2-Azetidinone, a β-lactam four member heterocyclic compound involved in research aimed to evaluate new products that possess interesting biological activities. These compounds reported for their ...antimicrobial and antifungal activities. Successful introduction of aztreonam as a potent inhibitor of cephalosporinase and ezetimibe as a cholesterol absorption inhibitor proved potential of 2-azetidinone moiety. Subsequently 2-azetidinones were highlighted as a potent mechanism based inhibitor of several enzymes like human tryptase, chymase, thrombin, leukocyte elastase, human cytomegalovirus protease and serine protease enzyme. These derivatives also known to possess antitubercular, anti-inflammatory, antitumor, anti-HIV, antiparkinsonian, antidiabetic and vasopressin V1a antagonist activity. The present review article focuses on the pharmacological profile of 2-azetidinones with their potential activities.
2-Azetidinone and their derivatives occupy a central place in medicinal chemistry due to their diverse and broad pharmacological profile. This article focuses on the various pharmacological profile of 2-azetidinone scaffold and development of novel derivatives with their potential activity.
Display omitted
There is an unmet need for topical treatments with good tolerability in management of acne vulgaris. The present study aimed to evaluate efficacy and safety of a novel tretinoin (microsphere, 0.04%) ...formulation in combination with clindamycin (1%) gel for treatment of acne vulgaris.
This phase 3 randomized, double-blind study included patients with moderate-to-severe acne. Patients were treated with tretinoin (microsphere, 0.04%) + clindamycin (1%) or one of the monotherapies (tretinoin, 0.025%; clindamycin, 1%). Key endpoints included percent change in lesion counts, and improvement in Investigator's Static Global Assessment (ISGA) score.
750 patients were randomized (combination, n = 300; tretinoin and clindamycin, each n = 150). At week 12, reductions in inflammatory (77%), non-inflammatory (71%) and total lesions (73%) were significantly greater with combination treatment versus either monotherapy (p < .03). Proportion of patients rated 'clear' or 'almost clear' with ≥2-grade ISGA improvement was higher with combination (46%) versus monotherapies (p < .02). Adverse events occurred in 20 patients, most were mild-moderate; no deaths or serious adverse events were reported. The discontinuation rates due to adverse events with combination therapy were low (≤1%).
The once-daily, microsphere-based formulation was generally tolerable with a positive impact on therapeutic outcomes and patients' compliance.
CTRI/2014/08/004830
Major depressive disorder (MDD) is a common, debilitating illness with high prevalence of comorbid anxiety. The incidence of depression and of comorbid anxiety is much higher in women than in men. ...These gender biases appear after puberty and their etiology is mostly unknown. Selective breeding of the Wistar Kyoto (WKY) rat strain, an accepted model of adult and adolescent depression, resulted in two fully inbred substrains. Adult WKY more immobile (WMI) rats of both sexes consistently show increased depression‐like behavior in the forced swim test when compared with the control WKY less immobile (WLI) strain. In contrast, here we show that while adult female WMIs and WLIs both display high anxiety‐like behaviors, only WLI males, but not WMI males, show this behavior. Moreover, the behavioral profile of WMI males is consistent from early adolescence to adulthood, but the high depression‐ and anxiety‐like behaviors of the female WMIs appear only in adulthood. These sex‐specific behavioral patterns are paralleled by marked sex differences in hippocampal gene expression differences established by genome‐wide transcriptional analyses of 13th generation WMIs and WLIs. Moreover, sex‐ and age‐specific differences in transcript levels of selected genes are present in the hippocampus of the current, fully inbred WMIs and WLIs. Thus, the contribution of specific genes and/or the influence of the gonadal hormonal environment to depression‐ and anxiety‐like behaviors may differ between male and female WMIs, resulting in their distinct behavioral and transcriptomic profiles despite shared sequences of the somatic chromosomes.
Depression‐like behavior is present only after puberty in the females of a genetic rat model.
