Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injury-induced pathological vascular remodeling / 中国天然药物

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.

Inhibitory effect of dehydroandrographolide on hepatocyte apoptosis induced by carbon tetrachloride in hepatic fibrosis model mice and its mechanism / 吉林大学学报(医学版)

Objective: To investigate the inhibitory effect of dehydroandrographolide (DA) on the hepatocyte apoptosis induced by carbon tetrachloride (CC14) in the hepatic fibrosis model mice, and to elucidate its possible mechanism. Methods: A total of 30 male C57BL/6J mice aged 6-8 weeks were randomly divided into control group, model group and treatment group; there were 10 mice in each group. Except the normal control group, the mice in other two groups were intraperitoneally injected with 20%CC14 2. 0 mL · kg-1, three times a week; the hepatic fibrosis models were establised. The mice in control group were given the same volume of olive oil. The mice in treatment group were intragastrically given 100 mg · kg-1 DA, three times a week; while the mice in control group and model group were given the equal volume of normal saline. Four weeks later, 24 h after the last administration, the eyeball blood was taken, the marrow was broken, and the liver was taken. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of the mice in various groups were detected; the activities of superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) in liver tissue of the mice in various groups were detected. The pathological performance of liver tissue of the mice in various groups were observed by HE staining and Sirius red staining. Western blotting method was used to detect the levels of 8-oxoguanine DNA glycosylase 1 (Oggl), Caspase-3, Bcl-2-associated X protein (Bax), and B-cell lymphoma-2 (Bcl-2) proteins in liver tissue of the mice in various groups. The expression levels of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) proteins in liver tissue of the mice in various groups were observed by immunohistochemistry. Results: Compared with control group, the activities of serum ALT and AST and the level of MDA in liver tissue of the mice in model group were significantly increased (P<0. 05), and the activity of SOD in liver tissue was significantly decreased (P<0. 05). Compared with model group, the activities of ALT and AST in serum and the level of MDA in liver tissue of the mice in treatment group were significantly decreased (P< 0. 05), and the activity of SOD in liver tissue was significantly increased (P<0. 05). The HE staining and Sirius red staining results showed that compared with model group, the inflammatory cell infiltration and collagen deposition in liver tissue of the mice in treatment group were significantly improved. Compared with control group, the expression levels of Oggl, Caspase-3, Bax, TGF-β1, α-SMA and Bcl-2 proteins in liver tissue of the mice in treatment group were significantly increased (P<0. 05); compared with model group, the expression levels of Oggl, Caspase-3, Bax, TGF-β1 and a-SMA proteins in liver tissue of the mice in treatment group were significantly decreased (P< 0.05), and the expression level of Bcl-2 protein was significantly increased (P<0. 05). Conclusion: DA has a protective effect in the mice with hepatic fibrosis induced by CCL, which might be related to reducing oxidative stress injury, inhibiting hepatocyte apoptosis and reducing hepatic stellate cell activation.

Determination of Five Index Components in Fuke Qianjin Tablets by Quantitative Analysis of Multi-compo-nents by Single Marker / 中国药师

Objective:To develop a method of quantitative analysis of multi-components by single marker ( QAMS) for the deter-mination of five index components in Fuke Qianjin tablets. Methods:Using erulic acid as the reference,an HPLC method with a Hy-persil GOLD C18 column (250 mm × 4. 6 mm,5 μm) was applied,the mobile phase was acetonitrile-0. 1% phosphoric acid with gradi-ent elution,the flow rate was 1. 0 ml·min-1 ,the detection wavelength was 254 nm,the column temperature was 30℃ and the injection volume was 10 μl. The relative correction factors among the five index components were detected by QAMS. The contents of the index components were determined respectively by an external standard method and QAMS, and the results were compared between them. The practicability and stability of QAMS were verified. Results:The established QAMS was used to determine the five index compo-nents in Fuke Qianjin tablets,and totally 6 batches of Fuke Qianjin tablets were determined. There were no significant differences be-tween the calculated values and the determined ones (P>0. 05). Conclusion:The QAMS method is simple,effective and accurate in determining the contents of five index components in Fukeqianjin tablets,which can be used for the quality control of Fuke Qianjin tab-lets and provide reference for the further studies.

