scholarly journals An update on the diagnosis and treatment of diabetic somatic and autonomic neuropathy

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 186 ◽  
Author(s):  
Shazli Azmi ◽  
Ioannis N. Petropoulos ◽  
Maryam Ferdousi ◽  
Georgios Ponirakis ◽  
Uazman Alam ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Autonomic Neuropathy ◽  
Advanced Disease ◽  
Single Agent ◽  
Trial Duration ◽  
Limited Efficacy ◽  
Risk Factor Reduction ◽  
Clinical Phenotyping ◽  
Anxiety Depression ◽  
Morbid Conditions

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes. It poses a significant challenge for clinicians as it is often diagnosed late when patients present with advanced consequences such as foot ulceration. Autonomic neuropathy (AN) is also a frequent and under-diagnosed complication unless it is overtly symptomatic. Both somatic and autonomic neuropathy are associated with increased mortality. Multiple clinical trials have failed because of limited efficacy in advanced disease, inadequate trial duration, lack of effective surrogate end-points and a lack of deterioration in the placebo arm in clinical trials of DPN. Multifactorial risk factor reduction, targeting glycaemia, blood pressure and lipids can reduce the progression of DPN and AN. Treatment of painful DPN reduces painful symptoms by about 50% at best, but there is limited efficacy with any single agent. This reflects the complex aetiology of painful DPN and argues for improved clinical phenotyping with the use of targeted therapy, taking into account co-morbid conditions such as anxiety, depression and sleep disturbance.

scholarly journals Principles and Challenges in anti-COVID-19 Vaccine Development

2021 ◽  
pp. 1-11
Author(s):  
Zuzana Strizova ◽  
Jitka Smetanova ◽  
Jirina Bartunkova ◽  
Tomas Milota
Keyword(s):  
Clinical Trials ◽  
Immune Responses ◽  
Vaccine Development ◽  
Viral Vector ◽  
Health It ◽  
Therapeutic Approaches ◽  
Clinical Phase ◽  
Adaptive Immune ◽  
Limited Efficacy ◽  
Safe Vaccine

The number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients keeps rising in most of the European countries despite the pandemic precaution measures. The current antiviral and anti-inflammatory therapeutic approaches are only supportive, have limited efficacy, and the prevention in reducing the transmission of SARS-CoV-2 virus is the best hope for public health. It is presumed that an effective vaccination against SARS-CoV-2 infection could mobilize the innate and adaptive immune responses and provide a protection against severe forms of coronavirus disease 2019 (COVID-19) disease. As the race for the effective and safe vaccine has begun, different strategies were introduced. To date, viral vector-based vaccines, genetic vaccines, attenuated vaccines, and protein-based vaccines are the major vaccine types tested in the clinical trials. Over 80 clinical trials have been initiated; however, only 18 vaccines have reached the clinical phase II/III or III, and 4 vaccine candidates are under consideration or have been approved for the use so far. In addition, the protective effect of the off-target vaccines, such as <i>Bacillus</i> Calmette-Guérin and measles vaccine, is being explored in randomized prospective clinical trials with SARS-CoV-2-infected patients. In this review, we discuss the most promising anti-COVID-19 vaccine clinical trials and different vaccination strategies in order to provide more clarity into the ongoing clinical trials.

scholarly journals Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer (OCTOVA): a study protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e041463
Author(s):  
Anita Mansouri ◽  
Naomi McGregor ◽  
Rachel Dunn ◽  
Sam Dobbie ◽  
Jane Holmes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Antiangiogenic Therapy ◽  
Single Agent ◽  
Unmet Need ◽  
Dropout Rate ◽  
Weekly Paclitaxel ◽  
Type I ◽  
Link Type ◽  
Platinum Based Chemotherapy

IntroductionPatients relapsing within 12 months of platinum-based chemotherapy usually have a poorer response to subsequent treatments. To date, extensive research into the mechanism of resistance to platinum agents in the treatment of ovarian cancer has not resulted in improved responses or longer survival. Further experimental work and clinical trials with novel agents are therefore justified to address this unmet need.Patients with ovarian, fallopian tube or primary peritoneal cancer that has relapsed within 12 months of platinum-based chemotherapy will be randomised with stratification for BReast CAncer gene (BRCA) status, prior poly (ADP-ribose) polymerase (PARP) exposure and prior antiangiogenic therapy into weekly paclitaxel (chemotherapy), olaparib or the combination of cediranib and olaparib. They will be followed until disease progression or unacceptable toxicity develops. Our trial design permits two investigations. We will compare the efficacy and tolerability of single-agent olaparib with weekly paclitaxel. We will also compare the efficacy and tolerability of olaparib with the combination of olaparib and cediranib. The required sample size of 138 participants (46 per arm) was calculated using a 20% one-sided type I error, 80% power and 15% dropout rate. Recruitment will last 34 months with a follow-up of 18 months.Methods and analysisEthics and disseminationThis study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency Clinical Trials Authorisation. Approval to conduct the study was obtained from the responsible authority before beginning the study. The sponsor will retain ownership of all data arising from the trial. We aim to publish this research in a specialist peer-reviewed scientific journal on study completion. EudraCT number: 2016-000559-28, ethics reference number: 16/LO/2150.Trial registration numberISRCTN: ISRCTN14784018, clinicaltrials.gov: NCT03117933; Pre-results.

