Assessing Similarity to Existing Drugs to Decide Whether to Continue Drug Development.
Ontology highlight
ABSTRACT:
SUBMITTER: Ma GJ
PROVIDER: S-EPMC3564656 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Introducing species to areas outside their historical range to secure their future under climate change is a controversial strategy for preventing extinction. While the debate over the wisdom of this strategy continues, such introductions are already taking place. Previous frameworks for analysing the decision to introduce have lacked a quantifiable management objective and mathematically rigorous problem formulation. Here we develop the first rigorous quantitative framework for deciding whether or not a particular introduction should go ahead, which species to prioritize for introduction, and where and how to introduce them. It can also be used to compare introduction with alternative management actions, and to prioritise questions for future research. We apply the framework to a case study of tuatara (Sphenodon punctatus) in New Zealand. While simple and accessible, this framework can accommodate uncertainty in predictions and values. It provides essential support for the existing IUCN guidelines by presenting a quantitative process for better decision-making about conservation introductions.
| S-EPMC3797766 | biostudies-literature
Project description:Poor sleep is thought to enhance pain via increasing peripheral and/or central sensitization. Aerobic exercise, conversely, relives pain via reducing sensitization, among other mechanisms. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) can exercise protect against this transition? This study tested these questions and explored underlying mechanisms in a controlled injury model. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce symptoms consistent with clinical acute-onset overuse injury. Rats were then divided into three groups and exposed for 4 weeks to either: voluntary exercise via access to a running wheel, sleep disturbance, or both. Pain-related behaviours (forepaw mechanical sensitivity, reflexive grip strength), systemic levels of brain derived neurotrophic factor (BDNF), estradiol and corticosterone, and white blood cells (WBC) were assessed pre-injury, post-injury and post-intervention. Mechanical sensitivity increased post-injury and remained elevated with sleep disturbance alone, but decreased to pre-injury levels with exercise both with and without sleep disturbance. Reflexive grip strength decreased post-injury but recovered post-intervention-more with exercise than sleep disturbance. BDNF increased with sleep disturbance alone, remained at pre-injury levels with exercise regardless of sleep, and correlated with mechanical sensitivity. WBCs and estradiol increased with exercise alone and together with sleep disturbance, respectively. Corticosterone was not impacted by injury/intervention. Findings provide preliminary evidence for a role of poor sleep in the transition from acute-to-persistent pain, and the potential for aerobic exercise to counter these effects. BDNF might have a role in these relationships.
| S-EPMC10727927 | biostudies-literature
Project description:Overuse of antibiotics in the treatment of acute respiratory tract infection (ARI) contributes to the growing problem of antibiotic-resistant infections.To identify factors that influence community practitioners to prescribe antibiotics and examine how they differ from the recommendations of the Centers for Disease Control and Prevention (CDC) guideline for treatment of ARI.Paper case vignette study using a fractional factorial design.One hundred one community practitioners and eight faculty members.We asked community practitioners to estimate how likely they would be to prescribe antibiotics in each of 20 cases of ARI and then used multiple regression to infer the importance weights of each of nine clinical findings. We then compared practitioners' weights with those of a panel of eight faculty physicians who evaluated the cases following the CDC guidelines rather than their own judgments.Practitioners prescribed antibiotics in 44.5% of cases, over twice the percentage treated by the panel using the CDC guidelines (20%). In deciding to prescribe antibiotic treatment, practitioners gave little or no weight to patient factors such as whether the patients wanted antibiotics. Although weighting patterns differed among practitioners, the majority (72%) gave the greatest weight to duration of illness. When illness duration was short, the rate of prescribing (20.1%) was the same as the rate of the faculty panel (20%).Based on hypothetical cases of ARI, community practitioners prescribed antibiotics at twice the rate of faculty following CDC practice guidelines. Practitioners were most strongly influenced by duration of illness. The effect of duration was strongest when accompanied by fever or productive cough, suggesting that these situations would be important areas for practitioner education and further clinical studies.
