Fosinopril Research Articles

Modified Fangji Huangqi Decoction alleviates renal interstitial fibrosis by inhibiting TGF-β1/Smad/Snail signaling pathway during epithelial-mesenchymal transition

This study investigated the effects of modified Fangji Huangqi Decoction on the expression of proteins related to epithelial-mesenchymal transition(EMT) in a mouse model of unilateral ureteral obstruction( UUO) and in a rat renal tubular epithelial cell(NRK-52E) model of fibrosis induced by transforming growth factor β1(TGF-β1). It aims to decipher the molecular mechanism by which modified Fangji Huangqi Decoction alleviates renal interstitial fibrosis. C57/BL mice were subjected to UUO.After the surgery, the mice were treated with 0. 5-fold and 2-fold concentrations of modified Fangji Huangqi Decoction and fosinopril sodium(positive control) for 7 days. The interstitial collagen deposition in the kidney was assessed by Masson staining. Western blot and RT-qPCR were employed to determine the expression levels of TGF-β1, phosphorylated Smad2/3(p-Smad2/3), Smad2/3, Snail,epithelial cadherin(E-cadherin), alpha smooth muscle actin(α-SMA), and vimentin. The NRK-52E cell model induced by TGF-β1was treated with the serum samples collected from SD rats treated with different concentrations of modified Fangji Huangqi Decoction.The CCK-8 assay was employed to examine the effects of the serum samples on NRK-52E cell proliferation. The cell morphology in different groups was observed under a microscope. Furthermore, the modeled cells were treated with the serum containing 1-fold decoction. Western blot and RT-qPCR were then employed to measure the expression levels of p-Smad2/3, Smad2/3, Snail,E-cadherin, α-SMA, and vimentin in the cells. Under the same conditions, sh RNA was used to silence the Snail gene, and measurements were repeated before and after treatment with the serum containing 1-fold decoction. The results indicated that modified Fangji Huangqi Decoction alleviated the fibrotic injury in the mouse model of UUO and the fibrosis in the NRK-52E cell model. The treatment with the decoction down-regulated the protein and m RNA levels of EMT-related indicators including p-Smad2/3, α-SMA,Snail, and vimentin, while it up-regulated the expression of E-cadherin. After sh RNA silencing of the Snail gene, the protein and m RNA levels of E-cadherin, α-SMA, and vimentin showed no significant differences before and after treatment with the serum containing the decoction. The results suggest that modified Fangji Huangqi Decoction may alleviate renal interstitial fibrosis by inhibiting the TGF-β1/Smad/Snail signaling pathway and regulating the EMT process.

Physicochemical and Stability Evaluation of Topical Niosomal Encapsulating Fosinopril/γ-Cyclodextrin Complex for Ocular Delivery.

This study aimed to develop a chemically stable niosomal eye drop containing fosinopril (FOS) for lowering intraocular pressure. The effects of cyclodextrin (CD), surfactant types and membrane stabilizer/charged inducers on physiochemical and chemical properties of niosome were evaluated. The pH value, average particle size, size distribution and zeta potentials were within the acceptable range. All niosomal formulations were shown to be slightly hypertonic with low viscosity. Span® 60/dicetyl phosphate niosomes in the presence and absence of γCD were selected as the optimum formulations according to their high %entrapment efficiency and negative zeta potential values as well as controlled release profile. According to ex vivo permeation study, the obtained lowest flux and apparent permeability coefficient values confirmed that FOS/γCD complex was encapsulated within the inner aqueous core of niosome and could be able to protect FOS from its hydrolytic degradation. The in vitro cytotoxicity revealed that niosome entrapped FOS or FOS/γCD formulations were moderate irritation to the eyes. Furthermore, FOS-loaded niosomal preparations exhibited good physical and chemical stabilities especially of those in the presence of γCD, for at least three months under the storage condition of 2–8 °C.