scholarly journals Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture

2021 ◽  
pp. 247263032110088
Author(s):  
Pouria Rafsanjani Nejad ◽  
Pradip Shahi Thakuri ◽  
Sunil Singh ◽  
Astha Lamichhane ◽  
Jacob Heiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Single Agent ◽  
Three Dimensional ◽  
Drug Combinations ◽  
Toxic Effects ◽  
Combination Drug ◽  
Normal Cells ◽  
Colon Cells

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase–protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAFmut and KRASmut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.

scholarly journals Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

2011 ◽  
Vol 29 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Bhuvanesh Dave ◽  
Ilenia Migliaccio ◽  
M. Carolina Gutierrez ◽  
Meng-Fen Wu ◽  
Gary C. Chamness ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Epidermal Growth

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

scholarly journals Impact of Micronutrients on Hypertension: Evidence from Clinical Trials with a Special Focus on Meta-Analysis

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 588
Author(s):  
Hui-Fang Chiu ◽  
Kamesh Venkatakrishnan ◽  
Oksana Golovinskaia ◽  
Chin-Kun Wang
Keyword(s):  
Clinical Trials ◽  
Meta Analysis ◽  
Review Article ◽  
Special Focus ◽  
Recommended Daily Allowance ◽  
Beneficial Effects ◽  
Daily Allowance ◽  
Regulation Of Blood Pressure ◽  
Morbid Conditions

Hypertension (HT) is one of the pivotal risk factors for various detrimental diseases like cardiovascular diseases (CVDs), cerebrovascular disease, and renal dysfunction. Currently, many researchers are paying immense attention to various diet formula (dietary approach) with a special focus on micro and macronutrients along with modified lifestyle and standard anti-hypertensive drugs. Micronutrients (minerals/vitamins) play a central role in the regulation of blood pressure (BP) as they aid the function of macronutrients and also improve the anti-hypertensive functions of some anti-hypertensive agents. Even though several studies have demonstrated the beneficial effects of micronutrients on controlling BP, still some ambiguity exists among the nutritionists/doctors, which combination or individual mineral (dietary approach) contributes to better BP regulation. Therefore, this critical review article was attempted to delineate the underlying role of micronutrients (minerals and vitamins) for the management and prevention or delaying of HT and their related complications with strong affirmation from clinical trials as well as its mechanism of controlling BP. Moreover, the major source and recommended daily allowance (RDA) of various micronutrients are included in this review for guiding common readers (especially HT subjects) and dieticians to choose/recommend a better micronutrient and their combinations (other nutrients and standard anti-hypertensive drugs) for lowering the risk of HT and its related co-morbid conditions like CVDs.

scholarly journals Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

2020 ◽  
Author(s):  
Adam C. Palmer ◽  
Benjamin Izar ◽  
Peter K. Sorger
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Combination Therapies ◽  
Anti Tumor Activity

ABSTRACTHundreds of clinical trials are testing whether combination therapies can increase the anti-tumor activity of Immune Checkpoint Inhibitors (ICIs). We find that the benefits of recently reported and approved combinations involving ICIs are fully accounted for by increasing the chance of a single-agent response (drug independence), with no requirement for additive or synergistic efficacy. Thus, the degree of success of combinations involving ICIs with other therapies is largely predictable.

scholarly journals Modeling Clinical Trial Attrition Using Machine Intelligence: A driver analytics case study using 1,325 trials representing one million patients

2021 ◽  
Author(s):  
Emmette Hutchison ◽  
Sreenath Nampally ◽  
Imran Khan Neelufer ◽  
Youyi Zhang ◽  
Jim Weatherall ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Machine Intelligence ◽  
Duration Of Treatment ◽  
Trial Duration ◽  
Major Barrier ◽  
Clinical Phase ◽  
Successful Execution ◽  
Patient Attrition ◽  
Data Driven Approach

The amount of time and resources invested in bringing novel therapeutics to market has increased year over year with fewer successful treatments reaching patients. In the lifecycle of drug development, the clinical phase is a major contributor to this decreasing efficiency in the development of clinical trials. One major barrier to the successful execution of a randomized control trial (RCT) is the attrition of patients who no longer participate in a trial either following enrollment or randomization. To address this problem, we have assembled a unique dataset by integrating multiple public databases including ClinicalTrials.gov and Aggregate Analysis of ClincalTrials.gov (AACT) to assemble a trial sponsor-independent dataset. This data spans 20 years of clinical trials and over 1 million patients (3,175 cohorts consisting of 1,020,085 patients and 79 curated features) in the respiratory domain and enabled a data-driven approach to identify top features influencing patient attrition in a trial. Top Features included Duration of Trial, Duration of Treatment, Indication, and Number of Adverse Events. We evaluated multiple machine learning models and found the best performance on the Test Set with Random Forest (Test subset: n=637 cohorts; RMSE 6.64). We envisage that our work will enable clinical trial sponsors to optimize trial run time by better anticipating and correcting for potential patient attrition using patient-centric strategies to improve patient engagement, thus enabling new therapies to be delivered to patients more quickly.

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