Polymer Matrix and Manufacturing Methods in Solid Dispersion System for Enhancing Andrographolide Solubility and Absorption: A Systematic Review.

Background: Andrographolide (ADG) has poor aqueous solubility and low bioavailability. This study systematically reviews the use of solid dispersion (SD) techniques to enhance the solubility and absorption of ADG, with a focus on the methods and polymers utilized. Methodology: We searched electronic databases including PubMed, Web of Science, Scopus®, Embase and ScienceDirect Elsevier® up to November 2023 for studies on the solubility or absorption of ADG in SD formulations. Two reviewers independently reviewed the retrieved articles and extracted data using a standardized form and synthesized the data qualitatively. Results: SD significantly improved ADG solubility with up to a 4.7-fold increase and resulted in a decrease in 50% release time (T1/2) to less than 5 min. SD could also improve ADG absorption, as evidenced by higher Cmax and AUC and reduced Tmax. Notably, Soluplus-based SDs showed marked solubility and absorption enhancements. Among the five SD techniques (rotary evaporation, spray drying, hot-melt extrusion, freeze drying and vacuum drying) examined, spray drying emerged as the most effective, enabling a one-step process without the need for post-milling. Conclusions: SD techniques, particularly using Soluplus and spray drying, effectively enhance the solubility and absorption of ADG. This insight is vital for the future development of ADG-SD matrices.

Comparative Inhibitory Efficacy on the iNOS/NO System of Curcuminand Tetrahydrocurcumin-Self-Microemulsifying Liquid Formulation in Chronic Gastric Ulcer Model.

BACKGROUND: Curcumin was found to accelerate gastric ulcer healing by the main mechanism, i.e., the suppression of iNOS mediated inflammation. Although Tetrahydrocurcumin (THC) is claimed to be an active antioxidant element of curcumin, its antiulcer activity has not been systematically examined. The utility of Self-Microemulsifying Drug Delivery Systems (SMEDDSs) for curcumin and THC formulations in the liquid form was also found to increase the rate and extent of release of curcumin- and THC-SMEDDS. Nevertheless, the beneficial antiulcer effect of these nanoproducts has not yet been evaluated. OBJECTIVE: This study aimed to evaluate and compare the antiulcer efficacy of curcumin- and THCSMEDDS through the inhibition of the iNOS/NO system in the rat model. METHODS: Antiulcer efficacy was compared in terms of the ability to accelerate healing of gastric ulcer including the efficient inhibitory action on inflammatory NO production in activated macrophages and iNOS mRNA expression at the ulcerated area. RESULTS: THC was found to have less ulcer healing capacity than curcumin with a lack of significant inhibitory effect on the iNOS/NO system. The SMEDDS used in the study significantly increased the inhibitory efficacy of THC on iNOS/NO production and iNOS mRNA expression compared to the inhibitory potency of curcumin. An oral administration of curcumin- or THC-SMEDDS once a day was appropriate for exerting a comparable curative efficacy to a twice-daily oral administration of curcumin or THC. CONCLUSION: The SMEDDS used in the study was observed to enhance the inhibitory efficacy of the antiulcer drug on the iNOS/NO system, leading to a reduction of daily dosing and dosing frequency.

Anti-inflammatory effect of isopimarane diterpenoids from Kaempferia galanga.