Nephroprotective mechanisms of Ambrette (Abelmoschus moschatus Medik.) leaf extracts in adriamycin mediated acute kidney injury model of Wistar rats

Ethnopharmacological relevanceAmbrette (Abelmoschus moschatus Medik., Family: Malvaceae) is a common Ayurvedic herbal medicine used in the treatment of kidney-related diseases, in the forms of tea, medicated oil, medicated wine, etc., however, its nephroprotective mechanisms remain unexploited. Aim of the studyTo investigate the mechanisms by which the hexane (A-HE), ethyl acetate (A-EE), butanol (A-BE), and aqueous (A-WE) leaf extracts of Ambrette protect against the adriamycin-mediated acute kidney injury in Wistar rats. Materials and methodsA-HE, A-EE, A-BE, A-WE, and fosinopril sodium were administered at therapeutically effective doses (55, 75, 60, 140, 0.09 mg/kg) to adriamycin-induced (5 mg/kg, ip) Wistar rats for 28 consecutive days. ResultsOral administration of the selected extracts of A. moschatus resulted in amelioration of kidney injury as observed by the significant changes of biomarkers of kidney function in serum and in urine, biochemical parameters of oxidative stress, and inflammation in kidney homogenates (p < 0.05). Furthermore, the administration of plant extracts caused a significant reduction in total kidney injury scores in H and E stained kidney sections (p < 0.05). The immunohistochemical expression of the inflammatory marker, COX-2, and the pro-apoptotic marker, Bax, were attenuated and the expression of the anti-apoptotic marker, BCL-2, was increased. A-HE exerted superior nephroprotective effects over the other three extracts and the drug reference standard. ConclusionsThe findings revealed that Ambrette exerts promising protective effects against adriamycin-mediated acute kidney injury through antioxidant, anti-inflammatory, and anti-apoptosis pathways. A-HE might serve as a potential candidate for the development of therapeutic drug leads that will be beneficial in the treatment of acute kidney injury.

An In-Vitro Evaluation of Microleakage in Resin-Based Restorative Materials at Different Time Intervals.

A vital feature of conservative dentistry is the adhesion of the restorative material to the tooth structure for restoration of the tooth substance lost due to dental decay, trauma, or dental imperfections. In a perfect world, a restorative material should generate a lasting adhesion by bonding the restoration with tooth tissues. The ingress of micro-organisms, oral fluids, molecules, and ions through microscopic spaces due to faulty adhesion between restoration and tooth structure is known as microleakage. This study is focuses on the evaluation of adhesive failures between the restorative materials. In the past, studies have focused more on the bonding potential of a restorative material with the tooth surface. Therefore, there is need to carry out a study that compares the microleakage between resin-based restorative materials in a sandwich manner with and without the intermediate bonding layer after immersion in 2% methylene blue dye at different time intervals. The restorative materials used were composite Ceram X Mono plus (DENTSPLY) and Z350 (3M ESPE), Vitremer resin modified glass ionomer cement (RMGIC) (3M ESPE), smart dentine replacement SDR (3M ESPE), Bond NT (DENTSPLY), and Universal Bond (3M ESPE). A light emitting diode (LED) was used to cure the specimens. Artificial saliva was used as a storage medium for the specimens. Thermocycling of specimens was carried out at 500 cycles/30 s and 1000 cycles/30 s. The world health organization (WHO) grading tool for microleakage was used to analyze fluid ingress in the specimens through disclosing by 2% methylene blue dye. The statistical analysis was carried out with one-way analysis of variance (ANOVA) and Tukey post hoc test, keeping the level of significance at p ≤ 0.05. In Grade 0 = 85 samples, Grade 1 = 10 samples, Grade 2 = 7 samples, Grade 3 = 16 samples, and in Grade 4 = 2 samples were identified. This study describes that no microleakage was observed in SDR and resin composite groups as compared to Vitremer and resin composite groups.

Clustering of low-mass stars around Herbig Be star IL Cep – evidence of ‘Rocket Effect’ using Gaia EDR3 ?

