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International Neurourology Journal Feb 2024Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of...
PURPOSE
Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of several lower urinary tract regions that have dual sympathetic and parasympathetic innervation. We tested the hypothesis that synergy is also a feature of prostate tissue obtained from men with benign prostatic enlargement.
METHODS
Isolated tissue strips were dissected from prostate 'chips', collected after transurethral prostate resection procedures for in vitro experiments, to measure isometric tension at 36°C.
RESULTS
Added separately to the superfusate, phenylephrine and carbachol generated contractions with mean pEC50 (-log10EC50) values of 5.36 and 5.58, respectively, although phenylephrine maximal responses were about six-fold greater. In the presence of carbachol, the mean phenylephrine pEC50 was significantly increased to 5.84 and maximal response increased by 28%; overall, a significant synergistic response was demonstrated. The synergistic response was reduced by muscarinic receptor antagonists, most potently by the M3-selective agent 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), and less so by M2 and M1-selective inhibitors gallamine and pirenzepine, but with an overall profile indicating M3/M2 mediation of the synergistic response. The magnitude of the synergistic response was variable between prostate chips that provided isolated preparations suggesting regional heterogenicity, although their zonal origin could not be determined.
CONCLUSION
These experiments show that adreno-muscarinic contractile synergy is a feature of human hyperplastic prostate tissue. This has implications for the use of a combination therapy of α-blockers and anti-muscarinic agent to relieve secondary symptoms associated with benign prostatic hyperplasia, at least in men who can tolerate antimuscarinics without a risk of retention.
PubMed: 38461856
DOI: 10.5213/inj.2346144.122 -
BMC Chemistry Oct 2023The development and validation of the stability indicating HPLC technique has contributed to the understanding of the stability profile of ibuprofen (IBU) and...
The development and validation of the stability indicating HPLC technique has contributed to the understanding of the stability profile of ibuprofen (IBU) and phenylephrine (PHE). Stability profile was achieved for PHE; the drug was found to be liable to be influenced by stress oxidative conditions; two oxidative degradants (Deg1 & Deg2) were formed and their structures were confirmed using IR and mass spectrometry. The drugs and degradation products were successfully separated using a gradient elution method on YMC-C8 column with 0.1% hexanesulfonic acid and acetonitrile as a mobile phase at pH 6.6. The flow rate was 1.0 mL/min, and a diode array detector operating at 220 nm was used for UV detection. The retention times of degradants Deg1, Deg2, ibuprofen (IBU), and phenylephrine hydrochloride (PHE) were 2.0, 2.2, 3.2 and 7.0 min, respectively. The proposed method was validated with respect to linearity, accuracy, precision, specificity, and robustness using ICH guidelines. The linearities of ibuprofen and phenylephrine hydrochloride were in the range of 10-100 μg/mL and 0.3-10 μg/mL, respectively. The % recoveries of the two drugs were found to be 100.75 ± 1.44%, 99.67% ± 1.67, and the LOD was found to be 2.75/mL and 0.09/mL for IBU, and PHE, respectively. The method was successfully applied to the estimation of ibuprofen and phenylephrine hydrochloride combination in pharmaceutical dosage form. The proposed technique was validated using ICH guidelines and its greenness was assessed according to Analytical Eco Scale metric (AES). Molecular docking was used to assess the two drugs and PHE oxidative degradants interaction with the stationary phase and to confirm the outcomes of the proposed method with regard to the order of elution of the two drugs and PHE degradation products. Eco-friendly and environmental safety were assessed through the application of one of the most applicable greenness assessment tool; Analytical Eco Scale metric (AES).
PubMed: 37876006
DOI: 10.1186/s13065-023-01056-4 -
Journal of Ethnopharmacology Sep 2023Angelica decursiva is a perennial herb that belongs to the Umbelliferae family. It is traditionally used to treat fever, upper respiratory tract infections, bleeding and...
ETHNOPHARMACOLOGICAL RELEVANCE
Angelica decursiva is a perennial herb that belongs to the Umbelliferae family. It is traditionally used to treat fever, upper respiratory tract infections, bleeding and hypertension. However, despite its extensive pharmacological potential, literature reports on its antihypertensive pharmacological properties are scarce.
AIM OF THE STUDY
In the study, crude extract from A. decursiva roots was examined for its antihypertensive activity and its molecular basis was explored.
MATERIALS AND METHODS
A. decursiva roots were extracted with ethanol, and isolated with silica gel normal-phase chromatography and reverse-phase high performance liquid chromatography. L-NAME-induced hypertensive mouse model was used to detect in vivo hypertensive activity. Thoracic aorta ring contraction activity and electrophysiology recordings were employed to evaluate in vitro antihypertensive activity and revealed an antihypertensive target, which was transiently expressed in HEK293T cells.
RESULTS
Angelica decursiva ethanol decoction (ADED) exhibited significant antihypertensive effects in L-NAME-induced hypertension models and phenylephrine-induced vasoconstriction. Further screening revealed that demethylsuberosin is an essential component accounting for the antihypertension effects of A. decursiva. Voltage-gated calcium channel Ca1.2 is the likely target of A. decursiva for its antihypertension effects.
