Changes In ALT Research Articles

Impacts of n-acetyl cysteine on gibberellic acid-induced hepatorenal dysfunction through modulation of pro-inflammatory cytokines, antifibrotic and antioxidant activity.

The extensive usage of gibberellic acid (GA3) in agriculture and plant growth is generally associated with enormous human and public health hazards. The present research assesses the impact of n-acetyl cysteine (NAC) on the hepatorenal injury persuaded by GA3 for this purpose, After two weeks of adaptation twenty-four rats allocated into four groups (6 rats/group) as follows: control group, supplied with saline only; n-acetyl cysteine (NAC) group, provided with 150mg/kg/bw by stomach tube (orally) dissolved in saline; Positive GA3 group, received GA3 (55mg/kg/bw) orally; Protective group received NAC (150mg/kg/bw) and GA3 (55mg/kg/bw) as in NAC and GA3 groups. Rats received their treatments for consecutive 3weeks. On day 22, rats were anesthetized, then euthanized. Blood and tissue samples were obtained for biochemical, antioxidants markers analysis, gene expression, and histopathological examination. Our results revealed significant changes in serum AST, ALT, urea, uric acid, total protein, and albumin levels with a substantial rise of MDA and NO concentration in GA3 treated rats along with a considerable decrease of the GSH and overexpression of the inflammatory hepatic and renal cytokines (IL-10, TNF-α, NOS) and fibrotic gene expression TGF-β1, and α-SMA, with boost expression of nuclear factor-kappa (NFk B). NAC co-administered with GA3 significantly normalized the kidney and liver function and the antioxidant state, besides normal histological structure of both liver and kidney tissue and downregulated expression of the pro-inflammatory cytokines as well as, fibrogenic gene expression. PRACTICAL APPLICATIONS: The current study confirmed that GA3 induced hepto-renal dysfunction that was ameliorated by NAC administration. Moreover, our findings confirmed the antioxidant capability of n-acetyl cysteine and afford robust evidence about the ameliorative effect of the n-acetyl cysteine to attenuate the hepatorenal injury induced by gibberellic acid through modulation of the antioxidant defense system fibrogenic, and pro-inflammatory cytokines expression.

Treatment of hyperglycemia not associated with NAFLD improvement in children with type 2 diabetes mellitus.

Background and objectivesNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have become public health problems in the pediatric population. However, the relationship between these two conditions is not well understood. The primary objective of this study was to assess whether treatment of hyperglycemia in obese, treatment-naive children with type 2 diabetes (T2DM) was associated with an improvement of surrogate markers of NAFLD.Materials and methodsThis retrospective, longitudinal study included 151 obese children with a diagnosis of T2DM (Age: 14 ± 1 years, 72% female children, BMI: 98.6th percentile, and A1c: 10.3 ± 0.2%). Clinical/demographic information was collected before patients started any diabetes treatment and 1 and 3 years after starting metformin and/or insulin therapy.ResultsForty-eight patients (32%) had abnormal ALT/AST (i.e., >40 U/L), suggestive of NAFLD. After 1 year of therapy, there were no significant differences in plasma ALT among patients started on insulin, metformin, or combination: 5±4 vs. −10 ± 3 vs. −2±2 IU/L, respectively, P = .07. Of note, changes in plasma ALT were small, despite a significant reduction of A1c in patients prescribed insulin (alone or with metformin): -2.8 ± 1.0%, P = .01, and −2.7 ± 0.3%, P < .001, respectively. In line with this, no significant correlations were found between changes in A1c and plasma aminotransferases. In contrast, changes in plasma AST/ALT were more strongly associated with BMI changes (r = 0.32, P < .001, and r = 0.19, P = .04, respectively). Similar results were observed after 3 years of follow-up.ConclusionsNonalcoholic fatty liver disease is highly prevalent in obese children with T2DM. Treatment of hyperglycemia with metformin and/or insulin did not result in any significant improvement in surrogate markers of NAFLD (i.e., plasma aminotransferases). While changes in ALT and/or AST may not perfectly reflect histological changes in NAFLD, our findings suggest that the treatment of hyperglycemia per se may not be associated with NAFLD improvement.