Determination of Five Index Components in Fuke Qianjin Tablets by Quantitative Analysis of Multi-compo-nents by Single Marker / 中国药师

Objective:To develop a method of quantitative analysis of multi-components by single marker ( QAMS) for the deter-mination of five index components in Fuke Qianjin tablets. Methods:Using erulic acid as the reference,an HPLC method with a Hy-persil GOLD C18 column (250 mm × 4. 6 mm,5 μm) was applied,the mobile phase was acetonitrile-0. 1% phosphoric acid with gradi-ent elution,the flow rate was 1. 0 ml·min-1 ,the detection wavelength was 254 nm,the column temperature was 30℃ and the injection volume was 10 μl. The relative correction factors among the five index components were detected by QAMS. The contents of the index components were determined respectively by an external standard method and QAMS, and the results were compared between them. The practicability and stability of QAMS were verified. Results:The established QAMS was used to determine the five index compo-nents in Fuke Qianjin tablets,and totally 6 batches of Fuke Qianjin tablets were determined. There were no significant differences be-tween the calculated values and the determined ones (P>0. 05). Conclusion:The QAMS method is simple,effective and accurate in determining the contents of five index components in Fukeqianjin tablets,which can be used for the quality control of Fuke Qianjin tab-lets and provide reference for the further studies.

Establishment of the HPLC Fingerprint of Qinghuo Zhimai Tablets and Determination of Three Constituents / 中国药师

Objective:To establish the HPLC fingerprint of Qinghuo Zhimai tablets and determine the contents of geniposide,andrographolide and dehydroandrographolide.Methods:The analysis was performed on a CAPCELL PAK C18 column (250 mm×4.6 mm,5 μm) with acetonitrile and water as the mobile phase with gradient elution at the flow rate of 1.0 ml·min-1.The detection wavelength was 225 nm,and the column temperature was 40℃.Totally 13 batches of Qinghuo Zhimai tablets from different manufacturers were analyzed to establish the fingerprint of Qinghuo Zhimai tablets.Results:There were 14 common peaks calibrated,and the HPLC fingerprint common pattern was established for the HPLC fingerprint of Qinghuo Zhimai tablets.Using the method of reference substance attribution,3 compounds were determined as geniposide,andrographolide and dehydroandrographolide.The similarity of 9 batches in the 13 batches of Qinghuo Zhimai tablets was higher than 0.9.The content determination of geniposide,andrographolide and dehydroandrographolide showed good linearity (r>0.999 8,n=6),the average recovery was 96.90%,97.55% and 97.07% and RSDs were 1.61%,1.45% and 1.47%(n=9),respectively.Conclusion:The method is simple and accurate with good repeatability,which can be used for the identification and evaluation of Qinghuo Zhimai tablets,and provides important scientific basis for the quality control of Qinghuo Zhimai tablets.

Simultaneous Determination of Andrographlide and Dehydroandrographolide in Ganmaoqing Tablet by HPLC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of andrographlide and dehydroandrographolide in Ganmaoqing tablet. METHODS:HPLC was performed on the column of Thermo BDS C18 with mobile phase of mathanol-water at a flow rate of 1.0 ml/min,detection wavelength was 225 nm for andrographlide and 254 nm for dehydroandrographolide,col-umn temperature was 30 ℃,and injection volume was 10 μl. RESULTS:The linear range was 2.25-45.00 μg/ml for andrographlide (r=0.9998) and 1.00-20.00 μg/ml for dehydroandrographolid(r=0.9990);RSDs of precision,stability and reproducibility tests were no more than 0.8%;average recoveries were 96.96%-99.80%(n=9) and 96.79%-100.65%(n=9). CONCLUSIONS:The method is simple,accurate and reliable,and can be used for the quality control of andrographlide and dehydroandrographolide in Ganmaoqing tablet.