Two new isopimarane diterpenes, 1α-hydroxy-14α-methoxyisopimara-8(9),15-diene (7) and 1α,14α-dihydroxyisopimara-8(9),15-diene (9) and eight known isopimarane diterpenes including (-)-sandaracopimaradiene (1), 6ß-acetoxysandaracopimaradiene-9α-ol (2), sandaracopimaradiene-7ß,9α-diol (3), sandaracopimaradiene-1α,9α-diol (4), 6ß-acetoxysandaracopimaradiene-9α-ol-1-one (5), 6ß-acetoxysandaracopimaradiene-1α,9α-diol (6), 6ß,14α-dihydroxyisopimara-8(9),15-diene (8), and 6ß,14ß-dihydroxyisopimara-8(9),15-diene (10) were isolated from hexane fraction of Kaempferia galanga ethanol extract. Compounds 5, 6, 8, and 9 exerted the good anti-inflammatory effect on lipopolysaccharide-stimulated nitric oxide production from RAW264.7 cells with IC50 of 11.2, 7.7, 14.3, and 12.1 µM, respectively. These four compounds inhibited nitric oxide synthase (iNOS) mRNA expression. Compounds 5 and 6 also suppressed cyclooxygenase 2 (COX-2) mRNA expression; in addition, compound 6 had mild inhibitory effect on TNF-α mRNA. Among these compounds, 5 dramatically inhibited iNOS and COX-2 mRNA expression. The influential structures were proposed to be oxygen substitute at C-1, C-6, and α-OH at C-14.

Antiinflammation constituents from Curcuma zedoaroides.

Curcuma zedoaroides, a Zingiberaceae species, has been used for snake bite antidote and wound care in Thailand. Seven compounds were isolated from the bioactive chloroform extract consisted of one new guaiane sesquiterpene lactone, 5-epiphaeocaulisin A (4) and one new diarylheptanoid, 1,2,3,5-tetrahydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl) heptane (7), together with five known guaiane-type sesquiterpene lactones including gweicurculactone (1), zedoalactone B (2), phaeocaulisin C (3), zedoalactone H (5), and zedoalactone E (6). The antiinflammation was investigated on NO and TNF-α production using RAW264.7 cells. In addition, the expressions of genes involved in inflammation including iNOS, COX-2, and TNF-α were assessed. The results found that Compounds 1-7 presented their antiinflammation against NO production. The most potential effects were demonstrated on Compounds 1 and 7 with IC50 of 27.3 and 32.6 µM, respectively. Although, Compounds 1 and 7 did not inhibit TNF-α production, their suppression on iNOS and COX-2 mRNA expression were revealed. These results support the ability of chloroform fraction, Compounds 1 and 7 on antiinflammation, whereas others exhibited moderate and mild effect.

Clinical outcomes of patients infected with carbapenem-resistant Acinetobacter baumannii treated with single or combination antibiotic therapy.

OBJECTIVE: To evaluate treatment outcomes in patients with carbapenem-resistant Acinetobacter baumannii (CRAB) nosocomial infections treated with antimicrobial agent either alone or in combination. MATERIAL AND METHOD: Clinical data were retrospectively evaluated in patients with CRAB nosocomial infections admitted to Songklanagarind Hospital, Songkhla, Thailand from January-December 2008. RESULTS: One hundred ten patients with CRAB nosocomial infections were identified. Most patients (57.3%) had site of infection in the lower respiratory tract and the majority of them (61.8%) received a single antimicrobial agent. Crude mortality was 30%. The presumptive success rate was 60.3% (41/68) for patients given monotherapy and 81.0% (34/42) for patients given combination therapy (p = 0.024). Patients given combination therapy were more likely to have been given at least one antibiotic to which the organism was susceptible (p = 0.004). In multivariate analysis, renal impairment, bloodstream infection, and inappropriate antimicrobial regimen were independent predictors of treatment failure. CONCLUSION: The combination therapy regimen yielded more presumptive treatment success by increasing the likelihood of an appropriate antimicrobial therapy. Additionally, inappropriate antimicrobial treatment, renal impairment, and bloodstream infection were associated with poor treatment outcomes in patients with CRAB nosocomial infections.

Antiinflammatory constituents from Eclipta prostrata using RAW264.7 macrophage cells.