Clinical, haemato-biochemical and ultrasonographic diagnostic tools of different urinary tract affections in dogs

Urinary tract affections are important clinical problems recorded in dogs affecting their health condition. The present study was carried out on 21 dogs of both sexes and different breeds having different urinary tract affections. The study aimed to evaluate clinical, hematological, biochemical, urinalysis, and ultrasonographic changes in dogs with different urinary tract affections. Acute renal failure, hydronephrosis, polycystic kidney disease, urolithiasis, and cystitis were diagnosed in 5,3,3,5,5 dogs, respectively. The most common clinical signs recorded in all affections were pollakiuria, hematuria, polyuria, dysuria, urine retention. Urinalysis showed the presence of proteinuria, blood in different affections of the urinary tract. There was decrease in RBCs count and Hemoglobin content above normal reference value in all urinary tract affections except in cystitis and there was increase in WBCs count above normal reference value in all different urinary tract affections. There was increase in urea and creatinine levels above normal reference value in all urinary tract affections except in cystitis. There were no changes in ALT, and AST levels in all affections except in acute renal failure were higher than normal reference value. Ultrasonographic examinations revealed structural abnormalities in all recorded urinary tract affections. The results of the present study revealed that clinical, hematological, biochemical, urinalysis, and ultrasonographic examinations are essential in dogs for accurate diagnosis of different urinary tract affections.

Vitamin D3 Protects Mice from Diquat-Induced Oxidative Stress through the NF-κB/Nrf2/HO-1 Signaling Pathway.

Vitamin D3, as an indispensable and fat-soluble micronutrient, plays an important role in the health of humans and animals. At present, studies are focusing on the calcium absorption and immunoregulation function of vitamin D3; this study was aimed at exploring the antioxidative stress ability of vitamin D3 on diquat-induced intestinal dysfunction of ICR mice and the underlying mechanism. The results showed that oral gavage of vitamin D3 daily significantly improved the body weight gain and immune organ index and significantly reverted the abnormal changes of ALT, AST, SOD, GSH-Px, T-AOC, and MDA in the serum and jejunum induced by diquat. The addition of vitamin D3 also significantly reduced the concentration of DAO, D-LA, and certain proinflammatory cytokines in serum. Moreover, vitamin D3 improved the pathological morphology of the duodenum, jejunum, colon, liver, and kidney tissues, and it also largely attenuated the degree of inflammatory infiltration of macrophages and cell apoptotic index of jejunal epithelial tissue induced by diquat. The results demonstrated that vitamin D3 significantly recovered the intestinal barrier injury by enhancing the expression of mucins and tight junction proteins in the jejunum. In addition, the results indicated that vitamin D3 could significantly reduce the phosphorylation level of NF-κB (p65) and enhance the expression of Nrf2 and HO-1 in the jejunum compared with the diquat-induced group. This study suggested that oral administration of vitamin D3 can protect mice against oxidative damage by inhibiting the phosphorylation level of NF-κB (p65) and activating Nrf2-related signaling pathways.

Establishment of reference intervals of biochemical analytes for South African adults: a study conducted as part of the IFCC global multicentre study on reference values

Objective: This study was conducted as a part of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) global study for establishing reference intervals (RIs) of common laboratory tests for the South African population considering gender, ethnicity, age and body mass index (BMI). Methods: The researchers recruited 1 143 apparently healthy volunteers aged 18–65: 551 African (Afr) and 592 non-African (NAfr) (comprising 383 Caucasian and 209 Mixed Ancestry). Serum samples were measured for 40 chemistry and immunochemistry analytes. The standard deviation ratio (SDR) guided the need for partitioning reference values according to gender, ethnicity and age using a threshold of ≥ 0.4. The latent abnormal values exclusion (LAVE) method was applied to reduce influences of latent diseases before deriving RIs using both parametric and non-parametric methods. Results: Based on SDRsex, males showed higher albumin, uric acid, creatinine, AST, CK and ferritin. Based on SDRRC, Afr compared to NAfr showed (i) higher total protein, amylase, CRP, immunoglobulin G and A and (ii) lower total bilirubin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), ALT and cholinesterase. Both age-related changes in glucose and LDL-C, and BMI-related changes in ALT, ALP and LDH were more prominent in NAfr. RIs were determined according to gender, age and ethnicity. The LAVE method was effective in lowering the upper RI limits (UL) of nutritional markers such as γGT and CRP. Compared to the non-parametric method, the parametric method gave narrower confidence intervals of ULs for analytes with skewed distributions. Conclusion: Establishing RIs by considering ethnicity was essential in many analytes in South Africa. Age and BMI-related changes differed greatly between Afr and NAfr.

