Resistance to β-lactam antibiotics can be mediated by metallo-β-lactamase enzymes (MBLs). An MBL inhibitor could restore the effectiveness of β-lactams. We report on the evaluation of approved thiol-containing drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed by a novel assay using a purchasable fluorescent substrate and thermal shift. Best compounds were tested in antimicrobial susceptibility assay. Using these orthogonal screening methods, we identified drugs that restored the activity of imipenem.

Approved Drugs Containing Thiols as Inhibitors of Metallo-β-lactamases: Strategy To Combat Multidrug-Resistant Bacteria.

Ergebnisse einer S2k-Konsensuskonferenz der Deutschen Gesellschaft fur Gastroenterologie, Verdauungsund Stoffwechselerkrankungen (DGVS) gemeinsam mit der Deutschen Gesellschaft fur Innere Medizin (DGIM), der Deutschen Gesellschaft fur Hygiene und Mikrobiologie (DGHM), der Deutschen Gesellschaft fur Infektiologie (DGI), der Deutschen Gesellschaft fur Krankenhaushygiene e. V. (DGKH), der Deutschen Gesellschaft fur Pathologie (DGP), der Deutschen Gesellschaft fur Tropenmedizin und Internationale Gesundheit (DTG), dem ROBERT-KOCHINSTITUT (RKI) und der Paul-Ehrlich Gesellschaft fur Chemotherapie e.V. (PEG)

/pdf/s2k-guideline-gastrointestinal-infectious-diseases-and-2npgdyu9jf.pdf

[S2k-guideline gastrointestinal infectious diseases and Whipple's disease].

Acute diarrhoea is a leading cause of child mortality in developing countries. Principal pathogens include Escherichia coli, rotaviruses, and noroviruses. 90% of diarrhoeal deaths are attributable to inadequate sanitation. Acute diarrhoea is the second leading cause of overall childhood mortality and accounts for 18% of deaths among children under five. In 2004 an estimated 1.5 million children died from diarrhoea, with 80% of deaths occurring before the age of two. Treatment goals are to prevent dehydration and nutritional damage and to reduce duration and severity of diarrhoeal episodes. The recommended therapeutic regimen is to provide oral rehydration solutions (ORS) and to continue feeding. Although ORS effectively mitigates dehydration, it has no effect on the duration, severity, or frequency of diarrhoeal episodes. Adjuvant therapy with micronutrients, probiotics, or antidiarrhoeal agents may thus be useful. The WHO recommends the use of zinc tablets in association with ORS. The ESPGHAN/ESPID treatment guidelines consider the use of racecadotril, diosmectite, or probiotics as possible adjunctive therapy to ORS. Only racecadotril and diosmectite reduce stool output, but no treatment has yet been shown to reduce hospitalisation rate or mortality. Appropriate management with validated treatments may help reduce the health and economic burden of acute diarrhoea in children worldwide.

/pdf/role-of-antidiarrhoeal-drugs-as-adjunctive-therapies-for-29u4xs0uum.pdf

Role of Antidiarrhoeal Drugs as Adjunctive Therapies for Acute Diarrhoea in Children

One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently-available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being employed in the treatment of constipation.

Intestinal secretory mechanisms and diarrhea.

Objective Racecadotril is an antisecretory agent that can prevent fluid/electrolyte depletion from the bowel as a result of acute diarrhoea without affecting intestinal motility. An up-to-date systematic review is indicated to summarise the evidence on racecadotril for the treatment of acute diarrhoea in children. Design A Cochrane format systematic review of randomised controlled trials (RCTs). Data extraction and assessment of methodological quality were performed independently by two reviewers. Methodological quality was assessed using the Cochrane risk of bias tool. Patients Children with acute diarrhoea, as defined by the primary studies. Interventions RCTs comparing racecadotril with placebo or other interventions. Main outcome measurs Duration of illness, stool output/volume and adverse events. Results Seven RCTs were included, five comparing racecadotril with placebo or no intervention, one with pectin/kaolin and one with loperamide. Moderate to high risk of bias was present in all studies. There was no significant difference in efficacy or adverse events between racecadotril and loperamide. A meta-analysis of three studies with 642 participants showed significantly shorter duration of symptoms with racecadotril compared with placebo (mean difference −53.48 h, 95% CI −65.64 to −41.33). A meta-analysis of five studies with 949 participants showed no significant difference in adverse events between racecadotril and placebo (risk ratio 0.99, 95% CI 0.73 to 1.34). Conclusions There is some evidence that racecadotril is more effective than placebo or no intervention in reducing the duration of illness and stool output in children with acute diarrhoea. However, the overall quality of the evidence is limited due to sparse data, heterogeneity and risk of bias. Racecadotril appears to be safe and well tolerated.

https://adc.bmj.com/content/archdischild/101/3/234.full.pdf

Racecadotril for acute diarrhoea in children: systematic review and meta-analyses

