About 130-170 million people, is estimated to be infected with the hepatitis C virus(HCV). Chronic HCV infection is one of the leading causes of liverrelated death and in many countries it is the primaryreason for hav...About 130-170 million people, is estimated to be infected with the hepatitis C virus(HCV). Chronic HCV infection is one of the leading causes of liverrelated death and in many countries it is the primaryreason for having a liver transplant. The main aim of antiviral treatment is to eradicate the virus. Until a few years ago the only treatment strategy was based on the combination of pegylated interferon and ribavirin(PEG/RBV). However, in genotypes 1 and 4 the rates of viral response did not surpass 50%, reaching up to 80% in the rest. In 2011 approval was given for the first direct acting antiviral agents(DAA), boceprevir and telaprevir, for treatment of genotype 1, in combination with traditional dual therapy. This strategy managed to increase the rates of sustained viral response(SVR) in both naive patients and in retreated patients, but with greater toxicity, interactions and cost, as well as being less safe in patients with advanced disease, in whom this treatment can trigger decompensation or even death. The recent, accelerated incorporation since 2013 of new more effective DAA, with pan-genomic properties and excellent tolerance, besides increasing the rates of SVR(even up to 100%), has also created a new scenario: shorter therapies, less toxicity and regimens free of PEG/RBV. This has enabled their almost generalised applicability in all patients. However, it should be noted that most of the scientific evidence available is based on expert opinion, case-control series, cohort studies and phase 2 and 3 trials, some with a reduced number of patients and select groups. Few data are currently available about the use of these drugs in daily clinical practice, particularly in relation to the appearance of side effects and interactions with other drugs, or their use in special populations or persons with the less common genotypes. This situation suggests the need for the generalised implementation of registries of patients receiving antiviral therapy. The main inconvenience of these new drugs is their high cost. This necessitates selection and prioritization of candidate patients to receive them, via strategies established by the various national organs, in accordance with the recommendations of scientific societies.展开更多
The metabolic syndrome(MS), which includes obesity,dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, wi...The metabolic syndrome(MS), which includes obesity,dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, with a prevalence of 44%-58%. The MS, together with the immunosuppression, is considered the main risk factor for the development of cardiovascular disease(CVD) in transplant recipients, which in turn accounts for 19%-42% of all deaths unrelated to the graft. The presence of MS represents a relative risk for the development of CVD and death of 1.78. On the other hand, non-alcoholic fatty liver disease(NAFLD), considered as the manifestation of the MS in the liver, is now the second leading reason for liver transplantation in the United States after hepatitis C and alcohol. NAFLD has a high rate of recurrence in the liver graft and a direct relation with the worsening of other metabolic disorders, such as insulin resistance or diabetes mellitus. Consequently, it is vitally important to identify and treat as soon as possible such modifiable factors as hypertension, overweight, hyperlipidaemia or diabetes in transplanted patients to thus minimise the impact on patient survival. Additionally, steroid-free regimens are favoured, with minimal immunosuppression to limit the possible effects on the development of the MS.展开更多
Although artificial intelligence(AI)was initially developed many years ago,it has experienced spectacular advances over the last 10 years for application in the field of medicine,and is now used for diagnostic,therape...Although artificial intelligence(AI)was initially developed many years ago,it has experienced spectacular advances over the last 10 years for application in the field of medicine,and is now used for diagnostic,therapeutic and prognostic purposes in almost all fields.Its application in the area of hepatology is especially relevant for the study of hepatocellular carcinoma(HCC),as this is a very common tumor,with particular radiological characteristics that allow its diagnosis without the need for a histological study.However,the interpretation and analysis of the resulting images is not always easy,in addition to which the images vary during the course of the disease,and prognosis and treatment response can be conditioned by multiple factors.The vast amount of data available lend themselves to study and analysis by AI in its various branches,such as deeplearning(DL)and machine learning(ML),which play a fundamental role in decision-making as well as overcoming the constraints involved in human evaluation.ML is a form of AI based on automated learning from a set of previously provided data and training in algorithms to organize and recognize patterns.DL is a more extensive form of learning that attempts to simulate the working of the human brain,using a lot more data and more complex algorithms.This review specifies the type of AI used by the various authors.However,welldesigned prospective studies are needed in order to avoid as far as possible any bias that may later affect the interpretability of the images and thereby limit the acceptance and application of these models in clinical practice.In addition,professionals now need to understand the true usefulness of these techniques,as well as their associated strengths and limitations.展开更多
