- Measurements and correlations in solution-state for charge transfer products caused from the 1:2 complexation of TCNE acceptor with several important drugs. [Journal Article]
- SASpectrochim Acta A Mol Biomol Spectrosc 2018 Dec 05; 211:166-177
- In our previous work, we highlighted the thermodynamic and spectroscopic characteristics of the 1:1 charge transfer (CT) complexation of TCNE acceptor with various medically important drugs. Continui...
In our previous work, we highlighted the thermodynamic and spectroscopic characteristics of the 1:1 charge transfer (CT) complexation of TCNE acceptor with various medically important drugs. Continuing that work, we further examine drugs that react with the TCNE acceptor via a 1:2 interaction. The examined drugs are atenolol, quinidine, cimetidine, reserpine, and levofloxacin. We aimed through this study to: i) make the spectrophotometric and thermodynamic data of the examined drugs, both initially and when reacted via a 1:2 M ratio with the TCNE acceptor, available to use in the determination or detection of these drugs in pharmaceuticals and other environments; and ii) compare the mode of interactions and the spectrophotometric and thermodynamic properties between drugs that react via a 1:1 or 1:2 ratio with the TCNE acceptor. To achieve these aims, the five examined drugs were reacted with TCNE in acetonitrile (MeCN) solvent at room temperature. Several thermodynamic and spectroscopic data were experimentally estimated using the van't Hoff and the Benesi-Hildebrand equations and discussed.
- StatPearls [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Medications that act by sodium channel blockade have a wide variety of clinical applications. Broadly they include Vaughn Williams Class 1 antiarrhythmics, local anesthetics, many medications us...
Medications that act by sodium channel blockade have a wide variety of clinical applications. Broadly they include Vaughn Williams Class 1 antiarrhythmics, local anesthetics, many medications used to treat neuropathic pain (including tricyclic antidepressants (TCA)), anticonvulsants, and cocaine. Specific examples include quinidine and procainamide, (class 1A antiarrhythmics), lidocaine, mexiletine, and phenytoin (class 1B), flecainide and propafenone (class 1C), carbamazepine and lamotrigine. There are many TCAs, but only imipramine and amitriptyline continue to be used in the US today. Insecticides also cause sodium channel blockade. Toxicity of all these substances, whether intentional or accidental, can lead to catastrophic effects including death. It is essential to understand how these medications work, in order to effectively treat their toxicity and side effects.
- Changes in tramadol enantioselective pharmacokinetics and metabolism in rats with experimental diabetes treated or not with insulin. [Journal Article]
- EJEur J Pharm Sci 2018 Nov 28
- This study aimed to investigate the impact of diabetes treated or not with insulin in the enantioselective pharmacokinetics of tramadol (trans-T) and its phase 1 metabolites O-desmethyltramadol (M1) ...
This study aimed to investigate the impact of diabetes treated or not with insulin in the enantioselective pharmacokinetics of tramadol (trans-T) and its phase 1 metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2). The CYP2D inhibitor quinidine was used to simulate the poor metabolizer phenotype. Male Wistar rats were divided into groups: control, quinidine (80-mg/kg quinidine intraperitoneally 4 h before trans-T), diabetic (45-mg/kg STZ i.v.), diabetes + insulin (2 IU/day insulin for 12 days), diabetes + quinidine and diabetes + insulin + quinidine. All animals (n = 6, per sampling time) received 20-mg/kg trans-T orally. The kinetic disposition of trans-T is enantioselective in control with higher AUC of (+)-trans-T than for its antipode. Quinidine reduced AUC ratios (+)-M1/(+)-trans-T and (-)-M1/(-)-trans-T compared to Control. Diabetes increased plasma concentrations of (+)-trans-T, (-)-trans-T, (+)-M1, (-)-M1 and (+)-M2 compared to control, but without changing AUC ratios M1/trans-T or M2/trans-T. Insulin reverted the effect of diabetes only for (-)-trans-T. The simulated diabetes in CYP2D poor metabolizers showed reduced metabolic ratios for M1 enantiomers. In conclusion, diabetes resulted in higher plasma concentrations of the active (+)-trans-T, (-)-trans-T and (+)-M1, suggesting down-regulation of CYP3A and OCT1. The glycemic control of diabetes by insulin reduces partially the impact of diabetes on trans-T pharmacokinetics.
- Effects of Quinine, Quinidine and Chloroquine on Human Muscle Nicotinic Acetylcholine Receptors. [Journal Article]
- FPFront Pharmacol 2018; 9:1339
- The genus Cinchona is known for a range of alkaloids, such as quinine, quinidine, cinchonine, and cinchonidine. Cinchona bark has been used as an antimalarial agent for more than 400 years. Quinine w...