ABSTRACT We study the formation and the kinematic evolution of the early-type Herbig Be star IL Cep and its environment. The young star is a member of the Cep OB3 association, at a distance of 798 ± 9 pc, and has a ‘cavity’ associated with it. We found that the B0V star HD 216658, which is astrometrically associated with IL Cep, is at the centre of the cavity. From the evaluation of various pressure components created by HD 216658, it is established that the star is capable of creating the cavity. We identified 79 co-moving stars of IL Cep at 2-pc radius from the analysis of Gaia EDR3 astrometry. The transverse velocity analysis of the co-moving stars shows that they belong to two different populations associated with IL Cep and HD 216658, respectively. Further analysis confirms that all the stars in the IL Cep population are mostly coeval (∼0.1 Myr). Infrared photometry revealed that there are 26 Class II objects among the co-moving stars. The stars without circumstellar disc (Class III) are 65 per cent of all the co-moving stars. There are nine intense H α emission candidates identified among the co-moving stars using IPHAS H α narrow-band photometry. The dendrogram analysis on the Hydrogen column density map identified 11 molecular clump structures on the expanding cavity around IL Cep, making it an active star-forming region. The formation of the IL Cep stellar group due to the ‘rocket effect’ by HD 216658 is discussed.

Simultaneous analysis of several antihypertensive drugs in different combinations: Application for determination of drug degradation products and process impurities

Hydrochlorothiazide is a widely used thiazide diuretic. Its combinations with either olmesartan medoxomil or fosinopril sodium are well known antihypertensive combinations that compare positively than other related combined therapies. A first RP-HPLC method was introduced for simultaneous estimation of two antihypertensive combinations containing hydrochlorothiazide with either olmesartan medoxomil or fosinopril sodium. The work was extended to quantify the drugs along with their degradation products; salamide as hydrochlorothiazide degradate and olmesartan as olmesartan medoxomil degradate. Also, it succeeded to determine the pharmacopoeial impurity of hydrochlorothiazide (chlorothiazide). The established RP-HPLC was performed on RP-C18 column utilizing gradient mixture of 0.05 M KH2PO4 (pH 3 with aqueous O-phosphoric acid), acetonitrile, and methanol. Temperature was adjusted to 35 °C and UV detection was done at 205 nm for fosinopril sodium and at 225 nm for the rest of the cited components.ICH guidelines were used to validate the method and all the results affirmed efficiency of the method. In addition, it was effectively used for measuring hydrochlorothiazide in binary mixtures with either olmesartan medoxomil or fosinopril sodium in their available pharmaceutical formulation. Also, the statistical comparison with published methods was executed and no noteworthy difference concerning accuracy and precision was detected.

Effects of antihypertensive treatment on systemic inflammation, oxidative stress and proinflammatory cytokine levels

Hypertension in its origin is a heterogeneous and multisystemic disease. Evaluation of oxidative stress activity based on the level of 8-iso-PgF2α, proinflammatory activity based on tumour necrosis factor-α, its type I soluble receptor, and C-reactive protein levels is relevant for further understanding of pathogenesis of hypertension and improvement of the early diagnostics of heart failure. 186 hypertensive patients were observed during a 2-months course of treatment, aged 30 to 65 years. Serum levels of 8-iso-PgF2α (n = 34), tumour necrosis factor-α and its type I soluble receptor were determined by ELISA before and after course of treatment. C-reactive protein level was determined by biochemical method. The control group included 16 clinically healthy individuals, aged 27 to 55 years. Hypertensive patients enrolled into the study were randomized into three groups that received different protocols of combined anti-hypertensive therapy: I clinical group – а combination of bisoprolol and indapamid, II – а combination of lacidipine and candesartan, III – а combination of fosinopril sodium and hydrochlorothiazide. On the background of combined antihypertensive therapy, we observed favourable dynamics of 8-iso-PgF2α, tumour necrosis factor-α and its type I soluble receptor, and C-reactive protein levels. Taking into account the insignificance of the correlations revealed, a one-factor dispersion analysis was applied which allowed us to determine the influence of the grade and duration of hypertension on the dynamics of the studied parameters. It has been found that the grade of hypertension is related to an increase in TNF-α and 8-iso-PgF2α serum levels, but not in TNF-α type I soluble receptor, and the duration of hypertension is related to an increase in C-reactive protein, TNF-α and its type I soluble receptor levels, with no relation to the level of 8-iso-PgF2α. Thus, oxidative stress possibly promotes the activation of potentially damaging immune mechanisms mediated by proinflammatory cytokines, nonspecific inflammation and drives the further progression of lesions in the target organs.

