Antinociception of petroleum ether fraction derived from crude methanol extract of Melastoma malabathricum leaves and its possible mechanisms of action in animal models.

BACKGROUND: Melastoma malabathricum L. (family Melastomaceae) has been traditionally used as remedies against various ailments including those related to pain. The methanol extract of M. malabathricum leaves has been proven to show antinociceptive activity. Thus, the present study aimed to determine the most effective fraction among the petroleum ether- (PEMM), ethyl acetate- (EAMM) and aqueous- (AQMM) fractions obtained through successive fractionation of crude, dried methanol extract of M. malabathricum (MEMM) and to elucidate the possible mechanisms of antinociception involved. METHODS: The effectiveness of fractions (100, 250 and 500 mg/kg; orally) were determine using the acetic acid-induced abdominal constriction test and the most effective extract was further subjected to the hot plate- or formalin-induced paw licking-test to establish its antinociceptive profile. Further elucidation of the role of opioid and vanilloid receptors, glutamatergic system, and nitric oxide/cyclic guanosine phosphate (NO/cGMP) pathway was also performed using the appropriate nociceptive models while the phytoconstituents analyses were performed using the phytochemical screening test and, HPLC-ESI and GCMS analyses. RESULTS: PEMM, EAMM and AQMM significantly (p < 0.05) attenuated acetic acid-induced nociception with the recorded EC50 of 119.5, 125.9 and 352.6 mg/kg. Based on the EC50 value, PEMM was further studied and also exerted significant (p < 0.05) antinociception against the hot plate- and formalin-induced paw licking-test. With regards to the mechanisms of antinociception,: i) PEMM significantly (p < 0.05) attenuated the nociceptive action in capsaicin- and glutamate-induced paw licking test.; ii) naloxone (5 mg/kg), a non-selective opioid antagonist, failed to significantly (p < 0.05) inhibit PEMM's antinociception iii) L-arginine (a nitric oxide precursor), but not NG-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase), methylene blue (MB; an inhibitor of cGMP), or their respective combination, significantly (p < 0.05) reversed the antinociception of PEMM. Phytochemical analyses revealed the presence of several antinociceptive-bearing bioactive compounds, such as triterpenes and volatile compounds like oleoamide and palmitic acid. The presence of low flavonoids, such as gallocatechin and epigallocatechin, saponins and tannins in PEMM might synergistically contribute to enhance the major compounds antinociceptive effect. CONCLUSION: PEMM exerted a non-opioid-mediated antinociceptive activity at the central and peripheral levels via the inhibition of vanilloid receptors and glutamatergic system, and the activation of NO-mediated/cGMP-independent pathway. Triterpenes, as well as volatile oleoamide and palmitic acid, might be responsible for the observed antinociceptive activity of PEMM.

Correction to: Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The article Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update, written by [Shiv Sarin], was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 06, 2019 without open access.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

Triple therapy with clarithromycin, omeprazole, and amoxicillin for eradication of Helicobacter pylori in duodenal ulcer patients in Asia and Africa.

BACKGROUND: Studies assessing the efficacy of triple therapy containing clarithromycin and amoxicillin for the eradication of Helicobacter pylori infection and healing of duodenal ulcers in Asian and African countries are limited. AIM: To determine the efficacy and safety of 1-week triple therapy with omeprazole, amoxicillin and clarithromycin for eradicating H. pylori infection in patients with active duodenal ulcer living in Asian and African regions. METHODS: This was an open-label, multicentre study in 11 centres in Asia and Africa. Patients with endoscopy-proven duodenal ulcer and who were H. pylori-positive were treated with clarithromycin 500 mg, omeprazole 20 mg, and amoxicillin 1000 mg, all given twice daily for 7 days. Upper endoscopy was repeated at week 6 to check for ulcer healing and H. pylori status. RESULTS: A total of 117 patients were recruited. H. pylori eradication rates were 85% by per protocol analysis and 80% by intention-to-treat analysis. Ulcer healing was found in 94% of subjects (per protocol analysis). Clinical success, measured by change of pre-treatment ulcer symptoms, was strongly supported by complete resolution or improvement in 100% of the evaluable patients (per protocol analysis). Since treatment-related adverse events, when present, were largely mild or moderate, the triple therapy regimen was considered safe. CONCLUSION: Seven-day triple therapy with omeprazole, amoxicillin, and clarithromycin was efficacious for treating Asian and African patients with duodenal ulcer disease associated with H. pylori infection, and the treatment regimen was well-tolerated.

Risk of transmission and features of hepatitis C after needlestick injuries.

The rate of transmission and management of needlestick injuries from hepatitis C virus (HCV) patients to healthcare workers is still a matter of debate. We used a stringent protocol using monthly transaminase levels and polymerase chain reaction for HCV RNA to monitor 53 healthcare workers prospectively for up to 6 months following needle injuries from HCV-positive patients. Evidence of transmission of HCV was found in only 2 workers (4%) with mild asymptomatic infection, one of which resolved spontaneously. Based on our experience, we now use a less-intensive follow-up protocol. Further investigation is required to determine the most cost-effective method to monitor individuals who suffer a needlestick injury from an HCV-positive patient.

