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Thyroid : Official Journal of the... Aug 2020The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis... (Review)
Review
The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.
Topics: Acetates; Anilides; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Diiodothyronines; Drug Design; Dyslipidemias; Humans; Liver Diseases; Male; Mice; Mutation; Non-alcoholic Fatty Liver Disease; Phenols; Pyridazines; Rats; Signal Transduction; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones; Thyronines; Triiodothyronine; Uracil
PubMed: 32098589
DOI: 10.1089/thy.2020.0071 -
Applied Microbiology and Biotechnology Nov 2019Insulin therapy remains the most effective method to treat diabetes mellitus (DM), and the demand for this valuable hormone has exceeded that of any other protein-based... (Review)
Review
Insulin therapy remains the most effective method to treat diabetes mellitus (DM), and the demand for this valuable hormone has exceeded that of any other protein-based medicine as a result of the dramatic increase in the number of diabetic patients worldwide. Understanding the structure of insulin and the interaction with its receptor is important for developing proper formulations. As a result of the relatively low thermal stability of native insulin and its two-chain analogues, the application of single-chain insulin (SCI) analogues, which can be obtained relatively easily by recombinant DNA technology or chemical synthetic methods, represents a promising alternative approach. In this review, the basic knowledge of insulin (discovery, biosynthesis, and structure) and the current model of the interaction with its receptor are outlined. Furthermore, we outline the strategies for the design and production of various SCI analogues and their reported applications.
Topics: Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin; Receptor, Insulin
PubMed: 31637493
DOI: 10.1007/s00253-019-10170-0 -
The Lancet. Gastroenterology &... Nov 2021Gastrointestinal angiodysplasias are vascular malformations that often cause red blood cell transfusion-dependent anaemia. Several studies suggest that somatostatin... (Meta-Analysis)
Meta-Analysis
Effectiveness and predictors of response to somatostatin analogues in patients with gastrointestinal angiodysplasias: a systematic review and individual patient data meta-analysis.
BACKGROUND
Gastrointestinal angiodysplasias are vascular malformations that often cause red blood cell transfusion-dependent anaemia. Several studies suggest that somatostatin analogues might decrease rebleeding rates, but the true effect size is unknown. We therefore aimed to investigate the efficacy of somatostatin analogues on red blood cell transfusion requirements of patients with gastrointestinal angiodysplasias and to identify subgroups that might benefit the most from somatostatin analogue therapy.
METHODS
We did a systematic review and individual patient data meta-analysis. We searched MEDLINE, Embase, and Cochrane on Jan 15, 2016, with an updated search on April 25, 2021. All published randomised controlled trials and cohort studies that reported on somatostatin analogue therapy in patients with gastrointestinal angiodysplasias were eligible for screening. We excluded studies without original patient data, single case reports, small case series (ie, <10 participants), studies in which patients had a specific aetiology of gastrointestinal angiodysplasias, and studies in which somatostatin analogue therapy was initiated simultaneously with other treatment modalities. Authors of eligible studies were invited to share individual patient data. Aggregated data was used if individual patient data were not provided. The primary outcome was the mean reduction in the number of red blood cell transfusions during somatostatin analogue therapy, compared with baseline, expressed as the incidence rate ratio (IRR) and absolute mean decrease. We defined patients as either good responders (≥50% reduction in the number of red blood cell transfusions) or poor responders (<50% reduction). A mixed-effects negative binomial regression was used to account for clustering of patients and skewness in data. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020213985.
FINDINGS
We identified 11 eligible studies (one randomised controlled trial and ten cohort studies) of moderate-to-high quality and obtained individual patient data from the authors of nine (82%) studies. The remaining two (18%) studies provided sufficient information in the published manuscript to extract individual patient data. In total, we analysed data from 212 patients. Somatostatin analogues reduced the number of red blood cell transfusions with an IRR of 0·18 (95% CI 0·14-0·24; p<0·0001) during a median treatment duration of 12 months (IQR 6·0-12·0) and follow-up period of 12 months (12·0-12·0), correlating with a mean absolute decrease in the number of red blood cell transfusions from 12·8 (95% CI 10·4-15·8) during baseline to 2·3 (1·9-2·9) during follow-up-ie, a reduction of 10·5 red blood cell transfusions (p<0·0001). 177 (83%) of 212 patients had a good response to somatostatin analogue therapy (defined as at least a 50% reduction in the number of red blood cell transfusions). Heterogeneity across studies was moderate (I=53%; p=0·02). Location of gastrointestinal angiodysplasias in the stomach compared with angiodysplasias in the small bowel and colon (IRR interaction 1·92 [95% CI 1·13-3·26]; p=0·02) was associated with worse treatment response. Octreotide was associated with a better treatment response than lanreotide therapy (IRR interaction 2·13 [95% CI 1·12-4·04]; p=0·02). The certainty of evidence was high for the randomised controlled trial and low for the ten cohort studies. Adverse events occurred in 38 (18%) of 212 patients receiving somatostatin analogue therapy, with ten (5%) discontinuing this therapy because of adverse events. The most common adverse events were loose stools (seven [3%] of 212), cholelithiasis (five [2%]), flatulence (four [2%]), and administration site reactions (erythema, five [2%]).
