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Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
The Medical Letter on Drugs and... May 2024
Review
Topics: Humans; Hypertension; Antihypertensive Agents; Blood Pressure
PubMed: 38771738
DOI: 10.58347/tml.2024.1703a -
Heliyon May 2024- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of...
PURPOSE
- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats.
METHODS
- The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.
RESULTS
-MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated.
CONCLUSION
- At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.
PubMed: 38726128
DOI: 10.1016/j.heliyon.2024.e29979 -
The Science of the Total Environment Jun 2024Pindolol (PIN) is a commonly used β-blocker drug and has been frequently detected in various natural waters. Comprehensive understanding of its environmental...
Pindolol (PIN) is a commonly used β-blocker drug and has been frequently detected in various natural waters. Comprehensive understanding of its environmental photochemical transformation is necessary to assess its environmental risk. In this study, the photodegradation kinetics and mechanisms of PIN in both freshwater and coastal water were investigated for the first time. The photodegradation experiments were carried out by steady-state photochemical experiment under simulated sunlight irradiation. The results showed that the photodegradation rate of PIN in the freshwater of the Pearl River estuary was significantly faster than that in its downstream coastal water. In river water, PIN can undergo both direct photolysis and indirect photolysis induced by riverine dissolved organic matter (DOM) mainly through excited triplet-state of DOM and singlet oxygen, while direct photolysis dominated its degradation in coastal water. The promotion effect was found to be much greater for Suwannee River Natural Organic Matter (SRNOM) than that of the sampled riverine DOM, due to its high steady-state concentrations of reactive species. Interestingly, coastal DOM in northern and southern China were found to have similar promotion effects on PIN photodegradation for the first time, but both less than that of riverine DOM. A total of seven degradation products of PIN resulting from hydroxylation, hydrogen abstraction and cleavage of ether bond were identified. Biological toxicity of one products were found to be higher than that of PIN. These results are of significance for knowing the persistence and ecological risk of PIN in natural waters.
PubMed: 38582123
DOI: 10.1016/j.scitotenv.2024.172236 -
Neurobiology of Disease May 2024Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial.
BACKGROUND
Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial.
OBJECTIVES
We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels.
METHODS
This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4.
RESULTS
PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I.
CONCLUSIONS
Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.
Topics: Humans; Parkinson Disease; REM Sleep Behavior Disorder; Surveys and Questionnaires; Pindolol
PubMed: 38479482
DOI: 10.1016/j.nbd.2024.106472 -
The Analyst Apr 2024This paper describes the electrochemical behavior of five β-blockers at the polarized liquid-liquid interface formed between aqueous solution (sodium chloride solution...
This paper describes the electrochemical behavior of five β-blockers at the polarized liquid-liquid interface formed between aqueous solution (sodium chloride solution or Britton-Robinson buffers) and bis(triphenylphosphoranylidene)ammonium tetrakis(4-chlorophenyl)borate (BTPPATPBCl) dissolved in 1,2-dichloroethane (the organic phase). All measurements reported in this work were conducted using cyclic voltammetry (CV). The effects of the concentration of analytes, the pH of the aqueous phase, and applied electrochemical parameters on the analytical performance of the studied system are studied and discussed. The linear dynamic ranges (LDRs) of the studied β-blockers were in the range of 5-200 μmol L and the lowest limit of detection (LOD) value was determined for pindolol (LOD = 1.96 μM μmol L). The highest LOD value was 4.96 μmol L found for nebivolol. In addition, physicochemical parameters such as the formal Galvani potential difference (Δaqorg), formal Gibbs free energies of the ion transfer reaction (Δaqorg') and partition coefficients (log ') for all studied molecules were determined. The latter were compared and correlated with the available literature values of log . Finally, a standard addition method was used to determine the concentration of nebivolol in pharmaceutical preparations using a platform based on the electrified liquid-liquid interface.
Topics: Nebivolol; Octanols; Pindolol; Water; Borates
PubMed: 38454902
DOI: 10.1039/d3an02051g -
Molecular Pharmaceutics Apr 2024Thermal ablation has been commonly used as an effective treatment for hepatocellular carcinoma; however, peri-necrotic tumor residues after ablation play a significant...