The whole plant extract of Eclipta prostrata and its isolated compounds were tested for their antiinflammatory effects against lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2 ) and tumor necrosis factor-alpha (TNF-α) release in RAW264.7 cells, as well as for the antiinflammatory mechanism of the active compound on mRNA expression. Among the isolated compounds, orobol (5) exhibited the highest activity against NO release with an IC50 value of 4.6 µm, followed by compounds 1, 2 and 4 with IC50 values of 12.7, 14.9 and 19.1 µm, respectively. The IC50 value of compound 5 against PGE2 release was found to be 49.6 µm, whereas it was inactive towards TNF-α (IC50 > 100 µm). The mechanism of orobol (5) was found to down-regulate iNOS and COX-2 mRNA expression in a concentration-dependent manner. The present study may support the traditional use of Eclipta prostrata for the treatment of inflammatory-related diseases.

Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizomes of Kaempferia parviflora Wall. ex Baker have been traditionally used in Thailand to treat abscesses, gout, and peptic ulcers. AIM: Previously, we reported that the chloroform fraction of a Kaempferia parviflora extract had an inhibitory effect on rat paw-edema. In the present study, we isolated the constituents of this fraction and investigated the anti-inflammatory mechanism against nitric oxide (NO) production, tumor necrosis factor-α (TNF-α) and the expression of inducible nitric oxide synthase (iNOS) as well as phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated c-Jun N-terminal kinase (p-JNK). In addition, effects of trimethylapigenin (4) on the enzyme activities of protein kinases possibly leading to iNOS expression were examined to clarify the targets. MATERIALS AND METHODS: The chloroform fraction was isolated using silica gel column chromatography and HPLC. Isolated compounds were tested against NO and TNF-α using RAW264.7 cells. Cytotoxicity and iNOS, p-ERK and p-JNK expression were also examined. RESULTS: Three active components, 5,7-dimethoxyflavone (2), trimethylapigenin (4), and tetramethylluteolin (5), markedly inhibited the production of NO in lipopolysaccharide (LPS)-activated RAW264.7 cells. Compounds 2, 4, and 5 moderately inhibited production of TNF-α. Compounds 2, 4, and 5 strongly inhibited expression of iNOS mRNA and iNOS protein in a dose-dependent manner, but did not inhibit p-ERK or p-JNK protein expression. The most active compound, 4, did not inhibit the enzyme activity of inhibitor of κB kinases or mitogen-activated protein kinases, but inhibited that of spleen tyrosine kinase (SYK). CONCLUSION: The mechanism responsible for the anti-inflammatory activity of methoxyflavonoids from the chloroform fraction of the rhizomes of Kaempferia parviflora is mainly the inhibition of iNOS expression, and the inhibition of SYK by 4 may be involved in the suppression of LPS-induced signaling in macrophages.

In vitro activity of colistin or sulbactam in combination with fosfomycin or imipenem against clinical isolates of carbapenem-resistant Acinetobacter baumannii producing OXA-23 carbapenemases.

This study investigated the in vitro activity of colistin or sulbactam in combination with fosfomycin or imipenem against eight strains of carbapenem-resistant A. baumannii (CRAB). The eight CRAB clinical isolates were collected from hospitalized patients admitted to Songklanagarind Hospital in southern Thailand during January-December 2008. The isolates were divided into 4 different patterns of clonal relationships using the Repetitive Extragenic Palindromic-Polymerase Chain Reaction method (REP-PCR). The in vitro activity of combination antibacterial agents against theses isolates were determined by chequerboard and time-kill methods. All isolates producing OXA-23 carbapenemases were universally susceptible to colistin but intermittently susceptible to other antimicrobial agents. A chequerboard assay showed the synergistic effects of sulbactam plus fosfomycin and colistin plus fosfomycin in 75% and 12.5% of isolates, respectively. Sulbactam at a concentration of 1 x MIC plus fosfomycin at 1 x MIC or at 1/4 x MIC showed synergism in 75% and 37.5% of clinical isolates, respectively. Bactericidal activity was observed for up to 12 hours of incubation. There was no synergism between colistin and sulbactam, sulbactam and imipenem, and colistin and imipenem, against the tested isolates. Combined use of sulbactam and fosfomycin may provide an alternative therapeutic option for CRAB infections.