CONCLUSION
The study suggests that A. decursiva and demethylsuberosin may be effective antihypertensive agents in preclinical studies. It appears that A. decursiva and demethylsuberosin exert antihypertensive effects by inhibiting the Ca1.2 channel, which contributes to the vasodilatory effect. The present study provides experimental evidence that A. decursiva is an effective remedy for hypertension in folklore. Demethylsuberosin could be a lead molecule for antihypertension drug development.
Topics: Mice; Animals; Humans; Antihypertensive Agents; Calcium Channels, L-Type; Plant Extracts; Angelica; HEK293 Cells; NG-Nitroarginine Methyl Ester; Hypertension; Ethanol
PubMed: 37088236
DOI: 10.1016/j.jep.2023.116527 -
The International Journal of... Apr 2024Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men worldwide that may result in lower urinary tract symptoms (LUTS). At present, the...
Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men worldwide that may result in lower urinary tract symptoms (LUTS). At present, the specific pathophysiological mechanism for BPH/LUTS LUTS remains unclear. S100 calcium binding protein A4 (S100A4), a member of the calcium binding protein family, regulates a variety of biological processes including cell proliferation, apoptosis and fibrosis. The aim of the current study was to explore and clarify the possible role of S100A4 in BPH/LUTS. The human prostate stromal cell line (WPMY-1), rat prostate epithelial cells, human prostate tissues and two BPH rat models were employed in this study. The expression and localization of S100A4 were detected by quantitative real time PCR (qRT-PCR), immunofluorescence microscopy, Western blotting and immunohistochemistry analysis. Also, S100A4 knockdown or overexpression cell models were constructed and a BPH rat model was induced with testosterone propionate (T) or phenylephrine (PE). The BPH animals were treated with Niclosamide, a S100A4 transcription inhibitor. Results demonstrated that S100A4 was mainly localized in human prostatic stroma and rat prostatic epithelium, and showed a higher expression in BPH. Knockdown of S100A4 induced cell apoptosis, cell proliferation arrest and a reduction of tissue fibrosis markers. Overexpression of S100A4 reversed the aforementioned changes. We also demonstrated that S100A4 regulated proliferation and apoptosis mainly through the ERK pathway and modulated fibrosis via Wnt/β-catenin signaling. In conclusion, our novel data demonstrate that S100A4 could play a crucial role in BPH development and may be explored as a new therapeutic target of BPH.
Topics: Aged; Animals; Humans; Male; Rats; Apoptosis; Cell Proliferation; Fibrosis; Prostate; Prostatic Hyperplasia; S100 Calcium-Binding Protein A4
PubMed: 38360265
DOI: 10.1016/j.biocel.2024.106551 -
Tuberkuloz Ve Toraks Dec 2023Iatrogenic bleeding during bronchoscopy may lead to early termination, insufficient sample collection, decreased diagnostic accuracy, and even death. Unlike rigid...
Iatrogenic bleeding during bronchoscopy may lead to early termination, insufficient sample collection, decreased diagnostic accuracy, and even death. Unlike rigid bronchoscopy, the management of bleeding during flexible fiberoptic bronchoscopy does not allow the use of methods such as cautery, direct pressure, etc. and is usually limited to the application of liquids. The management of endobronchial bleeding usually depends on two main mechanisms: 1) vasoconstriction; 2) enhancing coagulation to form fibrin clots. The data on cold saline, the most widely recognized agent, is based on case reports and the experience of centers, not randomized controlled trials. Vasoconstrictor agents consist of adrenaline, vasopressin analogues, phenylephrine, and xylometazoline hydrochloride. However, there are only a limited number of randomized controlled trials on adrenaline, and information on the remaining substances is limited to retrospective studies, case reports, and expert opinions. The endobronchial administration of tranexamic acid, which inhibits fibrin degradation, has been the subject of very few studies. Despite its documented efficacy, information regarding its dosage, frequency of use, and safety is lacking. Although Ankaferd Blood Stopper, which binds erythrocytes to the vascular endothelium, has been shown to be effective in controlling bleeding related to dental procedures, the gastrointestinal tract, and operations, only one retrospective study found it to be effective against endobronchial bleeding that could not be controlled with cold saline and adrenaline. Although there are a variety of agents that centers use in their routine procedures, there is not yet a consensus on the efficacy, dose, frequency, and safety of any of them.
Topics: Humans; Bronchoscopy; Retrospective Studies; Hemorrhage; Stroke; Epinephrine; Fibrin; Iatrogenic Disease
PubMed: 38152010
DOI: 10.5578/tt.20239608 -
RSC Advances Apr 2024Cucurbiturils (CB) are known to establish stable host-guest complexes with a variety of drug molecules. Herein, the supramolecular complexation between cucurbit[7]uril...
