Rapid determination and comparative pharmacokinetics of tetrahydropalmatine in spontaneously hypertensive rats and normotensive rats

A rapid high‐performance liquid chromatographic method was developed and validated for determination of tetrahydropalmatine (THP), an active component of Rhizoma Corydalis, in rat plasma. The samples were prepared using protein precipitation and separated on an Agilent XDB‐C₁₈ column (150 × 4.6 mm, 5 µm) with the mobile phase consisting of methanol–0.1% phosphate acid solution, adjusted with triethylamine to pH 5.5 (65:35). Good linearity was found within 0.10–10.00 µg/mL of THP in rat plasma sample. The intra‐ and inter‐day precision values were less than 10%. The developed method was successfully applied to assess the pharmacokinetics of THP in spontaneously hypertensive rats (SHR) and normotensive rats. After oral administration of a single dose of THP (60 mg/kg), the maximum plasma concentrations were 6.15 ± 2.1 and 7.54 ± 2.9 µg/mL for normotensive rats and SHR, respectively. The mean values of AUC_0–∞ of THP in SHR were 81.44 ± 45.0 µg h/mL, significantly higher (p < 0.05) than in normotensive rats (44.06 ± 19.6 µg h/mL). The t_1/2 and MRT in SHR were much longer than that in healthy Sprague–Dawley rats, indicating slow elimination of THP in SHR. The results indicated that there are some differences in pharmacokinetics of THP in SHR and Sprague–Dawley rats and it is very important to investigate the pharmacokinetic properties of drugs in pathological conditions. Copyright © 2011 John Wiley & Sons, Ltd.     

Changes of plasma L-arginine levels in spontaneously hypertensive rats under induced hypotension

Nicardipine, a dihydropyridine type calcium channel blocker, was infused at two flow-rates into spontaneously hypertensive (SH) and control normotensive Wistar-Kyoto (WKY) rats (young, 6-week-old and adult, 23-week-old, n = 5) under pentobarbital anesthesia, to cause hypotension. Mean arterial blood pressure and the concentrations of plasma amino acids and norepinephrine (NE) were measured before infusion and at each step of the infusion. The reduction in blood pressure caused by nicardipine induced a decrease in plasma L-arginine concentration in both young and adult SH rats, this effect being larger in adult rats. There was no significant change in plasma levels of L-arginine in age-matched WKY rats. The concentration of other amino acids did not change in both rat strains. On the contrary, there was an increase in plasma NE concentration in both SH and WKY rats after infusion with nicardipine. Plasma L-arginine concentration showed a good inverse correlation with the logarithm of plasma NE concentration in SH and WKY rats and the correlation was expressed as Y = -alpha log(X) + m (Y, plasma L-arginine concentration (nmol/mL); X, plasma NE concentration (pmol/mL); alpha, a slope; and m, an intercept). alpha, 43.0 and 4.35 for 23-week-old SH and WKY rats, respectively, and 17.0 and 4.0 for 6-week-old SH and WKY rats, respectively. The present data together with previous data suggest a direct noradrenergic stimulation of the synthesis of nitric oxide (NO) from L-arginine. The findings also indicate an impairment of the L-arginine metabolism or pools in SH rats compared with WKY rats. The deficiency of L-arginine increases with the age of SH rats and could be related to the development and maintenance of hypertension due to inefficient production of NO.     

Enzyme mediated-transesterification of verbascoside and evaluation of antifungal activity of synthesised compounds

Enzymatic acylation of verbascoside, a polyhydroxylated natural product, has been reported in this study using five different commercial lipases and taking p-nitrophenyl alkanoates as acyl donors. Out of these enzymes, the immobilised Candida antarctica lipase B was found as the enzyme of choice. Mono- and di-acylated products were formed, with mono as major product indicating high regioselective nature of such transformations. A series of acyl esters of verbascoside have been synthesised by this enzymatic transesterification methodology. The lipophilicity of the synthesised analogues was also checked. The analogues were further subjected to synergistic antifungal activity with amphotericin B (AmB) against Candida albicans. Fourfold reduction in minimum inhibitory concentration of AmB was observed with few synthesised analogues such as verbascoside 4″-octanoate (3b), verbascoside 4″-palmitate (3d) and verbascoside 4″,4′-dipalmitate (4d) at a concentration of 0.5 μg/mL.     

