-
Profiles of Drug Substances,... 2016Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of... (Review)
Review
Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of the drug: nomenclature, formulae, chemical structure, elemental composition, and appearance. The uses and applications of dacarbazine and the methods that were used for its preparation are reported. The methods which were used for the physical characterization of the drug are ionization constant, solubility, X-ray powder diffraction pattern, crystal structure, melting point, and differential scanning calorimetry. The profile contains the spectra of the drug: ultraviolet spectrum, vibrational spectrum, nuclear magnetic resonance spectra, and mass spectrum. The compendial methods of analysis for dacarbazine include the United States Pharmacopeia methods, British Pharmacopeia methods, and International Pharmacopeia methods. Other reported methods that are used for the analysis of the drug are high-performance liquid chromatography, high-performance liquid chromatography-mass spectrometry, and polarography. Metabolism, pharmacokinetics, and stability studies on dacarbazine are also included. Reviews of some analytical methods and physicochemical properties of the drug as well as the most important enzymes that are involved in the prodrug activation are provided. Sixty-four references are listed at the end of this monograph.
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Dacarbazine; Humans
PubMed: 26940170
DOI: 10.1016/bs.podrm.2015.12.002 -
Frontiers in Physiology 2018Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with... (Review)
Review
Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na) in diabetic cardiomyopathy and provides unique data on the linkage between Na flux and energy metabolism, studied with non-invasive Na, and P-NMR spectroscopy, polarography, and mass spectroscopy. Na NMR studies allow determination of the intracellular and extracellular Na pools by splitting the total Na peak into two resonances after the addition of a shift reagent to the perfusate. Using this technology, we found that intracellular Na is approximately two times higher in diabetic cardiomyocytes than in control possibly due to combined changes in the activity of Na-K pump, Na/H exchanger 1 (NHE1) and Na-glucose cotransporter. We hypothesized that the increase in Na activates the mitochondrial membrane Na/Ca exchanger, which leads to a loss of intramitochondrial Ca, with a subsequent alteration in mitochondrial bioenergetics and function. Using isolated mitochondria, we showed that the addition of Na (1-10 mM) led to a dose-dependent decrease in oxidative phosphorylation and that this effect was reversed by providing extramitochondrial Ca or by inhibiting the mitochondrial Na/Ca exchanger with diltiazem. Similar experiments with P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na (3-30 mM) led to significantly decreased ATP levels and that this effect was stronger in diabetic rats. These data suggest that in diabetic cardiomyocytes, increased Na leads to abnormalities in oxidative phosphorylation and a subsequent decrease in ATP levels. In support of these data, using P-NMR, we showed that the baseline β-ATP and phosphocreatine (PCr) were lower in diabetic cardiomyocytes than in control, suggesting that diabetic cardiomyocytes have depressed bioenergetic function. Thus, both altered intracellular Na levels and bioenergetics and their interactions may significantly contribute to the pathology of diabetic cardiomyopathy.
PubMed: 30405433
DOI: 10.3389/fphys.2018.01473 -
Methods in Molecular Biology (Clifton,... 2022Mitochondrial energy production is crucial for normal daily activities and maintenance of life. Herein, the logic and execution of two main classes of measurements are...
Mitochondrial energy production is crucial for normal daily activities and maintenance of life. Herein, the logic and execution of two main classes of measurements are outlined to delineate mitochondrial function: ATP production and oxygen consumption. Aerobic ATP production is quantified by phosphorus magnetic resonance spectroscopy (PMRS) in vivo in both human subjects and animal models using the same protocols and maintaining the same primary assumptions. Mitochondrial oxygen consumption is quantified by oxygen polarography and applied in isolated mitochondria, cultured cells, and permeabilized fibers derived from human or animal tissue biopsies. Traditionally, mitochondrial functional measures focus on maximal oxidative capacity-a flux rate that is rarely, if ever, observed outside of experimental conditions. Perhaps more physiologically relevant, both measurement classes herein focus on one principal design paradigm; submaximal mitochondrial fluxes generated by graded levels of ADP to map the function for ADP sensitivity. We propose this function defines the bioenergetic role that mitochondria fill within the myoplasm to sense and match ATP demands. Any deficit in this vital role for ATP homeostasis leads to symptoms often seen in cardiovascular and cardiopulmonary diseases, diabetes, and metabolic syndrome.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Energy Metabolism; Humans; Mitochondria; Oxidative Phosphorylation; Oxygen Consumption; Polarography
PubMed: 35771441
DOI: 10.1007/978-1-0716-2309-1_10 -
Journal of Pharmaceutical Sciences Jun 2023Nifurtimox is a nitroheterocyclic drug employed for treatment of trypanosomiases (Chagas disease and West African sleeping sickness); its use for certain cancers has... (Review)
Review
Nifurtimox is a nitroheterocyclic drug employed for treatment of trypanosomiases (Chagas disease and West African sleeping sickness); its use for certain cancers has also been assessed. Despite having been in the market for over 50 years, knowledge of nifurtimox is still fragmentary and incomplete. Relevant aspects of the chemistry and biology of nifurtimox are reviewed to summarize the current knowledge of this drug. These comprise its chemical synthesis and the preparation of some analogues, as well as its chemical degradation. Selected physical data and physicochemical properties are also listed, along with different approaches toward the analytical characterization of the drug, including electrochemical (polarography, cyclic voltammetry), spectroscopic (ultraviolet-visible, nuclear magnetic resonance, electron spin resonance), and single crystal X-ray diffractometry. The array of polarographic, ultraviolet-visible spectroscopic, and chromatographic methods available for the analytical determination of nifurtimox (in bulk drug, pharmaceutical formulations, and biological samples), are also presented and discussed, along with chiral chromatographic and electrophoretic alternatives for the separation of the enantiomers of the drug. Aspects of the drug likeliness of nifurtimox, its classification in the Biopharmaceutical Classification System, and available pharmaceutical formulations are detailed, whereas pharmacological, chemical, and biological aspects of its metabolism and disposition are discussed.