The use of direct-acting antivirals(DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response(around 90%-95%) as compared with the standard treatment of peginterfer...The use of direct-acting antivirals(DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response(around 90%-95%) as compared with the standard treatment of peginterferon/ribavirin. Despite this, however, the rates of therapeutic failure in daily clinical practice range from 10%-15%. Most of these cases are due to the presence of resistant viral variants, resulting from mutations produced by substitutions of amino acids in the viral target protein that reduce viral sensitivity to DAAs, thus limiting the efficacy of these drugs. The high genetic diversity of hepatitis C virus has resulted in the existence of resistance-associated variants(RAVs), sometimes even before starting treatment with DAAs, though generally at low levels. These preexisting RAVs do not appear to impact on the sustained viral response, whereas those that appear after DAA therapy could well be determinant in virological failure with future treatments. As well as the presence of RAVs, virological failure to treatment with DAAs is generally associated with other factors related with a poor response, such as the degree of fibrosis, the response to previous therapy, the viral load or the viral genotype. Nonetheless, viral breakthrough and relapse can still occur in the absence of detectable RAVs and after the use of highly effective DAAs, so that the true clinical impact of the presence of RAVs in therapeutic failure remains to be determined.展开更多
Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best ther...Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.展开更多
A series of benzimidazole bearing 2-pyridones 5a-k were synthesized and assessed in vitro for their activity as antimicrobial agents using the conventional broth dilution method. The results of the antimicrobial study...A series of benzimidazole bearing 2-pyridones 5a-k were synthesized and assessed in vitro for their activity as antimicrobial agents using the conventional broth dilution method. The results of the antimicrobial study revealed that compounds 5b, 5c, Sj and 5k exhibited substantial antibacterial activity while compound 5d emerged as amore potent antifungal agent compared to the standard drugs chloramphenicol and ketoconazole, respectively. It was observed that the presence of inductively electron withdrawing groups remarkably enhance the antibacterial activity of the newly synthesized compounds. Cytotoxicity studies suggested that none of the tested compounds exhibited any significant cytotoxic effects.展开更多
Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patien...Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the pho...Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.展开更多
Peripheral arterial disease, manifested as intermittent claudication or critical ischaemia, or identified by an ankle/brachial index < 0.9, is present in at least one in every four patients with type 2 diabetes mel...Peripheral arterial disease, manifested as intermittent claudication or critical ischaemia, or identified by an ankle/brachial index < 0.9, is present in at least one in every four patients with type 2 diabetes mellitus.Several reasons exist for peripheral arterial disease indiabetes. In addition to hyperglycaemia, smoking and hypertension, the dyslipidaemia that accompanies type2 diabetes and is characterised by increased triglyceride levels and reduced high-density lipoprotein cholesterol concentrations also seems to contribute to this association. Recent years have witnessed an increased interest in postprandial lipidaemia, as a result of various prospective studies showing that non-fasting triglycerides predict the onset of arteriosclerotic cardiovascular disease better than fasting measurements do. Additionally,the use of certain specific postprandial particle markers,such as apolipoprotein B-48, makes it easier and more simple to approach the postprandial phenomenon. Despite this, only a few studies have evaluated the role of postprandial triglycerides in the development of peripheral arterial disease and type 2 diabetes. The purpose of this review is to examine the epidemiology and risk factors of peripheral arterial disease in type 2 diabetes, focusing on the role of postprandial triglycerides and particles.展开更多
Objective Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also...Objective Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress. Methods The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior （locomotor activity, anxiety and memory） and biochemical （lipid peroxidation, nitrite level, reduced glutathione, and catalase） alterations were assessed. Results Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to na？ve mice （without chronic fatigue treatment）. Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen （14 mg/kg, i.p.）, rofecoxib （5 mg/kg, i.p.）, meloxicam （5 mg/kg, i.p.）, nimesulide （5 mg/kg, i.p.） and valdecoxib （10 mg/kg, i.p.） significantly attenuated these behavioral and biochemical （oxidative damage） alterations in chronic-stressed mice. Conclusion The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.展开更多
BACKGROUND The gut microbiota plays a key role in the maintenance of intestinal homeostasis and the development and activation of the host immune system. It has been shown that commensal bacterial species can regulate...BACKGROUND The gut microbiota plays a key role in the maintenance of intestinal homeostasis and the development and activation of the host immune system. It has been shown that commensal bacterial species can regulate the expression of host genes. 