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Topic Review
Thiopurines’ Metabolites and Drug Toxicity
Thiopurines (comprising azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine) have been used for over 5 decades in the treatment of a myriad of disorders, including acute lymphoblastic leukemia (ALL), inflammatory bowel disease (IBD), auto-immune hepatitis (AIH), and also in the prophylaxis of rejection in organ transplant recipients. Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 108 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 108 RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 108 RBC). We established a significant correlation between 6-TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95%CI 2.24;9.57). An optimal cut-off of 135 pmol/8 × 108 RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 108 RBC; OR 4.28; 95%CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.
  • 797
  • 16 Aug 2020
Topic Review
Natural Polymer Nanofibrous Scaffold
Nanofibrous scaffolds mimicking artificial extracellular matrices provide a natural environment for tissue regeneration owing to their large surface area, high porosity, and appreciable drug loading capacity. Electrospun nanofibrous scaffolds have demonstrated promising potential in bone tissue regeneration using a variety of nanomaterials. Natural and synthetic polymeric nanofibrous scaffolds are extensively inspected to regenerate bone tissue. Bone tissue engineering (BTE) procedures make usage of various scaffolds (e.g., composite scaffolds, nanofibrous scaffolds, porous scaffolds, hydrogel scaffolds) in conjunction with biological materials.
  • 797
  • 17 Oct 2022
Topic Review
Cyclodextrins as Anti-inflammatory Agents
Cyclodextrins (CDs) are a well-known excipient for complexing and drug delivery. Anti-inflammatory drugs and bioactive compounds with similar activities have been favored from these CD processes. CDs also illustrate anti-inflammatory activity per se.
  • 794
  • 12 Oct 2021
Topic Review
Potential Therapeutic Targets for TNBC Therapy
TNBC exhibits high heterogeneity, which is the major limitation of chemotherapy. Also, TNBC is regarded as an aggressive type of cancer that grows faster and metastasizes to the brain and visceral organs, providing a much shorter average survival time of about 12 months to patients suffering from advanced TNBC. Therefore, the recognition of definitive targets, for providing efficient treatment against TNBC, becomes a noteworthy task.
  • 794
  • 31 May 2022
Topic Review
Enhancing Brain Drug Bioavailability in Depression and Anxiety
Depression and anxiety are high incidence and debilitating psychiatric disorders, usually treated by antidepressant or anxiolytic drug administration, respectively. Three main strategies have been used to improve brain drug targeting: the intranasal route of administration, which allows the drug to be directly transported to the brain by neuronal pathways, bypassing the blood–brain barrier and avoiding the hepatic and gastrointestinal metabolism; the use of nanosystems for drug encapsulation, including polymeric and lipidic nanoparticles, nanometric emulsions, and nanogels; and drug molecule functionalization by ligand attachment, such as peptides and polymers. Pharmacokinetic and pharmacodynamic in vivo studies’ results have shown that intranasal administration can be more efficient in brain targeting than other administration routes, and that the use of nanoformulations and drug functionalization can be quite advantageous in increasing brain–drug bioavailability. These strategies could be the key to future improved therapies for depressive and anxiety disorders.
  • 794
  • 31 Mar 2023
Topic Review
Practical Considerations for Next-Generation Adjuvant Development and Translation
Throughout the last two decades, there has been increasing focus on the discovery and translation of new immune-stimulating agents. These compounds are often collectively referred to as adjuvants due to their precedent of use in vaccine development. There has been an expansion in the application of adjuvants in oncology and other areas as the understanding and definition of adjuvants continue to grow. Adjuvants stimulate key cell types in the innate immune system and can influence the scale and class of immune response directed towards a given antigen or antigens.
  • 793
  • 07 Jul 2023
Topic Review
Pathophysiology of Takotsubo Syndrome
Takotsubo syndrome (TTS) is a transient dysfunction of the left and/or right ventricle, without the presence of ruptured atherosclerotic plaque, thrombus, dissection of the artery or other condition, which may cause the aforementioned symptoms. The term “tako-tsubo” was first used by Sato et al in 1990 because of the similarities between LV morphologic features and the shape of a ceramic fishing pot used since ancient times in Japan for trapping octopi.
  • 792
  • 07 Sep 2021
Topic Review
Phytocannabinoids
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in adults in developed countries, with a global prevalence as high as one billion. The pathogenesis of NAFLD is a multifactorial and multi-step process. Nowadays, a growing body of research suggests the considerable role of the endocannabinoid system (ECS) as a complex cell-signaling system in NAFLD development. 
  • 790
  • 18 Mar 2021
Topic Review
Biologics in Uveitis Treatment
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. 
  • 788
  • 15 Mar 2023
Topic Review
Faces of Autophagy Inhibition in Cisplatin Therapy
Cisplatin treatment promotes autophagy in both cisplatin-sensitive and cisplatin-resistant cells. Consequently, inhibition of autophagy can be considered a strategy for improving cisplatin chemosensitivity. This is the positive side, which is called Yang. However, the functional activity of cisplatin-induced autophagy is related to different genetic phenotypes and tumor types as well as the microenvironment of the tumor. In addition, preclinical studies have found that pharmacological autophagy inhibitors are not uniformly effective in enhancing the effectiveness of cisplatin and may also exacerbate the side effects of cisplatin toward normal tissue. This is the negative side, which is called Yin. 