Simultaneous Determination of Four Components in Compound Chuanxinlian Tablet by HPLC / 中国药房

OBJECTIVE:To establish a method for the simultaneous determination of andrographolide,quercetin-3-O-gluco-side,dehydroandrographolide and kaempferol-3-O-glucoside in Compound chuanxinlian tablet. METHODS:HPLC was performed on the column of Phenomenex C18 with mobile phase of acetonitrile- 0.1% phosphoric acid aqueous(gradient elution)at a flow rate of 1.0 ml/min,the detection wavelength was 225 nm for andrographolide,335 nm for quercetin-3-O-glucoside and 254 nm for de-hydroandrographolide and kaempferol-3-O-glucoside,column temperature was 25 ℃,and the volume injection was 10 μl. RE-SULTS:The linear range was 0.111-2.770 μg for andrographolide(r=0.999 9),0.064-1.605 μg for quercetin-3-O-glucoside (r=0.999 9),0.086-2.138 μg for dehydroandrographolide(r=0.999 9)and 0.050-1.260 μg for kaempferol-3-O-glucoside(r=0.999 9);the limits of quantitation were 0.48 ng,0.88 ng,0.93 ng and 1.03 ng,the limits of detection were 0.79 ng,1.15 ng,0.96 ng and 1.07 ng,respectively;RSDs of precision,stability and reproducibility tests were lower than 2.0%;recoveries were 96.57%-100.30%(RSD=1.3%,n=9),95.04%-98.87%(RSD=1.3%,n=9),95.74%-102.92%(RSD=2.4%,n=9) and 96.73%-100.95%(RSD=1.6%,n=9),respectively. CONCLUSIONS:The method is sensitive,reliable and reproducible,and can be used for the si-multaneous determination of andrographolide,quercetin-3-O-glucoside,dehydroandrographolide and kaempferol-3-O-glucoside in Compound chuanxinlian tablet.

Potassium Dehydroandrographolide Succinate Injection for the treatment of child epidemic parotitis: A systematic review and meta-analysis / 中国结合医学杂志

<p><b>OBJECTIVE</b>To systematically evaluate the clinical efficacy and safety of Potassium Dehydroandrographolide Succinate Injection (PDSI) in the treatment of child epidemic parotitis (EP).</p><p><b>METHODS</b>Randomized controlled trials (RCTs) regarding PDSI in the treatment of child EP were searched in China National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database, PubMed, and Cochrane Library from inception to July 30, 2013. Two reviewers independently retrieved RCTs and extracted information. The Cochrane risk of bias method was used to assess the quality of included studies, and a meta-analysis was conducted with RevMan 5.2 software.</p><p><b>RESULTS</b>A total of 11 studies with 818 participants were included. The quality of the studies was generally low, among which only one study mentioned the random method. The meta-analysis indicated that PDSI was more effective than the conventional therapy with Western medicine for EP in the outcomes of the total effective rate [relative risk (RR)=1.23, 95% confidence interval (CI) [1.14, 1.33], P<0.01], the time of temperature return to normal, the time of detumescence [mean difference (MD)=-2.10, 95% CI [-2.78,-1.41], P<0.01], and the incidence of complications (RR=0.14, 95% CI [0.03, 0.72], P=0.02). There were 6 adverse drug reactions (ADRs) in this systematic review, 2 of which were mainly represented rash and diarrhea in the experiment group, while another 4 ADRs occurred in the control group.</p><p><b>CONCLUSIONS</b>Based on the systematic review, PDSI was effectiveness and relatively safety in the treatment of child EP. But further rigorously designed trials are warranted to determine its effectiveness.</p>

Study on active components of Andrographis paniculata at various growth periods and differential expression of key enzyme gene / 中草药

