Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury

Introduction: Acute respiratory distress syndrome (ARDS) is an acute form of diffuse lung injury characterized by (i) an intense inflammatory response, (ii) increased pulmonary vascular permeability, and (iii) the loss of respiratory pulmonary tissue. In this article we explore the therapeutic potential of hexarelin, a synthetic hexapeptide growth hormone secretagogue (GHS), in an experimental model of ARDS. Hexarelin has anti-inflammatory properties and demonstrates cardiovascular-protective activities including the inhibition of cardiomyocyte apoptosis and cardiac fibrosis, both of which may involve the angiotensin-converting enzyme (ACE) system. Methods: In our experimental model, ARDS was induced by the instillation of 100 mM HCl into the right bronchus; these mice were treated with hexarelin (320 μg/kg, ip) before (Pre) or after (Post) HCl challenge, or with vehicle. Respiratory system compliance, blood gas analysis, and differential cell counts in a selective bronchoalveolar lavage (BAL) were determined 6 or 24 hours after HCl instillation. In an extended study, mice were observed for a subsequent 14 days in order to assess lung fibrosis. Results: Hexarelin induced a significant improvement in lung compliance and a reduction of the number of total immune cells in BAL 24 hours after HCl instillation, accompanied with a lower recruitment of neutrophils compared with the vehicle group. At day 14, hexarelin-treated mice presented with less pulmonary collagen deposition compared with vehicle-treated controls. Conclusions: Our data suggest that hexarelin can inhibit the early phase of the inflammatory response in a murine model of HCl-induced ARDS, thereby blunting lung remodeling processes and fibrotic development.

Clinical factors predictive of appropriate treatment in COPD: a community hospital setting

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. The appropriate treatment according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline was 19-60%. However, there are limited data on predictors of appropriate treatment in patients with COPD. This study aimed to evaluate risk factors of appropriate treatment in patients with COPD according to the GOLD guideline in a real-world community setting. Methods: This is a retrospective study conducted at a community hospital. Inclusion criteria were adult patients diagnosed as COPD treated at a COPD clinic. The primary outcome was the appropriate treatment, defined by correct pharmacological treatment by the GOLD guideline according to the ABCD severity assessment. Clinical predictors of appropriate treatment were executed by stepwise multivariate logistic regression analysis. Results: 136 patients with COPD met the study criteria. Of those, 100 patients had inappropriate treatment according to the GOLD guideline. Three factors were independently associated with the appropriate treatment including number of admissions, modified Medical Research Council (mMRC) score, and CAT score. These factors had adjusted odds ratio of 3.11, 2.86, and 1.26, respectively. Causes of inappropriate treatment were unavailability of long-acting muscarinic antagonist (LAMA) (51 patients; 79.69%), treated by inhaled corticosteroid (ICS) alone (12 patients; 18.75%), and treated with only bronchodilator (1 patient; 1.56%). Conclusions: Appropriate COPD patients’ treatment according to the GOLD guideline was 26.47% in community setting. Factors associated with severity of COPD were associated with prescribing appropriate treatments.

The role of patient preferences in adherence to treatment in chronic disease: a narrative review

Adherence to prescribed medication is important to the management of all diseases, especially those of chronic nature. Drug effectiveness is substantially compromised by therapy nonadherence. We reviewed the available evidences on the impact of patient preferences for therapy on adherence to a prescribed treatment in chronic diseases requiring long-term treatment. A search on PubMed retrieved 699 publications, leading to a selection of 12 publications: 6 on osteoporosis, 2 on moderate-to-severe asthma, 1 on type 1 diabetes, 1 on type 2 diabetes, 1 on kidney transplantation, and 1 on atrial fibrillation. Overall, 8 studies found a positive association between patient preference and adherence to therapy, while the others found no association. In general, overall adherence was considered to be high in the published studies. The reasons for a positive association included reduced dosing frequency, route of administration, lower costs, and favorable safety profile, which is related to the diverse nature of the pathology and its type and duration of treatment. A literature review suggests that achieving good adherence and persistence to therapy requires evaluation of patient preferences. In a period of increasingly limited resources, more effort is warranted to promote better adherence to therapy, especially when patients must self-manage their disease in the long term. Our results further highlight that insufficient attention has been given to the relationship between patient preference and adherence and point out the complex nature of adherence and the need for adequate patient education. More efforts are also needed to better understand the entity of cost savings for payers for specific treatments and the link with patient preference.