Thermal ablation has been commonly used as an effective treatment for hepatocellular carcinoma; however, peri-necrotic tumor residues after ablation play a significant role in tumor recurrence and poor prognosis. Therefore, developing agents that can effectively target and eliminate residual tumors is critically needed. Necrosis targeting strategies have potential implications for evaluating tumor necrosis areas and treating the surrounding residual tumors. To address this issue, we have developed a biodegradable nanoparticle with necrosis avidity that is compatible with fluorescence imaging, single photon emission computed tomography (SPECT) imaging, and necrosis targeted radiotherapy. The nanoparticles were synthesized using iodine-131-labeled hypericin (I-Hyp) as the core and amphiphilic copolymer poly(ethylene glycol)--poly(ε-caprolactone) (PEG-PCL) as the shell. The developed nanoparticle, PNP@(I-Hyp), has a uniform spherical morphology with a size of 33.07 ± 3.94 and 45.93 ± 0.58 nm determined by cryogenic transmission electron microscopy (cryo-TEM) and dynamic light-scattering analysis (polydispersity index = 0.19 ± 0.01), respectively, and having a good stability and blood compatibility . In mouse subcutaneous ablated-residual tumor models, fluorescence and SPECT imaging demonstrated that PNP@(I-Hyp) prominently accumulated in the tumor and was retained for as long as 168 h following intravenous injection. Moreover, analyses showed that PNP@(I-Hyp) mainly gathered in the necrotic zones of subcutaneous tumors and inhibited residual tumors by radiotherapy. In addition, histological examination of harvested organs and hematological analysis demonstrated that intravenous injection of 5 mCi/kg nanoparticles caused no gross abnormalities. This multifunctional nanoparticle, therefore, has necrosis imaging and targeted therapeutic effects on residual tumors after thermal ablation of hepatocellular carcinoma, showing potential for clinical application.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Neoplasm, Residual; Precision Medicine; Liver Neoplasms; Neoplasm Recurrence, Local; Necrosis; Polyethylene Glycols; Tomography, Emission-Computed, Single-Photon; Nanoparticles; Optical Imaging; Lactones; Pindolol
PubMed: 38449426
DOI: 10.1021/acs.molpharmaceut.3c01081 -
Chirality Feb 2024A novel bis-triazolyl bridged β-cyclodextrin was first synthesized by the Click reaction between azido-β-cyclodextrin and 1,6-heptadiyne. Then it was bonded onto...
A novel bis-triazolyl bridged β-cyclodextrin was first synthesized by the Click reaction between azido-β-cyclodextrin and 1,6-heptadiyne. Then it was bonded onto silica gel to obtain a bis-triazolyl bridged β-cyclodextrin-based chiral stationary phase (BCDP). After structure characterization, the HPLC performance of BCDP was systematically evaluated by using different types of compounds as probes. The results showed that BCDP could well separate 18 kinds of achiral aromatic compounds (homologues, positional isomers, etc.) and 35 kinds of chiral drugs or pesticides, such as triazoles (Rs = 1.33-3.15), flavanones (Rs = 1.49-2.62), dansyl amino acids (Rs = 0.96-1.99), and β-blocker drugs (Rs = 0.68-2.78). BCDP could separate a wider range of compounds (53 kinds); especially, some chiral substance pairs that were difficult to be resolved on the ordinary cyclodextrin CSPs, including triazoles containing two chiral carbons (triadimenol, bitertanol, metconazole, and triticonazole), strongly ionized amino acids (acidic Asp, alkalic Arg, and polar Thr) and β-blockers with bulky groups (carvedilol, propranolol, and pindolol). Obviously, the unique synergistic inclusion effect of bridged cyclodextrin with double cavities and the bis-triazole bridging group could provide multiple action sites, such as hydrogen bonding, π-π stacking and acid-base action sites, thus improving its chiral chromatographic performance.
PubMed: 38353340
DOI: 10.1002/chir.23644 -
The Journal of Pharmacology and... Jan 2024The determination of affinity by using functional assays is important in drug discovery because it provides a more relevant estimate of the strength of interaction of a...
The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with Values Distinct From Their Equilibrium Dissociation Constants as -Adrenoceptor Antagonists: Evidence for Functional Affinity.