The genus Cinchona is known for a range of alkaloids, such as quinine, quinidine, cinchonine, and cinchonidine. Cinchona bark has been used as an antimalarial agent for more than 400 years. Quinine was first isolated in 1820 and is still acknowledged in the therapy of chloroquine-resistant falciparum malaria; in lower dosage quinine has been used as treatment for leg cramps since the 1940s. Here we report the effects of the quinoline derivatives quinine, quinidine, and chloroquine on human adult and fetal muscle nicotinic acetylcholine receptors (nAChRs). It could be demonstrated that the compounds blocked acetylcholine (ACh)-evoked responses in Xenopus laevis oocytes expressing the adult nAChR composed of αβ𝜀δ subunits in a concentration-dependent manner, with a ranked potency of quinine (IC50 = 1.70 μM), chloroquine (IC50 = 2.22 μM) and quinidine (IC50 = 3.96 μM). At the fetal nAChR composed of αβγδ subunits, the IC50 for quinine was found to be 2.30 μM. The efficacy of the block by quinine was independent of the ACh concentration. Therefore, quinine is proposed to inhibit ACh-evoked currents in a non-competitive manner. The present results add to the pharmacological characterization of muscle nAChRs and indicate that quinine is effective at the muscular nAChRs close to therapeutic blood concentrations required for the therapy and prophylaxis of nocturnal leg cramps, suggesting that the clinically proven efficacy of quinine could be based on targeting nAChRs.
- Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility. [Journal Article]
- EHEur Heart J 2018 Nov 28
- CONCLUSIONS: Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.
- Detection of Cutting Agents in Drug-Positive Seized Exhibits within the United States. [Journal Article]
- JFJ Forensic Sci 2018 Nov 28
- The following report summarizes a study performed on seized drug exhibits collected in two U.S. states to evaluate the presence and identification of cutting agents. Aliquots of seized drug materials...
The following report summarizes a study performed on seized drug exhibits collected in two U.S. states to evaluate the presence and identification of cutting agents. Aliquots of seized drug materials from Kentucky (n = 200) and Vermont (n = 315) were prepared using a dilute-and-shoot procedure. Initial analysis was performed using gas chromatography-mass spectrometry (GC-MS) followed by analysis using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF). Active compounds detected overall included caffeine (31.0%), quinine/quinidine (24.7%), levamisole (11.6%), acetaminophen, (8.2%) and procaine (8.2%). These compounds were found with several drugs of abuse, such as heroin, fentanyl, methamphetamine, and cocaine. This novel information about cutting agents used to dilute or alter drugs of abuse is important to criminal investigations and in the management of acute intoxications at health centers. However, common methodologies for analysis and standard reporting practices frequently do not include cutting agents, resulting in lacking or inadequate information regarding prevalence of these substances.
- A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome. [Journal Article]
- CPCell Physiol Biochem 2018 Nov 27; 51(3):1301-1312
- CONCLUSIONS: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation.
- The Fever Tree: from Malaria to Neurological Diseases. [Review]
- TToxins (Basel) 2018 Nov 23; 10(12)
- This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in...
This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives.
- Cardiac Targeting Peptide, a Novel Cardiac Vector: Studies in Bio-Distribution, Imaging Application, and Mechanism of Transduction. [Journal Article]
- BBiomolecules 2018 Nov 14; 8(4)
- Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical applicat...
Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution studies of cyanine5.5-N-Hydroxysuccinimide (Cy5.5) labeled CTP were undertaken in wild-type mice. Cardiac targeting peptide was labeled with Technetium 99m (99mTc) using the chelator hydrazino-nicotinamide (HYNIC), and imaging performed using micro-single photon emission computerized tomography/computerized tomography (SPECT/CT). Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMCs) were incubated with dual-labeled CTP, and imaged using confocal microscopy. TriCEPs technology was utilized to study the mechanism of transduction. Bio-distribution studies showed peak uptake of CTP at 15 min. 99mTc-HYNIC-CTP showed heart-specific uptake. Robust transduction of beating human iPSC-derived CMCs was seen. TriCEPs experiments revealed five candidate binding partners for CTP, with Kcnh5 being felt to be the most likely candidate as it showed a trend towards being competed out by siRNA knockdown. Transduction efficiency was enhanced by increasing extracellular potassium concentration, and with Quinidine, a Kcnh5 inhibitor, that blocks the channel in an open position. We demonstrate that CTP transduces the normal heart as early as 15 min. 99mTc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99mTc Sestamibi. Cardiac targeting peptide's transduction ability is not species limited and has human applicability. Cardiac targeting peptide appears to utilize Kcnh5 to gain cell entry, a phenomenon that is affected by pre-treatment with Quinidine and changes in potassium levels.
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- Probable drug-drug interaction between dabigatran and quinidine resulting in thrombin time rebound despite multiple idarucizumab doses. [Journal Article]
- BCBlood Coagul Fibrinolysis 2018 Nov 13
- : Dabigatran is a direct thrombin inhibitor that was approved as an alternative to warfarin because it offers the benefit of predictable pharmacokinetic properties, favorable safety profile and ease ...
: Dabigatran is a direct thrombin inhibitor that was approved as an alternative to warfarin because it offers the benefit of predictable pharmacokinetic properties, favorable safety profile and ease of administration. Despite the improved safety profile, dabigatran use can lead to bleeding events. The bleeding risk associated with dabigatran is higher in the setting of renal impairment or drug-drug interactions resulting in supratherapeutic serum concentrations. Unfortunately, clinically significant interactions are not always identified by providers, especially in the case of infrequent drug-drug combinations. Dabigatran-related coagulopathy can be effectively reversed by idarucizumab. However, high dabigatran serum concentrations can lead to increased tissue distribution resulting in decreased idarucizumab efficacy and repeat idarucizumab doses may be warranted. This case describes a patient presenting with uncontrolled bleeding due to a significant drug-drug interaction between quinidine and dabigatran resulting in acute kidney injury and persistent coagulopathy despite multiple idarucizumab doses and transfusion measures.