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using 1H-NMR- and MS-based metabolomics

Duzhong Jiangya Tablet (DJT) composed of Eucommia ulmoides Oliv. and several other traditional Chinese medicines is a Chinese herbal compound, which is clinically used to treat hypertension. The aim of this study was to evaluate the antihypertensive effect of DJT and amlodipine besylate (AB) on the synergistic treatment of spontaneously hypertensive rats (SHRs), and to explore its antihypertensive mechanism. The synergistic therapeutic effect of DJT in combination with AB on SHR was studied using two metabolomics methods based on mass spectrum (MS) and nuclear magnetic resonance. Metabolomics analysis of plasma, urine, liver, and kidney and the combination of orthogonal partial least squares discriminant analysis was performed to expose potential biomarkers. Then, the overall metabolic characteristics and related abnormal metabolic pathways in hypertensive rats were constructed. Blood pressure measurements showed that DJT combined with AB has better effects in treating hypertension than it being alone. A total of 30 biomarkers were identified, indicating that hypertension disrupted the balance of multiple metabolic pathways in the body, and that combined administration restored metabolite levels better than their administration alone. The changes of biomarkers revealed the synergistic therapeutic mechanism of DJT combined with AB, which provided a reference for the combination of Chinese and Western medicines.     

Fibrinolytic effect of tissue plasminogen activator on cerebral embolism in stroke-prone spontaneously hypertensive rats.

To study the thrombolytic effect of tissue plasminogen activator (t-PA) on cerebral emboli, we characterized cerebral embolization in stroke-prone spontaneously hypertensive rats (SHRSPs) and Wistar Kyoto rats (WKYs). [125I]Fibrin clot particles (20-100 microns diameter) were injected twice at an interval of 90 min into the left internal carotid artery of WKYs and SHRSPs. After each injection, spontaneous embolus dissolution was monitored with a gamma-ray detector placed on the head of the embolic rats. Embolus dissolution was spontaneously generated in 15 min after the injection of fibrin clots. In WKYs, 21% and 42% of the clots were dissolved 30 and 90 min after the second embolization, respectively. On the other hand, the spontaneous embolus dissolution in SHRSPs was significantly lower than that of WKYs, indicating that the endogenous fibrinolytic ability of SHRSPs is less potent than that of normotensive rats. The intravenous administration of t-PA at doses of 75, 250 and 750 micrograms/kg caused a dose-dependent embolus dissolution in SHRSPs. Furthermore, systematically applied t-PA produced embolus dissolution without causing systemic plasminogen activation, fibrinogen breakdown or bleeding. In conclusion, the intravenous administration of t-PA produces selective embolus dissolution without systemic fibrino(geno)lysis in a cerebral embolic SHRSP.     

Chemical composition and antifungal activity of essential oils from Senecio nutans,Senecio viridis,Tagetes terniflora and Aloysia gratissima against toxigenic Aspergillus and Fusarium species

Abstract

Essential oils from aerial parts of Senecio nutans, Senecio viridis, Tagetes terniflora and Aloysia gratissima were analysed by GC-MS and their antifungal activities were assayed on toxigenic Fusarium and Aspergillus species. Sabinene (27.6?±?0.1%), α-phellandrene (15.7?±?0.3%), o-cymene (9.6?±?0.2%) and β-pinene (6.1?±?0.2%) in S. nutans, 9,10-dehydrofukinone (92.7?±?0.2%) in S. viridis, β-thujone (36.1?±?0.1%), α-thujone (32.2?±?0.2%), 1,8-cineol (10.7?±?0.1%) and sabinene (6.2?±?0.2%) in A. gratissima, and cis-tagetone (33.6?±?0.2%), cis-β-ocimene (17.1?±?0.2%), trans-tagetone (17.0?±?0.1%), cis-ocimenone (8.0?±?0.2%) and trans-ocimenone (8.2?±?0.1%) in T. terniflora. The oils showed moderate antifungal activity (1.2?mg/mL?>?MIC >0.6?mg/mL) on the Fusarium species and a weak effect on Aspergillus species. The antifungal activity was associated on F. verticillioides to the high content of cis-tagetone, trans-tagetone, cis-β-ocimene, cis-ocimenone, trans-ocimenone and on F. graminearum due to the total content of oxygenated sesquiterpenes and 9,10- dehydrofukinone. The oil of S. viridis synergized the effect of fungicides and food preservatives on F. verticillioides.