Standardized aqueous stem bark extract of Gmelina arborea roxb. possesses nephroprotection against adriamycin-induced nephrotoxicity in Wistar rats

Nephrotoxicity is a major limitation of adriamycin (ADR) chemotherapy. We hypothesized that administration of standardized aqueous bark extract of Gmelina arborea Roxb. (GA) (Family; Verbenaceae), a traditional therapeutic agent, may reduce the nephrotoxicity caused by ADR in Wistar rats. The dose-dependent nephroprotective activity of the standardized GA extract was investigated in ADR-induced (20 mg/kg, ip) nephrotoxicity in male Wistar rats (n = 6/group). The lyophilized powder of the aqueous refluxed (4 h) GA extract was administered at 100, 300 and 500 mg/kg doses orally for three consecutive days. Fosinopril sodium (0.09 mg/kg) was used as the positive control. Assessment of biochemical parameters on serum, urine and histopathology on H and E stained kidney sections were done at the end of the intervention. The treatment with GA and fosinopril decreased the elevation of serum creatinine, blood urea nitrogen, cystatin C, β2-microglobulin and loss of total protein in urine in nephrotoxic rats in a dose-dependent manner (p < 0.05). In contrast, serum concentrations of albumin and total protein were increased significantly (p < 0.05). H and E stained kidney sections showed an attenuation of renal parenchymal injury following the treatment. The aqueous extract of GA demonstrated antioxidant potential in vitro. Present findings conclude that the standardized aqueous extract of GA stem bark exerted a dose-dependent protection against ADR-induced nephrotoxicity in vivo and may be a promising adjunct in ADR chemotherapy.

Protective effects of three selected standardized medicinal plant extracts used in Sri Lankan traditional medicine in adriamycin induced nephrotoxic Wistar rats

Ethnopharmacological relevanceAbelmoschus moschatus Medik. (family: Malvaceae), Asparagus falcatus (family: Asparagaceae) and Barleria prionitis Linn. (family: Acanthaceae) have been used in the treatment of kidney diseases in Sri Lankan traditional medicine. Besides the traditional use, scientific scrutinization of safe therapeutic use of these medicinal plants in the management of kidney diseases has not been reported to date. Aim of the studyThe three selected doses of the aqueous extracts of the selected medicinal plants were studied for their protective effects against adriamycin (ADR) induced nephrotoxicity in Wistar rats. Materials and methodsChemically standardized plant materials were used in the study. The nephroprotective activity of the lyophilized powder of the aqueous refluxed (4hr) leaf extracts of A. moschatus, A. falcatus and the whole plant extract of B. prionitis was investigated in adriamycin (20 mg/kg, ip) induced nephrotoxicity in Wistar rats (n = 6/group). The treatment regimens were initiated 24 h after the induction of nephrotoxicity and continued daily as a single dose for three consecutive days at three selected doses (200, 400 and 600 mg/kg). Fosinopril sodium (0.09 mg/kg) was used as the standard drug. Nephroprotective activity was assessed by estimating the selected biochemical parameters and by the assessment of histopathology on H and E stained sections of the kidney. ResultsThe plant extracts at the three selected doses significantly attenuated the elevations in serum creatinine, blood urea nitrogen and the loss of urine total protein in a dose related manner in ADR induced nephrotoxic rats (p < 0.001). The serum concentration of albumin and total protein increased significantly (p < 0.001). Histopathological findings corroborated the biochemical evidence of nephroprotective activity. The aqueous extracts of the three selected medicinal plants exerted a relatively high antioxidant activity in vitro. ConclusionsEvaluation of the protective effects based on biochemical parameters and histopathology assessment revealed that the aqueous leaf extracts of A. moschatus, A. falcatus and the whole plant extract of B. prionitis possess significant nephroprotective activity against ADR induced acute nephrotoxicity. The secondary metabolites present in the plant extracts may attribute to the total antioxidant activities of the selected medicinal plant extracts thereby exerting protective effects against nephrotoxicity in Wistar rats.