16 S rRNA gene sequencing has shown that the microbiota in inflammatory bowel disease(IBD) is abnormal and characterized by reduced diversity. Micro RNAs(miRNAs) have been explored as biomarkers and therapeutic targets, since they are able to regulate specific genes associated with Crohn's disease(CD). In this work, we aim to investigate the composition of gut microbiota of active treatment-na?ve adult CD patients, with miRNA profile from gut microbiota.AIM To investigate the composition of gut microbiota of active treatment-na?ve adult CD patients, with miRNA profile from gut microbiota.METHODS Patients attending the outpatient clinics at Valme University Hospital without relevant co-morbidities were matched according to age and gender. Faecal samples of newonset CD patients, free of treatment, and healthy controls were collected. Faecal samples were homogenized, and DNA was amplified by PCR using primers directed to the 16 S bacterial rRNA gene. Pyrosequencing was performed using GS-Junior platform. For sequence analysis, MGRAST server with the database Ribosomal Project was used. MiRNA profile and their relative abundance were analyzed by quantitative PCR.RESULTS Microbial community was characterized using 16 S rRNA gene sequencing in 29 samples(n = 13 CD patients, and n = 16 healthy controls). The mean Shannon diversity was higher in the healthy control population compared to CD group(5.5 vs 3.7). A reduction in Firmicutes and an increase in Bacteroidetes were found. Clostridia class was also significantly reduced in CD. Principal components analysis showed a grouping pattern, identified in most of the subjects in both groups, showing a marked difference between control and CD groups. A functional metabolic study showed that a lower metabolism of carbohydrates(P = 0.000) was found in CD group, while the metabolism of lipids was increased. In CD patients, three miRNAs were induced in affected mucosa: mir-144(6.2 ± 1.3 fold), mir-519(21.8 ± 3.1) and mir-211(2.3 ± 0.4). CONCLUSION Changes in microbial function in active non-treated CD subjects and three miRNAs in affected vs non-affected mucosa have been found. miRNAs profile may serve as a biomarker.展开更多
AIM: Stress is recognized to precipitate anxiety and related psychological problems characterized by a wide range of biochemical and behavioral changes. The present study was carried out to investigate the protective ...AIM: Stress is recognized to precipitate anxiety and related psychological problems characterized by a wide range of biochemical and behavioral changes. The present study was carried out to investigate the protective effects of melatonin and buspirone, and their combination, against six hours immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice. METHOD: Male Laca mice were pre-treated with melatonin(2.5, 5 mg·kg–1), buspirone(5, 10 mg·kg–1), and their combination for consecutive five days. On the 6th day, animals were immobilized for six hours, and thereafter various behavioral tests were performed followed by biochemical tests. RESULTS: Immobilization stress significantly impaired body weight, locomotor activity, and caused anxiety-like behavior, along with increased oxidative damage. Pretreatment with melatonin and buspirone significantly improved the loss in body weight and locomotor activity, attenuated anxiety-like behavior(in both the mirror chamber and plus maze performance tasks), further restored the levels of brain total proteins, and caused antioxidant-like effects, as evidenced by reduced lipid peroxidation, nitrite concentration, and restoration of reduced glutathione and catalase activity, as compared to control animals. In addition, combination of melatonin(2.5, 5 mg·kg–1) with buspirone(5 mg·kg–1) significantly potentiated their protective effects, as compared to their effects individually. CONCLUSION: The present study suggests that melatonin potentiates the beneficial effect of buspirone against immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice possibly by involving a serotonergic mechanism.展开更多
COVID-19,a disease caused by the novel coronavirus SARS-Co V-2,has produced a serious emergency for global public health,placing enormous stress on national health systems in many countries.Several studies suggest tha...COVID-19,a disease caused by the novel coronavirus SARS-Co V-2,has produced a serious emergency for global public health,placing enormous stress on national health systems in many countries.Several studies suggest that cytokine storms(interleukins)may play an important role in severe cases of COVID-19.Neutralizing key inflammatory factors in cytokine release syndrome(CRS)could therefore be of great value in reducing the mortality rate.Tocilizumab(TCZ)in its intravenous(IV)form of administration-Ro Actemra?20 mg/m L(Roche)-is indicated for treatment of severe CRS patients.Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe,with several ongoing clinical trials.This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals,which has resulted in drug shortages.Here,we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion,at 6 mg/m L and 4 mg/m L,prepared from Ro Actemra?20 mg/m L(IV form)and from Ro Actemra?162 mg(0.9 m L solution pre-filled syringe,subcutaneous(SC)form),to evaluate the use of the latter for preparing clinical solutions required for IV administration,so that in a situation of shortage of the IV medicine,the SC form could be used to prepare the solutions for IV delivery of TCZ.It is important to remember that during the current pandemic all the medicines are used off-label,since none of them has yet been approved for the treatment of COVID-19.展开更多
BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe ac...BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults.AIM To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency.METHODS Multiple searches in MEDLINE,PubMed were performed using the search terms“COVID-19”or“SARS-CoV-2"were used in combination with“myocardial injury”or"arrhythmia"or“cardiovascular involvement”or"heart disease"or"congenital heart disease"or“pulmonary hypertension”or"long QT"or“cardiomyopathies”or“channelopathies”or"Multisystem inflammatory system"or"PMIS"or“MIS-C”or”Pediatric multisystem inflammatory syndrome"or"myocarditis"or"thromboembolism to identify articles published in English language from January 1st,2020 until July 31st,2020.The websites of World Health Organization,Centers for Disease control and Prevention,and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts concerning the subject were reviewed by the authors,and the data were extracted using a standardized collection tool.Data were subsequently analyzed with descriptive statistics.For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19(PMIS),multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients.RESULTS A total of 193 articles were included.Most publications used in this review were single case reports,small case series,and observational small-sized studies or literature reviews.The meta-analysis of 16 studies with size>10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart,accounting for most cases of pediatric COVID-19 mortality.They frequently presented cardiogenic shock(53%),ECG alterations(27%),myocardial dysfunction(52%),and coronary artery dilation(15%).Most cases required PICU admission(75%)and inotropic support(57%),with the rare need for extracorporeal membrane oxygenation(4%).Almost all of these children wholly recovered in a few days,although rare deaths have been reported(2%).Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis,pulmonary hypertension and cardiac arrythmias in previously healthy children.We also found another 10 studies reporting patients with preexisting heart diseases.Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support,but cases of death were also identified.The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations.CONCLUSION There is still scarce data about the role of cardiovascular involvement in COVID-19 in children.Based on our review,children(previously healthy or with preexisting heart disease)with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.展开更多
Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and...Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and tolerable NaCI concentration up to 13.5% （w/v）. 29 out of 57 isolates were identified using 16S rDNA amplification and the sequences were submitted to National Center for Biotechnology Information （NCBI）. All the isolates were classified by using Ribosomal Database Project （RDP） and found that isolates belongs to Proteobacteria and Bacteriodes. The average G＋C content was 56.4%. The isolates were screened for the presence of extracellular enzymes, viz. amylase, catalase, urease, esterase, lipase and protease. The disc diffusion method is used to screen antibiotic production by the isolates against four pathogenic bacteria, viz. Salmonella typhimurium （NCIM 2501）, Staphylococcus aureus （NCIM 2122）, Bacillus subtilis （NCIM 2193）, and Pseudomonas aeruginosa （NCIM 2036）. Nine out of 29 were found to be antibiotic producer.展开更多
Cetuximab （CTX） is a potent chimeric mouse/human monoclonal antibody （mAb） approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses per- formed for full ...Cetuximab （CTX） is a potent chimeric mouse/human monoclonal antibody （mAb） approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses per- formed for full study on this biopharmaceutic, the determination of the concentration preparations throughout manufacturing and subsequent handling in hospital is particularly relevant. In the present work, the study and validation of a method for quantifying intact CTX by reverse-phase high-perfor- mance liquid chromatography with diode array detection （（RP）HPLC/DAD） is presented. With that end, we checked the performance of a chromatographic method for quantifying CTX and conducted a study to validate the method as stability-indicating in accordance with the International Conference on Harmo- nization guidelines （ICH） for biotechnological drugs; therefore, we evaluated linearity, accuracy, preci- sion, detection and quantification limits, robustness and system suitability. The specificity of the method and the robustness of the mAb formulation against external stress factors were estimated by compre- hensive chromatographic analysis by subjecting CTX to several informative stress conditions. As de- monstrated, the method is rapid, accurate, and reproducible for CTX quantification. It was also suc- cessfully used to quantify CTX in a long-term stability study performed under hospital conditions.展开更多
Objective The neuroprotective roles of cyclooxygenase （COX） and lipooxygenase （LOX） inhibitors have been well documented. Quinolinic acid （QA） is a well-known excitotoxic agent that could induce behavioral, morp...Objective The neuroprotective roles of cyclooxygenase （COX） and lipooxygenase （LOX） inhibitors have been well documented. Quinolinic acid （QA） is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington’s disease （HD）, by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid （a specific inhibitor for LOX）, rofecoxib （a specific inhibitor for COX-2）, and their combination in ameliorating QA-induced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration （300 nmol） not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status （decreased glutathione and increased oxidized glutathione level） in striatum, as compared to the sham group. Moreover, chronic treatment with caffeic acid （5 mg/kg and 10 mg/kg, respectively, p.o.） or rofecoxib （10 mg/kg, p.o.） could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib （10 mg/kg） and caffeic acid （5 mg/kg） could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.展开更多