Racecadotril, via its active metabolite thiorphan, is an inhibitor of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), thereby increasing exposure to NEP substrates including enkephalins and atrial natriuretic peptide (ANP). Upon oral administration racecadotril is rapidly and effectively converted into the active metabolite thiorphan, which does not cross the blood–brain-barrier. Racecadotril has mainly been tested in animal models and patients of three therapeutic areas. As an analgesic the effects of racecadotril across animal models were inconsistent. In cardiovascular diseases such as hypertension or congestive heart failure results from animal studies were promising, probably related to increased exposure to ANP, but clinical results have not shown substantial therapeutic benefit over existing treatment options in cardiovascular disease. In contrast, racecadotril was consistently effective in animal models and patients with various forms of acute diarrhea by inhibiting pathologic (but not basal) secretion from the gut without changing gastro-intestinal transit time or motility. This included studies in both adults and children. In direct comparative studies with loperamide in adults and children, racecadotril was at least as effective but exhibited fewer adverse events in most studies, particularly less rebound constipation. Several guidelines recommend the use of racecadotril as addition to oral rehydration treatment in children with acute diarrhea.

/pdf/a-comprehensive-review-of-the-pharmacodynamics-3p5bdzd1s5.pdf

A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

Background: Quality of life
(QoL) is impaired in chronic constipation. Among nonprescription laxatives QoL
data out of randomized controlled trials are available only for bisacodyl and
sodium picosulfate (SPS). Methods: In two randomized, double-blind,
placebo-controlled, parallel-group trials, the
efficacy and safety of treatment with either bisacodyl or SPS, respectively, were assessed. After a 2-week baseline period patients
with functional constipation were randomized to a 4-week treatment with either
bisacodyl (2 tablets = 10 mg), SPS (18 drops = 10 mg), or matching placebo in a
ratio of active drug to placebo of 2:1. Dose reduction as well as resuming the
original dose was permitted. Patients who did not experience a bowel movement
for more than 72 h were allowed to use a bisacodyl suppository. The primary
endpoint was the mean number of Complete Spontaneous Bowel Movements (CSBMs)
per week during the trial. QoL was assessed using the Patient Assessment of
Constipation (PAC)-QoL questionnaire. Results: Active treatment led to a
greater improvement of PAC-QoL scores for every domain. Active treatment was
also superior to placebo for all individual questions of the questionnaire. Of
note, SPS or bisacodyl not only improved satisfaction with stool patterns (“quite a bit/extremely satisfied” in 12.8% of patients on
placebo and 50.3% on active treatment) but bloating was also considerably
ameliorated (“not at all feeling bloated” in
24.5% on placebo and 41.4% on active treatment). Conclusion: Bisacodyl and SPS
not only improve stool variables but also quality of life in patients with
chronic functional constipation. (EudraCT Nos. 2007-001991-34 and
2007-002087-10).

/pdf/bisacodyl-and-sodium-picosulfate-improve-bowel-function-and-k6bor8xz7i.pdf

Bisacodyl and Sodium Picosulfate Improve Bowel Function and Quality of Life in Patients with Chronic Constipation—Analysis of Pooled Data from Two Randomized Controlled Trials

Aim: To explore the relationship between pathophysiological factors and premature lung ageing in a cohort of community-dwelling subjects in a health-screening setting. Methods: 16,107 pharmacy customers in Germany (5954 males, 10153 females; mean age 59.7 years)) participated in a lung function screening project by providing demographic data including smoking status and known airway conditions and performing spirometry with a Vitalograph, a spirometry screening device. Lung age was calculated from the spirometric findings, and the difference between chronological age and calculated lung age was analyzed in its relationship to the demographic data in general linear models. Results: In the overall cohort, calculated lung age exceeded chronological age by 10.0 years. Based on the subset of non-smokers not reporting any airway conditions, Vitalograph data in this setting may underestimate FEV1 to some degree but this apparently had little impact on the detection of association of lung age with pathophysiological factors or the corresponding effect sizes. The most important factors associated with greater lung age based on strength of association were presence of dyspnea, being a smoker and reporting a history of COPD or asthma. Corresponding effect sizes for the difference between age and lung age were 6.5, 5.7, 13.9 and 8.3 years over the chronological age. Discussion and Conclusions: These data confirm the usefulness of screening devices of lung function testing for epidemiological but potentially also for pharmaco-epidemiological studies.

/pdf/pathophysiological-factors-in-the-relationship-between-f588k2zqva.pdf

Pathophysiological Factors in the Relationship between Chronological Age and Calculated Lung Age as Detected in a Screening Setting in Community-Dwelling Subjects.

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A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

Bisacodyl and Sodium Picosulfate Improve Bowel Function and Quality of Life in Patients with Chronic Constipation—Analysis of Pooled Data from Two Randomized Controlled Trials

Pathophysiological Factors in the Relationship between Chronological Age and Calculated Lung Age as Detected in a Screening Setting in Community-Dwelling Subjects.