scholarly journals Identification of longevity compounds with minimized probabilities of side effects

2020 ◽  
Vol 21 (6) ◽  
pp. 709-719 ◽  
Author(s):  
Georges E. Janssens ◽  
Riekelt H. Houtkooper
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Side Effect ◽  
Aging Population ◽  
Model Organisms ◽  
Lifespan Extension ◽  
Clinical Testing ◽  
Healthy Individuals ◽  
Maximum Lifespan ◽  
Age Related

Abstract It is hypothesized that treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society, including a reduction of age-related diseases. It is intuitive that such compounds should cause minimal side effects, since they would be distributed to otherwise healthy individuals for extended periods of time. The question therefore emerges of how we should prioritize geroprotectors discovered in model organisms for clinical testing in humans. In other words, which compounds are least likely to cause harm, while still potentially providing benefit? To systematically answer this question we queried the DrugAge database—containing hundreds of known geroprotectors—and cross-referenced this with a recently published repository of compound side effect predictions. In total, 124 geroprotectors were associated to 800 unique side effects. Geroprotectors with high risks of side effects, some even with risk for death, included lamotrigine and minocycline, while compounds with low side effect risks included spermidine and d-glucosamine. Despite their popularity as top geroprotector candidates for humans, sirolimus and metformin harbored greater risks of side effects than many other candidate geroprotectors, sirolimus being the more severe of the two. Furthermore, we found that a correlation existed between maximum lifespan extension in worms and the likelihood of causing a side effect, suggesting that extreme lifespan extension in model organisms should not necessarily be the priority when screening for novel geroprotectors. We discuss the implications of our findings for prioritizing geroprotectors, suggesting spermidine and d-glucosamine for clinical trials in humans.

The influence of age on lithium efficacy and side-effects in out-patients

1983 ◽  
Vol 13 (1) ◽  
pp. 53-60 ◽  
Author(s):  
N. Murray ◽  
S. Hopwood ◽  
D. J. K. Balfour ◽  
S. Ogston ◽  
D. S. Hewick
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Lithium Treatment ◽  
The Other ◽  
Hand Tremor ◽  
Age Related

SynopsisOne hundred and sixty-six unipolar and bipolar out-patients (21–78 years) on long-term lithium treatment were studied on a prospective basis. Although there was a possible tendency for manic attacks to increase in prevalence and severity with age, it was difficult to demonstrate a general age-related decline in lithium efficacy. There was a tendency for the prevalence and severity of fine hand tremor to increase with age. This was not seen with polydipsia/polyuria, the other typical lithium side-effect.

scholarly journals Patient-Reported Outcomes in Online Communications on Statins, Memory, and Cognition: Qualitative Analysis Using Online Communities (Preprint)

2019 ◽  
Author(s):  
Farris Timimi ◽  
Sara Ray ◽  
Erik Jones ◽  
Lee Aase ◽  
Kathleen Hoffman
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Online Communities ◽  
Side Effect ◽  
Online Communication ◽  
Linguistic Analysis ◽  
Control Group ◽  
Patient Reported ◽  
Hands On ◽  
The Impact