The utility of laboratory monitoring among patients with acne vulgaris receiving different doses of oral isotretinoin

Background and study aim: Adverse events of isotretinoin are in mucocutaneous and hepatic tissues, alterations in lipid levels and teratogenicity. This study was aimed to evaluate the alterations in aminotransferases and serum lipids in patients using different doses of oral isotretinoin. Patients and methods: 300 patients with moderate to severe acne were enrolled and randomized to receive isotretinoin for 24 weeks in three groups: 40 mg daily (group A: continuous conventional dose), 20 mg daily (group B: continuous low dose) or 40 mg daily for one week out of every 4 weeks (group C: intermittent dose). Baseline liver enzymes and lipid profile were done and repeated at 4,12 and 24 weeks after starting. Results: There were no statistical differences in the patients in sex, age and body mass index (BMI) in three groups. Only in group A, there was a non-significant increase in serum triglyceride (p=0.17) and non-significant decrease in HDL after 12 weeks of treatment (p=0.36). Both AST and ALT increased non-significantly after 4 weeks of treatment in this group (p=0.09). No difference was seen in serum lipids and liver aminotransferases during the study in group B and C. Conclusion: The results showed that use of oral isotretinoin for the treatment of acne did not lead to permanent and significant change in serum lipids, ALT and AST levels and these alterations did not require treatment to be interrupted. Laboratory monitoring is not necessary among patients receiving intermittent or continuous low dose of oral isotretinoin.

Post-transfusion hemoglobin response in patients with cirrhosis: Can we expect a 1 g/dL rise per unit transfused?

A patient's hemoglobin is typically expected to rise by 1 g/dL/unit transfused PRBCs. However, it has been theorized that mechanisms such as hyperbilirubinemia and splenomegaly might lead to either a direct lysis or sequestration of red blood cells that could decrease this proportionate response. Patients with resolved GI bleeding but still requiring transfusion to correct anemia were compared in cirrhosis and control groups. A retrospective chart review between 2015 and 2020 was conducted at a single institution. Data collected included age, sex, BMI, GI bleed diagnosis, number of PRBCs transfused, presence of splenomegaly and spleen size, alcohol use history, type of cirrhosis, MELD-Na at admission, GFR, and pre-and post-transfusion labs: total bilirubin, ALT, hemoglobin, hematocrit. A logic regression was performed for each group looking at which factors were associated with a successful response (defined as >0.9 g/dL hemoglobin per unit transfused). Mean change in hemoglobin was 0.77 g/dL in patients with cirrhosis compared to 1.46 g/dL in patients without (P < .001, N = 103). Odds ratios for presence of splenomegaly (0.22, N = 78) and female sex (4.39, N = 102) in predicting adequate response (>0.9 g/dL/unit) were both significant (P = .002) as well as portal hypertensive bleed diagnosis (0.28, N = 85, P = .0015). Factors that did not contribute included: age, race, BMI, alcohol use, GFR, change in ALT, and change in total bilirubin. Patients with cirrhosis have an approximately 50% decreased response to transfusion with PRBCs after resolution of a gastrointestinal bleed in comparison to patients without cirrhosis. Risk factors included splenomegaly, portal hypertension, and male sex.

Association of ACEI/ARB, inflammatory cytokines, and antiviral drugs with liver dysfunction in patients with hypertension and COVID-19

ABSTRACT Background: Currently, SARS-CoV-2 liver invasion, inflammatory cytokines, and antiviral drugs are widely thought to be associated with liver dysfunction in COVID-19 patients. Besides, previous studies indicated that ACEI/ARB drugs can increase the expression of hepatic ACE2, a cell entry receptor for SARS-CoV-2. This study aims to investigate whether ACEI/ARB aggravates liver injury and the association of inflammatory cytokines and antiviral drugs with liver dysfunction in patients with hypertension and COVID-19.Method: This retrospective study included 127 hypertensive patients with long-term use or nonuse of ACEI/ARBs hospitalized for COVID-19 from January 30 to April 7, 2020, in Tongji hospital of Wuhan, China. Demographic, clinical, laboratory, treatment, and outcome data were collected.Results: Of the 127 patients with COVID-19 and hypertension, 43 taking long-term of ACEI/ARBs and 84 without using ACEI/ARBs. Abnormal liver function was observed in part of ACEI/ARB and non-ACEI/ARB users but without significant differences between these two groups. Serum inflammatory cytokines, IL-6, IL-8, and TNFα, as well as inflammation-related markers, ferritin, procalcitonin, and C-reactive protein, were significantly elevated in patients with liver dysfunction. IL-6 level was positively correlated with liver function tests on admission and highly consistent with the changes of abnormal ALT, AST, and GGT during hospitalization, but the correlations of other inflammatory cytokines were low. There was no significant association between the use of antiviral drugs and liver dysfunction in these patients.Conclusion: The elevation of inflammatory cytokine, IL-6, but not ACEI/ARB and antiviral drugs, is closely associated with liver dysfunction in patients with hypertension and COVID-19.