Regulation of epithelial mesenchymal transition by the renin-angiotensin system: a role for klotho in renal tubular epithelial cells.

Klotho is a putative aging suppressor gene that is primarily expressed in renal tubular epithelial cells. Its expression has been reported to protect against fibrosis in human chronic kidney disease. However, the roles of klotho in epithelial-mesenchymal transition (EMT) and renal fibrosis are yet to be elucidated. The present study aimed to investigate the putative roles of klotho in angiotensin (Ang) II-induced damage of renal tubular epithelial cells. NRK-52E rat cells were treated with various combinations of Ang II, the Ang-converting enzyme inhibitor fosinopril (Fos) and the Ang II receptor antagonist valsartan (Val). The levels of transforming growth factor (TGF)-β1, soluble klotho, α-smooth muscle actin (α-SMA) and E-cadherin in NRK-52E culture supernatants were measured using enzyme-linked immunosorbent assays. Furthermore, the mRNA and protein expression of TGF-β1, klotho, α-SMA and E-cadherin was detected using semiquantitative reverse transcription-polymerase chain reaction, immunocytochemistry and Western blot analysis. The results demonstrated that Ang II inhibited the expression of klotho and E-cadherin, while it upregulated the expression of TGF-β1 and α-SMA, in NRK52E cells. Fos and/or Val were revealed to enhance klotho and E-cadherin expression, and suppress the expression of TGF-β1 and α-SMA, compared with the Ang II-only group. Furthermore, a positive linear correlation was detected between the expression of klotho and E-cadherin, while negative linear correlations with klotho expression were detected for TGF-β1 and α-SMA expression. In conclusion, the expression of klotho was demonstrated to be enhanced following treatment with Fos and Val in Ang II-treated NRK-52E cells. The present results indicate that klotho may be involved in the inhibition of Ang II-induced EMT in renal tubular epithelial cells. Therefore, klotho may serve as a protective factor in renal tubulointerstitial fibrosis and aid the treatment of chronic kidney disease (CKD) patients using precision therapy.

The Herbig Be Star IL Cep A as a Long-Periodic Spectroscopic Binary

The results of long-term spectral monitoring of the Herbig Be star IL Cep A are presented. A smooth variation in the parameters of the Нα and Нβ line emission component has been discovered. The helium absorption lines He I λ4922 and 5876 A show seasonal changes, however, these changes do not correlate with changes in hydrogen emission. The radial velocities of the narrow lines D Na I and DIB λ5780, 5796 A correspond to that of the interstellar medium. The hydrogen emission lines are apparently formed in a triple system, including a close pair of B stars and a remote low-mass K–A component. The orbital elements of this system were calculated using an approximate spectral binary model, where a close pair of massive B stars was considered as one massive component. The rationale for this approach for determining the elements of the orbit is given. The orbital period P = 3550 ± 28 days is determined and some other parameters of the orbit are estimated.

Effect of fosinopril on the renal cortex protein expression profile of Otsuka Long-Evans Tokushima Fatty rats.

Angiotensin-converting enzyme inhibitors (ACEIs) can reduce urinary protein excretion and postpone the deterioration of renal function. However, the mechanisms of renal protection are not yet fully understood. To investigate the mechanisms of ACEIs in the treatment of diabetic nephropathy (DN), the present study determined the effects of the ACEI fosinopril (FP) on the profiling of renal cortex protein expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats using Long-Evans Tokushima Otsuka (LETO) rats as controls. Urinary protein levels at 24 h were examined using the Broadford method. PAS staining was performed to observe renal histopathological changes. The kidney cortices of OLETF, FP-treated OLETF and LETO rats were examined using soluble and insoluble high-resolution subproteomic analysis methodology at age of 36 and 56 weeks. Differentiated proteins were further confirmed using western blotting analysis. The results demonstrated that FP significantly decreased the glomerulosclerosis index and reduced the 24 h urinary protein excretion of OLETF rats. Additionally, 17 proteins significantly changed following FP-treatment. Amongst these proteins, the abundances of the stress-response protein heat shock protein family A member 9 and the antioxidant glutathione peroxidase 3 were particularly increased. These results indicated that FP ameliorated diabetic renal injuries by inhibiting oxidative stress. In conclusion, the differentially expressed proteins may improve our understanding of the mechanism of ACEIs in the OLETF rats.