BACKGROUND In drug development clinical trials, there is a need for balance between restricting variables by setting eligibility criteria and representing the broader patient population that may use a product once it is approved. Similarly, although recent policy initiatives focusing on the inclusion of historically underrepresented groups are being implemented, barriers still remain. These limitations of clinical trials may mask potential product benefits and side effects. To bridge these gaps, online communication in health communities may serve as an additional population signal for drug side effects. OBJECTIVE The aim of this study was to employ a nontraditional dataset to identify drug side-effect signals. The study was designed to apply both natural language processing (NLP) technology and hands-on linguistic analysis to a set of online posts from known statin users to (1) identify any underlying crossover between the use of statins and impairment of memory or cognition and (2) obtain patient lexicon in their descriptions of experiences with statin medications and memory changes. METHODS Researchers utilized user-generated content on Inspire, looking at over 11 million posts across Inspire. Posts were written by patients and caregivers belonging to a variety of communities on Inspire. After identifying these posts, researchers used NLP and hands-on linguistic analysis to draw and expand upon correlations among statin use, memory, and cognition. RESULTS NLP analysis of posts identified statistical correlations between statin users and the discussion of memory impairment, which were not observed in control groups. NLP found that, out of all members on Inspire, 3.1% had posted about memory or cognition. In a control group of those who had posted about TNF inhibitors, 6.2% had also posted about memory and cognition. In comparison, of all those who had posted about a statin medication, 22.6% (<italic>P</italic>&lt;.001) also posted about memory and cognition. Furthermore, linguistic analysis of a sample of posts provided themes and context to these statistical findings. By looking at posts from statin users about memory, four key themes were found and described in detail in the data: memory loss, aphasia, cognitive impairment, and emotional change. CONCLUSIONS Correlations from this study point to a need for further research on the impact of statins on memory and cognition. Furthermore, when using nontraditional datasets, such as online communities, NLP and linguistic methodologies broaden the population for identifying side-effect signals. For side effects such as those on memory and cognition, where self-reporting may be unreliable, these methods can provide another avenue to inform patients, providers, and the Food and Drug Administration.

scholarly journals Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19

2020 ◽  
Author(s):  
SARAH M LOFGREN ◽  
Melanie R Nicol ◽  
Ananta S Bangdiwala ◽  
Katelyn A Pastick ◽  
Elizabeth C Okafor ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Side Effect ◽  
Randomized Clinical Trials ◽  
Safety Data ◽  
Post Exposure Prophylaxis ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Gastrointestinal Side Effects ◽  
Exposure Prophylaxis

Introduction: Use of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials. Methods: We conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. Results: We enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred. Conclusion: Data from three outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials can safely investigate whether hydroxychloroquine is efficacious for COVID-19.

scholarly journals The Geometric Sparse Matrix Completion Model for Predicting Drug Side effects

2019 ◽  
Author(s):  
Diego Galeano ◽  
Alberto Paccanaro
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Side Effect ◽  
Large Scale ◽  
Learning Algorithm ◽  
Sparse Matrix ◽  
Matrix Completion ◽  
Optimal Solution ◽  
Drug Side Effects ◽  
Chemical Structures

AbstractPair-input associations for drug-side effects are obtained through expensive placebo-controlled experiments in human clinical trials. An important challenge in computational pharmacology is to predict missing associations given a few entries in the drug-side effect matrix, as these predictions can be used to direct further clinical trials. Here we introduce the Geometric Sparse Matrix Completion (GSMC) model for predicting drug side effects. Our high-rank matrix completion model learns non-negative sparse matrices of coefficients for drugs and side effects by imposing smoothness priors that exploit a set of pharmacological side information graphs, including information about drug chemical structures, drug interactions, molecular targets, and disease indications. Our learning algorithm is based on the diagonally rescaled gradient descend principle of non-negative matrix factorization. We prove that it converges to a globally optimal solution with a first-order rate of convergence. Experiments on large-scale side effect data from human clinical trials show that our method achieves better prediction performance than six state-of-the-art methods for side effect prediction while offering biological interpretability and favouring explainable predictions.

scholarly journals Rapamycin and Rapalogs

2021 ◽  
Author(s):  
Dudley Lamming
Keyword(s):  
Side Effects ◽  
Selective Inhibition ◽  
Model Organisms ◽  
Intermittent Treatment ◽  
Negative Side ◽  
Related Disease ◽  
The Past ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Negative Side Effects

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) signaling promotes health and longevity in diverse model organisms. Over the past decade, excitement has built over the possibility that treatment with the mTORC1 inhibitor rapamycin can be utilized to treat or prevent age-related disease in humans. However, concerns over the side effects of rapamycin on immunity and metabolism have precluded the routine use of rapamycin as a geroprotective therapy. Here, we discuss the evidence that these negative side effects of rapamycin are largely mediated by off-target inhibition of a second mTOR Complex (mTORC2). Further, we discuss how intermittent treatment with rapamycin, specific dietary regimens, and new molecules may provide routes to the safer and more selective inhibition of mTORC1. We conclude that the time is ripe for the development of therapies based on the safe and selective inhibition of mTORC1 for the treatment or prevention of diseases of aging.