Thymosin alpha 1 in combination with interferon alpha and ribavirin in chronic hepatitis C patients who are non-responders or relapsers to interferon alpha plus ribavirin.

OBJECTIVE: Interferon alpha (IFN-alpha) with or without ribavirin is an approved therapy for patients with chronic hepatitis C. However, a sustained response is achieved in less than 40% of all treated cases. Retreatment of relapsers or non-responders usually fails. Thymosin alpha 1 (Ta-1) is a polypeptide with immunomodulatory properties that has been suggested to increase response rates in patients with chronic hepatitis C. The aim of present study was to evaluate the efficacy of a novel triple regimen which includes Ta-1 for relapsers and non-responders to the combination of TA-1 and ribavirin. METHODS: In the present study, 11 patients who relapsed (n=5) or did not respond (n=6) to previous INF-alpha-based therapy were retreated with combination Ta-1, INF-alpha and ribavirin for 12 months, and followed up for a further six months. RESULTS: Four out of five relapsers had a sustained response. One of the non-responders cleared the HCV RNA during the post-treatment follow-up. Minor adverse effects were observed during treatment with this combination therapy and no dose reduction or discontinuations were needed. CONCLUSION: This data suggests that thymosin alpha 1 may add to the efficacy of INF-alpha plus ribavirin in the retreatment of relapsers or non-responders to previous INF-alpha-based hepatitis C therapy.

Generation and characterization of a high-affinity monoclonal antibody for MUC1 measurement in breast cancer.

Breast mucin is secreted by breast tumor cells and serves as a marker for breast cancer. Thus, antibodies against breast mucin will be valuable in the development of immunotherapy and laboratory diagnostic tests. Monoclonal antibodies (MAbs) against breast cancer-associated antigen were generated and characterized. Balb/c mice were immunized with breast cancer-associated antigen CA15-3, and subsequently splenocytes from immunized mice were fused with myeloma cells. After fusion, culture supernatants from hybridomas surviving HAT medium were screened by enzyme-linked immunosorbent assay (ELISA). A total of eight hybridomas producing MAbs against breast cancer showed significant levels of antibody activity against CA15-3. Two selected stable hybridomas were adapted into CELLine CL 350 bioreactors, and the MAbs produced were characterized for their subclass, specificity, and affinity. The MAbs were of high specificity and affinity as shown by ELISA. The MAbs produced may represent a powerful tool and are considered promising reagents for use in diagnosis and detection of early stage of the disease.

Fulminant hepatic failure in pregnant women: acute fatty liver or acute viral hepatitis?

BACKGROUND: Hepatitis E virus, which is endemic in our region, can cause severe liver dysfunction in pregnant women and this can be clinically confused with acute fatty liver of pregnancy. METHODS: We studied the clinical and laboratory data as well as the maternal and fetal outcomes of 12 pregnant women presenting with fulminant hepatic failure in order to determine the etiology of the disease. The clinical diagnoses were subsequently correlated with serologic assays for acute HEV infection. All patients were severely ill with deep jaundice, grade 3-4 encephalopathy and abnormal prothrombin times. RESULTS: A clinical diagnosis of acute viral hepatitis was made in nine patients and of acute fatty liver in the other three cases. IgM and IgG antibodies confirmed acute viral hepatitis E in six of the nine patients while one had acute hepatitis A infection. HEV IgM and IgG antibodies were, however, also positive in two of the three patients thought to have acute fatty liver. Maternal and fetal mortality were 16.6% and 50%, respectively. CONCLUSIONS: We conclude that hepatitis E is the usual cause of acute liver failure in our pregnant women and that clinical and laboratory features do not permit accurate distinction between acute HEV infection and acute fatty liver of pregnancy. The prognosis in patients with acute HEV infection is much better than in other groups with severe liver failure (mortality 16% vs 68%).

Duodenal erosions and ulcers in patients with pancreatobiliary obstruction.

In order to determine whether obstructive pancreatobiliary lesions increase the risk of duodenal erosions and ulcers, the duodenal mucosa of patients with these lesions were prospectively examined before endoscopic retrograde cholangiopancreatography (ERCP). During the study period, 133 patients underwent ERCP for various reasons in the Department of Medicine, The Aga Khan University Hospital. One hundred and twenty-three patients were eligible for final analysis. Sixty-five patients with bilirubin > or = 35 mumol/L and alkaline phosphatase > or = 2.5 times normal levels along with radiological evidence of pancreatobiliary obstruction were included in the obstruction group. Fifty-eight patients who did not fulfil these criteria were used in the control group. Acid peptic lesions, which included erosions and ulcers, were seen in 16 patients of the obstruction group and four patients of the control group (P = 0.016, odds ratio (OR) = 4.41). Patients with carcinoma of the pancreas had a greater number of lesions than the rest of the obstruction group (P = 0.001, OR = 8.75). Individual variables like age, sex, serum bilirubin, alanine aminotransferase, alkaline phosphatase, amylase levels, and duration of jaundice did not increase the vulnerability to acid peptic injury. The degree of obstruction multiplied by duration of jaundice (alkaline phosphatase x days) increased the susceptibility for duodenal disease (P = 0.047). From this data it was concluded that patients with obstructive pancreatobiliary lesions are more prone to acid peptic duodenal lesions.