INTERPRETATION
Somatostatin analogue therapy is safe and effective in most patients with red blood cell transfusion-dependent bleeding due to gastrointestinal angiodysplasias. Somatostatin analogue therapy is more effective in patients with angiodysplasias located in the small bowel and colon, and octreotide therapy seems to be more effective than lanreotide therapy.
FUNDING
The Netherlands Organisation for Health Research and Development and the Radboud University Medical Center.
Topics: Angiodysplasia; Erythrocyte Transfusion; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Humans; Octreotide; Peptides, Cyclic; Somatostatin; Treatment Outcome
PubMed: 34508668
DOI: 10.1016/S2468-1253(21)00262-4 -
Mini Reviews in Medicinal Chemistry 2019The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from... (Review)
Review
The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from their selective interaction with DNA in the minor groove and from their ability to interfere with biological processes such as enzyme catalysis, replication and transcription. The discovery of the details of minor groove binding drugs, such as netropsin and distamycin A, oligoamides built of 4-amino-1-methylpyrrole-2-carboxylic acid residues, allowed to develop various DNA sequence-reading molecules, named lexitropsins, capable of interacting with DNA precisely, strongly and with a high specificity, and at the same time exhibiting significant cytotoxic potential. Among such compounds, lexitropsins built of carbocyclic sixmembered aromatic rings occupy a quite prominent place in drug research. This work is an attempt to present current findings in the study of carbocyclic lexitropins, their structures, syntheses and biological investigations such as DNA-binding and antiproliferative activity.
Topics: Acids, Carbocyclic; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Proliferation; DNA; Distamycins; Drug Design; Humans; Neoplasms; Netropsin
PubMed: 30626311
DOI: 10.2174/1389557518666181009143203 -
ACS Sensors May 2022Nucleoside analogues are reagents that resemble the structure of natural nucleosides and are widely applied in antiviral and anticancer therapy. Molnupiravir, a recently...
Nucleoside analogues are reagents that resemble the structure of natural nucleosides and are widely applied in antiviral and anticancer therapy. Molnupiravir, a recently reported nucleoside analogue drug, has shown its inhibitory effect against SARS-CoV-2. Rapid tracing of molnupiravir and its metabolites is important in the evaluation of its pharmacology effect, but direct sensing of molnupiravir as a single molecule has not been reported to date. Here, we demonstrate a nanopore-based sensor with which direct sensing of molnupiravir and its two major metabolites β-d-4-hydroxycytidine and its triphosphate can be achieved simultaneously. In conjunction with a custom machine learning algorithm, an accuracy of 92% was achieved. This sensing strategy may be useful in the current pandemic and is in principle suitable for other nucleoside analogue drugs.
Topics: Cytidine; Humans; Hydroxylamines; Nanopores; Nucleosides; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35427117
DOI: 10.1021/acssensors.2c00447 -
Current Opinion in Insect Science Aug 2023Analogous to multicellular organisms, social insect colonies are characterized by division of labor with queens and workers reflecting germline and soma, respectively.... (Review)
Review
Analogous to multicellular organisms, social insect colonies are characterized by division of labor with queens and workers reflecting germline and soma, respectively. In multicellular organisms, such division is achieved through epigenetic factors regulating cell differentiation during development. Analogously, epigenetic regulation is postulated to regulate caste differences in social insects. We summarize recent findings about the role of epigenetics in social insects, focusing on DNA methylation and histone modifications. We specifically address (i) queen versus worker caste differentiation, (ii) queen versus worker caste differences, and (iii) division of labor among workers. Our review provides an overview of an exciting and controversially discussed field in developmental and molecular biology. It shows that our current understanding about the role of epigenetics in regulating division of labor in social insects is still fragmentary but that refined methods with well-replicated samples and targeted questions offer promising insights into this emerging field of socio-epigenomics.