Development and Validation of Different Spectrophotometric and High-Performance Thin-Layer Chromatographic Methods for the Determination of Fosinopril Sodium, Hydrochlorothiazide, and Chlorothiazide as Hydrochlorothiazide Impurity

Three simple, sensitive, and validated methods were developed for the quantitative determination of fosinopril sodium (FOS) and hydrochlorothiazide (HCZ) in the presence of an HCZ impurity, chlorothiazide (CZ). The first method (I) was the ratio difference spectrophotometric method (RD), in which a standard spectrum of 8 μg mL-1 HCZ was used as a divisor, and the difference in amplitude values at 204.6 and 231.2 nm and 290 and 302.6 nm was used for the determination of FOS and CZ, respectively. Meanwhile, for the determination of HCZ, a standard spectrum of 6 μg mL-1 CZ was the chosen divisor, and the amplitude difference at 275 nm and 293.6 nm was selected for the calculation of its concentrations. The second method (II) was mean centering of ratio spectra spectrophotometric method (MCR), which depended on the implementation of the mean-centered ratio spectra in two successive steps and the measurement of the amplitudes of the mean-centered second ratio spectra at 243.4 nm for CZ and peak-to-peak amplitudes at 215.6 and 215.8 nm for FOS and at 223.8 and 224 nm for HCZ. On the other hand, the third method (III) was thin-layer chromatography (TLC)—densitometry at which the chromatographic separation of this ternary mixture was performed using pre-activated silica gel 60 F254 TLC plates and a developing system mixture consisting of ethyl acetate—chloroform—methanol—formic acid (60:40:5:0.5, by volume) with ultraviolet (UV) scanning at 215 nm. The developed methods were validated according to the International Conference of Harmonization (ICH) guidelines and were successfully used for the determination of FOS and HCZ in their pharmaceutical formulations. Also, a statistical comparison between the developed methods and the reported HPLC method was attained. Using Student’ s t-test and F-test, the results confirmed that there was not any significant difference between them regarding accuracy and precision.

Extract of Plantago asiatica L. Seeds Ameliorates Hypertension in Spontaneously Hypertensive Rats by Inhibition of Angiotensin Converting Enzyme.

Plantago asiatica L. seeds is a common folk medicine with a long history of medical use in China because of its antipyretic, diuretic, and expectorant properties. It has been applied to treat hypertension clinically due to its diuresis, however, its efficacy and mechanisms on anti-hypertension has not been reported yet to our knowledge. In this study, we investigated the antihypertensive effect and underlying mechanisms of P. asiatica L. seeds extract (PASE) in spontaneously hypertensive rat (SHR). Male SHRs were treated with 2.5 mg/kg of fosinopril (FOS) and 400 mg/kg of PASE orally per day for once or 12 weeks. SHR or Wistar-Kyoto rats (WKY) receiving vehicle (distilled water) was used as control. The results demonstrated systolic, diastolic, and mean blood pressures (SBP, DBP, and MBP) were significantly lowered after single and long-term intragastric administration of PASE. The cardiac and aortic index and collagen accumulation were improved in the PASE group compared with the SHRs group. Meanwhile, PASE treatment remarkably reduced urine total protein, the ratio of serum urea nitrogen to serum creatinine, and increased serum potassium. The levels of serum angiotensin I (Ang I), angiotensin II (Ang II), the ratio of Ang II to Ang I, and aldosterone (ALD) were lowered after treatment of PASE. Besides, PASE and its major active constituents of phenylethanoid glycosides, including isoacteoside, plantamajoside and acteoside, were found to effectively inhibit angiotensin-converting enzyme (ACE) activation in vitro. These findings suggest that PASE has the antihypertensive effect that may involve a mechanism of ACE inhibition and simultaneously protect organ damage against hypertension.