Objective: To study the dynamic changes of the active components from Andrographis paniculata at various growth periods grown in Suixi in Guangdong province, Zhangpu in Fujian province as well as introduced and cultivated in Nanjing and Huaian in Jiangsu province, and to investigate the expression level of the key enzyme gene at the same time in order to obtain the accumulation trend of the active contents from A. paniculata and explore a reasonable harvest and its molecular mechanism. Methods: The contents of andrographolide and dehydroandrographolide were analyzed by HPLC. The expression of key enzyme gene, ent-copalyl diphosphate synthase (CPS) was measured at mRNA level with QRT-PCR. Results: The growth periods of A. paniculata were similar in different areas. It grew fast at vegetative stage while slowly at reproductive stage. The contents of active ingredients in A. paniculata from four areas showed the same change tendency. The content of andrographolide reached the highest level at flowering period. At the same time, the changes of dehydroandrographolide was flatting out. The expression of CPS reached its maximum at bud to flowering period. There was a significant positive correlation between the content of andrographolide and the expression of CPS. Conclusion: The optimal harvest time of A. paniculata should be judged on phenological period and the best harvest period is flowering period.

Intestinal absorptive characteristics of andrographolide and dehydroandrographolide in extract from Andrographis paniculata in rats / 中草药

Objective: To investigate the intestinal absorptive characteristics of andrographolide (A) and dehydroandrographolide (DDA) in the extract of Andrographis paniculata in rats. Methods: The intestine of rat was cannulated for in situ perfusion. UV was used to determine the concentration of phenol red, and HPLC was used to determine the concentration of A and DDA. The effects of drug concentration, pH value, and absorption site on the absorption had been studied. Results: In 111.22-335.78 μg/mL dose range of A. paniculata extract, Ka and P of A were reduced with the increase of concentration. With the pH value increasing from 5.34 to 6.38, Ka and P were increased slightly. With the pH value increasing from 6.38 to 7.40, Ka and P had a downward trend. A was absorbed in various sections of intestines, and the P descended in the order of duodenum, jejunum, ileum, and colon. In 111.22-222.78 μg/mL dose range of A. paniculata extract, Ka and P were reduced with the increase of concentration. In 222.78-335.78 μg/mL dose range, Ka and P had no change with the increase of concentration. Under the condition of pH 5.34, the absorption was better. With the pH value increasing from 5.34 to 7.40, Ka and P showed a slight downward trend, and P descended in the order of ileum, jejunum, colon, and duodenum. Conclusion: The intestinal absorption mechanism of A and DDA in A. paniculata extract is not just passive transport, but also including the carrier medium transport which are both affected by pH value. The best absorption site of A is duodenal, and the best absorption site of DDA is ileumother. Other components may have no significant influence to the intestinal absorption of A, but they may promote the intestinal absorption of DDA.

Preparation technology and quality control of Chuanxinlian Soft Capsule / 中草药

Objective: To establish the preparation technology and a method for the quality control of Chuanxinlian Soft Capsule. Methods: According to the Andrographis Herba Tablets item in Chinese Pharmacopoeia 2010, the Chuanxinlian extracts were prepared; The contents of capsule and capsule shell were evaluated by single factor. The content of dehydroandrographolide and the dissolution of Chuanxinlian Soft Capsule were determined by HPLC. Results: The best formulation of Chuanxinlian Soft Capsule content (1 000 capsules) was determined as follows: Chuanxinlian 1 000 g, span 80 5.5 g, beeswax 27.5 g, and soybean oil 422 g. The final formulation of capsule shell was fixed as gelatin-glycerin-water (100:40:100). The prepared Chuanxinlian Soft Capsule was in accordance with the regulation in Chinese Pharmacopoeia. The content and dissolution of dehydroandrographolide had no significant difference among different batches of Chuanxinlian Soft Capsule. Conclusion: This prescription of Chuanxinlian Soft Capsule is reasonable and effective; The method is simple and accurate and can be used for the quality control of Chuanxinlian Soft Capsule.