The determination of affinity by using functional assays is important in drug discovery because it provides a more relevant estimate of the strength of interaction of a ligand to its cognate receptor than radioligand binding. However, empirical evidence for so-called, "functional affinity" is limited. Herein, we determined whether the affinity of carvedilol, a -adrenoceptor antagonist used to treat heart failure that also promotes extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, differed between these two pharmacological activities. Four structurally related -adrenoceptor antagonists (alprenolol, carazolol, pindolol, propranolol) that also activated ERK1/2 were included as comparators to enhance our understanding of how these drugs work in the clinical setting. In HEK293 cells stably expressing the human -adrenoceptor carvedilol and related aryloxypropanolamines were of ERK1/2 phosphorylation with potencies ([A]s) that were than their equilibrium dissociation constants ( s) as -adrenoceptor antagonists. As the [A] of a partial agonist is a good approximation of its , then these data indicated that the affinities of carvedilol and related ligands for these two activities were distinct. Moreover, there was a significant negative rank order correlation between the [A] of each ligand to activate ERK1/2 and their intrinsic activities (i.e., as intrinsic activity for ERK1/2 phosphorylation increased, so did affinity). Genome editing revealed that the transducer that coupled the -adrenoceptor to ERK1/2 phosphorylation in response to carvedilol and other -adrenoceptor antagonists was Gs. Collectively, these data support the concept of "functional affinity" and indicate that the ability of the -adrenoceptor to recruit Gs may influence the affinity of the activating ligand. SIGNIFICANCE STATEMENT: In HEK293 cells overexpressing the human β-adrenoceptor carvedilol and four related aryloxypropanolamines behaved as β-adrenoceptor antagonists partial agonists of ERK1/2 phosphorylation with rank orders of affinity that were distinct. These data imply that carvedilol and other β-blockers can stabilize the β-adrenoceptor in different affinity conformations that are revealed when functionally distinct responses are measured. This is the basis for the pharmacological concept of "functional affinity."
Topics: Humans; Carvedilol; HEK293 Cells; Phosphorylation; Ligands; MAP Kinase Signaling System; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Propanolamines
PubMed: 38129128
DOI: 10.1124/jpet.123.001920 -
BMC Cardiovascular Disorders Sep 2023Older adults with heart failure often experience adverse drug events with high doses of heart failure medications. Recognizing whether a patient is on a high or low dose... (Review)
Review
BACKGROUND
Older adults with heart failure often experience adverse drug events with high doses of heart failure medications. Recognizing whether a patient is on a high or low dose intensity heart failure medication can be helpful for daily practice, since it could potentially guide the physician on which symptoms to look for, whether from overdosing or underdosing. However, the current guideline does not provide sufficient information about the dose intensity below the target dose. Furthermore, the definition of high or low-intensity heart failure medication is unclear, and there is no consensus.
METHODS
To close the knowledge gap, we conducted a scoping review of the current literature to identify the most frequently used definition of high versus low doses of heart failure medications. We searched Pubmed, Embase, CINAHL, and Cochrane Library using comprehensive search terms that can capture the intensity of heart failure medications.
RESULTS
We reviewed 464 articles, including 144 articles that had information about beta-blockers (BB), 179 articles about angiotensin-converting enzyme inhibitors (ACEi), 75 articles about angiotensin receptor blockers (ARB), 80 articles about diuretics, 37 articles about mineralocorticoid receptor antagonists (MRA), and 33 articles about angiotensin receptor-neprilysin inhibitor (ARNI). For hydralazine with isosorbide dinitrate or ivabradine, we could not identify any eligible articles. We identified 40 medications with most frequently used definitions of dose intensity. Four medications (nadolol, pindolol, cilazapril, and torsemide) did not reach consensus in definitions. Most of the BBs, ACEis, or ARBs used the definition of low being < 50% of the target dose and high being ≥ 50% of the target dose from the guideline. However, for lisinopril and losartan, the most commonly used definitions of high or low were from pivotal clinical trials with a pre-defined definition of high or low.
CONCLUSION
Our comprehensive scoping review studies identified the most frequently used definition of dose intensity for 40 medications but could not identify the definitions for 4 medications. The results of the current scoping review will be helpful for clinicians to have awareness whether the currently prescribed dose is considered high - requiring close monitoring of side effects, or low - requiring more aggressive up-titration.
Topics: Humans; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Isosorbide Dinitrate; Adrenergic beta-Antagonists; Stroke Volume
PubMed: 37759279
DOI: 10.1186/s12872-023-03514-2