14-Day Repeated Intraperitoneal Toxicity Test of Ivermectin Microemulsion Injection in Wistar Rats.

To evaluate the safety of ivermectin microemulsion injection, 100 Wistar rats were injected intraperitoneally at 0.38 g/kg, 0.19 g/kg, and 0.1 g/kg for 14 days. The 14-day repeated toxicity test of ivermectin microemulsion injection was systematically evaluated by clinical observation, organ coefficient, hematological examination, clinical chemistry examination, and histopathological examination. The results showed that no rats died during the test. At the initial stage of treatment, the rats in the high dose group had mild clinical reaction, which disappeared after 4 days. Clinical chemistry showed that the high dose of ivermectin microemulsion could cause significant changes in ALT and LDH parameters in male rats; high and medium doses could increase the liver coefficients of male and female rats. The toxic target organ may be the liver as indicated by histopathological findings. No significant toxic injury was found in the heart, liver, spleen, lung, kidney, brain, ovary, and testes of all groups of rats. No drug-related toxic effects were found at low doses, and thus the NOVEL of ivermectin microemulsion injection was 0.19 g/kg.

Assessment of Some Biochemical Changes in Wistar Rats Following Administration of Three Polyherbal Preparations Repurposed for COVID-19

Background and Aims: The current pandemic known as Coronavirus Disease-19 (COVID-19) is a significant public health menace. Currently, there is no specific treatment for this disease, although some medicinal agents are under investigation. Some published articles have reported Severe Acute Respiratory Distress Syndrome Coronavirus-2 (SARS CoV-2) involvement in other organs, including the liver and kidneys, which can impair the metabolism and excretion of the medications taken to treat the disease. This study evaluated the effects of 3 herbal mixtures on some biochemical parameters of the liver and kidney of laboratory animals.&#x0D; Methods: Liver enzymes such as serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin and total serum protein were quantified. Urea, creatinine and bilirubin (total and direct) were also evaluated. These parameters were determined for all three polyherbal combinations (CoV Pla-1, CoV Pla-2, CoV Pla-3).&#x0D; Results: The extracts did not produce any mortality up to 5000 mg/kg per oral. Results showed that the polyherbal extracts (CoV Pla-1, CoV Pla-2 CoV Pla-3) did not cause any significant changes in ALT, AST, ALP, compared to control. The mean values of urea showed an insignificant (P&gt;0.05) decrease across all test doses in the three extracts, compared to the control. In the current study, the mean creatinine concentration showed slight decrease across all three extracts. Total protein was observed to be lower in CoV Pla-1 and CoV Pla-2, and increased in CoV Pla-3, though these changes were not statistically significant. Serum albumin decreased at the low and intermediate doses for the three polyherbal extracts in an insignificant manner compared to control.&#x0D; Conclusion: The results obtained in this study indicate that the extracts did not cause significant changes in biochemical parameters evaluated and support their use in the treatment of Covid-19.

Retrospective analysis of a dedicated care pathway for nonalcoholic fatty liver disease in an integrated US healthcare system demonstrates support of weight management and improved ALT