Topics: Humans; Nifurtimox; Chagas Disease; Pharmacy; Pharmaceutical Preparations
PubMed: 36822273
DOI: 10.1016/j.xphs.2023.02.015 -
Journal of Biological Inorganic... Mar 2020Oxygen affinity is an important property of metalloproteins that helps elucidate their reactivity profile and mechanism. Heretofore, oxygen affinity values were... (Review)
Review
Oxygen affinity is an important property of metalloproteins that helps elucidate their reactivity profile and mechanism. Heretofore, oxygen affinity values were determined either using flash photolysis and polarography techniques that require expensive instrumentation, or using oxygen titration methods which are erroneous at low nanomolar and at high millimolar oxygen concentrations. Here, we describe an inexpensive, easy-to-setup, and a one-pot method for oxygen affinity measurements that uses the enzyme chlorite dismutase (Cld) as a precise in situ oxygen source. Using this method, we measure thermodynamic and kinetic oxygen affinities (K and K) of different classes of heme and non-heme metalloproteins involved in oxygen transport, sensing, and catalysis. The method enables oxygen affinity measurements over a wide concentration range from 10 nM to 5 mM which is unattainable by simply diluting oxygen-saturated buffers. In turn, we were able to precisely measure oxygen affinities of a model set of eight different metalloproteins with affinities ranging from 48 ± 3 nM to 1.18 ± 0.03 mM. Overall, the Cld method is easy and inexpensive to set up, requires significantly lower quantities of protein, enables precise oxygen affinity measurements, and is applicable for proteins exhibiting nanomolar-to-millimolar affinity values.
Topics: Kinetics; Models, Molecular; Oxidoreductases; Oxygen; Thermodynamics
PubMed: 31897725
DOI: 10.1007/s00775-019-01750-6 -
International Journal of Molecular... Jul 2022Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical... (Review)
Review
Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and amino acid levels, as well as urine organic acids. Recently, hormone-like cytokines, such as fibroblast growth factor-21 (FGF-21), have also been used as a means of assessing evidence of MRC dysfunction, although work is still required to confirm their diagnostic utility and reliability. The assessment of evidence of oxidative stress may also be an important parameter to consider in the diagnosis of MRC function in view of its association with mitochondrial dysfunction. At present, due to the lack of reliable biomarkers available for assessing evidence of MRC dysfunction, the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ is considered the 'Gold Standard' biochemical method to provide evidence of MRC dysfunction. The purpose of this review is to outline a number of biochemical methods that may provide diagnostic evidence of MRC dysfunction in patients.
Topics: Electron Transport; Humans; Mitochondrial Diseases; Mitochondrial Membranes; Pyruvic Acid; Reproducibility of Results
PubMed: 35806492
DOI: 10.3390/ijms23137487 -
Medicina (Kaunas, Lithuania) Mar 2022Background and Objectives: Due to the nutritional and behavioral patterns of children, their teeth can be a good indicator of heavy metal uptake from over the years. To...
Background and Objectives: Due to the nutritional and behavioral patterns of children, their teeth can be a good indicator of heavy metal uptake from over the years. To determine the amount of Zn, Cu, Cd, and Pb accumulated in the body, primary teeth of children in Zanjan, Iran, were examined with a polarography device. Materials and Methods: Samples were collected from dentistry clinics of Zanjan, Iran, and were prepared for acid digestion, and then were analyzed by a polarography device for determining the concentration of lead, copper, zinc, and cadmium. Results: Data were analyzed by a t-independent test to compare different groups (p < 0.05). Based on the results obtained from this study, the mean concentrations of zinc, lead, copper, and cadmium were 245, 7.66, 5.33, and 0.0879 µg/g, respectively, which shows that the amount of each of the four elements was more than the amounts that have been reported for different countries. The results showed no significant difference between age, tooth type, and jaw groups. Conclusions: We conclude that primary teeth are an important biological indicator to evaluate the concentration of heavy elements in the human body. The high concentrations of these elements in the primary teeth analyzed in this study could be attributed to the high concentrations of these elements in the environment of Zanjan.
