scholarly journals Selective Carboxylesterase Inhibitors for Improving Efficacy, Safety and Rational use of Ester-Containing Drugs

2018 ◽  
Vol 1 (3) ◽  
pp. e00026 ◽  
Author(s):  
N.P. Boltneva ◽  
G.F. Makhaeva ◽  
E.V. Shchegol’kov ◽  
Ya.V. Burgart ◽  
V.I. Saloutin
Keyword(s):  
Clinical Practice ◽  
Drug Therapy ◽  
Side Effects ◽  
Medicinal Chemistry ◽  
The Body ◽  
Toxic Effects ◽  
Selective Inhibitors ◽  
Rational Use ◽  
Key Enzyme

In clinical practice, a large number of prodrugs and active drugs containing an ester, carbamate or amide moiety are used. Carboxylesterase (CaE, EC 3.1.1.1) is the key enzyme of hydrolytic metabolism of such drugs in the body, it largely determines their pharmacokinetics, bioavailability, efficacy and possible toxic effects. Using CaE selective inhibitors as components of combined drug therapy it is possible us to regulate the rate of hydrolytic transformation of ester-containing drugs and opens the possibility of their rational use. The development of effective and selective CaE inhibitors suitable for in vivo application is a new promising approach in medicinal chemistry and pharmacology that allows to improve the efficacy, bioavailability and reduce the side effects of ester-containing drugs.

scholarly journals Potential Toxicity of Iron Oxide Magnetic Nanoparticles: A Review

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3159 ◽  
Author(s):  
Nemi Malhotra ◽  
Jiann-Shing Lee ◽  
Rhenz Alfred D. Liman ◽  
Johnsy Margotte S. Ruallo ◽  
Oliver B. Villaflores ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Iron Oxide ◽  
Magnetic Nanoparticles ◽  
Cell Lines ◽  
Current Knowledge ◽  
Volume Ratio ◽  
The Body ◽  
Toxic Effects ◽  
Iron Oxide Magnetic Nanoparticles

The noteworthy intensification in the development of nanotechnology has led to the development of various types of nanoparticles. The diverse applications of these nanoparticles make them desirable candidate for areas such as drug delivery, coasmetics, medicine, electronics, and contrast agents for magnetic resonance imaging (MRI) and so on. Iron oxide magnetic nanoparticles are a branch of nanoparticles which is specifically being considered as a contrast agent for MRI as well as targeted drug delivery vehicles, angiogenic therapy and chemotherapy as small size gives them advantage to travel intravascular or intracavity actively for drug delivery. Besides the mentioned advantages, the toxicity of the iron oxide magnetic nanoparticles is still less explored. For in vivo applications magnetic nanoparticles should be nontoxic and compatible with the body fluids. These particles tend to degrade in the body hence there is a need to understand the toxicity of the particles as whole and degraded products interacting within the body. Some nanoparticles have demonstrated toxic effects such inflammation, ulceration, and decreases in growth rate, decline in viability and triggering of neurobehavioral alterations in plants and cell lines as well as in animal models. The cause of nanoparticles’ toxicity is attributed to their specific characteristics of great surface to volume ratio, chemical composition, size, and dosage, retention in body, immunogenicity, organ specific toxicity, breakdown and elimination from the body. In the current review paper, we aim to sum up the current knowledge on the toxic effects of different magnetic nanoparticles on cell lines, marine organisms and rodents. We believe that the comprehensive data can provide significant study parameters and recent developments in the field. Thereafter, collecting profound knowledge on the background of the subject matter, will contribute to drive research in this field in a new sustainable direction.

The new target therapy to prevent weight gain associated to atypical antipsychotics: PKCβ

2017 ◽  
Vol 41 (S1) ◽  
pp. S370-S371
Author(s):  
C. Pavan ◽  
A. Rimessi ◽  
B. Zavan ◽  
V. Vindigni ◽  
P. Pinton
Keyword(s):  
Clinical Practice ◽  
Weight Gain ◽  
Side Effects ◽  
Cell Biology ◽  
Target Therapy ◽  
Premature Death ◽  
Preclinical Model ◽  
Psychomotor Tests

Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Clozapine is the most effective medication for treatment-resistant schizophrenia, in controlling aggression and suicidal behavior in psychosis. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, weight gain and metabolic side effects are well known in clinical practice exposing the patient to a greater risk of cardiovascular disorders, premature death, as well as psychosocial issues leading to non-adherence. The mechanisms underlying this pharmacologically activated disorders are still controversial. Based on our in vitro results, we have characterized in vivo the effects of the selective PKCβ inhibitor, Ruboxistaurin (LY-333531) on a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry and psychomotor tests have been performed on wild type and PKCβ (-/-) mutant mice to investigate the contribution of endogenous PKCβ and its pharmacological inhibitor on the neuroleptic effect of clozapine. Lastly, we also shed light on a novel aspect of the mechanism underlying of clozapine-induced weight gain, demonstrating that the clozapine-dependent PKCβ activation promote the inhibition of the lipid droplet-selective autophagy process, opening the way to new therapeutic intervention approach.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Hyperammonemia in clinical practice: analysis of own clinical observations

2020 ◽  
Vol 4 (38) ◽  
pp. 23-26
Author(s):  
Z. M. Galeeva ◽  
O. F. Galiullin ◽  
E. G. Yeziukova ◽  
R. G. Tukhbatullina
Keyword(s):  
Clinical Practice ◽  
Drug Therapy ◽  
Human Body ◽  
Scientific Data ◽  
The Body ◽  
Mechanism Of Formation ◽  
Practice Analysis ◽  
Clinical Observations ◽  
The Brain

The article presents scientific data on the role of ammonia in the human body, examines in detail the mechanism of formation and utilization of ammonia in the body. The questions of etiology and separate forms of pathogenesis of hyperammonemia, and its influence on the processes of fibrosis in the liver and the role of stellate liver cells in it are highlighted separately. The data on the influence of hyperammonemia on cognitive functions of the brain with the development of encephalopathy are presented, which is of great importance in clinical practice, during medical examination. The data of own observations are given, the questions of drug therapy are highlighted.

scholarly journals Nanomaterial-mediated autophagy: coexisting hazard and health benefits in biomedicine

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiaoli Feng ◽  
Yaqing Zhang ◽  
Chao Zhang ◽  
Xuan Lai ◽  
Yanli Zhang ◽  
...  
Keyword(s):  
Biological Effects ◽  
Relevant Literature ◽  
Health Benefits ◽  
The Body ◽  
Toxic Effects ◽  
Main Body ◽  
Administration Routes ◽  
Biosafety Evaluation

Abstract Background Widespread biomedical applications of nanomaterials (NMs) bring about increased human exposure risk due to their unique physicochemical properties. Autophagy, which is of great importance for regulating the physiological or pathological activities of the body, has been reported to play a key role in NM-driven biological effects both in vivo and in vitro. The coexisting hazard and health benefits of NM-mediated autophagy in biomedicine are nonnegligible and require our particular concerns. Main body We collected research on the toxic effects related to NM-mediated autophagy both in vivo and in vitro. Generally, NMs can be delivered into animal models through different administration routes, or internalized by cells through different uptake pathways, exerting varying degrees of damage in tissues, organs, cells, and organelles, eventually being deposited in or excreted from the body. In addition, other biological effects of NMs, such as oxidative stress, inflammation, necroptosis, pyroptosis, and ferroptosis, have been associated with autophagy and cooperate to regulate body activities. We therefore highlight that NM-mediated autophagy serves as a double-edged sword, which could be utilized in the treatment of certain diseases related to autophagy dysfunction, such as cancer, neurodegenerative disease, and cardiovascular disease. Challenges and suggestions for further investigations of NM-mediated autophagy are proposed with the purpose to improve their biosafety evaluation and facilitate their wide application. Databases such as PubMed and Web of Science were utilized to search for relevant literature, which included all published, Epub ahead of print, in-process, and non-indexed citations. Conclusion In this review, we focus on the dual effect of NM-mediated autophagy in the biomedical field. It has become a trend to use the benefits of NM-mediated autophagy to treat clinical diseases such as cancer and neurodegenerative diseases. Understanding the regulatory mechanism of NM-mediated autophagy in biomedicine is also helpful for reducing the toxic effects of NMs as much as possible.