Effect evaluation of potassium sodium dehydroandrographolide succinate for injection in combination with smecta enema treatment for children with autumn diarrhea / 中国实用护理杂志

Objective To observe the effect of potassium sodium dehydroandrographolide succinate for injection (PSDS)combining with smecta enema treatment on children with autumn diarrhea.Methods 102 children patients with autumn diarrhea were selected and divided into the control group,the PSDS group and the combination group with 34 patients in each group.The control group received symptomatic supportive treatment,based upon this,the PSDS group received PSDS,and the combination group adopted PSDS and smecta enema treatment.The treatment effect was compared between the three groups.Results The effect of the PSDS group and the combination group was better than the control group,the effect of the combination group was better than the PSDS group.Conclusions Combination of PSDS with smecta enema treatment for children with autumn diarrhea has significant effect,but enough attention should be paid to peri-anal nursing.

Absorption mechamism of dehydroandrographolide in human caco-2 cell monolayer model / 中草药

Objective: To study the absorption mechanism of dehydroandrographolide (DAL) in human Caco-2 cell monolayer model. Methods: Caco-2 cell monolayer model was applied to investigate the bidirectional transport of DAL. The effects of time, drug concentration, temperature, and P-gp inhibitor (Verapamil) on the absorption of DAL were observed. Drug concentration was measured by LC/MS/MS and the apparent permeability coefficients (Papp) were calculated. Results: With the time and concentration increasing, the bidirection transport of DAL in Caco-2 cell monolayer model was of time and concentration dependence, without saturation. And it was not influenced by the change of temperature and the presence of Verapamil. Conclusion: The absorption and transport of DAL are passive diffusion as the dominating process in Caco-2 cell monolayer model.

Content Mensuration of Dehydroandrographolide in Ganmaoqing Capsule by HPLC / 中国基层医药

Objective To establish the determination of Dehydroandrographolide in Ganmaoqing Capsule. MethodsThe determination was carried out by HPLC with a KromasilC-18 column(250 mm ×4.6 mm,5μm),methanol-water(65:35)severed as the mobile phase,the speed was 1mL/min and the detection wavelength was at 254 nm. ResultsDehydroandrographolide showed a good linear relationship at the range of 0.04872 μg ～0.38976 μg(r2 =0.9995,n= 8);The average recovery of Dehydroandrographolide was 100.1%(RSD= 2.92%). ConclusionHPLC method was sensitive,accurate,reproducible,specific and could be used for quality control of Ganmaoqing Capsule efficiently.

Preparation and Quality Control of Potassium Dehydroandrographolide Succinate Hollow Suppository / 中国药房

OBJECTIVE:To prepare Potassium dehydroandrographolide succinate(PDS)hollow suppository and establish a method for its quality control.METHODS:The PDS hollow suppository was prepared with semisynthesis fatty acid glyceride as ground substances and PEG300 or 1,2 propylene glycol as disperse medium.The content of PDS was determined by ultraviolet spectrophotometry at a detection wavelength of 251nm.RESULTS:The linear concentration range of PDS was 6.0～50.0?g?mL-1(r=0.999 9,n=5).The two kinds of PDS hollow suppository were all up to the quality standard.CONCLUSION:This method is reasonable in design and feasible in technology.

Determination of Dehydroandrographolide in Fufang Kumu Xiaoyan Pian by HPLC / 中国中医药信息杂志

Objective To establish a HPLC method for the assay of Dehydroandrographolide in Fufang Kumu Xiaoyan Pian. Methods Standard was Dehydroandrographolide, HPLC was used with Agilent ZORBAX SB-C18 column (4.6 mm?150 mm, 5 ?m). The mobile phrase was consisted of acetonitrile-0.1% Ammonia slution (30∶70). The detection wavelength at 253 nm. The flow rate was 1 mL/min. Results The assay displayed good linearity. The linear range of ephedrine Hydrochloride was 0.049 92~4.992 ?g (r =0.999 9, n =7). The average recovery was 99.70% and RSD was 0.63% (n =9). Conclusion This method is simple, accurate and can be used for the quality control of Fufang Kumu Xiaoyan Pian.