BackgroundA care pathway for nonalcoholic fatty liver disease (NAFLD) in Kaiser Permanente San Diego, California was instituted in August 2017 to improve efficiency of disease staging and promote lifestyle modification.MethodsThe NAFLD Care Pathway includes: (1) patient education (2) vibration controlled transient elastography (VCTE) examination (3) hepatology consultation for VCTE ≥ 8 kPa and (4) referral to weight management (WM). Patients referred to the pathway during the first 6 months of its implementation were studied for adherence to its components and impact on weight change and ALT values in the 12 months following referral. Retrospective assessment of WM participation, change in weight, and change in ALT were evaluated in the 12-months following referral and compared to changes 12-months prior. Student’s t-test or Wilcoxon signed rank test were used as appropriate (p < 0.05).Results632 patients were included. 575 (91.0%) completed VCTE examination with mean liver stiffness 8.5 kPa (SD 9.2). 52 patients had mean liver stiffness ≥ 15 kPa. 180/632 (28.5%) attended NAFLD education. 153/632 (24.2%) were offered hepatology clinic and 136/153 (88.9%) completed at least 1 appointment. Participation in WM was 24/632 (3.8%) prior to referral and 67/632 (10.6%) after referral and increased among patients who attended NAFLD education. Mean weight change following referral was − 0.69 kg (SD 6.58 kg) among patients without WM and − 7.78 kg (SD 13.43 kg) with WM. Overall, 44.2% of participants experienced weight gain after referral, 40.8% had weight loss < 5% and 15% had weight loss ≥ 5%. Variables associated with weight loss included WM (p < 0.0001) and higher liver stiffness (p = 0.0066). Mean ALT change was − 15.2 (SD 38.5) U/L without WM and − 28.8 (SD 29.6) U/L with WM.ConclusionsA care pathway for NAFLD within a large, integrated healthcare system provides non-invasive disease staging and minimizes hepatology clinic utilization to those with more advanced disease. Referral was associated with increased enrollment in WM, weight loss, and decreased ALT. Given its impact on healthcare resources, strategies to improve NAFLD identification, staging, and promotion of lifestyle modification are imperative.

Phytochemical characterization and hepatoprotective effect of active fragment from Adhatoda vasica Nees. against tert-butyl hydroperoxide induced oxidative impairment via activating AMPK/p62/Nrf2 pathway

Ethnopharmacological relevanceAdhatoda vasica Nees., which existed in a large; number of Tibetan medicine prescriptions for hepatopathy, used as an adjuvant to treat liver diseases. Hypothesis/purposeOxidative stress is the key player in the development and progression of liver pathogenesis. In recent years, research is increasingly being focused on exploitation of the active components from medicinal plants to combat the liver oxidative injury. In our study, we aimed to screen the active principles from A. vasica and clarify whether they could relieve oxidative damage induced by tert-Butyl hydroperoxide (t-BHP) and its potential mechanism via activating AMPK/p62/Nrf2 pathway. Materials and methodsUltra performance liquid chromatography (UPLC) was adopted for analysis of chemical composition in the extracts. Furthermore, the antioxidant activity of the fractions was evaluated using DPPH, ABTS and reducing power assay. Along with this, the compounds in this fraction with highest antioxidant activity were analyzed using UPLC-MS. Based on this, the condition for extracting flavonoids of this subfraction was optimized via response surface method. CCK-8 assay was used to detect cell viability. Detection kits were used to measure the activity changes of AST, ALT, LDH and CAT as well as MDA and GSH levels induced by t-BHP. Detection of reactive oxygen species (ROS) production was used DCFH-DA probe. DAPI staining and flow cytometry was used to detect cell apoptosis. In terms of the mechanistic studies, the expression of proteins involved in AMPK/p62/Nrf2 pathway was measured using western blotting. ResultsEventually, 70% ethanol extract from leaf of A. vasica was chosen due to its highest active components compared with other extracts. Further, ethyl acetate fraction derived from 70% ethanol extract in A. vasica (AVEA) possess highest ability for scavenging DPPH and ABTS free radicals as well as strongest reducing power than other fractions. Chemical composition analysis showed that AVEA contained 17 compounds, including 1 quinazoline alkaloid, 12 flavonoid-C-glycosides and 4 flavonoid-O-glycosides. In addition, the conditions (ratio of solid-liquid 1:14, the concentration of ethanol 73%, and the temperature 65 °C) were selected to enrich the flavonoids in AVEA. Furthermore, AVEA could attenuate t-BHP induced hepatocyte damage via increasing the cell viability, restoring abnormal the activities of AST, ALT, LDH and CAT as well as the levels of MDA and GSH. ROS fluorescence intensity was reduced by AVEA. Meanwhile, it could inhibit the cell apoptosis of BRL 3 A cells, as evidenced by restoration of cell morphology and decreasing the number of apoptotic cells. Further mechanistic studies indicated AVEA could promote p-AMPK expression to further induce autophagy adaptor-p62 protein expression, which could autophagic degradation of Keap1, leading to Nrf2 release and translocation into nucleus to induce antioxidant genes (HO-1, NQO-1, GCLC and GCLM) expression. ConclusionIn our study, AVEA was first to screen as the active fraction in A. vasica with alkaloids and abundant flavones. Moreover, the fraction potentiates its beneficial aspect by displaying the protective role on relieving t-BHP induced oxidative stress and activating AMPK/p62/Nrf2 pathway. AVEA helps maintain the redox homeostasis of hepatic cells and could be considered as an effective candidate against oxidative stress related liver disorders.

