Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents , Coronavirus Infections/drug therapy , Coronavirus/drug effects , Receptors, Virus , Angiotensin II Type 1 Receptor Blockers/chemical synthesis , Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/isolation & purification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/physiology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/isolation & purification , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/virology , Coronavirus/physiology , Humans , Immunity/drug effects , Immunity/physiology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Receptor, Angiotensin, Type 1/physiology , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/drug effects , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , COVID-19 Drug TreatmentABSTRACT
New analytical methods have been developed and validated on high performance liquid chromatography (HPLC) to assess the assay, content uniformity and dissolution of immediate release candesartan cilexetil 32 mg tablets. Method development studies were performed on cyano column. Mobile phase of assay and content uniformity test consisted of mixture of 0.05 M phosphate buffer, pH 4.5 and methanol (40 : 60, v/v) adjusted to pH 4.0 with trifluoroacetic acid, whereas mobile phase of dissolution test consisted of mixture of I mM phosphate buffer and acetonitrile (50 : 50, v/v) adjusted to pH 2.0 with trifluoroacetic acid. Mobile phases were pumped at flow rate of 1.0 mL/min, ultraviolet-visible (UV) detector was operated at 254 nm, injection volume was set at 20 µL, column temperature was held at 25°C. Dissolution medium was 0.05 M phosphate buffer, pH 6.5 including 0.70% (w/v) polysorbate 20. Validation studies met acceptance criteria of system suitability, specificity, linearity and range, accuracy, precision, detection limit (LOD), quantitation limit (LOQ) and robustness parameters.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/isolation & purification , Benzimidazoles/analysis , Biphenyl Compounds/analysis , Chromatography, High Pressure Liquid , Tetrazoles/analysis , Angiotensin II Type 1 Receptor Blockers/chemistry , Benzimidazoles/chemistry , Biphenyl Compounds/chemistry , Buffers , Chemistry, Pharmaceutical , Drug Compounding , Drug Liberation , Hydrogen-Ion Concentration , Limit of Detection , Linear Models , Reproducibility of Results , Solubility , Solvents/chemistry , Tablets , Temperature , Tetrazoles/chemistryABSTRACT
First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5µm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/analysis , Chromatography, High Pressure Liquid/methods , Angiotensin II Type 1 Receptor Blockers/isolation & purification , Limit of Detection , Linear Models , Reproducibility of Results , TabletsABSTRACT
QSRR are mathematically derived relationships between the chromatographic parameters determined for a representative series of analytes in given separation systems and the molecular descriptors accounting for the structural differences among the investigated analytes. Artificial neural network is a technique of data analysis, which sets out to emulate the human brain's way of working. The aim of the present work was to optimize separation of six angiotensin receptor antagonists, so-called sartans: losartan, valsartan, irbesartan, telmisartan, candesartan cilexetil and eprosartan in a gradient-elution HPLC method. For this purpose, ANN as a mathematical tool was used for establishing a QSRR model based on molecular descriptors of sartans and varied instrumental conditions. The optimized model can be further used for prediction of an external congener of sartans and analysis of the influence of the analyte structure, represented through molecular descriptors, on retention behaviour. Molecular descriptors included in modelling were electrostatic, geometrical and quantum-chemical descriptors: connolly solvent excluded volume non-1,4 van der Waals energy, octanol/water distribution coefficient, polarizability, number of proton-donor sites and number of proton-acceptor sites. Varied instrumental conditions were gradient time, buffer pH and buffer molarity. High prediction ability of the optimized network enabled complete separation of the analytes within the run time of 15.5 min under following conditions: gradient time of 12.5 min, buffer pH of 3.95 and buffer molarity of 25 mM. Applied methodology showed the potential to predict retention behaviour of an external analyte with the properties within the training space. Connolly solvent excluded volume, polarizability and number of proton-acceptor sites appeared to be most influential paramateres on retention behaviour of the sartans.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/isolation & purification , Chromatography, High Pressure Liquid/methods , Neural Networks, ComputerABSTRACT
A simple, rapid and robust LC method was developed and validated for the enantiomeric separation of valsartan in bulk drug and formulation. The enantiomers of valsartan were resolved on a Chiralpak AD-H (amylose based stationary phase) column using a mobile phase consisting of n-hexane: 2-propanol: trifluoroacetic acid (85:15:0.2, v/v/v) at a flow rate of 1.0 mL/min. The resolution between the enantiomers was found to be not less than 3.2. The presence of trifluoroacetic acid in the mobile phase played an important role in enhancing chromatographic efficiency and resolution between the enantiomers. The calibration curve for the (R)-enantiomer showed excellent linearity over the concentration range of 600 ng/mL (LOQ) to 6000 ng/mL. The limit of detection and limit of quantification for the (R)-enantiomer were 200 and 600 ng/mL, respectively. The percentage recovery of the (R)-enantiomer ranged between 98.7 to 100.05 % in bulk drug samples of valsartan. The proposed method was found to be suitable and accurate for quantitative determination of (R)-enantiomer in bulk drug substance.