文摘About 130-170 million people, is estimated to be infected with the hepatitis C virus(HCV). Chronic HCV infection is one of the leading causes of liverrelated death and in many countries it is the primaryreason for having a liver transplant. The main aim of antiviral treatment is to eradicate the virus. Until a few years ago the only treatment strategy was based on the combination of pegylated interferon and ribavirin(PEG/RBV). However, in genotypes 1 and 4 the rates of viral response did not surpass 50%, reaching up to 80% in the rest. In 2011 approval was given for the first direct acting antiviral agents(DAA), boceprevir and telaprevir, for treatment of genotype 1, in combination with traditional dual therapy. This strategy managed to increase the rates of sustained viral response(SVR) in both naive patients and in retreated patients, but with greater toxicity, interactions and cost, as well as being less safe in patients with advanced disease, in whom this treatment can trigger decompensation or even death. The recent, accelerated incorporation since 2013 of new more effective DAA, with pan-genomic properties and excellent tolerance, besides increasing the rates of SVR(even up to 100%), has also created a new scenario: shorter therapies, less toxicity and regimens free of PEG/RBV. This has enabled their almost generalised applicability in all patients. However, it should be noted that most of the scientific evidence available is based on expert opinion, case-control series, cohort studies and phase 2 and 3 trials, some with a reduced number of patients and select groups. Few data are currently available about the use of these drugs in daily clinical practice, particularly in relation to the appearance of side effects and interactions with other drugs, or their use in special populations or persons with the less common genotypes. This situation suggests the need for the generalised implementation of registries of patients receiving antiviral therapy. The main inconvenience of these new drugs is their high cost. This necessitates selection and prioritization of candidate patients to receive them, via strategies established by the various national organs, in accordance with the recommendations of scientific societies.
文摘The metabolic syndrome(MS), which includes obesity,dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, with a prevalence of 44%-58%. The MS, together with the immunosuppression, is considered the main risk factor for the development of cardiovascular disease(CVD) in transplant recipients, which in turn accounts for 19%-42% of all deaths unrelated to the graft. The presence of MS represents a relative risk for the development of CVD and death of 1.78. On the other hand, non-alcoholic fatty liver disease(NAFLD), considered as the manifestation of the MS in the liver, is now the second leading reason for liver transplantation in the United States after hepatitis C and alcohol. NAFLD has a high rate of recurrence in the liver graft and a direct relation with the worsening of other metabolic disorders, such as insulin resistance or diabetes mellitus. Consequently, it is vitally important to identify and treat as soon as possible such modifiable factors as hypertension, overweight, hyperlipidaemia or diabetes in transplanted patients to thus minimise the impact on patient survival. Additionally, steroid-free regimens are favoured, with minimal immunosuppression to limit the possible effects on the development of the MS.
文摘Although artificial intelligence(AI)was initially developed many years ago,it has experienced spectacular advances over the last 10 years for application in the field of medicine,and is now used for diagnostic,therapeutic and prognostic purposes in almost all fields.Its application in the area of hepatology is especially relevant for the study of hepatocellular carcinoma(HCC),as this is a very common tumor,with particular radiological characteristics that allow its diagnosis without the need for a histological study.However,the interpretation and analysis of the resulting images is not always easy,in addition to which the images vary during the course of the disease,and prognosis and treatment response can be conditioned by multiple factors.The vast amount of data available lend themselves to study and analysis by AI in its various branches,such as deeplearning(DL)and machine learning(ML),which play a fundamental role in decision-making as well as overcoming the constraints involved in human evaluation.ML is a form of AI based on automated learning from a set of previously provided data and training in algorithms to organize and recognize patterns.DL is a more extensive form of learning that attempts to simulate the working of the human brain,using a lot more data and more complex algorithms.This review specifies the type of AI used by the various authors.However,welldesigned prospective studies are needed in order to avoid as far as possible any bias that may later affect the interpretability of the images and thereby limit the acceptance and application of these models in clinical practice.In addition,professionals now need to understand the true usefulness of these techniques,as well as their associated strengths and limitations.
文摘The use of direct-acting antivirals(DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response(around 90%-95%) as compared with the standard treatment of peginterferon/ribavirin. Despite this, however, the rates of therapeutic failure in daily clinical practice range from 10%-15%. Most of these cases are due to the presence of resistant viral variants, resulting from mutations produced by substitutions of amino acids in the viral target protein that reduce viral sensitivity to DAAs, thus limiting the efficacy of these drugs. The high genetic diversity of hepatitis C virus has resulted in the existence of resistance-associated variants(RAVs), sometimes even before starting treatment with DAAs, though generally at low levels. These preexisting RAVs do not appear to impact on the sustained viral response, whereas those that appear after DAA therapy could well be determinant in virological failure with future treatments. As well as the presence of RAVs, virological failure to treatment with DAAs is generally associated with other factors related with a poor response, such as the degree of fibrosis, the response to previous therapy, the viral load or the viral genotype. Nonetheless, viral breakthrough and relapse can still occur in the absence of detectable RAVs and after the use of highly effective DAAs, so that the true clinical impact of the presence of RAVs in therapeutic failure remains to be determined.