| S-EPMC2533389 | biostudies-other
Project description:BackgroundBronchiolitis guidelines suggest that neither bronchodilators nor corticosteroids, antiviral and antibacterial agents should be routinely used. Although recommendations, many clinicians persistently prescribe drugs for bronchiolitis.Aim of the studyTo unravel main reasons of pediatricians in prescribing drugs to infants with bronchiolitis, and to possibly correlate therapeutic choices to the severity of clinical presentation. Also possible influence of socially deprived condition on therapeutic choices is analyzed.MethodsPatients admitted to Pediatric Division of 2 main Hospitals of Naples because of bronchiolitis in winter season 2008-2009 were prospectively analyzed. An RDAI (Respiratory Distress Assessment Instrument) score was assessed at different times from admission. Enrollment criteria were: age 1-12 months; 1st lower respiratory infection with cough and rhinitis with/without fever, wheezing, crackles, tachypnea, use of accessory muscles, and/or nasal flaring, low oxygen saturation, cyanosis. Social deprivation status was assessed by evaluating school graduation level of the origin area of the patients. A specific questionnaire was submitted to clinicians to unravel reasons of their therapeutic behavior.ResultsEighty-four children were enrolled in the study. Mean age was 3.5 months. Forty-four per cent of patients presented with increased respiratory rate, 70.2% with chest retractions, and 7.1% with low SaO2. Mean starting RDAI score was 8. Lung consolidation was found in 3.5% on chest roentgenogram. Data analysis also unraveled that 64.2% matched clinical admission criteria. Social deprivation status analysis revealed that 72.6% of patients were from areas "at social risk". Evaluation of length of stay vs. social deprivation status evidenced no difference between "at social risk" and "not at social risk" patients. Following therapeutic interventions were prescribed: nasal suction (64.2%), oxygen administration (7.1%), antibiotics (50%), corticosteroids (85.7%), bronchodilators (91.6%). Statistically significant association was not found for any used drug with neither RDAI score nor social deprivation status. The reasons of hospital pediatricians to prescribe drugs were mainly the perception of clinical severity of the disease, the clinical findings at chest examination, and the detection of some improvement after drug administration.ConclusionsWe strongly confirm the large use of drugs in bronchiolitis management by hospital pediatricians. Main reason of this wrong practice appears to be the fact that pediatricians recognize bronchiolitis as a severe condition, with consequent anxiety in curing so acutely ill children without drugs, and that sometimes they feel forced to prescribe drugs because of personal reassurance or parental pressure. We also found that social "at risk" condition represents a main reason for hospitalization, not correlated to clinical severity of the disease neither to drug prescription. Eventually, we suggest a "step-by-step" strategy to rich a more evidence based approach to bronchiolitis therapy, by adopting specific and shared resident guidelines.
| S-EPMC2958958 | biostudies-literature
Project description:Body-awareness is one of the fundamental modules of self-representation. We investigated how body-awareness could contribute to dogs' decision making in a novel spatial problem where multiple solutions are possible. Family dogs (N = 68) had to obtain a treat from behind a transparent fence. They had two options: either detour around the fence (7 m), or take a shortcut through a doorway (2 m). We had three conditions: small door open, large door open, and doors closed. Our results indicated that dogs assess the size of the doorway, and if they find it too small, they decide to detour instead, while in the case of the open large door, they rather opted for the shortcut without hesitation. Shorter headed dogs tended to choose open doors more often, while longer headed dogs rather chose detours, probably because of their better peripheral vision. While body size awareness did not manifest differently in dogs with short or long heads, we showed for the first time a connection between head shape and physical cognition in dogs. We showed that dogs rely on their body-awareness in a naturalistic setting where multiple solutions exist simultaneously. Dogs make decisions without lengthy trial-and-error learning and choose between options based on their body-awareness.
| S-EPMC10587091 | biostudies-literature
Project description:Interventions: Three Bevacizumab Preperations
Arm 1: DRL_BZ
100 mg in 4 mL - 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
Arm 2: Avastin (Registered Trademark) United States-licenced (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
Arm 3: Avastin (Registered Trademark) European Approved (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
As the Infusion will be administered while the participants are inpatients of the facility, no strategy for adherence is required.
Primary outcome(s): To demonstrate pharmacokinetic (PK) similarity of DRL_BZ versus the Reference Medicinal Product (RMP; Avastin (Registered Trademark) [EU-approved]) and the Reference Product (RP; Avastin (Registered Trademark) [US-licensed]) after administration of a single 1 mg/kg intravenous (IV) dose in healthy male subjects.[Blood samples for analysis of serum concentrations of the study drugs will be collected at the following specified times to perform a comparison of PK similarity.
All PK sampling time points are relative to end of infusion (i.e., after fixed infusion of 90 minutes, or up to 93 minutes, considering the maximum of 3 minutes infusion
interruption allowed). Sampling time points relative to end of infusion will have a designated nominal time point: End of infusion, 1 hour, 2 hours, 5 hours, 8 hours, 12 hours, and 24 hours post end of infusion and so on up to Day 85.