Subject(s)
Amylose/chemistry , Angiotensin II Type 1 Receptor Blockers/chemistry , Tetrazoles/chemistry , Valine/analogs & derivatives , Angiotensin II Type 1 Receptor Blockers/isolation & purification , Chromatography, High Pressure Liquid , Indicators and Reagents , Regression Analysis , Reproducibility of Results , Stereoisomerism , Tablets/analysis , Tetrazoles/isolation & purification , Valine/chemistry , Valine/isolation & purification , ValsartanABSTRACT
Hypertension is a lifestyle-related disease which often leads to serious conditions such as heart disease and cerebral hemorrhage. Angiotensin II (Ang II) plays an important role in regulating cardiovascular homeostasis. Consequently, antagonists that block the interaction of Ang II with its receptors are thought to be effective in the suppression of hypertension. In this study, we searched for plant compounds that had antagonist-like activity toward Ang II receptors. From among 435 plant samples, we found that EtOH extract from the resin of sweet gum Liquidambar styraciflua strongly inhibited Ang II signaling. We isolated benzyl benzoate and benzyl cinnamate from this extract and found that those compounds inhibited the function of Ang II in a dose-dependent manner without cytotoxicity. An in vivo study showed that benzyl benzoate significantly suppressed Ang II-induced hypertension in mice. In addition, we synthesized more than 40 derivatives of benzyl benzoate and found that the meta-methyl and 3-methylbenzyl 2'-nitrobenzoate derivatives showed about 10-fold higher activity than benzyl benzoate itself. Thus, benzyl benzoate, its derivatives, and benzyl cinnamate may be useful for reducing hypertension.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Antihypertensive Agents/isolation & purification , Benzoates/pharmacology , Hypertension/drug therapy , Liquidambar/chemistry , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/antagonists & inhibitors , Angiotensin II/metabolism , Angiotensin II Type 1 Receptor Blockers/isolation & purification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Benzoates/chemistry , Benzoates/isolation & purification , Benzyl Compounds/chemistry , Benzyl Compounds/isolation & purification , Benzyl Compounds/pharmacology , Blood Pressure/drug effects , CHO Cells , Calcium/analysis , Calcium/metabolism , Cell Survival/drug effects , Cinnamates/chemistry , Cinnamates/isolation & purification , Cinnamates/pharmacology , Cricetinae , Cricetulus , HeLa Cells , Humans , Magnetic Resonance Spectroscopy , Male , Mice , Spectrometry, Mass, Electrospray IonizationABSTRACT
In this work, an SPE-HPLC method coupled to photodiode array detection was validated in human urine matrix, in order to monitor four antihypertensive angiotensin II receptor antagonist drugs in patients under cardiovascular treatment. For that purpose, experimental design was used. Quantitation was accomplished by the internal standard method. The obtained LOQs were 95, 113, 125, and 85 ng/mL for eprosartan, telmisartan, irbesartan, and valsartan, respectively. The intraday and interday precision and accuracy at four concentration levels in the working range (LOQ-15 microg/mL) were always lower than 11% RSD and 8% relative error. The urine samples proved to be stable during 4 h at room temperature, after three thaw-freeze cycles, and for 2 months at -20 degrees C. No interferences from other endogenous compounds or co-administered drugs were found. The method has been successfully applied to monitor the renal elimination of eprosartan and valsartan during 24 h.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/urine , Angiotensin Receptor Antagonists , Antihypertensive Agents/urine , Solid Phase Extraction/methods , Acrylates/analysis , Acrylates/isolation & purification , Acrylates/urine , Aged , Aged, 80 and over , Angiotensin II Type 1 Receptor Blockers/analysis , Angiotensin II Type 1 Receptor Blockers/isolation & purification , Antihypertensive Agents/analysis , Antihypertensive Agents/isolation & purification , Benzimidazoles/analysis , Benzimidazoles/isolation & purification , Benzimidazoles/urine , Benzoates/analysis , Benzoates/isolation & purification , Benzoates/urine , Biphenyl Compounds/analysis , Biphenyl Compounds/isolation & purification , Biphenyl Compounds/urine , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Female , Humans , Imidazoles/analysis , Imidazoles/isolation & purification , Imidazoles/urine , Irbesartan , Male , Middle Aged , Solid Phase Extraction/instrumentation , Telmisartan , Tetrazoles/analysis , Tetrazoles/isolation & purification , Tetrazoles/urine , Thiophenes/analysis , Thiophenes/isolation & purification , Thiophenes/urine , Valine/analogs & derivatives , Valine/analysis , Valine/isolation & purification , Valine/urine , ValsartanABSTRACT
Three hydroxylated metabolites of 2-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (Pratosartan), which is a selective angiotensin II receptor antagonist, were synthesized in confirmation of their structures and in studies of their pharmacological properties. An MTPA ester of the human main metabolite was identified with the synthesized compound by comparing (1)H-NMR spectra, MS spectra, and HPLC retention time. The structure of the human main metabolite was confirmed to be (S)-(-)-2-(1-hydroxypropyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one ((S)-(-)-1). Also, the rat main metabolites were confirmed to be 8-hydroxylated compound (2) and 5-hydroxylated compound (3). These metabolites showed lower antagonistic activity than that of the parent compound.