Anti-allergic principles of Rhinacanthus nasutus leaves.

Three naphthoquinone derivatives, rhinacanthin-C (1), -D (2) and -N (3) were isolated from the extract of Rhinacanthus nasutus Kurz leaves and were tested for anti-allergic effect. The result indicated that all three compounds possessed very potent anti-allergic activity against antigen-induced beta-hexosaminidase release as a marker of degranulation in RBL-2H3 cells with IC(50) values of 6.9, 8.9 and 6.4 microM, respectively. In addition, the effects of rhinacanthin-C, -D and -N on antigen-induced release of TNF-alpha and IL-4 were also examined. It was found that rhinacanthin-C showed the most potent on antigen-induced TNF-alpha release with an IC(50) value of 0.7 microM, followed by rhinacanthin-D (IC(50)=3.8 microM) and rhinacanthin-N (IC(50)=10.3 microM), whereas those for IL-4 were rhinacanthin-D (IC(50)=5.4 microM), rhinacanthin-C (IC(50)=7.0 microM) and rhinacanthin-N (IC(50)=12.0 microM), respectively. The mechanisms in the late phase reaction of rhinacanthin-C, -D and -N were found to inhibit TNF-alpha and IL-4 gene expression in antigen-induced TNF-alpha and IL-4 releases on from RBL-2H3 cells as dose-dependent manners. The structure-activity trends of rhinacanthin-C,-D and-N on the inhibition of TNF-alpha release are as follow; substitution with octadienoic acid (rhinacanthin-C) conferred much higher activity than that of benzodioxo carboxylic acid ester (rhinacanthin-D) as well as naphthalene carboxylic acid ester (rhinacanthin-N). For the inhibition of IL-4 release, the substitution with octadienoic acid (rhinacanthin-C) and benzodioxo carboxylic acid ester (rhinacanthin-D) possessed the effect two-fold higher than that of naphthalene carboxylic acid ester (rhinacanthin-N). As regards active constituents for anti-allergic activity of R. nasutus, rhinacanthin-C, -D and -N are responsible for anti-allergic effect of this plant on both the early phase and late phase reactions. The finding may support the traditional use of R. nasutus leaves for treatment of allergy and allergy-related diseases.

Anti-inflammatory mechanism of Kaempferia parviflora in murine macrophage cells (RAW 264.7) and in experimental animals.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizomes of Kaempferia parviflora Wall. ex Baker have been used in Thailand for treatment of gout, apthous ulcer, peptic ulcer and abscesses. AIM OF THE STUDY: In our previous study, the crude ethanol extract of Kaempferia parviflora and its compound (5, 5-hydroxy-3,7,3',4'-tetramethoxyflavone), was reported to show nitric oxide (NO) inhibition in RAW 264.7 cells. The present study is thus investigated the anti-inflammatory mechanism of Kaempferia parviflora extract and compound 5 against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expressions. MATERIALS AND METHODS: The extract of Kaempferia parviflora and its compound were tested against NO and prostaglandin E(2) (PGE(2)) releases using RAW264.7 cells as well as studied on anti-inflammatory activity in carrageenan-induced rat paw edema and acute toxicity in mice. RESULTS: The results revealed that the ethanol extract of Kaempferia parviflora markedly inhibited PGE(2) release with an IC(50) value of 9.2 microg/ml. This plant extract and compound 5 also suppressed mRNA expression of iNOS in dose-dependent manners, whereas COX-2 mRNA expression was partly affected. According to the in vivo study, chloroform and hexane fractions greater decreased rat paw edema than ethanol, ethyl acetate and water fractions. CONCLUSION: The mechanisms for anti-inflammatory activity of Kaempferia parviflora and compound 5 are mainly due to the inhibition of iNOS mRNA expression but partly through that of COX-2 mRNA.

Effects of rhinacanthins from Rhinacanthus nasutus on nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha releases using RAW264.7 macrophage cells.