Cucurbiturils (CB) are known to establish stable host-guest complexes with a variety of drug molecules. Herein, the supramolecular complexation between cucurbit[7]uril (CB7) and phenylephrine hydrochloride is reported in aqueous solution. Phenylephrine forms inclusion complex with CB7 with high binding affinity ( = 4.0 × 10 M), which allows for the development of a fluorescence-based sensing assay applying the dye displacement strategy. The structure of the host-guest inclusion complex is investigated by H NMR spectroscopy, in which complexation-induced chemical shifts indicate the immersion of the aromatic ring inside the hydrophobic cavity of CB7. Density functional theory (DFT) calculations support the H NMR results, and reveal that the complex is stabilized through intermolecular interactions between the polar groups on the phenylephrine and the carbonyl rims of CB7, as well as the hydrophobic effect. Moreover, preferential binding of phenylephrine in its protonated over the neutral form results in a complexation-induced p shift.
PubMed: 38655473
DOI: 10.1039/d4ra01910e -
Journal of Clinical Medicine Oct 2023The purpose of this study is to evaluate choroidal thickness (ChT) at the subfoveal and peripheral level after the instillation of 0.5% tropicamide + 10% phenylephrine 9...
The purpose of this study is to evaluate choroidal thickness (ChT) at the subfoveal and peripheral level after the instillation of 0.5% tropicamide + 10% phenylephrine 9 hydrochloride eye drops by using OCT scans in enhanced depth image (EDI) mode. In total, 53 patients (30 males and 23 females) were involved, and the mean age was 25.62 ± 2.41 (age range: 23-36). The dominant eye was treated with tropicamide + phenylephrine (Visumidriatic Fenil 100 mg/mL + 5 mg/mL, Visufarma) while the nondominant eye was used as the control. An OCT analysis was performed on both eyes before and 30 min after the instillation of a drop of mydriatic in the dominant eye. The ChT was measured by using the OCT software measurement tool (Spectralis; Heidelberg Engineering; Heidelberg, Germany, version 6.0). The results showed a statistically significant ChT decrease ( = 0.009) in the temporal sector after the treatment with tropicamide + phenylephrine. In the subfoveal and nasal sectors, no statistically significant ChT changes were detected ( = 0.94; = 0.85) following the administration of the mydriatic eye drops. The ChT thinning in the temporal sector following the instillation of the tropicamide + phenylephrine eye drops suggests that in the case of ChT studies, mydriatic administration should be avoided.
PubMed: 37834998
DOI: 10.3390/jcm12196355 -
International Journal of Molecular... Dec 2023Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the...
Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole--biphenyl tetrazole (ACC519T), benzimidazole--,'-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K)), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K) to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K) significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K) to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.
Topics: Rabbits; Male; Animals; Angiotensin II Type 1 Receptor Blockers; Telmisartan; Angiotensin-Converting Enzyme 2; Angiotensin Receptor Antagonists; Iliac Artery; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Tetrazoles; Hypertension; Blood Pressure
PubMed: 38139391
DOI: 10.3390/ijms242417559 -
Science Advances May 2024Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in...
Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
Topics: Animals; Ventricular Remodeling; Proline; Myocytes, Cardiac; Mice; Mice, Knockout; Rats; Proline Oxidase; Energy Metabolism; Myocardium; Cardiomegaly; Disease Models, Animal; Oxidation-Reduction; Male; Metabolic Reprogramming
PubMed: 38718121
DOI: 10.1126/sciadv.adl3549 -
Graefe's Archive For Clinical and... May 2024To determine how high myopia impacts pharmacological pupillary dilation, and to evaluate the relationship between the extent of pharmacologic pupillary dilation and...
PURPOSE
To determine how high myopia impacts pharmacological pupillary dilation, and to evaluate the relationship between the extent of pharmacologic pupillary dilation and axial length.
METHODS
Patients were grouped into high myopes, defined as one or both eyes having a refractive error greater than - 6 diopters, and controls (between - 2 and + 2 diopters). Dilation was achieved with 1 drop each of tropicamide 1% and phenylephrine 2.5%. Pupil size was measured at full and dim light prior to dilation, then 15 and 30 min after dilation. Biometry was measured for each patient. Statistical analyses were performed using the Mann-Whitney-Wilcoxon tests, two-sample Welch's t-tests, and linear mixed effect models and generalized estimating equations models accounting for inter-eye correlation.
RESULTS
Forty patients (20 high myopes and 20 controls, 80 eyes total) participated in the study. High myopes had larger pupils at baseline and achieved significantly greater pupillary size (7.08 mm, 95% CI: 6.97 to 7.19 mm) than controls (6.23 mm, 95% CI: 5.94 to 6.52 mm) after 30 min of dilation (P < .0005). Fully dilated pupil size at 30 min was significantly correlated with both refractive error (r = - 0.57, P < .0005) and axial length (r = 0.47, P < .0005). Generalized estimating equations and linear mixed effect models identified other predictive variables of pupil size after dilation including age and white-to-white diameter.
CONCLUSIONS
Highly myopic patients dilate to a larger pupillary size compared to other patients. Predicting dilation based on extent of myopia could facilitate intraocular surgery planning and reduce clinic wait times for myopic patients.
Topics: Humans; Mydriatics; Dilatation; Tropicamide; Phenylephrine; Myopia; Axial Length, Eye
PubMed: 37999774
DOI: 10.1007/s00417-023-06296-7