Editorial

Open AccessEditorial

Current Knowledge and Novel Therapeutic Approaches Based on Pharmacokinetics and Pharmacodynamics in Stress-Induced Pathology

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Cornelia Amalinei

Medicina 2022, 58(7), 839; https://doi.org/10.3390/medicina58070839 - 22 Jun 2022

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Abstract

There have been numerous progresses recently made in the knowledge of different types of stress involvement in human pathology, in an effort to counteract or to prevent their etiopathogenic pathways or to find novel therapeutic approaches [...] Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

Research

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Open AccessArticle

High Fat Diet Exaggerate Metabolic and Reproductive PCOS Features by Promoting Oxidative Stress: An Improved EV Model in Rats

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Dejana Rakic

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Jovana Joksimovic Jovic

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Aleksandra Dimitrijevic

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Medicina 2023, 59(6), 1104; https://doi.org/10.3390/medicina59061104 - 07 Jun 2023

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Abstract

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent multifactorial endocrinopathy affecting women in the reproductive period, often associated with infertility and metabolic disorders. The use of animal models helps to better understand etiopathogenesis, enabling the examination of the effects of [...] Read more.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent multifactorial endocrinopathy affecting women in the reproductive period, often associated with infertility and metabolic disorders. The use of animal models helps to better understand etiopathogenesis, enabling the examination of the effects of certain drugs in order to discover the best possible therapeutic approach. We tried to investigate the additional effect of estradiol-valerate (EV) and high-fat diet (HFD) in female rats to explore PCOS-related alterations with special focus on oxidative stress. Materials and Methods: Animals were divided into three groups: control group (CTRL, n = 6), estradiol-valerate group (EV, n = 6), and estradiol-valerate group on HFD (EV + HFD, n = 6). PCOS was induced by single subcutaneous injection of long-acting EV in a dose of 4 mg/per rat. We tried to improve the metabolic characteristics of the PCOS animal model by adding HFD, so the CTRL and EV group had a regular diet, while the EV + HFD group had HFD during the induction period of 60 days. Results: We observed alterations of anthropometric parameters and hormonal disturbances, along with estrus cycle impairment reassembly to obese-type PCOS phenotype. Moreover, glucose metabolism was impaired after addition of HFD to EV protocol, contrary to EV administered alone. Histological analysis confirmed more numerous cystic follicles after the combination of EV and HFD protocol. The alterations of oxidative stress markers could be related to and serve as the mechanistic base for development of PCOS-related endocrine, reproductive, and metabolic properties. Conclusions: The additive effect of EV and HFD was obvious in the majority of the parameters observed. Our study strongly demonstrated metabolic as well as reproductive properties of PCOS in rats. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessFeature PaperArticle

Selenium Status and Oxidative Stress in SARS-CoV-2 Patients

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Medicina 2023, 59(3), 527; https://doi.org/10.3390/medicina59030527 - 08 Mar 2023

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Abstract

Background and Objectives: Insufficient intake of essential micronutrient selenium (Se) increases the susceptibility to diseases associated with oxidative stress. The study aim was to assess Se status and oxidative stress in COVID-19 patients depending on severity of the disease. Materials and Methods [...] Read more.

Background and Objectives: Insufficient intake of essential micronutrient selenium (Se) increases the susceptibility to diseases associated with oxidative stress. The study aim was to assess Se status and oxidative stress in COVID-19 patients depending on severity of the disease. Materials and Methods: Blood plasma of 80 post-COVID-19 disease patients and 40 acutely ill patients were investigated. Concentration of Se was detected by a fluorometric method with di-amino-naphthalene using acidic hydrolysis. Selenoprotein P (Sepp1), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) and their metabolite adducts were evaluated by spectrophotometric methods using commercial assay kits. Results: Obtained results demonstrated that Se and Sepp1 concentration in acute patients were significantly (p < 0.05 for Se and p < 0.001 for Sepp1) decreased compared with post-COVID-19 disease patients. However, in post-COVID-19 disease patients, Se values were close to the low limit of the norm for the European population. 4-HNE adducts concentration as a marker of lipid peroxidation was significantly increased in the acute patients group compared to the recovery group (p < 0.001). Conclusions: COVID-19 pathology is characterized by the induction of oxidative stress and suppression of antioxidant defenses during the acute phase. Lower levels of Se and Sepp1 and higher levels of reactive oxygen species reflect this imbalance, highlighting the role of oxidative stress in the disease’s pathogenesis. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessArticle

Zinc Chloride Enhances the Antioxidant Status, Improving the Functional and Structural Organic Disturbances in Streptozotocin-Induced Diabetes in Rats

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Irina Claudia Anton

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Liliana Mititelu-Tartau

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Liliana Lacramioara Pavel

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Ilie Cristian Drochioi

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Gina Eosefina Botnariu

Medicina 2022, 58(11), 1620; https://doi.org/10.3390/medicina58111620 - 10 Nov 2022

Cited by 1 | Viewed by 966

Abstract

Background and Objectives: Diabetes mellitus (DM) is a complex disease affecting the whole metabolic balance of the body and resulting in multiple organ complications: cardiovascular, neuronal, renal, etc. Our study focuses on investigating the effect of zinc chloride (Zn) on certain blood [...] Read more.

Background and Objectives: Diabetes mellitus (DM) is a complex disease affecting the whole metabolic balance of the body and resulting in multiple organ complications: cardiovascular, neuronal, renal, etc. Our study focuses on investigating the effect of zinc chloride (Zn) on certain blood parameters suggestive for assessing the metabolic disturbances, the liver and kidney function, the oxidative stress and the immune defense capacity in experimental-induced DM with streptozotocin (STZ) and cholesterol in rats. Materials and Methods: The animals were assigned to three groups, as follows: Group 1 (Control): buffer citrate solution 0.1 mL/100 g body; Group 2 (STZ): 20 mg/kg body STZ and fat diet (10 g cholesterol/100 g diet); Group 3 (STZ+Zn): 20 mg/kg body STZ + 5 mg/kg body Zn chloride and the same fat diet. DM was induced by administering STZ in a single take daily, for three consecutive days, Zn and citrate buffer were administered orally for a month. The protocol was approved by the Ethics Committee of the University ‘Grigore T Popa’ Iasi, in agreement with the International Regulations about the handling of laboratory animals. Results: The use of STZ in rats fed with cholesterol was correlated with important weight gain, hyperglycemia, the intensification of the transaminases activity and the increase in serum alkaline phosphatase, cholesterol, triglyceride, urea, creatinine and in malondialdehyde. Conclusions: The treatment with Zn resulted in weight loss and a decrease in blood sugar in diabetic rats. Supplementation with Zn notably reduced oxidative stress, preserved the pancreatic architecture and restored the liver and kidney function and structure in STZ-induced DM in rats. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessArticle

The Value of Myocardium and Kidney Histopathological and Immunohistochemical Findings in Accidental Hypothermia-Related Fatalities

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Andreea Alexandra Hleșcu

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Medicina 2022, 58(11), 1507; https://doi.org/10.3390/medicina58111507 - 23 Oct 2022

Viewed by 986

Abstract

Background and Objectives: The post-mortem diagnosis of hypothermia is challenging in forensics. The aim of our study was to detect the kidney and heart histopathological changes that occurred in a group of hypothermia-related fatalities. Materials and Methods: The cohort included 107 cases identified [...] Read more.

Background and Objectives: The post-mortem diagnosis of hypothermia is challenging in forensics. The aim of our study was to detect the kidney and heart histopathological changes that occurred in a group of hypothermia-related fatalities. Materials and Methods: The cohort included 107 cases identified in the database of our department between 2007 and 2021, which have been associated with extreme cold stress. Demographic and clinicopathological data were collected from the medico-legal reports. Archived tissue samples were evaluated to identify the histopathological features, in routine haematoxylin-eosin (H&E), Periodic acid-Schiff (PAS), and Masson’s trichrome stainings, while cardiac sirtuin1 (SIRT1) and renal ubiquitin (Ub) immunostaining have been performed. Results: The majority of cases exposed to low temperatures were males (76%) from rural regions (68.2%) during the cold season. Paradoxical undressing was documented in 9.3% of cases. The common comorbidities included alcoholism (50.5%), neuropsychiatric diseases (10.3%), diabetes mellitus (3.7%), and lung tuberculosis (4.7%). The microscopic heart exam revealed areas of myocardial degeneration (100%), contraction bands (95.3%), fatty change (13.1%) and focal wavy contractile myocardial cells. Basal vacuolisation of renal tubular epithelial cells (Armanni-Ebstein lesions) (21.5%), focal tubular necrosis (7.5%), tubular renal cysts (7.5%), interstitial haemorrhages (5.6%), diabetic kidney disease (3.7%), background benign nephroangiosclerosis (42.1%), variable thickening of tubules and corpuscles basement membranes, capsular space amorphous material, and intratubular casts were identified in kidney tissue samples. Myocardial cells displayed SIRT1 weak expression, with a loss of immunopositivity correlated with areas with contraction bands, while a variable Ub expression was observed in renal corpuscles capsules, proximal, distal, and collecting renal tubules, Henle’s loops, urothelium, and intratubular casts. Conclusions: In the context of the current concept that death associated with hypothermia is still a diagnosis of exclusion, our findings suggest that the microscopic exam provides relevant data that support the diagnosis of hypothermia-related fatalities in appropriate circumstances of death. A deeper insight into the histopathologic findings in hypothermic patients may lead to new therapeutic approaches in these cases. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessArticle

Magnesium Potentiates the Vortioxetine’s Effects on Physical Performances and Biological Changes in Exercise-Induced Stress in Rats

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Paula Alina Fotache

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Liliana Mititelu-Tartau

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Maria Bogdan

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Beatrice Rozalina Buca

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Liliana Lacramioara Pavel

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Ana-Maria Pelin

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Andreea-Daniela Meca

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Cosmin-Gabriel Tartau

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Gratiela Eliza Popa

Medicina 2022, 58(10), 1363; https://doi.org/10.3390/medicina58101363 - 28 Sep 2022

Viewed by 1204

Abstract

Background and objectives: Vortioxetine (VRT) is a relatively new selective serotonin reuptake inhibitor (SSRI) antidepressant and serotonin receptor modulator, approved for the treatment of major depression and generalized anxiety disorder. Depression has been linked with psychomotor disengagement, oxidative stress burden and decreased blood [...] Read more.

Background and objectives: Vortioxetine (VRT) is a relatively new selective serotonin reuptake inhibitor (SSRI) antidepressant and serotonin receptor modulator, approved for the treatment of major depression and generalized anxiety disorder. Depression has been linked with psychomotor disengagement, oxidative stress burden and decreased blood levels of brain-derived neurotrophic factor (BDNF). In our study we performed the experimental investigation of VRT, magnesium and of their association on the rats’ endurance capacity, motor behavior and blood biological disturbances in rats subjected to forced exercise in treadmill test. Materials and Methods: The substances were administered orally for 14 consecutive days, as follows: group 1 (control): distilled water 0.3 mL/100 g body; group 2 (Mg): magnesium chloride 200 mg/kg body; group 3 (VRT): VRT 20 mg/kg body; group 4 (VRT+Mg): VRT 20 mg/kg body + magnesium chloride 200 mg/kg body. Magnesium was used as positive control substance with known effects in treadmill test. The consequences of VRT treatment on glucose, cortisol, BDNF and oxidative stress biomarkers (superoxide-dismutase, malondialdehyde, glutathione-peroxidase, lactate dehydrogenase) were also assessed. Results and conclusions: The use of VRT resulted in an improvement in motor capacity and an increase of the rats’ endurance to physical effort. The administration of VRT increased the serum BDNF levels and reduced the oxidative stress in rats subjected to physical effort. The association of magnesium potentiated the effects of VRT on physical performances, the antioxidant activity and the decreasing in serum stress markers in treadmill test in rats. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Review

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Open AccessReview

360-Degree Perspectives on Obesity

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Magdalena Cuciureanu

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Cătălin-Cezar Caratașu

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Levon Gabrielian

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Otilia Elena Frăsinariu

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Laura Elisabeta Checheriță

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Laura Mihaela Trandafir

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Gabriela Dumitrița Stanciu

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Călin Vasile Andrițoiu

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Maria Mihalache Anghel

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Diana Munteanu

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Irina Teodora Cernescu

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Bogdan Ionel Tamba

Medicina 2023, 59(6), 1119; https://doi.org/10.3390/medicina59061119 (registering DOI) - 09 Jun 2023

Viewed by 409

Abstract

Alarming statistics show that the number of people affected by excessive weight has surpassed 2 billion, representing approximately 30% of the world’s population. The aim of this review is to provide a comprehensive overview of one of the most serious public health problems, [...] Read more.