Acute and subchronic toxicity studies of rhein in immature and d-galactose-induced aged mice and its potential hepatotoxicity mechanisms

Rhein is a key ingredient in many herbal remedies and is widely used. However, herbs containing rhein are frequently associated with poisoning incidents, especially in elderly subjects. Acute and subchronic toxicity of rhein in Kunming mice (KM) was investigated in this experiment. Acute toxicity tests showed a 40% lethality at a given rhein dose of 4000 mg/kg, and the LD50 of rhein was calculated by the bliss method to be greater than 2185.6 mg/kg. In subchronic toxicity, d-gal-induced aged and immature animals were randomized into three groups that were exposed to rhein of 0, 175, and 375 mg/kg/d for 75 days, respectively. No mortality was observed in immature mice group, whereas 55.5% (5/9) subjects in aged mice groups died in the high dosage group. AST, ALT, IL-6, TNF-α levels and typical histopathological changes indicate that rhein causes liver injury. In addition, our investigation explored possible hepatotoxic mechanisms of rhein and experimental results showed increased ROS production, NRF-2 and MDA levels and decreased SOD levels, demonstrating that rhein causes oxidative stress. MMP and mitochondrial swelling levels were able to assess the impact of rhein on mitochondrial function. Furthermore, the effect of rhein on apoptosis can be detected by flow cytometry. Our studies suggested that rhein induces oxidative stress leading to mitochondria dysfunction and apoptotic activation. Multidrug resistance protein (MRP) is an efflux transporter protein and is capable of transporting cellular oxidative stress-related substances. To further clarify the role of MRP in rhein induced oxidative stress, we examined MRP expression in the liver. However, the expression of MRP has no statistical significance.

SAT457 - Longer-term experience with tenofovir alafenamide (TAF) in HBV-infected patients; changes in EGFR, FIB4, ALT, and DNA suppression

SAT457 - Longer-term experience with tenofovir alafenamide (TAF) in HBV-infected patients; changes in EGFR, FIB4, ALT, and DNA suppression

The association between markers of liver injury and clinical outcomes in patients with COVID-19 in Wuhan.

SummaryBackgroundThe outbreak of coronavirus disease 2019 (COVID‐19) is a critical challenge for public health. The effect of COVID‐19 on liver injury has not been fully established.AimsTo evaluate the dynamic changes in liver function and the relationship between liver damage and prognosis in patients with COVID‐19.MethodsRetrospective analysis of clinical data of 675 patients with COVID‐19 in Zhongnan Hospital of Wuhan University from January 3 to March 8, 2020. Patients were classified as having normal or abnormal liver function and liver injury.ResultsOf 675 patients, 253 (37.5%) had abnormal liver function during hospitalisation, and 52 (7.7%) had liver injury. The dynamic changes of ALT and AST levels were more significant in patients with liver injury and in those who died. AST >3‐fold upper limit of normal (ULN) had the highest risk of death and mechanical ventilation. Compared to patients with normal AST levels, mortality and risk of mechanical ventilation significantly increased 19.27‐fold (95% confidence interval [CI], 4.89‐75.97; P < 0.0001) and 116.72‐fold (95% CI, 31.58‐431.46; P < 0.0001), respectively, in patients with AST above 3‐fold ULN. Increased leucocytes, decreased lymphocytes and female sex were independently associated with liver injury.ConclusionsThe dynamic changes in liver function may have a significant correlation with the severity and prognosis of COVID‐19. Increased index of liver injury was closely related to mortality and need for mechanical ventilation. Therefore, these indicators should be closely monitored during hospitalisation.

Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials

IntroductionThis post hoc exploratory analysis examined the effects of ertugliflozin on liver enzymes in patients with type 2 diabetes mellitus (T2DM).MethodsData were pooled from seven randomized, double-blind VERTIS phase 3 trials that evaluated ertugliflozin (5 mg and 15 mg) versus non-ertugliflozin (placebo, glimepiride, or sitagliptin) treatment in patients with T2DM. Change from baseline at week 52 of treatment in alanine and aspartate aminotransferase (ALT and AST, respectively) serum levels (overall and categorized into tertiles by baseline ALT and AST), Fibrosis-4 Index (FIB-4), glycated hemoglobin (HbA1c), and body weight were evaluated, along with the association between changes in ALT and AST and changes in HbA1c and body weight by treatment.ResultsBaseline characteristics were balanced across treatment groups (ertugliflozin 5 mg, n = 1716; ertugliflozin 15 mg, n = 1693; non-ertugliflozin, n = 1450). At week 52 of treatment, serum levels of ALT and AST were reduced in patients in the ertugliflozin treatment groups (5 and 15 mg, respectively) compared with those in the non-ertugliflozin group. The comparator-adjusted mean (95% confidence interval [CI]) difference in change from baseline at week 52 for ALT was − 3.35 (− 4.40, − 2.31) IU/L for ertugliflozin 5 mg and − 4.08 (− 5.13, − 3.03) IU/L for ertugliflozin 15 mg; for AST, the respective values were − 1.81 (− 2.50, − 1.11) IU/L and − 2.12 (− 2.82, − 1.42) IU/L. The effects of ertugliflozin were detected across all baseline ALT and AST tertiles, with the highest tertile showing the greatest treatment differences. No meaningful differences were observed between treatment groups for FIB-4. Changes in ALT and AST showed a weak but statistically significant association with changes in HbA1c and body weight in all treatment groups.ConclusionsTreatment with ertugliflozin resulted in a reduction in the levels of hepatic transaminases compared with the non-ertugliflozin group after 52 weeks of treatment. Changes in body weight and HbA1c contributed at least in part to the effects of ertugliflozin on liver enzymes.Trial RegistrationClinicaltrials.gov registry numbers: NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

HLA-mismatched GPBSC infusion therapy in refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: an observational study from a single center

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory state. Epstein–Barr virus (EBV) infection-associated HLH (EBV-HLH) is one of the most common secondary HLH and suffers a very poor prognosis. Allo-HSCT is often required for refractory EBV-HLH, but some patients still cannot proceed to the next allo-HSCT due to various factors. This study aimed to observe the efficacy of HLA-mismatched granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (GPBSCs) infusion for refractory EBV-HLH.MethodsA retrospective case-control study of refractory EBV-HLH patients with GPBSC infusion from HLA-mismatched donors after chemotherapy (as GPBSC group) and sole chemotherapy (as control group) was performed. Efficacy was evaluated 2 and 4 weeks and all patients were followed-up until March 1, 2018.ResultsThere were 18 cases who accepted infusion between March 2016 and Sep 2017 and 19 were randomly selected from refractory EBV-HLH patients who underwent salvage therapy during the same period for the control group. In GPBSC group, WBC (p = 0.017), Fbg (p = 0.040), and ferritin (p = 0.039) improved significantly after treatment. The overall response rate was 66.7% (CR 22.2%, PR 44.4%). However, there are no significant differences in changes of WBC, HGB, PLT, TG, Fbg, Ferritin, AST, ALT, and T-bil between two groups. Only the Fbg level was recovered better in the GPBSC infusion group (p = 0.003). In the GPBSC group, EBV-DNA decreased significantly after 2 weeks (p = 0.001) and 4 weeks (p = 0.012) after treatment, and the effect of the decrease was significantly better than that of the chemotherapy alone group in 2 weeks but not 4 weeks (p2w = 0.011, p4w = 0.145). The median survival time in the infusion group was 20.4 weeks [95% CI 10.9, 29.9], and the median survival time in the control group was 10.8 weeks [95% CI 0–24.34]. In the short-term, the infusion group’s survival rate was better (2-month 88.89% vs. 52.63%, p = 0.008; 3-month 83.33% vs. 47.09%, p = 0.012), but there was no difference in OS (p = 0.287).ConclusionsInfusing GPBSCs combined with chemotherapy is effective, especially in decreasing EBV-DNA, performs better than chemotherapy alone, and improves short-term survival rate. GPBSC infusion is suggested as a bridging treatment method to allo-HSCT.