Chemotherapy-induced cognitive impairment (CICI) is a novel clinical condition characterized by memory, learning, and motor function deficits. Oxidative stress and inflammation are potential factors ...contributing to chemotherapy's adverse effects on the brain. Inhibition of soluble epoxide hydrolase (sEH) has been proven effective in neuroinflammation and reversal of memory impairment. The research aims to evaluate the memory protective effect of sEH inhibitor and dual inhibitor of sEH and COX and compare its impact with herbal extracts with known nootropic activity in an animal model of CICI. In vitro sEH, the inhibitory activity of hydroalcoholic extracts of Sizygium aromaticum, Nigella sativa, and Mesua ferrea was tested on murine and human sEH enzyme as per the protocol, and IC50 was determined. Cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and fluorouracil (5 mg/kg) combination (CMF) were administered intraperitoneally to induce CICI. The known herbal sEH inhibitor, Lepidium meyenii and the dual inhibitor of COX and sEH (PTUPB) were tested for their protective effect in the CICI model. The herbal formulation with known nootropic activity viz Bacopa monnieri and commercial formulation (Mentat) were also used to compare the efficacy in the CICI model. Behavioral parameter such as cognitive function was assessed by Morris Water Maze besides investigating oxidative stress (GSH and LPO) and inflammatory (TNFα, IL-6, BDNF and COX-2) markers in the brain. CMF-induced CICI, which was associated with increased oxidative stress and inflammation in the brain. However, treatment with PTUPB or herbal extracts inhibiting sEH preserved spatial memory via ameliorating oxidative stress and inflammation. S. aromaticum and N. sativa inhibited COX2, but M. Ferrea did not affect COX2 activity. Lepidium meyenii was the least effective, and mentat showed superior activity over Bacopa monnieri in preserving memory. Compared to untreated animals, the mice treated with PTUPB or hydroalcoholic extracts showed a discernible improvement in cognitive function in CICI.
•Soluble epoxide hydrolase converts neuroprotective Epoxyeicosatrienoic acid (EET) to less active trans-dihydro diols.•EETs alleviate inflammation, and cellular ageing by rebalancing cellular components via the ER stress pathway.•Inhibition of EH results in increased levels of EET, which has a neuroprotective effect conferring the reversal of cognitive impairment.
Neophobia, pickiness and diet variety are associated with diet quality and health outcomes in young children. Limited research has examined these associations among youth with type 1 diabetes (T1D), ...a population at risk for poor health outcomes when dietary quality is inadequate.
Youth (n=252, age 13.2 ± 2.8 years, 92% white, diabetes duration 6.3 ± 3.4 years) with T1D and their parents completed 3-day youth diet records; parents completed questionnaires regarding youth neophobia, pickiness and diabetes management adherence. Medical records provided biomedical data. Dietary quality indicators included Nutrient-Rich Foods Index 9.3 (NRF9.3), Healthy Eating Index-2005 (HEI-2005), Whole Plant Food Density (WPFD) and key single nutrients. Dietary variety was operationalized as a count of 20 recommended food groups consumed. Relationships of dietary quality and diabetes management adherence with neophobia, pickiness and dietary variety as independent variables were examined using multiple linear regression analyses adjusted for total energy intake, age, height and weight.
In multiple linear regression analyses, NRF9.3 and HEI-2005 were each inversely associated with neophobia and pickiness, and positively associated with dietary variety. WPF and potassium were each positively associated and saturated fat was inversely associated with dietary variety. However, in models simultaneously including neophobia, pickiness and dietary variety as independent correlates of dietary quality, only relationships with dietary variety remained significant. Diabetes management adherence was negatively associated with both neophobia and pickiness and positively associated with dietary variety.
Findings suggest that increasing dietary variety may contribute toward improved dietary quality among youth with T1D, despite potentially adverse influences of neophobia and pickiness.
Noninvasive ventilation Mehta, S; Hill, N S
American journal of respiratory and critical care medicine,
02/2001, Letnik:
163, Številka:
2
Journal Article
Aims
To evaluate the psychometric properties of the Diabetes Management Questionnaire, a brief, self‐report measure of adherence to contemporary diabetes management for young people with Type 1 ...diabetes and their caregivers.