文摘Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.
文摘A series of benzimidazole bearing 2-pyridones 5a-k were synthesized and assessed in vitro for their activity as antimicrobial agents using the conventional broth dilution method. The results of the antimicrobial study revealed that compounds 5b, 5c, Sj and 5k exhibited substantial antibacterial activity while compound 5d emerged as amore potent antifungal agent compared to the standard drugs chloramphenicol and ketoconazole, respectively. It was observed that the presence of inductively electron withdrawing groups remarkably enhance the antibacterial activity of the newly synthesized compounds. Cytotoxicity studies suggested that none of the tested compounds exhibited any significant cytotoxic effects.
文摘Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.
基金supported by the European Regional Development Funds-European Union(ERDF-EU),FATZHEIMER project(EU-LAC HEALTH 2020,16/T010131 to FRdF),“Una manera de hacer Europa”Ministerio de Economía,Industria y Competitividad,Gobierno de Espa?a,Programa Estatal de Investigación,Desarrollo e Innovación Orientada a los Retos de la Sociedad(RTC2019-007329-1 to FRdF)+2 种基金Consejería de Economía,Conocimiento y Universidad,Junta de Andalucía,Plan Andaluz de Investigación,Desarrollo e Innovación(P18TP-5194 to FRdF)Instituto de Salud CarlosⅢ(DTS22/00021 to FRdF)DMV(FI20/00227)holds a“PFIS’’predoctoral contract from the National System of Health,EU-ERDF-Instituto de Salud CarlosⅢ。
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.
基金Supported by Grant to Grupo CTS-159 of PAIDI(Plan Andaluz de Investigación,Desarrollo e Innovación) de la Junta de Andalucía
文摘Peripheral arterial disease, manifested as intermittent claudication or critical ischaemia, or identified by an ankle/brachial index < 0.9, is present in at least one in every four patients with type 2 diabetes mellitus.Several reasons exist for peripheral arterial disease indiabetes. In addition to hyperglycaemia, smoking and hypertension, the dyslipidaemia that accompanies type2 diabetes and is characterised by increased triglyceride levels and reduced high-density lipoprotein cholesterol concentrations also seems to contribute to this association. Recent years have witnessed an increased interest in postprandial lipidaemia, as a result of various prospective studies showing that non-fasting triglycerides predict the onset of arteriosclerotic cardiovascular disease better than fasting measurements do. Additionally,the use of certain specific postprandial particle markers,such as apolipoprotein B-48, makes it easier and more simple to approach the postprandial phenomenon. Despite this, only a few studies have evaluated the role of postprandial triglycerides in the development of peripheral arterial disease and type 2 diabetes. The purpose of this review is to examine the epidemiology and risk factors of peripheral arterial disease in type 2 diabetes, focusing on the role of postprandial triglycerides and particles.
文摘Objective Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress. Methods The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior （locomotor activity, anxiety and memory） and biochemical （lipid peroxidation, nitrite level, reduced glutathione, and catalase） alterations were assessed. Results Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to na？ve mice （without chronic fatigue treatment）. Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen （14 mg/kg, i.p.）, rofecoxib （5 mg/kg, i.p.）, meloxicam （5 mg/kg, i.p.）, nimesulide （5 mg/kg, i.p.） and valdecoxib （10 mg/kg, i.p.） significantly attenuated these behavioral and biochemical （oxidative damage） alterations in chronic-stressed mice. Conclusion The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.