Corrigendum to "Cardioprotective Effects of Qishenyiqi Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin-Converting Enzyme 2".

[This corrects the article DOI: 10.1155/2012/978127.].

FORMULATION AND EVALUATION OF FAST DISSOLVING FILM OF FOSINOPRIL

The mouth dissolving film overcomes the shortfalls of conventional quick dispersing/dissolving intraoral tablets. Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure.It undergoes extensive hepatic first pass metabolism, with bioavailability being only 36%. In the present investigation, an attempt was made to formulate fast dissolving film of fosinopril sodium by Solvent casting method using various film forming polymers such as HPMC 5cps, HPMC E-3, HPMC E-15 each being varied at three different concentration(6%,8%,10%). Drug-excipient compatibility studies were carried out by FTIR spectroscopy and DSC. in order to establish compatibility between drug and excipients The results revealed that the drug and excipients were satisfactorily compatible, without any significant changes in the chemical nature of the drug. Prepared films were subjected to different evaluation parameters such as folding endurance, physical appearance, %moisture absorption,drug content uniformity, in vitro disintegration time, in vitro dissolution studies and stability studies. All the formulations show name accurred compliance with pharmacopoeial standards. The stability study shows that no significant changes in films after one month study. Results revealed that the formulations F1 containing 6% HPMC 5cps showed better release property, low disintegration time, good folding endurance and good physical appearance compared to other formulations, so it was selected as the best formulation.

Simultaneous ultraperformance liquid chromatography/tandem mass spectrometry determination of four antihypertensive drugs in human plasma using hydrophilic-lipophilic balanced reversed-phase sorbents sample preparation protocol.

Therapeutic drug monitoring of angiotensin-converting enzyme inhibitors has a great impact on blood pressure control in patients with heart failure and hepatic and renal impairment. To provide an efficient tool for drug assessment in plasma, a UPLC-MS/MS method was developed for simultaneous determination of benazepril hydrochloride, fosinopril sodium, captopril and hydrochlorothiazide in human plasma samples. Solid phase extraction was applied for sample preparation using OASIS® hydrophilic-lipophilic balanced reversed-phase sorbents cartridges. Chromatographic separation was performed using an Agilent SB-C18 column and methanol-0.1% formic acid in water (95:5, v/v) as mobile phase, at flow rate 0.3 mL/min. Detection was accomplished using a tandem mass spectrometer. The method was validated according to US Food and Drug Administration guidelines. It showed good linearity over concentration ranges 5-400 ng/mL for benazepril hydrochloride, fosinopril sodium and hydrochlorothiazide and 100-3500 ng/mL for captopril. CV% values were <13.92% whereas the mean accuracy ranged from 94.50 to 113.82% for quality control samples and their extraction recoveries ranged from 90.60 to 99.38%. In conclusion, the present study revealed method selectivity and sensitivity; it can be applied for estimation of angiotensin converting enzyme inhibitors and hydrochlorothiazide in human plasma for dose adjustment and therapeutic drug monitoring.

Clinical analysis of angiotensin-converting enzyme inhibitor in treatment of Alport syndrome