Mid infusion (at 45 minutes) and end of infusion (at 90 minutes +/- 3 minutes) are relative to the start of infusion.
The primary PK parameters will consist of:
- Cmax, AUC(08) and AUC(0t).]
Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Pharmacokinetics
| 2462876 | ecrin-mdr-crc
Project description:Interventions: Three Bevacizumab Preperations
Arm 1:BAT1706
100 mg in 4 mL - 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
Arm 2: Avastin (Registered Trademark) United States-licenced (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
Arm 3: Avastin (Registered Trademark) European Approved (bevacizumab)
100 mg in 4 mL- 1mg/kg
Recombinant humanised monoclonal antibody - bevacizumab
1 time only Intravenous infusion.
As the Infusion will be administered while the participants are inpatients of the facility, no strategy for adherence is required.
Primary outcome(s): To establish pairwise pharmacokinetic (PK) similarity between BAT1706, EU Avastin and US-Avastin after a single intravenous (IV) infusion in healthy male subjects.
The primary PK parameters will consist of:
Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf).[Blood samples for analysis of serum concentrations of the study drugs will be collected at the following specified times to perform a comparison of PK similarity.
Pre infusion - 0 hour or within 1 hour prior to the start of the infusion.
Mid infusion - at 45 minutes - relative to the start of infusion.
End of infusion - 1 hour, 2 hours, 5 hours, 8 hours, 12 hours from the end of infusion, and 24 hours (Day 2), 48 hours (Day 3), 96 hours (day 5), 168 hours (day 8), 240 hours (Day 11), 336 hours (Day 15), 504 hours (day 22), 672 hours (Day 29), 840 hours (Day 36), 1008 hours (Day 43), 1344 hours (Day 57), 1680 hours (Day 71), 2016 hours (Day85) and 2352 hours (Day 99) post start of infusion.
]
Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Pharmacokinetics
| 2463333 | ecrin-mdr-crc
Project description:The versatile microbial rhodopsin family performs a variety of biological tasks using a highly conserved architecture, making it difficult to understand the mechanistic basis for different functions. Besaw et al. now report structures of a recently discovered cyanobacterial Cl--pumping rhodopsin and its functionally divergent mutant that reveal how these transmembrane proteins create a gradient of activity with subtle changes. These insights are paralleled by a second recent report, which in combination answers long-standing questions about rhodopsin selectivity and will facilitate future engineering efforts.
| S-EPMC7606678 | biostudies-literature
Project description:Due to the speed, efficiency, relative risk, and lower costs compared to traditional drug discovery, the prioritization of candidate drugs for repurposing against cancers of interest has attracted the attention of experts in recent years. Herein, we present a powerful computational approach, termed prioritization of candidate drugs (PriorCD), for the prioritization of candidate cancer drugs based on a global network propagation algorithm and a drug-drug functional similarity network constructed by integrating pathway activity profiles and drug activity profiles. This provides a new approach to drug repurposing by first considering the drug functional similarities at the pathway level. The performance of PriorCD in drug repurposing was evaluated by using drug datasets of breast cancer and ovarian cancer. Cross-validation tests on the drugs approved for the treatment of these cancers indicated that our approach can achieve area under receiver-operating characteristic curve (AUROC) values greater than 0.82. Furthermore, literature searches validated our results, and comparison with other classical gene-based repurposing methods indicated that our pathway-level PriorCD is comparatively more effective at prioritizing candidate drugs with similar therapeutic effects. We hope that our study will be of benefit to the field of drug discovery. In order to expand the usage of PriorCD, a freely available R-based package, PriorCD, has been developed to prioritize candidate anticancer drugs for drug repurposing.
| S-EPMC6763777 | biostudies-literature
Project description:Classical land rent theories imply that the best land is cultivated first. This principle forms the basis of many land-use studies, but empirical evidence remains limited, especially on a global scale. In this paper, we estimate the effects of agricultural suitability and market accessibility on the spatial allocation of cultivated areas at a 30 arc-min resolution in 15 world regions. Our results show that both determinants often have a significant positive effect on the cropland fraction, but with large variations in strength across regions. Based on a quantile analysis, we find that agricultural suitability is the dominant driver of cropland allocation in North America, Middle East and North Africa and Eastern Europe, whereas market accessibility shows a stronger effect in other regions, such as Western Africa. In some regions, such as South and Central America, both determinants have a limited effect on cropland fraction. Comparison of high versus low quantile regression coefficients shows that, in most regions, densely cropped areas are more sensitive to agricultural suitability and market accessibility than sparsely cropped areas.
| S-EPMC7728207 | biostudies-literature