Tamarind (Tamarindus indica L.) Seed a Candidate Protein Source with Potential for Combating SARS-CoV-2 Infection in Obesity

Introduction: Obesity and coronavirus disease (COVID)-19 are overlapping pandemics, and one might worsen the other. Methods: This narrative review discusses one of the primary mechanisms to initiate acute respiratory distress syndrome, uncontrolled systemic inflammation in COVID-19, and presents a potential candidate for adjuvant treatment. Blocking the S protein binding to angiotensin-converting enzyme 2 (ACE-2) and the 3C-like protease (3CL pro) is an effective strategy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results: Host proteases such as FURIN, trypsin, and transmembrane serine protease 2 (TMPRSS) act in S protein activation. Tamarind trypsin inhibitor (TTI) shows several beneficial effects on the reduction of inflammatory markers (tumor necrosis factor α [TNF-α], leptin) and biochemical parameters (fasting glycemia, triglycerides, and very low-density lipoprotein [VLDL]), in addition to improving pancreatic function and mucosal integrity in an obesity model. TTI may inhibit the action of proteases that collaborate with SARS-CoV-2 infection and the neutrophil activity characteristic of lung injury promoted by the virus. Conclusion: Thus, TTI may contribute to combating two severe overlapping problems with high cost and social complex implications, obesity and COVID-19.

Corticosteroid treatment reduces headache in eosinophilic meningitis: a systematic review

Background: Eosinophilic meningitis (EOM) is an emerging parasitic disease that can be found worldwide, of which acute severe headache is a presenting symptom. Although such headaches may persist for up to 2 months, studies have found corticosteroid to be effective in reducing this symptom. As the most recent systematic review was published in 2015, the aim of this study was to provide a more up-to-date examination of the role of corticosteroids in EOM. Methods: We included randomized controlled trials of corticosteroid treatment for EOM regardless of comparators. Research articles published in five databases were searched and evaluated. The primary outcome was headache, which was compared among various treatment regimens. Results: We found a total of 257 articles after duplication removal. Of those, two met the study criteria. According to these studies, oral prednisolone alone or in a combination of albendazole resulted in fewer patients with headache after a 2-week course of treatment compared with placebo (maximum of 9.1% vs. 45.5%). The duration of headache was also shorter in the prednisolone arm vs. placebo (maximum of 5 vs. 13 days). There were no serious side effects reported. Conclusion: A 2-week course of treatment with oral corticosteroid with or without albendazole reduced headaches in patients with EOM.

Interaction of drugs with lipid raft membrane domains as a possible target

Introduction: Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes. Methods: Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance. Results: The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption. Conclusion: Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.

Targeting Streptococcus pneumoniae UDP-glucose pyrophosphorylase (UGPase): in vitro validation of a putative inhibitor

Background: Genome plasticity of Streptococcus pneumoniae is responsible for the reduced efficacy of various antibiotics and capsular polysaccharide based vaccines. Therefore targets independent of capsular types are sought to control the pneumococcal pathogenicity. UcrDP-glucose pyrophosphorylase (UGPase) is one such desired candidate being responsible for the synthesis of UDP-glucose, a sugar-precursor in capsular biosynthesis and metabolic Leloir pathway. Being crucial to pneumococcal pathobiology, the effect of UGPase inhibition on virulence was evaluated in vitro. Methods: A putative inhibitor (UDP) was evaluated for effective inhibitory concentration in S. pneumoniae and A549 cells, its efficacy and toxicity. Effect of UDP on adherence and phagocytosis was measured in human respiratory epithelial (A549 and HEp-2) and macrophage (THP1 and J774.A.1) cell lines respectively. Results: A differential effective inhibitory concentration of UDP for UGPase inhibition was observed in S. pneumoniae and A549 cells i.e. 5 µM and 100 µM respectively. UDP treatments lowered percent cytotoxicity in pneumococcal infected monolayers and didn't exert adverse effects on viabilities. S. pneumoniae adherence to host cells was decreased significantly with UDP treatments. UDP induced the secretion of IL-1β, TNF-α, IL-6, and IL-8 and increased pneumococcal phagocytosis. Conclusion: Our study shows UDP mediated decrease in the virulence of S. pneumoniae and demonstrates UDP as an effective inhibitor of pneumococcal UGPase.

