twenty pts were enrolled in the NSCLC ECs: 15 pts in EC1, 2 pts in EC2, and 3 pts in EC3 (n = 1 ALK+, n = 2 RET+). The median duration of treatment was 28.1 (3-156) weeks (wks) in the DE cohorts, and 13.3 (4-49) wks in the NSCLC ECs. Grade 3-4 AEs experienced by ≥3 pts were gamma glutamyl transferase increase (n = 4), hypertension (n = 3), and lymphopenia (n = 3) in the DE cohorts, and hypertension (n = 6), neutropenia (n = 5), alanine aminotransferase increase (n = 3), hand foot syndrome (n = 3), hypophosphatemia (n = 3), and dyspnea (n = 3) in the ECs. Serious AEs in ≥3 pts were dyspnea (n = 3), lung infection/pneumonia (n = 3), and pleural effusion (n = 3). The final PK analysis demonstrated that Cabo plasma exposures in Japanese pts were approximately 34% higher than reported previously in non-Japanese pts at the 60 mg tablet dose, and were within the range of inter-subject variability (%CV: 34% Japanese; 48% non-Japanese). Objective responses were observed in NSCLC pts: 4/9 NSCLC pts enrolled in the DE cohorts had a confirmed partial response (cPR) (2 pts ALK+, 1 pt RET+, 1 pt EGFR+), and 4/20 pts enrolled in the NSCLC EC cohorts had a cPR (all 4 pts were in EC1 [EGFR+]). Best change in sum of longest diameters (SLD) for all NSCLC pts with measureable disease (n = 28) ranged from 0 - 82% decrease (median = 24% decrease). For pts with a cPR, the time to initial response ranged from 4 - 20 wks and time from response to radiographic progression ranged from 4 - 64 wks. Conclusions: The RP2D of Cabo in Japanese pts was determined to be 60 mg. The safety and pharmacokinetic profiles are consistent with data from studies in non-Japanese pts. Antitumor activity with Cabo has been observed, including in pts with molecularly-defined NSCLC. Citation Format: Hiroshi Nokihara, Makoto Nishio, Noboru Yamamoto, Yutaka Fujiwawa, Hidehito Horinouchi, Shintaro Kanda, Asushi Horiike, Fumiyoshi Ohyanagi, Yifah Yaron, Anne Borgman, Tomohide Tamura. Final results of a phase 1 study of cabozantinib (Cabo) in Japanese patients (pts) with expansion cohorts in non-small cell lung cancer (NSCLC) with defined molecular alterations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B179.

Urinary polycyclic aromatic hydrocarbons and measures of oxidative stress, inflammation and renal function in adolescents: NHANES 2003–2008

ObjectiveRecent evidence has suggested that polycyclic aromatic hydrocarbons (PAHs) may contribute to cardiometabolic and kidney dysfunction by increasing oxidative stress, but little is known about impacts in childhood. Study designWe performed cross-sectional analyses of 660 adolescents aged 12–19 years in the 2003–2008 National Health and Nutrition Examination Survey (NHANES), using levels of 10 monohydroxylated urinary PAH metabolites as our exposure. Our primary outcomes of interest were biomarkers of oxidative stress and renal function, including estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (ACR), insulin resistance, and serum uric acid, gamma glutamyl transferase (GGT) and C-reactive protein (CRP). ResultsWe observed statistically significant associations between PAH metabolites and levels of serum GGT, CRP, uric acid and eGFR. Each 100% increase in 2-hydroxyphenanthrene was related to a 3.36% increase in uric acid (95% CI: 0.338–6.372; p=0.032), a 3.86% increase in GGT (95% CI: 1.361–6.362; p=0.005) and a 16.78% increase in CRP (95% CI: 1.848–31.689; p=0.029). Each 100% increase in 4-hydroxyphenanthrene was associated with a 6.18% increase in GGT (95% CI: 4.064–8.301; p<0.001) and a 13.66% increase in CRP (95% CI: 2.764–24.564; p=0.017). Each 100% increase in 9-hydroxyfluorene was associated with a 2.58% increase in GGT (95% CI: 0.389–4776; p=0.024). Each 100% increase in 3-hydroxyphenanthrene was associated with a 2.66% decrease in eGFR (95% CI: −4.979 to −0.331; p=0.028). ConclusionsUrinary PAH metabolites were associated with serum uric acid, GGT and CRP, suggesting possible impacts on cardiometabolic and kidney function in adolescents. Prospective work is needed to investigate the potential long-term health consequences of these findings.

Predictive Value of Gamma-Glutamyl Transferase Levels for Contrast-Induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Who Underwent Primary Percutaneous Coronary Intervention

Contrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (PPCI) is associated with adverse short- and long-term outcomes. The aim of this study was to evaluate the predictive value of gamma-glutamyl transferase (GGT) for risk of CIN in patients with ST-segment elevation myocardial infarction who underwent PPCI. A total of 473 patients were enrolled in the study. A relative increase in serum creatinine ≥25%, or an absolute increase ≥0.5mg/dl, from the baseline within 72hours of contrast exposure was defined as CIN. Patients were divided into 3 groups according to GGT tertiles (tertile 1, GGT <19 U/L; tertile 2, GGT 19 to 33 U/L; and tertile 3, GGT >33 U/L) on admission. Demographics, clinical risk factors, laboratory parameters, CIN incidence, and other inhospital clinical outcomes were compared among GGT tertiles. CIN incidence was significantly higher in tertile 3 (29%) compared with tertiles 1 (11%) and 2 (11%, p <0.001). Inhospital death incidence was significantly increased across tertiles (from tertile 1 to tertiles 2 and 3, 1%, 4%, and 5%, respectively, p <0.05). In receiver operating characteristic analysis, a threshold value of GGT >26.5 U/L had 70% sensitivity and 60% specificity for CIN. After including variables found significant in univariate analysis, the presence of diabetes mellitus (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.22 to 2.31, p <0.001), C-reactive protein (for each 1mg/L increase; OR 1.01, 95% CI 1.00 to 1.02, p= 0.007), contrast volume (for each 1-ml increase; OR 1.01, 95% CI 1.00 to 1.02, p= 0.012), and GGT >26.5 U/L (OR 2.59, 95% CI 1.48 to 4.53, p <0.001) were found as independent associates of CIN in multivariate regression analysis. Each 1 U/L increase in GGT was also associated with CIN risk (OR 1.04, 95% CI 1.03 to 1.06, p <0.001). In conclusion, GGT on admission was a significant and independent predictor of CIN after PPCI in patients withST-segment elevation myocardial infarction.