Alarming statistics show that the number of people affected by excessive weight has surpassed 2 billion, representing approximately 30% of the world’s population. The aim of this review is to provide a comprehensive overview of one of the most serious public health problems, considering that obesity requires an integrative approach that takes into account its complex etiology, including genetic, environmental, and lifestyle factors. Only an understanding of the connections between the many contributors to obesity and the synergy between treatment interventions can ensure satisfactory outcomes in reducing obesity. Mechanisms such as oxidative stress, chronic inflammation, and dysbiosis play a crucial role in the pathogenesis of obesity and its associated complications. Compounding factors such as the deleterious effects of stress, the novel challenge posed by the obesogenic digital (food) environment, and the stigma associated with obesity should not be overlooked. Preclinical research in animal models has been instrumental in elucidating these mechanisms, and translation into clinical practice has provided promising therapeutic options, including epigenetic approaches, pharmacotherapy, and bariatric surgery. However, more studies are necessary to discover new compounds that target key metabolic pathways, innovative ways to deliver the drugs, the optimal combinations of lifestyle interventions with allopathic treatments, and, last but not least, emerging biological markers for effective monitoring. With each passing day, the obesity crisis tightens its grip, threatening not only individual lives but also burdening healthcare systems and societies at large. It is high time we took action as we confront the urgent imperative to address this escalating global health challenge head-on. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessReview

The Ethnopharmacological Properties of Green-Engineered Metallic Nanoparticles against Metabolic Disorders

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Medicina 2023, 59(6), 1022; https://doi.org/10.3390/medicina59061022 - 25 May 2023

Viewed by 425

Abstract

Metabolic syndrome is a multifaceted pathophysiologic condition that is largely caused by an imbalance between caloric intake and energy expenditure. The pathogenesis of metabolic syndrome is determined by an individual’s genetic/epigenetics and acquired factors. Natural compounds, notably plant extracts, have antioxidant, anti-inflammatory, and [...] Read more.

Metabolic syndrome is a multifaceted pathophysiologic condition that is largely caused by an imbalance between caloric intake and energy expenditure. The pathogenesis of metabolic syndrome is determined by an individual’s genetic/epigenetics and acquired factors. Natural compounds, notably plant extracts, have antioxidant, anti-inflammatory, and insulin-sensitizing properties and are considered to be a viable option for metabolic disorder treatment due to their low risk of side effects. However, the limited solubility, low bioavailability, and instability of these botanicals hinder their performance. These specific limitations have prompted the need for an efficient system that reduces drug degradation and loss, eliminates unwanted side effects, and boosts drug bioavailability, as well as the percentage of the drug deposited in the target areas. The quest for an enhanced (effective) drug delivery system has led to the formation of green-engineered nanoparticles, which has increased the bioavailability, biodistribution, solubility, and stability of plant-based products. The unification of plant extracts and metallic nanoparticles has helped in the development of new therapeutics against metabolic disorders such as obesity, diabetes mellitus, neurodegenerative disorders, non-alcoholic fatty liver, and cancer. The present review outlines the pathophysiology of metabolic diseases and their cures with plant-based nanomedicine. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessReview

An Updated Review on the Role of Nanoformulated Phytochemicals in Colorectal Cancer

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Medicina 2023, 59(4), 685; https://doi.org/10.3390/medicina59040685 - 30 Mar 2023

Cited by 1 | Viewed by 1172

Abstract

The most common cancer-related cause of death worldwide is colorectal cancer. It is initiated with the formation of polyps, which further cause the development of colorectal cancer in multistep phases. Colorectal cancer mortality is high despite recent treatment breakthroughs and a greater understanding [...] Read more.

The most common cancer-related cause of death worldwide is colorectal cancer. It is initiated with the formation of polyps, which further cause the development of colorectal cancer in multistep phases. Colorectal cancer mortality is high despite recent treatment breakthroughs and a greater understanding of its pathophysiology. Stress is one of the major causes of triggering different cellular signalling cascades inside the body and which might turn toward the development of cancer. Naturally occurring plant compounds or phytochemicals are being studied for medical purposes. Phytochemicals’ benefits are being analyzed for inflammatory illnesses, liver failure, metabolic disorders, neurodegenerative disorders, and nephropathies. Cancer treatment with fewer side effects and better outcomes has been achieved by combining phytochemicals with chemotherapy. Resveratrol, curcumin, and epigallocatechin-3-gallate have been studied for their chemotherapeutic and chemopreventive potentiality, but hydrophobicity, solubility, poor bioavailability, and target selectivity limit the clinical uses of these compounds. The therapeutic potential is maximized by utilizing nanocarriers such as liposomes, micelles, nanoemulsions, and nanoparticles to increase phytochemical bioavailability and target specificity. This updated literature review discusses the clinical limitations, increased sensitivity, chemopreventive and chemotherapeutic effects, and the clinical limitations of the phytochemicals. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessReview

Optimization of Therapy and the Risk of Probiotic Use during Antibiotherapy in Septic Critically Ill Patients: A Narrative Review

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Maria Ioana Onofrei

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Cristina Mihaela Ghiciuc

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Catalina Mihaela Luca

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Paraschiva Postolache

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Cristina Sapaniuc

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Georgiana Enache Leonte

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Florin Manuel Rosu

Medicina 2023, 59(3), 478; https://doi.org/10.3390/medicina59030478 - 28 Feb 2023

Viewed by 733

Abstract

Optimizing the entire therapeutic regimen in septic critically ill patients should be based not only on improving antibiotic use but also on optimizing the entire therapeutic regimen by considering possible drug–drug or drug–nutrient interactions. The aim of this narrative review is to provide [...] Read more.