基金Supported by Instituto de Salud CarlosⅢ,and Consejería de Salud Junta de Andalucía PI14/01349
文摘BACKGROUND The gut microbiota plays a key role in the maintenance of intestinal homeostasis and the development and activation of the host immune system. It has been shown that commensal bacterial species can regulate the expression of host genes. 16 S rRNA gene sequencing has shown that the microbiota in inflammatory bowel disease(IBD) is abnormal and characterized by reduced diversity. Micro RNAs(miRNAs) have been explored as biomarkers and therapeutic targets, since they are able to regulate specific genes associated with Crohn's disease(CD). In this work, we aim to investigate the composition of gut microbiota of active treatment-na?ve adult CD patients, with miRNA profile from gut microbiota.AIM To investigate the composition of gut microbiota of active treatment-na?ve adult CD patients, with miRNA profile from gut microbiota.METHODS Patients attending the outpatient clinics at Valme University Hospital without relevant co-morbidities were matched according to age and gender. Faecal samples of newonset CD patients, free of treatment, and healthy controls were collected. Faecal samples were homogenized, and DNA was amplified by PCR using primers directed to the 16 S bacterial rRNA gene. Pyrosequencing was performed using GS-Junior platform. For sequence analysis, MGRAST server with the database Ribosomal Project was used. MiRNA profile and their relative abundance were analyzed by quantitative PCR.RESULTS Microbial community was characterized using 16 S rRNA gene sequencing in 29 samples(n = 13 CD patients, and n = 16 healthy controls). The mean Shannon diversity was higher in the healthy control population compared to CD group(5.5 vs 3.7). A reduction in Firmicutes and an increase in Bacteroidetes were found. Clostridia class was also significantly reduced in CD. Principal components analysis showed a grouping pattern, identified in most of the subjects in both groups, showing a marked difference between control and CD groups. A functional metabolic study showed that a lower metabolism of carbohydrates(P = 0.000) was found in CD group, while the metabolism of lipids was increased. In CD patients, three miRNAs were induced in affected mucosa: mir-144(6.2 ± 1.3 fold), mir-519(21.8 ± 3.1) and mir-211(2.3 ± 0.4). CONCLUSION Changes in microbial function in active non-treated CD subjects and three miRNAs in affected vs non-affected mucosa have been found. miRNAs profile may serve as a biomarker.
基金supported by CSIR,New Delhi,provided to Dr.Anil Kumar for carrying out this work
文摘AIM: Stress is recognized to precipitate anxiety and related psychological problems characterized by a wide range of biochemical and behavioral changes. The present study was carried out to investigate the protective effects of melatonin and buspirone, and their combination, against six hours immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice. METHOD: Male Laca mice were pre-treated with melatonin(2.5, 5 mg·kg–1), buspirone(5, 10 mg·kg–1), and their combination for consecutive five days. On the 6th day, animals were immobilized for six hours, and thereafter various behavioral tests were performed followed by biochemical tests. RESULTS: Immobilization stress significantly impaired body weight, locomotor activity, and caused anxiety-like behavior, along with increased oxidative damage. Pretreatment with melatonin and buspirone significantly improved the loss in body weight and locomotor activity, attenuated anxiety-like behavior(in both the mirror chamber and plus maze performance tasks), further restored the levels of brain total proteins, and caused antioxidant-like effects, as evidenced by reduced lipid peroxidation, nitrite concentration, and restoration of reduced glutathione and catalase activity, as compared to control animals. In addition, combination of melatonin(2.5, 5 mg·kg–1) with buspirone(5 mg·kg–1) significantly potentiated their protective effects, as compared to their effects individually. CONCLUSION: The present study suggests that melatonin potentiates the beneficial effect of buspirone against immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice possibly by involving a serotonergic mechanism.
基金Project FIS PI-17/00547(Instituto CarlosⅢ,Ministerio de Economía y Competitividad,Spain),which means that it was also partially supported by European Regional Development Funds(ERDF)the University of Granada(Spain)for the support。
文摘COVID-19,a disease caused by the novel coronavirus SARS-Co V-2,has produced a serious emergency for global public health,placing enormous stress on national health systems in many countries.Several studies suggest that cytokine storms(interleukins)may play an important role in severe cases of COVID-19.Neutralizing key inflammatory factors in cytokine release syndrome(CRS)could therefore be of great value in reducing the mortality rate.Tocilizumab(TCZ)in its intravenous(IV)form of administration-Ro Actemra?20 mg/m L(Roche)-is indicated for treatment of severe CRS patients.Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe,with several ongoing clinical trials.This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals,which has resulted in drug shortages.Here,we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion,at 6 mg/m L and 4 mg/m L,prepared from Ro Actemra?20 mg/m L(IV form)and from Ro Actemra?162 mg(0.9 m L solution pre-filled syringe,subcutaneous(SC)form),to evaluate the use of the latter for preparing clinical solutions required for IV administration,so that in a situation of shortage of the IV medicine,the SC form could be used to prepare the solutions for IV delivery of TCZ.It is important to remember that during the current pandemic all the medicines are used off-label,since none of them has yet been approved for the treatment of COVID-19.