Assessment of Efficacy and Safety of Clindamycin Against Methicillin- Resistant Staphylococcus aureus (MRSA) Infected Subcutaneous Abscess Model

Background: Methicillin-resistant Staphylococcus aureus (MRSA) causes infection in the wound leading to life-threatening bacteriemia. It causes recalcitrant infections because of being resistant to various antibiotics. The recent studies reported clindamycin to be effective against MRSA rather than inducible clindamycin resistance and decrease the incidence of new infections after clindamycin treatment. The study focused on assessing the efficacy and safety of clindamycin against MRSA infected rats. Methods: The rats become neutropenic by intraperitoneal administration of cyclophosphamide at a dose of 150 mg/kg and 100 mg/kg for 4 days and 5th day respectively. The neutropenic rats were infected with MRSA by subcutaneous administration of 106 CFU/ml of MRSA. The 3 groups of rats such as Normal, MRSA infected, MRSA infected rats that were administered clindamycin orally at a dose of 90 mg/kg/ thrice daily for 14 days were used in the study. The abscess size, weight, and bacterial load were measured at the end of the study. The blood and liver samples were collected for biochemical analysis and histopathological evaluation. Results: The MRSA was confirmed by Polymerase Chain Reaction (PCR) method. The clindamycin minimum inhibitory concentration was 0.125 - 0.5 μg/ml. The MRSA showed negative D test for clindamycin indicating the absence of inducible clindamycin resistance. The decreased abscess size, weight, bacterial count, Intestinal Alkaline Phosphatase (IAP), weight loss, alteration in hematological parameters, mild changes in cholesterol, ALT and liver histology, no significant (P &gt; 0.05) change in triglycerides, AST, ALP, bilirubin, lactate, urea, and creatinine were seen in clindamycin treated MRSA infected rats. The MRSA infected clindamycin treated rats showed mild irritation and diarrhea. Conclusion: Our study concludes that the clindamycin showed better anti- MRSA activity and tolerable adverse effects such as anemia, weight loss, and mild irritation after oral treatment, but the intestinal dysbiosis is a severe adverse effect and causes diarrhea.

Clinical Evaluation on Digestive and Metabolic Parameters of a Prodosomed Enzyme Formulation, N-SORB: A Randomized, Double-Blind, Placebo-Controlled Study

Abstract Objectives Optimal nutrition and natural digestive enzymes play a critical role in enhancing healthy digestion. N-SORB, a novel KD120 liquid multienzyme complex was developed and encapsulated using a SK713 SLP absorption technology (Prodosome®). A randomized, double-blind placebo-controlled investigation over a period of 90 consecutive days was conducted to determine the safety and efficacy of N-SORB on diverse parameters of the blood, immune health and physical health. Methods Forty-six (age: 25.8 ± 12.1 years) healthy volunteers received either N-SORB or placebo for 90 consecutive days. Complete blood count, as well as blood glucose, liver enzymes, and lipid profile were assessed pre- and post-intervention. Serum cytokine levels were determined using ELISA. Whole Body composition analysis was performed by DEXA to determine body fat mass, lean mass and android and gynoid fat. Body weight, blood pressure, and physical health were assessed. Changes in quality of life (QOL) were examined using WHOQOL-BREF questionnaire. Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI) questionnaire. Adverse events were monitored. This clinical investigation was followed by three case studies. Results 40 subjects completed the study. Compared to placebo, changes in blood cell counts including hematocrit, hemoglobin, mean corpuscular volume, platelets and lymphocytes provide evidence indicating consistent trends of improvement. QOL parameters showed significant improvement in N-SORB group. A significant increase was observed in AST level in the placebo group, while, no increase was observed in the N-SORB group. In either group, no significant changes in BUN, serum creatinine, ALP, ALT, and lipid profile were observed. No adverse effects were reported. Case study volunteers also reported encouraging results. Conclusions N-SORB exhibited trends of improvement in some RBC and immune parameters and found improvements in QOL and PSQI; but didn't significantly alter cardiometabolic parameters, lipid profile or body composition. N-SORB induced significant improvement in digestive health, metabolism and sleep pattern. Case studies indicated significant improvement in digestion, sleep pattern and metabolic health. Funding Sources This Project was funded by VNI Inc, Lederach, PA.

Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

BackgroundCabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.ObjectivesTo investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).MethodsPlasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).ResultsStatistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.ConclusionsThis modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.