Objective To investigate the clinical efficacy and safety of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in treatment of children with Alport syndrome (AS). Methods A total of 22 children with AS in Department of Pediatrics, Guangzhou First People′s Hospital and Department of Pediatrics, Shenzhen People′s Hospital between January 2013 and December 2017 were selected.But four children were not included in this study since they did not take medication regularly, and the other 18 cases were included in this study.All the 18 children were initially treated with ACEI.The observation time was from 1 to 5 years.If the symptoms were not effectively controlled, treatment plan would be changed to ACEI combined with ARB treatment.The observation time was from 1 to 3 years.The clinical data and laboratory examination results[including 24-hour urine protein (mg/24 h), urine red blood cell count, plasma albumin (Alb), urea nitrogen (BUN), serum creatinine (Scr), total cholesterol (TC)] were collected for retrospective analysis. Results Eighteen patients started their treatment with ACEI inhibitors (Fosinopril). Within 2 years of treatment, the urinary protein and urinary red blood cells in the children decreased to 47.7% and 41.3%, respectively, and the differences were all statistically significant (all P<0.05), and the renal function was stable within the normal range.Two years later, 7 patients had elevation of urinary protein and urinary erythrocyte elevations and decrease of renal function, and they were treated with ACEI and ARB (Losartan). The other children had no significant change in urine protein and urine red blood cells in the 3rd, 4th, and 5th year, and their renal function was stable.After ACEI treatment alone for 5 years, urinary protein was 47.8% lower than before treatment, and the difference was statistically significant (P<0.05); urinary red blood cells decreased to 32.0% compared with before treatment, and the difference was statistically significant (P<0.05). Seven patients with ACEI alone had poor efficacy, after the treatment with ACEI combined with ARB, the urinary protein and urine red blood cells were lower in the first year and the renal function improved.There was no significant change in urinary protein and urine red blood cells in the 2nd and 3rd year, and renal function was stable.After ACEI combined with ARB treatment for 3 years, urinary protein decreased to 42.3%before treatment, and the difference was statistically significant (P<0.05), and urinary red blood cells decreased to 46.9% compared with before treatment, and the difference was statistically significant(P<0.05). Conclusions ACEI treatment of children with AS can reduce urine protein and help delay renal failure.For children with poor efficacy of ACEI treatment, ACEI combined with ARB may have a certain effect.ARB can be used as an adjunctive treatment for patients with AS who have a poor response to ACEI alone. Key words: Alport syndrome; Clinical treatment; Angiotensin-converting enzyme inhibitor; Angiotensin receptor blocker

Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice.

BACKGROUND:Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC).OBJECTIVE:We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC.METHODS:HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups.RESULTS:The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice.CONCLUSION:Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies.

Effect of Klotho protein on renal oxidative stress in rat with calcium oxalate nephrolithiasis

Objective To investigate the protective effect and mechanism of Klotho protein on oxidative stress in renal tubular epithelial cells of experimental rat models of renal calcium oxalate stone. Methods The 30 SD rats, 6-8 weeks old, were randomly divided into 3 groups(10 of each), normal control group(group A), calcium oxalate model group(group B), drug plus calcium oxalate model group(group C). Group A was established with physiological saline by garage each day, group B was established with 1% ethylene glycol in drinking water+ 2% ammonium chloride by garage(2 ml/d), group C was established with Fosinopril 2.5mg+ Valsartan 15mg aqueous solution 2 ml by gavage on the basis of group B(2 ml/d). 4 weeks later, the level of malondialdehyde (MDA), superoxide dismutase(SOD), catalase(CAT) and glutathione peroxidase(GSH) in the kidney homogenate were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA), Polymerase chain reaction (RT-PCR) was used to measure expression of Klotho and Nrf2 mRNA, and Western Blot was used to measure the expression of Klotho and Nrf2 protein. Results The level of MDA in group B [(12.43±0.43)μmol/mg] was significantly increased compared to group A[(8.67±0.84)μmol/mg, P 0.05). In group A, B, and C, the levels of SOD were (247.89±2.45), (109.54±4.21), and (189.74±10.47)U/mg, respectively; the levels of GSH were (38.98±4.55), (26.87±3.92), and (31.29±2.54)μmol/mg, respectively; CAT were (138.47±8.74), (119.87±8.45), and(127.46±7.45)U/mg, respectively. The levels of SOD, GSH, CAT in group B were significantly lower than that in group A and C, while those in group B were close to group A (P>0.05). The expression of Klotho and Nrf2 mRNA in group B [(0.208±0.036)and (0.499±0.086)] were significantly lower than group A(1.011±0.174 and 1.023±0.139, P<0.05)and group C(1.123±0.248 and 1.023±0.139, P<0.05). The expression of Klotho and Nrf2 protien were also significantly lower than that in group A and C (P<0.05). Conclusions Valsartan and Fosinopril could prevent the formation of renal CaOx stones by upregulating expression of low level Klotho gene induced by ethylene glycol.This effect may be involved with activation of Keapl-Nrf2-ARE signaling pathway. Key words: Klotho; Nuclear factor-E2 related factor 2(Nrf2); Calcium oxalate stone; Oxidative stress