Methods
A total of 273 parent‐child dyads completed parallel versions of the Diabetes Management Questionnaire. Eligible children (aged 8–18 years) had Type 1 diabetes for ≥1 year. A multidisciplinary team designed the Diabetes Management Questionnaire as a brief, self‐administered measure of adherence to Type 1 diabetes management over the preceding month; higher scores reflect greater adherence. Psychometrics were evaluated for the entire sample and according to age of the child.
Results
The children (49% female) had a mean ± sd (range) age 13.3 ± 2.9 (8–18) years and their mean ± sd HbA1c was 71 ± 15 mmol/mol (8.6 ± 1.4%). Internal consistency was good for parents (α = 0.83) and children (α = 0.79). Test‐retest reliability was excellent for parents (intraclass correlation coefficient =0.83) and good for children (intraclass correlation coefficient = 0.65). Parent and child scores had moderate agreement (intraclass correlation coefficient = 0.54). Diabetes Management Questionnaire scores were inversely associated with HbA1c (parents: r = –0.41, P < 0.0001; children: r = –0.27, P < 0.0001). Psychometrics were stronger in the children aged ≥13 years compared with those aged < 13 years, but were acceptable in both age groups. Mean ± sd Diabetes Management Questionnaire scores were higher among children who were receiving insulin pump therapy (n = 181) than in children receiving multiple daily injections (n = 92) according to parent (75.9 ± 11.8 vs. 70.5 ± 15.5; P = 0.004) and child report (72.2 ± 12.1 vs. 67.6 ± 13.9; P = 0.006).
Conclusions
The Diabetes Management Questionnaire is a brief, valid self‐report measure of adherence to contemporary diabetes self‐management for people aged 8–18 years who are receiving either multiple daily injections or insulin pump therapy.
What's new?
Adherence to diabetes self‐management is associated with better glycaemic control in young people with Type 1 diabetes. Young people with Type 1 diabetes and their parents often share in diabetes‐related tasks.
Most available measures to assess diabetes adherence have been validated in adolescents and many require significant time to administer. The Diabetes Management Questionnaire (DMQ) was developed to provide clinicians and clinical investigators with an efficient, easy‐to‐use and self‐administered tool to assess adherence to diabetes self‐management in people with Type 1 diabetes aged 8–18 years and their parents. The DMQ was validated in children treated using multiple daily injections or insulin pump therapy.
Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the ...efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.
In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34).
Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 4% in the vaccine consistency lot group, and 29 5% in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 33% of 657 vs 181 33% of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five 1% vs five 1%; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 29% vs 36 7%; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001).
This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated.
Merck & Co., Inc.
The nickel‐containing enzymes hydrogenase and urease require accessory proteins in order to incorporate properly the nickel atom(s) into the active sites. The Helicobacter pylori genome contains the ...full complement of both urease and hydrogenase accessory proteins. Two of these, the hydrogenase accessory proteins HypA (encoded by hypA) and HypB (encoded by hypB), are required for the full activity of both the hydrogenase and the urease enzymes in H. pylori. Under normal growth conditions, hydrogenase activity is abolished in strains in which either hypA (HypA:kan) or hypB (HypB:kan) have been interrupted by a kanamycin resistance cassette. Urease activity in these strains is 40 (HypA:kan)‐ and 200 (HypB:kan)‐fold lower than for the wild‐type (wt) strain 43504. Nickel supplementation in the growth media restored urease activity to almost wt levels. Hydrogenase activity was restored to a lesser extent, as has been observed for hyp mutants in other (H2‐oxidizing) bacteria. Expression levels of UreB (the urease large subunit) were not affected by inactivation of either hypA or hypB, as determined by immunoblotting. Urease activity was not affected by lesions in the genes for either the hydrogenase accessory proteins HypD or HypF or the hydrogenase large subunit structural gene, indicating that the urease deficiency was not caused by lack of hydrogenase activity. When crude extracts of wt, HypA:kan and HypB:kan were separated by anion exchange chromatography, the urease‐containing fractions of the mutant strains contained about four (HypA:kan)‐ and five (HypB:kan)‐fold less nickel than did the urease from wt, indicating that the lack of urease activity in these strains results from a nickel deficiency in the urease enzyme.
PDF