Topics: Cadmium; Child; Dentistry; Humans; Metals, Heavy; Polarography; Zinc
PubMed: 35334624
DOI: 10.3390/medicina58030448 -
Angewandte Chemie (International Ed. in... Jul 2015Oxygen monitoring has been a topic of exhaustive study given its central role in the biochemistry of life. The ability to quantify the physiological distribution and... (Review)
Review
Oxygen monitoring has been a topic of exhaustive study given its central role in the biochemistry of life. The ability to quantify the physiological distribution and real-time dynamics of oxygen from sub-cellular to macroscopic levels is required to fully understand the mechanisms associated with both normal physiology and disease states. This Review will present the most significant recent advances in the development of oxygen-sensing materials and techniques, including polarographic, nuclear medicine, magnetic resonance, and optical approaches, that can be applied specifically for the real-time monitoring of oxygen dynamics in cellular and tissue environments. As some of the most exciting recent advances in synthetic methods and biomedical applications have been in the field of optical oxygen sensors, a major focus will be on the development of these toolkits.
Topics: Animals; Biosensing Techniques; Diagnostic Techniques, Radioisotope; Hemoglobins; Humans; Luminescent Measurements; Magnetic Resonance Spectroscopy; Oxygen; Polarography
PubMed: 26084034
DOI: 10.1002/anie.201410646 -
PloS One 2023Glycemic variability has been suggested as a risk factor for diabetes complications but the precise deleterious mechanisms remain poorly understood. Since mitochondria...
AIMS
Glycemic variability has been suggested as a risk factor for diabetes complications but the precise deleterious mechanisms remain poorly understood. Since mitochondria are the main source of energy in heart and cardiovascular diseases remain the first cause of death in patients with diabetes, the aim of the study was to evaluate the impact of glucose swings on mitochondrial functions in the cardiomyocyte cell line HL-1.
METHODS
HL-1 cells were exposed to low (LG, 2.8 mmol/l), normal (NG, 5.5 mmol/l), high (HG, 25 mmol/l) or intermittent high glucose (IHG, swing between low and high) every 2h during 12h (short-time treatment) or every 12h during 72h (long-time treatment). Anaerobic catabolism of glucose was evaluated by measuring glucose consumption and lactate production, oxidative phosphorylation was evaluated by polarography and ATP measurement, mitochondrial superoxide anions and the mitochondrial membrane potential (MMP) were analysed using fluorescent probes, and the protein oxidation was measured by oxyblot.
RESULTS
IHG and HG increased glucose consumption and lactate production compared to LG and NG but without any difference between short- and long-time treatments. After 72h and unlike to LG, NG and HG, we didn't observe any increase of the mitochondrial respiration in the presence of succinate upon IHG treatment. IHG, and to a lesser extent HG, promoted a time-dependent decrease of the mitochondrial membrane potential compared to LG and NG treatments. HG and IHG also increased superoxide anion production compared to LG and NG both at 12 and 72h but with a higher increase for IHG at 72h. At last, both HG and IHG stimulated protein oxidation at 72h compared to LG and NG treatments.
CONCLUSIONS
Our results demonstrated that exposure of HL-1 cells to glucose swings promoted time-dependent mitochondrial dysfunctions suggesting a deleterious effect of such condition in patients with diabetes that could contribute to diabetic cardiomyopathy.
Topics: Humans; Myocytes, Cardiac; Mitochondria; Cell Line; Glucose; Lactic Acid
PubMed: 37733770
DOI: 10.1371/journal.pone.0289475 -
Methods in Molecular Biology (Clifton,... 2021Platelet mitochondria can be used in the study of mitochondrial dysfunction in various complex diseases and can help in finding biological markers for diagnosing the...
Platelet mitochondria can be used in the study of mitochondrial dysfunction in various complex diseases and can help in finding biological markers for diagnosing the disease, monitoring its course and the effects of treatment. The aim of this chapter was to describe in detail the method of measuring mitochondrial respiration in platelets using high-resolution respirometry. The described method was successfully used for the study of mitochondrial dysfunction in neuropsychiatric diseases.
Topics: Blood Platelets; Cell Respiration; Humans; Mitochondria; Polarography
PubMed: 34080156
DOI: 10.1007/978-1-0716-1270-5_16