scholarly journals TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body

2020 ◽  
Author(s):  
Claudia Goettsch ◽  
Agnieszka Strzelecka-Kiliszek ◽  
Laurence Bessueille ◽  
Thibaut Quillard ◽  
Laura Mechtouff ◽  
...  
Keyword(s):  
Pyridoxal Phosphate ◽  
The Body ◽  
Aortic Valves ◽  
Full Spectrum ◽  
Promising Target ◽  
Key Enzyme ◽  
Pleiotropic Functions ◽  
Dental Mineralization

Abstract Cardiovascular calcification (CVC) is associated with increased morbidity and mortality. It develops in several diseases and locations, such as in the tunica intima in atherosclerosis plaques, in the tunica media in type 2 diabetes and chronic kidney disease, and in aortic valves. In spite of the wide occurrence of CVC and its detrimental effects on cardiovascular diseases (CVD), no treatment is yet available. Most of CVC involve mechanisms similar to those occurring during endochondral and/or intramembranous ossification. Logically, since tissue-nonspecific alkaline phosphatase (TNAP) is the key-enzyme responsible for skeletal/dental mineralization, it is a promising target to limit CVC. Tools have recently been developed to inhibit its activity and preclinical studies conducted in animal models of vascular calcification already provided promising results. Nevertheless, as its name indicates, TNAP is ubiquitous and recent data indicate that it dephosphorylates different substrates in vivo to participate in other important physiological functions besides mineralization. For instance, TNAP is involved in the metabolism of pyridoxal phosphate and the production of neurotransmitters. TNAP has also been described as an anti-inflammatory enzyme able to dephosphorylate adenosine nucleotides and lipopolysaccharide. A better understanding of the full spectrum of TNAP’s functions is needed to better characterize the effects of TNAP inhibition in diseases associated with CVC. In this review, after a brief description of the different types of CVC, we describe the newly uncovered additional functions of TNAP and discuss the expected consequences of its systemic inhibition in vivo.

scholarly journals Clinical Delivery of Therapeutic Agents Based on Metals

1997 ◽  
Vol 4 (3) ◽  
pp. 133-135
Author(s):  
John Fox
Keyword(s):  
Clinical Practice ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
The Body ◽  
Toxic Effects ◽  
Metal Chemistry

Metals have been used in clinical practice for hundreds of years and for a variety of indications. Although potent agents whose activity may be adapted by manipulation of their chemistry and that of associated ligands, their use has been limited by toxic effects. There is now a burgeoning series of delivery technologies available which may be adapted to the administration of metal based drugs. Together with greater understanding of metal chemistry and their mechanisms of action in disease processes, there is an opportunity to increase the use of metals in medicine by targeting their action more effectively to the therapeutic site and/or protecting the body from toxic effects.

New Concepts in Phototherapy: Photoisomerization of Bilirubin IXα and Potential Toxic Effects of Light

PEDIATRICS ◽  
1980 ◽  
Vol 65 (4) ◽  
pp. 740-750 ◽  
Author(s):  
Arnold N. Cohen ◽  
J. Donald Ostrow
Keyword(s):  
Side Effects ◽  
Neonatal Jaundice ◽  
Toxic Effects ◽  
Minor Role ◽  
Major Mechanism ◽  
New Information ◽  
New Concepts ◽  
A Minor

New information is summarized, indicating that configurational photoisomerization of bilirubin at the 5 and 15 carbon bridges is the major mechanism of bilirubin photocatabolism in vivo, and that singlet oxygen photooxidation plays only a minor role. The literature is reviewed concerning potentially damaging photodynamic reactions that are observed in vitro with vitamins, proteins, lipids, and nucleic acids, and their possible relationship to the limited number of toxic side-effects that have been detected with clinical phototherapy of neonatal jaundice. Secondary toxic effects, mediated by bilirubin photoderivatives or by retina-neuroendocrine pathways are also considered. Areas requiring further investigation are delineated.

scholarly journals The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2682 ◽  
Author(s):  
Miguel Muñoz ◽  
Rafael Coveñas
Keyword(s):  
Clinical Practice ◽  
Side Effects ◽  
Cancer Patients ◽  
Antitumor Agent ◽  
Antitumor Action ◽  
Tumor Mass ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