文摘BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults.AIM To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency.METHODS Multiple searches in MEDLINE,PubMed were performed using the search terms“COVID-19”or“SARS-CoV-2"were used in combination with“myocardial injury”or"arrhythmia"or“cardiovascular involvement”or"heart disease"or"congenital heart disease"or“pulmonary hypertension”or"long QT"or“cardiomyopathies”or“channelopathies”or"Multisystem inflammatory system"or"PMIS"or“MIS-C”or”Pediatric multisystem inflammatory syndrome"or"myocarditis"or"thromboembolism to identify articles published in English language from January 1st,2020 until July 31st,2020.The websites of World Health Organization,Centers for Disease control and Prevention,and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts concerning the subject were reviewed by the authors,and the data were extracted using a standardized collection tool.Data were subsequently analyzed with descriptive statistics.For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19(PMIS),multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients.RESULTS A total of 193 articles were included.Most publications used in this review were single case reports,small case series,and observational small-sized studies or literature reviews.The meta-analysis of 16 studies with size>10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart,accounting for most cases of pediatric COVID-19 mortality.They frequently presented cardiogenic shock(53%),ECG alterations(27%),myocardial dysfunction(52%),and coronary artery dilation(15%).Most cases required PICU admission(75%)and inotropic support(57%),with the rare need for extracorporeal membrane oxygenation(4%).Almost all of these children wholly recovered in a few days,although rare deaths have been reported(2%).Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis,pulmonary hypertension and cardiac arrythmias in previously healthy children.We also found another 10 studies reporting patients with preexisting heart diseases.Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support,but cases of death were also identified.The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations.CONCLUSION There is still scarce data about the role of cardiovascular involvement in COVID-19 in children.Based on our review,children(previously healthy or with preexisting heart disease)with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.
基金the Expedition support to MoES, New Delhi and NCAOR, Goa (No. Mo ES/NCAOR/SOS/1/2007-PC-I dated January 4, 2011)+5 种基金the Cumulative Professional Development Grant (CPDG Ref No. GO/PD/2011-12/269/3523 dated, August 04, 2011) from BIT, MesraBTISNet Sub DIC (BT/BI/065/2004) for providing internet facilities and the Government of JharkhandDepartment of Agriculture for providing infrastructure development fund (5/B.K.V/Misc/12/2001)the financial support as research fellowship to Centre of Excellence (COE) (Ref No. NPIU/TEQIP II/FIN/31/158, dated April 16, 2013) at the Department of BioEngineering
文摘Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and tolerable NaCI concentration up to 13.5% （w/v）. 29 out of 57 isolates were identified using 16S rDNA amplification and the sequences were submitted to National Center for Biotechnology Information （NCBI）. All the isolates were classified by using Ribosomal Database Project （RDP） and found that isolates belongs to Proteobacteria and Bacteriodes. The average G＋C content was 56.4%. The isolates were screened for the presence of extracellular enzymes, viz. amylase, catalase, urease, esterase, lipase and protease. The disc diffusion method is used to screen antibiotic production by the isolates against four pathogenic bacteria, viz. Salmonella typhimurium （NCIM 2501）, Staphylococcus aureus （NCIM 2122）, Bacillus subtilis （NCIM 2193）, and Pseudomonas aeruginosa （NCIM 2036）. Nine out of 29 were found to be antibiotic producer.
基金funded by Project FIS:PI10/00201 (Instituto Carlos III, Ministerio de Economía y Competitividad, Spain)partially supported by European Regional Development Funds (ERDF)
文摘Cetuximab （CTX） is a potent chimeric mouse/human monoclonal antibody （mAb） approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses per- formed for full study on this biopharmaceutic, the determination of the concentration preparations throughout manufacturing and subsequent handling in hospital is particularly relevant. In the present work, the study and validation of a method for quantifying intact CTX by reverse-phase high-perfor- mance liquid chromatography with diode array detection （（RP）HPLC/DAD） is presented. With that end, we checked the performance of a chromatographic method for quantifying CTX and conducted a study to validate the method as stability-indicating in accordance with the International Conference on Harmo- nization guidelines （ICH） for biotechnological drugs; therefore, we evaluated linearity, accuracy, preci- sion, detection and quantification limits, robustness and system suitability. The specificity of the method and the robustness of the mAb formulation against external stress factors were estimated by compre- hensive chromatographic analysis by subjecting CTX to several informative stress conditions. As de- monstrated, the method is rapid, accurate, and reproducible for CTX quantification. It was also suc- cessfully used to quantify CTX in a long-term stability study performed under hospital conditions.
基金support from University Grants Commission, New Delhi, for carrying out the present study
文摘Objective The neuroprotective roles of cyclooxygenase （COX） and lipooxygenase （LOX） inhibitors have been well documented. Quinolinic acid （QA） is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington’s disease （HD）, by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid （a specific inhibitor for LOX）, rofecoxib （a specific inhibitor for COX-2）, and their combination in ameliorating QA-induced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration （300 nmol） not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status （decreased glutathione and increased oxidized glutathione level） in striatum, as compared to the sham group. Moreover, chronic treatment with caffeic acid （5 mg/kg and 10 mg/kg, respectively, p.o.） or rofecoxib （10 mg/kg, p.o.） could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib （10 mg/kg） and caffeic acid （5 mg/kg） could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.