Topics: Animals; Social Behavior; Epigenesis, Genetic; Insecta; DNA Methylation; Epigenomics
PubMed: 37164259
DOI: 10.1016/j.cois.2023.101051 -
Cortex; a Journal Devoted To the Study... Aug 2018This article investigates whether, and how, an artificial intelligence (AI) system can be said to use visual, imagery-based representations in a way that is analogous to... (Review)
Review
This article investigates whether, and how, an artificial intelligence (AI) system can be said to use visual, imagery-based representations in a way that is analogous to the use of visual mental imagery by people. In particular, this article aims to answer two fundamental questions about imagery-based AI systems. First, what might visual imagery look like in an AI system, in terms of the internal representations used by the system to store and reason about knowledge? Second, what kinds of intelligent tasks would an imagery-based AI system be able to accomplish? The first question is answered by providing a working definition of what constitutes an imagery-based knowledge representation, and the second question is answered through a literature survey of imagery-based AI systems that have been developed over the past several decades of AI research, spanning task domains of: 1) template-based visual search; 2) spatial and diagrammatic reasoning; 3) geometric analogies and matrix reasoning; 4) naive physics; and 5) commonsense reasoning for question answering. This article concludes by discussing three important open research questions in the study of visual-imagery-based AI systems-on evaluating system performance, learning imagery operators, and representing abstract concepts-and their implications for understanding human visual mental imagery.
Topics: Artificial Intelligence; Humans; Imagery, Psychotherapy; Imagination; Memory, Short-Term; Problem Solving; Visual Perception
PubMed: 29980282
DOI: 10.1016/j.cortex.2018.01.022 -
Drugs Jun 2015Pasireotide (Signifor(®), Signifor(®) LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide... (Review)
Review
Pasireotide (Signifor(®), Signifor(®) LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40 mg every 28 days was superior to that of intramuscular octreotide 20 mg every 28 days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6 months, the efficacy of pasireotide 40 or 60 mg was superior to that of continued octreotide 30 mg or lanreotide autogel 120 mg (each drug was administered once every 28 days) with regard to biochemical control. The tolerability profile of intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed.
Topics: Acromegaly; Humans; Hyperglycemia; Octreotide; Peptides, Cyclic; Somatostatin
PubMed: 26017304
DOI: 10.1007/s40265-015-0413-y -
Studies in History and Philosophy of... Oct 2020We examine the interrelationships between analog computational modelling and analogue (physical) modelling. To this end, we attempt a regimentation of the informal...
We examine the interrelationships between analog computational modelling and analogue (physical) modelling. To this end, we attempt a regimentation of the informal distinction between analog and digital, which turns on the consideration of computing in a broader context. We argue that in doing so, one comes to see that (scientific) computation is better conceptualised as an epistemic process relative to agents, wherein representations play a key role. We distinguish between two, conceptually distinct, kinds of representation that, we argue, are both involved in each case of computing. Based on the semantic and syntactic properties of each of these representations, we put forward a new account of the distinction between analog and digital computing. We discuss how the developed account is able to explain various properties of different models of computation, and we conceptually compare analog computational modelling to analogue (scale) modelling. It is concluded that, contrary to the standard view, the two practices are orthogonal, differing both in their foundations and in the epistemic functions they fulfil.
Topics: Computer Simulation; Semantics
PubMed: 32958274
DOI: 10.1016/j.shpsa.2020.05.001 -
Frontiers in Pharmacology 2021Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis... (Review)
Review
Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis treatment exists despite decades of research on developing potential therapies. Annexins are molecules that show efficacy in preclinical models of sepsis but have not been investigated as a potential therapy in patients with sepsis. Human annexins play important roles in cell membrane dynamics, as well as mediation of systemic effects. Most notably, annexins are highly involved in anti-inflammatory processes, adaptive immunity, modulation of coagulation and fibrinolysis, as well as protective shielding of cells from phagocytosis. These discoveries led to the development of analogous peptides which mimic their physiological function, and investigation into the potential of using the annexins and their analogous peptides as therapeutic agents in conditions where inflammation and coagulation play a large role in the pathophysiology. In numerous studies, treatment with recombinant human annexins and annexin analogue peptides have consistently found positive outcomes in animal models of sepsis, myocardial infarction, and ischemia reperfusion injury. Annexins A1 and A5 improve organ function and reduce mortality in animal sepsis models, inhibit inflammatory processes, reduce inflammatory mediator release, and protect against ischemic injury. The mechanisms of action and demonstrated efficacy of annexins in animal models support development of annexins and their analogues for the treatment of sepsis. The effects of annexin A5 on inflammation and platelet activation may be particularly beneficial in disease caused by SARS-CoV-2 infection. Safety and efficacy of recombinant human annexin A5 are currently being studied in clinical trials in sepsis and severe COVID-19 patients.
PubMed: 34566657
DOI: 10.3389/fphar.2021.735472