scholarly journals Patient-Reported Outcomes in Online Communications on Statins, Memory, and Cognition: Qualitative Analysis Using Online Communities

10.2196/14809 ◽  
2019 ◽  
Vol 21 (11) ◽  
pp. e14809 ◽  
Author(s):  
Farris Timimi ◽  
Sara Ray ◽  
Erik Jones ◽  
Lee Aase ◽  
Kathleen Hoffman
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Online Communities ◽  
Side Effect ◽  
Online Communication ◽  
Linguistic Analysis ◽  
Control Group ◽  
Patient Reported ◽  
Hands On ◽  
The Impact

Background In drug development clinical trials, there is a need for balance between restricting variables by setting eligibility criteria and representing the broader patient population that may use a product once it is approved. Similarly, although recent policy initiatives focusing on the inclusion of historically underrepresented groups are being implemented, barriers still remain. These limitations of clinical trials may mask potential product benefits and side effects. To bridge these gaps, online communication in health communities may serve as an additional population signal for drug side effects. Objective The aim of this study was to employ a nontraditional dataset to identify drug side-effect signals. The study was designed to apply both natural language processing (NLP) technology and hands-on linguistic analysis to a set of online posts from known statin users to (1) identify any underlying crossover between the use of statins and impairment of memory or cognition and (2) obtain patient lexicon in their descriptions of experiences with statin medications and memory changes. Methods Researchers utilized user-generated content on Inspire, looking at over 11 million posts across Inspire. Posts were written by patients and caregivers belonging to a variety of communities on Inspire. After identifying these posts, researchers used NLP and hands-on linguistic analysis to draw and expand upon correlations among statin use, memory, and cognition. Results NLP analysis of posts identified statistical correlations between statin users and the discussion of memory impairment, which were not observed in control groups. NLP found that, out of all members on Inspire, 3.1% had posted about memory or cognition. In a control group of those who had posted about TNF inhibitors, 6.2% had also posted about memory and cognition. In comparison, of all those who had posted about a statin medication, 22.6% (P<.001) also posted about memory and cognition. Furthermore, linguistic analysis of a sample of posts provided themes and context to these statistical findings. By looking at posts from statin users about memory, four key themes were found and described in detail in the data: memory loss, aphasia, cognitive impairment, and emotional change. Conclusions Correlations from this study point to a need for further research on the impact of statins on memory and cognition. Furthermore, when using nontraditional datasets, such as online communities, NLP and linguistic methodologies broaden the population for identifying side-effect signals. For side effects such as those on memory and cognition, where self-reporting may be unreliable, these methods can provide another avenue to inform patients, providers, and the Food and Drug Administration.

scholarly journals Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes

2018 ◽  
Author(s):  
Jennifer C Regan ◽  
Yu-Xuan Lu ◽  
Ekin Bolukbasi ◽  
Mobina Khericha ◽  
Linda Partridge
Keyword(s):  
Mek Inhibitor ◽  
Model Organisms ◽  
Laboratory Model ◽  
Lifespan Extension ◽  
Parallel Mechanisms ◽  
Beneficial Effects ◽  
Age Related ◽  
Ras Inhibition ◽  
Female Specific ◽  
Female Lifespan

AbstractFemales of most species live longer than do males. Furthermore, lifespan-extending interventions in laboratory model organisms are often more effective in females (Regan and Partridge 2013). For instance, genetic and pharmacological suppression of activity of the insulin/insulin-like signalling - target of rapamycin (IIS-TOR) network generally extends female lifespan more than that of males in both Drosophila and mice (Clancy et al. 2001; Selman et al. 2009). We previously showed that attenuation of Ras-dependent IIS signalling by treatment with the FDA-approved MEK inhibitor, trametinib extends lifespan in females (Slack et al. 2015). Here, we demonstrate that trametinib treatment has beneficial effects on female-specific, age-related gut pathologies, similar to those obtained through dietary restriction (Regan et al. 2016). Importantly, we identify Ras inhibition as an effective lifespan-extending manipulation in males as well as females, pointing to parallel mechanisms of lifespan extension by trametinib in both sexes.