Investigation of the Stability of the Potassium Sodium Dehydroandrographolide Succinate Injection in 6 Kinds of Infusions / 中国药房

OBJECTIVE:To study the compatible stability of potassium sodium dehydroandrographolide succinate injection in six infusions.METHODS:The changes of potassium sodium dehydroandrographolide succinate injection in appearance,pH value,content and insoluble micrones after mixing with six infusions(0.9% NaCl solution,Compound sodium chloride injection,Glucose saline,DX 40 glucose injection,5% glucose injection in glass or plastic containers)were determined respectively.RESULTS:No significant changes were noted for the mixture within 4 h in appearance,pH value and content.Except the micrones in potassium sodium dehydroandrographolide succinate mixed with compound sodium chloride injection were up to the standard(China Pharmacopeia,2005 edition),the micrones in all the other mixtures failed to meet the standard.CONCLUSION:Potassium sodium dehydroandrographolide succinate injection can be used in combination with compound sodium chloride injection.

The Effect of Hydroxypropyl-?-Cyclodextrin on the Stability of Potassium Dehydroandrographolide Succinate Solution / 中国药房

OBJECTIVE:To study the effect of HP-?-CD on the stability of potassium dehydroandrographolide succina_ te solution.METHODS:The stability of the testing group(potassium dehydroandrographolide succinate solution+HP-?-CD)was determined by a thermostatic accelerated test with the content variation of potassium dehydroandrographolide succi?nate solution as an index and the potassium dehydroandrographolide succinate solution that was free of HP-?-CD as the control.RESULTS:The content variation of the testing group was less as against the control group,the terms of validity for the2groups were0.657y and3.40y respectively.CONCLUSION:The stability of potassium dehydroandrographolide succi?nate solution can be increased by adding HP-?-CD to which.

Effects of density,phosphorous,and nitrogen fertilizers on yield and quality of Andrographis paniculata / 中草药

Objective To study the effects of density,phosphorous(P),and nitrogen(N)fertilizers on yield and quality of Andrographis paniculata.Methods Randomized block design in yield was used and HPLC was used to analyze the content of andrographolide and dehydroandrographolide.Results Plant height,fresh weight,dry weight,content of dehydroandrographolide were influenced significantly by density.The quality character and economic yield of content of andrographolide,dehydroandrographolide,total content of both andrographolide and dehydroandrographolide were significantly influenced by P nutrition.The economic yield of dry weight,content of andrographolide and dehydroandrographolide,and total content of both andrographolide and dehydroandrographolide were influenced significantly or extreme significantly by N nutrition.P and the interaction of P and N fertilizer extremely influenced the economic yield.The relative influences between plant weight and dry weight was extremely significance,that between quality character and quality character,that between quality character and economic yield were significant or extremely significant.Conclusion When planted with 1.8?105 /hm2,fertilizered with P2O5 540 kg/hm2 and pure N 225 kg/hm2,the hightest economic yield is gained.

Study on the Stability of Potassium Dehydroandrographolide Succinate Solution in Different Conditions / 中药新药与临床药理

Objective To study the stability of potassium dehydroandrographolide succinate solution in different conditions.Methods The classical thermostatic test was adopted to investigate the stability of potassium dehydroandrographolide succinate in phosphate buffer solutions of different pH values,in different buffer solutions of the same pH value and in citrate buffer solutions of different concentrations.Results The stability of potassium dehydroandrographolide succinate solution was different at different pH values and was the best at pH 6.5.In various buffer solutions of pH 6.5,the hydrolyzation of potassium dehydroandrographolide succinate solution was delayed by citrate buffer solution,and the stability of the solution had no correlation with the concentration of citrate buffer solution.Conclusion The stability of potassium dehydroandrographolide succinate solution varies in different conditions.This will supply a reference for the study on potassium dehydroandrographolide succinate solution and its similar preparations.