Optimizing the entire therapeutic regimen in septic critically ill patients should be based not only on improving antibiotic use but also on optimizing the entire therapeutic regimen by considering possible drug–drug or drug–nutrient interactions. The aim of this narrative review is to provide a comprehensive overview on recent advances to optimize the therapeutic regimen in septic critically ill patients based on a pharmacokinetics and pharmacodynamic approach. Studies on recent advances on TDM-guided drug therapy optimization based on PK and/or PD results were included. Studies on patients <18 years old or with classical TDM-guided therapy were excluded. New approaches in TDM-guided therapy in septic critically ill patients based on PK and/or PD parameters are presented for cefiderocol, carbapenems, combinations beta-lactams/beta-lactamase inhibitors (piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam), plazomicin, oxazolidinones and polymyxins. Increased midazolam toxicity in combination with fluconazole, nephrotoxic synergism between furosemide and aminoglycosides, life-threatening hypoglycemia after fluoroquinolone and insulin, prolonged muscle weakness and/or paralysis after neuromuscular blocking agents and high-dose corticosteroids combinations are of interest in critically ill patients. In the real-world practice, the use of probiotics with antibiotics is common; even data about the risk and benefits of probiotics are currently spares and inconclusive. According to current legislation, probiotic use does not require safety monitoring, but there are reports of endocarditis, meningitis, peritonitis, or pneumonia associated with probiotics in critically ill patients. In addition, probiotics are associated with risk of the spread of antimicrobial resistance. The TDM-guided method ensures a true optimization of antibiotic therapy, and particular efforts should be applied globally. In addition, multidrug and drug–nutrient interactions in critically ill patients may increase the likelihood of adverse events and risk of death; therefore, the PK and PD particularities of the critically ill patient require a multidisciplinary approach in which knowledge of clinical pharmacology is essential. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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Open AccessReview

Oral Papillomatosis: Its Relation with Human Papilloma Virus Infection and Local Immunity—An Update

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Elena Cristina Andrei

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Ileana Monica Baniță

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Maria Cristina Munteanu

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Cristina Jana Busuioc

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Garofița Olivia Mateescu

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Ramona Denise Mălin

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Cătălina Gabriela Pisoschi

Medicina 2022, 58(8), 1103; https://doi.org/10.3390/medicina58081103 - 15 Aug 2022

Cited by 1 | Viewed by 2265

Abstract

Oral papilloma lesions may appear as a result of HPV infection, or not, and only special molecular methods could differentiate them. Low-risk and high-risk HPV types could induce oral HPV papillomatosis with different natural evolution, clearance and persistence mechanisms. The pathogenic mechanisms are [...] Read more.

Oral papilloma lesions may appear as a result of HPV infection, or not, and only special molecular methods could differentiate them. Low-risk and high-risk HPV types could induce oral HPV papillomatosis with different natural evolution, clearance and persistence mechanisms. The pathogenic mechanisms are based on the crosstalk between the oral epithelial and immune cells and this very efficient virus. HPV acts as a direct inducer in the process of transforming a benign lesion into a malignant one, the cancerization process being also debated in this paper. According to the degree of malignity, three types of papillomatous lesions can be described in the oral cavity: benign lesions, potential malign disorders and malignant lesions. The precise molecular diagnostic is important to identify the presence of various virus types and also the virus products responsible for its oncogenicity. An accurate diagnostic of oral papilloma can be established through a good knowledge of etiological and epidemiological factors, clinical examination and laboratory tests. This review intends to update the pathogenic mechanisms driving the macroscopic and histological features of oral papillomatosis having HPV infection as the main etiological factor, focusing on its interreference in the local immunity. In the absence of an accurate molecular diagnostic and knowledge of local immunological conditions, the therapeutic strategy could be difficult to decide. Full article

(This article belongs to the Special Issue Environmental, Metabolic and Drug-Induced Stress Pathology – Diagnosis, Pharmacokinetics, Pharmacodynamics, and Modern Therapeutic Approaches)

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