Paradoxical bronchoconstriction caused by β2-adrenoceptor agonists

Introduction: Salbutamol and terbutaline are short-acting β2 adrenergic agonists that produce bronchial smooth muscle relaxation and are widely used in obstructive pulmonary diseases. Nevertheless, their use has been the cause of a paradoxical bronchoconstriction, which is a rare and potentially serious adverse reaction. The aim of this study is to report a case of paradoxical bronchoconstriction caused by β2 adrenergic agonists. Methods: This case is about a 50-year-old asthmatic patient who describes a history of repeated acute asthma attacks after salbutamol inhalation or terbutaline nebulization. A double-blind crossover study was performed over 3 days, in order to compare the effects of each bronchodilator. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and maximal expiratory flow 25-75 (MEF25-75) were measured. Results: On the first day, a bronchoconstriction caused by deep and repeated inhalations was eliminated. On the second day, an airway obstruction was confirmed by a decrease in FEV1 at 40% from baseline values after nebulization of a standard dose of terbutaline. On the third day, a spirometry was performed before and after nebulization of a standard dose of ipratropium bromide, and there were no significant changes in the spirometric parameters. Finally the patient was discharged with a written warning mentioning the danger of salbutamol and terbutaline use. Conclusion: Salbutamol and terbutaline are generally well-tolerated β2 adrenergic agonists. Nevertheless, in rare cases, these substances can cause a paradoxical bronchoconstriction. Doctors must therefore remain vigilant about its side effect and possibly investigate each case.

Prevalence of multidrug-resistant and extended-spectrum beta-lactamase (ESBL)-producing gram-negative bacilli: A meta-analysis report in Ethiopia

Multidrug-resistant (MDR) extended-spectrum beta-lactamase (ESBL)-producing bacterial isolates have emerged as a global threat to human health. Little is known about the overall prevalence of multidrug resistance profile and ESBL-producing gram-negative bacilli (GNB) in Ethiopia. Therefore, this meta-analysis was performed to produce proportional estimates of multidrug resistance and ESBL-producing GNB in Ethiopia. A web-based search was conducted in PubMed, Google Scholar, Research Gate, Scopus and other databases. Articles published till 2019 on the prevalence and antimicrobial resistance profiles of ESBL-producing GNB in Ethiopia were included in the study. Relevant data were extracted and statistical analysis was performed using comprehensive meta-analysis version 3.3.0 software. Publication bias was analyzed and presented with funnel plots. In this meta-analysis, the overall proportional estimate of ESBL-producing GNB was 48.9% (95% confidence interval [CI]: 0.402, 0.577). The pooled proportional estimates of ESBL-producing Klebsiella pneumoniae, Escherichia coli and other GNB were 61.8%, 41.2% and 42.9%, respectively. Regarding antimicrobial resistance profiles against selected drugs, the pooled proportional estimates of resistance against amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, cefotaxime, ceftazidime, tetracycline, gentamicin and ciprofloxacin was 79.0%, 78.4%, 78.0%, 72.4%, 72.7%, 58.9% and 43.8%, respectively. The pooled proportional estimates of MDR isolates were found to be 82.7% (95% CI: 0.726, 0.896), which are relatively high as compared to other countries. This highlights a need for active surveillance systems which can help understand the actual epidemiology of ESBL, aid in formulating national guidelines for proper screening of ESBL and support developing standardized approaches for managing patients colonized with ESBL

Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4

Background: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression. Aim: Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways. Methods: Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software. Results: Six genes – AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 – were significantly overexpressed. Thirteen genes – ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1 – were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive. Conclusions: The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.