scholarly journals Severe Persistent Eczema in a Recipient of the Gam-COVID-Vac vaccine

2022 ◽  
Author(s):  
Maryam Ameri ◽  
Meysam Abolmaali ◽  
Sayed Mohammed Jawad Alwedaie ◽  
Mohammad Nabavi ◽  
Neda Rahimian ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Allergic Reaction ◽  
Healthcare Worker ◽  
Side Effect ◽  
Severe Allergic Reaction ◽  
Potential Side Effect

Since the beginning of the COVID-19 pandemic, efforts have been made to design safe and effective vaccines against SARS-CoV-2. Numerous vaccines have been designed and tested in limited clinical trials in various countries. Among them, the Sputnik V vaccine has shown a relatively safe profile and, to our knowledge, has no associated major side effects. We describe the case of a 40-year-old female healthcare worker who developed severe persistent eczematous lesions on the second day after she received the first dose of the Sputnik vaccine. The eczematous lesions were refractory to an antihistamine and persisted at the 1 month follow-up. Severe persistent eczematous lesions should be viewed as a potential side effect of vaccination with the Sputnik V vaccine. Moreover, a severe allergic reaction to a COVID-2019 vaccine may indicate the vaccine is ineffective in the recipient.

Exploration of baseline patient-reported side effect bother from cancer therapy

2020 ◽  
Vol 17 (3) ◽  
pp. 332-337
Author(s):  
Jessica K Roydhouse ◽  
Bellinda L King-Kallimanis ◽  
Pourab Roy ◽  
Chana Weinstock ◽  
Danielle Krol ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Cancer Therapy ◽  
Functional Assessment ◽  
Side Effect ◽  
Completion Rates ◽  
Single Item ◽  
Patient Reports ◽  
Investigational Agent ◽  
Patient Reported

Background: Patient reports of expected treatment side effects are increasingly collected as part of the assessment of patient experience in clinical trials. A global side effect item that is patient-reported has the potential to inform overall tolerability. Therefore, the aim of this study was to examine the completion and distribution of such a global single-item measure of side effect burden in five cancer clinical trials. Methods: Data from five trials from internal Food and Drug Administration databases that included the Functional Assessment of Cancer Therapy–General single-item measure of overall side effect burden (i.e. impact on degree of bother) were analyzed. Completion rates for the side effect bother item, items adjacent to this item, and two non-adjacent items on the Functional Assessment of Cancer Therapy–General that are related to health-related quality of life were calculated at the baseline assessment and at the 3-month assessment. To evaluate the distribution, the percentage of patients reporting high levels (quite a bit or very much bother) of side effect bother at baseline and 3 months was assessed. Results: Completion rates for all items were at least 80% regardless of time point or trial population. However, in three of the five trials, completion rates for the side effect bother item were lower at baseline compared to adjacent and non-adjacent items. This difference was not observed at 3 months. Up to 9.4% of patients reported high levels of side effect bother at baseline. Conclusion: Patients may enter trials already reporting some bother from side effects. This can make interpretation of results with respect to the investigational agent under study challenging. Patients may skip an item evaluating side effect bother at baseline, suggesting some difficulty with interpretation of what is being asked. Further study of the wording and utility of a baseline side effect bother assessment is warranted.

scholarly journals Next Generation Strategies for Geroprotection via mTORC1 Inhibition

2019 ◽  
Vol 75 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Sabrina N Dumas ◽  
Dudley W Lamming
Keyword(s):  
Side Effects ◽  
Selective Inhibition ◽  
Target Of Rapamycin ◽  
Model Organisms ◽  
Next Generation ◽  
Rapamycin Treatment ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Mtorc1 Signaling

Abstract Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.

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