  • 786
  • 23 Mar 2022
Topic Review
Capsaicin in Weight Control
Capsaicin is the main ingredient in chili peppers, responsible for the characteristic “hot” sensation that this spice evokes in the human mouth. Capsaicin is eaten on a daily basis by an estimated quarter of the world‘s population. This is surprising since the same “hot” taste which is found pleasurable by many humans repels most animals. It was posited that the pepper pod uses capsaicin as a chemical weapon to deter herbivores. Indeed, capsaicin is added to bird-feed to keep it safe from squirrels and other rodents.
  • 785
  • 19 Jul 2022
Topic Review
Seaweed as a Marine Source for Anti-Inflammatory Activity
Inflammation is a defense mechanism of the body in response to harmful stimuli such as pathogens, damaged cells, toxic compounds or radiation. However, chronic inflammation plays an important role in the pathogenesis of a variety of diseases. Marine organisms produce a broad spectrum of bioactive compounds with anti-inflammatory activities. Several are considered as lead compounds for development into drugs. Anti-inflammatory compounds have been extracted from algae, corals, seaweeds and other marine organisms. Seaweed is a popular food source rich in bioactive compounds, polysaccharides, fatty acids, peptides, proteins and vitamins. Seaweeds have several potential therapeutic activities, including anti-bacterial, anti-viral, anti-cancer, antioxidant and anti-inflammatory.
  • 784
  • 18 Oct 2023
Topic Review
Therapeutic Indications and Mechanisms of Action in Biologics
The year 2022 witnessed the control of the COVID-19 pandemic in most countries through social and hygiene measures and also vaccination campaigns. It also saw a decrease in total approvals by the U.S. Food and Drug Administration (FDA). Nevertheless, there was no fall in the Biologics class, which was boosted through the authorization of 15 novel molecules, thus maintaining the figures achieved in previous years. Indeed, the decrease in approvals was only for the category of small molecules. Monoclonal antibodies (mAbs) continued to be the drug class with the most approvals, and cancer remained the most targeted disease, followed by autoimmune conditions, as in previous years. Interestingly, the FDA gave the green light to a remarkable number of bispecific Biologics (four), the highest number in recent years. Indeed, 2022 was another year without the approval of an antimicrobial Biologic, although important advancements were made in targeting new diseases, which are discussed herein. This work analyzes the Biologics authorized in 2022. Furthermore, the orphan drugs authorized was considered. A quantitative analysis was applied to this year’s harvest, the efficacy of the Biologics with those authorized in previous years was compared. On the basis of their chemical structure, the Biologics addressed fall into the following classes: monoclonal antibodies; antibody-drug conjugates; and proteins/enzymes.
  • 783
  • 17 May 2023
Topic Review
Clinical Studies in IGU
Iguratimod (IGU) is a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) routinely prescribed in Japan since 2012 to patients with rheumatoid arthritis (RA). Iguratimod acts directly on B cells by inhibiting the production of inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, IL-17), thereby suppressing the production of immunoglobulin and inhibiting the activity of nuclear factor kappa-light chain enhancer of activated B cells. In Japan, it is one of the most used csDMARDs in daily practice, but it is not recommended as a treatment for RA due to the lack of large-scale evidence established overseas.
  • 782
  • 01 Jun 2021
Topic Review
Sex-Related Differences in Pharmacological Response to Opioids
Clinical experience proves that pharmacological response may vary between the two sexes since pathophysiological dissimilarities between men and women significantly influence the pharmacokinetics and pharmacodynamics of drugs. Opioids seem to produce better analgesia in women especially when they are administered for a prolonged period of time.
  • 781
  • 15 Jun 2022
Topic Review
Lycopene Metabolism, Bioavailability and Immunomodulatory Effects
Lycopene is a carotenoid found commonly in fruits and vegetables such as tomatoes, pink grapefruit and watermelons with non-provitamin A activity. It is the compound responsible for the red coloration of the fruits. It shares the same molecular mass and chemical formula with beta-carotene, but lycopene is an open-polyene chain which lacks the β-ionone ring structure found in beta-carotene. 
  • 781
  • 13 Feb 2023
Topic Review
STING Agonists/Antagonists
The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the faulty regulation of this pathway is involved in many type I IFN autoinflammatory disorders. 
  • 780
  • 24 May 2022
Topic Review
Histone Deacetylases in Human Cancers
Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. 
  • 779
  • 20 Apr 2022
Topic Review
Neuronal Nitric Oxide Synthase in Central Nervous System
The dysregulated activation of nNOS in neurons is critical in the development of different conditions affecting the SNC. An excessive production of NO by nNOS is responsible for a number of proteins’ posttranslational modifications (PTMs) which can lead to aberrant biochemical pathways, impairing the SNC functions. Researchers briefly revised the main implications of the dysregulated nNOS activation in the progression of the most prevalent CNS diseases, suggesting that compounds able to modulate the nNOS activity could be  promising therapeutics to tackle different neuronal pathologic conditions.
  • 778
  • 10 Oct 2023
Topic Review
TG2 in Inflammation and Sepsis
Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival.
  • 777
  • 10 Mar 2021
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