     

Synthesis and biological activity of new 1,3-dioxolanes as potential antibacterial and antifungal compounds

A series of new enantiomerically pure and racemic 1,3-dioxolanes 1-8 was synthesized in good yields and short reaction times by the reaction of salicylaldehyde with commercially available diols using a catalytic amount of Mont K10. Elemental analysis and spectroscopic characterization established the structure of all the newly synthesized compounds. These compounds were tested for their possible antibacterial and antifungal activity. Biological screening showed that all the tested compounds, except 1, show excellent antifungal activity against C. albicans, while most of the compounds have also shown significant antibacterial activity against S. aureus, S. epidermidis, E. faecalis and P. aeruginosa.     

Prolongation of life span of stroke-prone spontaneously hypertensive rats (SHRSP) ingesting persimmon tannin

The effects of persimmon tannin on pathophysiological changes in stroke-prone spontaneously hypertensive rats (SHRSP) were investigated. When the persimmon tannin was chronically ingested by SHRSP, the life span was significantly prolonged, yet the effect on blood pressure was slight. The incidences of brain hemorrhage and infarction were also significantly decreased by this treatment. To elucidate the mechanisms involved in these events, the effects of condensed tannins, including persimmon tannin, on free radicals and lipid peroxidation were examined in vitro. Using electron spin resonance analysis, we found that these tannins have a potent, concentration-dependent scavenging action toward active oxygen free radicals. These tannins strongly inhibited lipid peroxidation in rat brain homogenates, in a concentration-dependent manner. Persimmon tannin inhibited lipid peroxidation similarly to (-)-epigallocatechin. Persimmon tannin was 20 times more effective than alpha-tocopherol in terms of the 50%-inhibitory concentration. The radical scavenging action and inhibition of lipid peroxidation by persimmon tannin may explain, in part, the prolongation of the life span of the SHRSP ingesting persimmon tannin.     

Antifungal activities of amino acid ester functional pyrazolyl compounds against Fusarium oxysporum f.sp. albedinis and Saccharomyces cerevisiae yeast

Series of functional multidendate ligands based on pyrazole and amino acid derivatives were prepared in good and excellent yields (75–5%) by condensation of one equivalent of amino acid ester hydrochloride substrates with two equivalents of (3,5-dimethyl-1H–pyrazol-1-yl)methanol. These tridentate functionalized compounds and their starting materials were screened for their antifungal activities against Fusarium oxysporum f.sp. albedinis and the yeast of Saccharomyces cerevisiae. Considerable activities were recorded with respect to the two studied microorganisms.     

Effect of chemical compounds on amino acid content of some Fusarium species and its significance to fungal chemotaxonomy

The cellular amino acid profiles of nine species of Fusarium; namely, Fusarium anthophilum, Fusarium avenaceum, Fusarium cerealis, Fusarium graminearum, Fusarium graminum, Fusarium oxysporum f. sp. conglutinans, Fusarium pseudograminearum, Fusarium roseum, and Fusariumsacchari var. elongatum growing on malt extract medium were determined. The amino acid profiles of the investigated fungi were varied and could be used for identification and characterisation of certain Fusarium species. Addition of certain chemical compounds including aspartic acid, glutamic acid, methionine, selenium, and urea to the growth medium affected the amino acid profiles. However, susceptibility of amino acid content to environmental conditions increased the variation of amino acid profiles among all the investigated Fusarium species. Some amino acids were only produced when certain chemical compounds were added to the growth medium. Valine was produced by F. anthophilum only in the presence of aspartic acid or selenium, while serine was produced in the presence of aspartic acid, glutamic acid, or methionine. Also, cysteine was produced by F. avenaceum in the presence of glutamic acid or urea. F. cerealis produced tryptophan only in the presence of aspartic acid or urea, while F. graminearum produced leucine in glutamic, methionine or urea. Similarly, many different amino acids were produced by each Fusarium species only in the presence of certain chemical compounds. The results revealed that the amino acid profiles will be more useful for characterisation and identification of fungi if they are determined under different conditions.     

Reaction of 1-formyladamantane with heterocyclic compounds. Mass spectra,antibacterial and antifungal activity

1-Formyladamantane reacts with some amino derivatives to give I, II, III and IV. 3-Substiluted 2-adamantyl-4-thiazolidinones (V), (VI) and (VII) were obtained by reacting the above compounds with mercaptoacetic acid. Their structure was established by ir, pmr and mass spectroscopy. All compounds synthesized inhibit the growth of gram-negative and gram-positive bacteria and fungi.     