Neurokinin-1 receptor (NK-1R) antagonists exert antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exert multiple actions against cancer: antiproliferative and anti-Warburg effects and apoptotic, anti-angiogenic and antimetastatic effects. These multiple effects have been shown for a broad spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as an antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed, as is the possible link, through the substance P (SP)/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant, and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

Medicinal Chemistry and Therapeutic Potential of Agonists, Antagonists and Allosteric Modulators of A1 Adenosine Receptor: Current Status and Perspectives

2019 ◽  
Vol 25 (25) ◽  
pp. 2697-2715 ◽  
Author(s):  
Pran Kishore Deb ◽  
Satyendra Deka ◽  
Pobitra Borah ◽  
Sara N. Abed ◽  
Karl-Norbert Klotz
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Medicinal Chemistry ◽  
Therapeutic Potential ◽  
The Body ◽  
Current Status ◽  
Target Tissue ◽  
Allosteric Modulators ◽  
Partial Agonists ◽  
Wide Range

Adenosine is a purine nucleoside, responsible for the regulation of a wide range of physiological and pathophysiological conditions by binding with four G-protein-coupled receptors (GPCRs), namely A1, A2A, A2B and A3 adenosine receptors (ARs). In particular, A1 AR is ubiquitously present, mediating a variety of physiological processes throughout the body, thus represents a promising drug target for the management of various pathological conditions. Agonists of A1 AR are found to be useful for the treatment of atrial arrhythmia, angina, type-2 diabetes, glaucoma, neuropathic pain, epilepsy, depression and Huntington’s disease, whereas antagonists are being investigated for the treatment of diuresis, congestive heart failure, asthma, COPD, anxiety and dementia. However, treatment with full A1 AR agonists has been associated with numerous challenges like cardiovascular side effects, off-target activation as well as desensitization of A1 AR leading to tachyphylaxis. In this regard, partial agonists of A1 AR have been found to be beneficial in enhancing insulin sensitivity and subsequently reducing blood glucose level, while avoiding severe CVS side effects and tachyphylaxis. Allosteric enhancer of A1 AR is found to be potent for the treatment of neuropathic pain, culminating the side effects related to off-target tissue activation of A1 AR. This review provides an overview of the medicinal chemistry and therapeutic potential of various agonists/partial agonists, antagonists and allosteric modulators of A1 AR, with a particular emphasis on their current status and future perspectives in clinical settings.

HSF1 Promotes the Development of Endometriosis by Up-regulating PFKFB3 Expression

2020 ◽  
Author(s):  
yixin wang ◽  
jing xiu ◽  
tingting yang ◽  
chune ren ◽  
zhenhai yu
Keyword(s):  
Animal Studies ◽  
Lactic Acid Production ◽  
Glucose Consumption ◽  
The Body ◽  
Childbearing Age ◽  
Real Time Quantitative Pcr ◽  
Glucose Levels ◽  
Key Enzyme

Abstract BackgroundEndometriosis is a chronic hormonal inflammatory disease characterized by the presence of endometrial tissue (glands and stroma) outside the uterus. Endometriosis seriously affects the physical health of women of childbearing age, often causes infertility, and affects the body and mind of patients and their families.MethodsWe examined the effect of HSF1 on endometriosis through cell count, scratch and clone formation experiments. We used real-time quantitative PCR and western blotting to detect the effect of HSF1 on mRNA and protein of endometriosis cells. Collect the cell culture medium and Glucose levels and lactate levels were determined using a glucose (GO) assay kit and a lactate assay kit. Furthermore, we established a mouse model of endometriosis, and the effect of HSF1 on endometriosis was observed by inhibiting HSF1 with KRIBB11 in the mice.ResultsHSF1 is highly expressed in endometriosis and plays an indispensable role in endometriosis development in both cell and animal studies. We found that HSF1 promotes endometriosis development and glucose consumption and lactic acid production. Further research showed that HSF1 functions in endometriosis by up-regulating PFKFB3, a key enzyme in glycolysis. And the HSF1 inhibitor KRIBB11 can abrogate all of the above experimental effects both in vivo and in vitro. ConclusionsOur study shows that HSF1 plays a significant role in the occurrence and development of endometriosis, which may become a new target for the treatment of endometriosis and provide a new idea for the clinical treatment of endometriosis.

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