Studies on pyrazine derivatives LII: Antibacterial and antifungal activity of nitrogen heterocyclic compounds obtained by pyrazinamidrazone usage

Using reactivity of pyrazinamidrazones and their N′‐substituted derivatives 1–8 in reaction with sulfonyl chlorides sulfone derivatives 9–17 were obtained, with orthoformate cyclized to sulfonyl compounds 18–20 . Amidrazones in reaction with pyraziniminoesters gave dihydrazidines 21–23 , which cyclized to 3,5‐dipyrazine derivatives of 1,2,4‐triazole 24–26 . 1‐Methyl‐ or 1‐phenyl‐3‐pyrazine‐1,2,4‐triazole 27–38 was formed in reaction of amidrazones 1–8 with orthoformate and orthoacetate or benzoyl chloride. N′‐Phenylamidrazones 3, 8 in reaction with thionyl chloride were transformed to 1,2,3,5‐thiatriazole S‐oxides 39, 40 . Obtained compounds exhibited low antibacterial activity. Antifungal activity was affirmed for compounds 1, 3, 4, 5, 8, 37, 39, and 40 , for which minimal inhibitory concentration (MIC) was in the concentration range of 16–128 μg/mL. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:49–58, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20751     

Electron ionisation mass spectrometry of the pentafluoropropionate esters of trichothecene analogues and culmorin compounds from Fusarium species

This paper reports the mass spectra, obtained after electron ionisation (EI) at 70 eV, of 34 trichothecenes and five culmorin compounds after acylation with pentafluoropropionic anhydride. The derivatised fungal metabolites were separated by gas chromatography, and the mass spectra were obtained by scanning of a single quadrupole mass filter in the scan range m/z 200‐900. The fragmentation pathways of three trichothecenes (triacetyl‐deoxynivalenol, 4,15‐diacetoxy‐scirpenol, T‐2 toxin) have been studied in more detail by linked scan – high‐resolution mass spectrometry. The most common trichothecenes are today more often routinely analysed using LC/MS‐based methodologies. However, EI‐MS may give complementary structural information, and the data that are summarised in this article may help to identify analogues of one of the largest class of mycotoxins, the tricothecenes, as well as culmorin compounds that are commonly co‐produced by Fusarium culmorum and F. graminearum in cultures or naturally contaminated samples. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of novel selenium and tellurium-containing tetrazoles: a class of chalcogen compounds with antifungal activity

We describe herein the synthesis and antifungal activity of new 5-arylchalcogenoalkyl-1H-tetrazoles 4. Arylchalcogenoalkyl-1H-tetrazoles 4 have been synthesized in high yields by reaction of arylchalcogenolate anions with chloronitriles 2, and subsequent [2+3] cycloaddition of resulting arylchalcogenoalkylnitriles 3 with sodium azide by zinc catalysis in aqueous solution. The obtained compound 4a was screened for antifungal activity and presented inhibitory property against seven fungal strains. This protocol is an efficient method to produce new selenium–nitrogen compounds with antifungal activity.     

Pharmacologic analysis of 7-O-ethyl-fangchinoline-induced vasodilation properties in isolated perfused common carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats.

Using the cannula insertion method, we investigated vascular effects of 7-O-ethyl-fangchinoline (TJN-220) derived from tetrandrine in isolated and perfused common carotid arteries of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single dose of TJN-220 caused a vasodilation in a dose-related manner in arteries preconstricted by phenylephrine. The vasodilation was not inhibited by propranolol, a potent beta-adrenoceptor antagonist. A potent alpha-antagonist bunazosin inhibited the vasoconstriction to norepinephrine while TJN-220 did not modify the norepinephrine-induced constriction, indicating TJN-220 had no alpha-blocking activity. A potent calcium entry blocker, diltiazem, markedly attenuated the KCl-induced vasoconstriction, and TJN-220 slightly but significantly attenuated the KCl-induced one in large doses. The vasodilation of TJN-220 was not abolished after removing the endothelium by an intraluminal administration of saponin, although the ACh-induced dilation was completely abolished by it. A comparison of vascular responses in WKY and SHR revealed no significant differences. From these results, it is concluded that 1) a new tetrandrine derivative, TJN-220 has relatively long-lasting vasorelaxant properties, 2) the dilatory effects might not be related to adrenergic, muscarinic or endothelium-dependent mechanisms, and 3) the effects might partially be due to calcium entry antagonistic properties.