Three naphthoquinone derivatives, rhinacanthin-C (1), -D (2) and -N (3) were isolated from the leaves of Rhinacanthus nasutus extract and were tested for anti-inflammatory activity. The result indicated that all three compounds possessed very potent anti-inflammatory activity against lipopolysaccharide (LPS)-induced nitric oxide release with IC(50) values of 1.8, 6.2 and 3.0 microM, respectively. In addition, the effects of rhinacanthin-C, -D and -N on LPS induced release of prostaglandin E(2) (PGE(2)) and tumor necrosis factor (TNF-alpha) were also examined. It was found that rhinacanthin-C exhibited the most potent on PGE(2) release with an IC(50) value of 10.4 microM, followed by rhinacanthin-D (IC(50)=14.4 microM) and rhinacanthin-N (IC(50)=52.1 microM), whereas those for TNF-alpha were inactive (IC(50)>100 microM). The mechanisms in transcriptional level of rhinacanthin-C were found to inhibit iNOS and COX-2 gene expressions in LPS-induced NO and PGE(2) releases from RAW264.7 cells in concentration-dependent manners. Regarding active constituents for anti-inflammatory activity of R. nasutus, rhinacanthins are responsible for this effect through the inhibition of NO and PGE(2) releases. The finding may support the traditional use of R. nasutus leaves for treatment of the inflammatory-related diseases.

Identification of a product specific beta-amyrin synthase from Arabidopsis thaliana.

Triterpene skeletons are produced by oxidosqualene cyclases (OSCs). The genome sequencing of Arabidopsis thaliana revealed the presence of thirteen OSC homologous genes including At1g78950, which has been revised recently as two independent ORFs, namely At1g78950 and At1g78955. The cDNA corresponding to the revised At1g78950 was obtained by RT-PCR, ligated into Saccharomyces cerevisiae expression vector pYES2, and expressed in a lanosterol synthase deficient S. cerevisiae strain. LC-MS and NMR analyses of the accumulated product in the host cells showed that the product of At1g78950 is beta-amyrin, indicating that At1g78950 encodes a beta-amyrin synthase (EC 5.4.99.-).

Transcription profiles analysis of genes encoding 1-deoxy-D-xylulose 5-phosphate synthase and 2C-methyl-D-erythritol 4-phosphate synthase in plaunotol biosynthesis from Croton stellatopilosus.

Genes encoding 1-deoxy-D-xylulose 5-phosphate synthase (DXS; EC 2.2.1.7) and 2C-methyl-D-erythritol 4-phosphate synthase (MEPS; EC 1.1.1.267), the first two enzymes in the deoxyxylulose phosphate (DXP) pathway, were cloned from young leaves of Croton stellatopilosus, and designated as 1-deoxy-D-xylulose 5-phosphate synthase (CSDXS) and 2C-methyl-D-erythritol 4-phosphate synthase (CSMEPS), respectively. Analysis of deduced amino acid sequences of the CSDXS and the CSMEPS confirmed their nucleotide sequences as they shared high identities to other known DXSs and MEPSs in higher plants. Physiological roles of the CSDXS and the CSMEPS were determined for the mRNA expressions in leaves, twigs and roots. Transcription profiles analyses of the CSDXS and the CSMEPS genes were investigated using semi-quantitative RT-PCR technique. Relative intensities of the CSDXS and the CSMEPS expressions to house-keeping gene (18S rRNA) were calculated. The results indicated that the levels of mRNAs expressions of the CSDXS and the CSMEPS were high in leaves and twigs. This evidence was in line with the high content of plaunotol, accumulated in leaves and twigs. Neither the CSDXS nor the CSMEPS were expressed in roots, where plaunotol was not detected. From this study, it can be concluded that plaunotol is biosynthesized in the chloroplastic tissue and regulated by the CSDXS and the CSMEPS.

Production of triterpene acids by cell suspension cultures of Olea europaea.

Olive (Olea europaea) contains large quantity of triterpene acids including oleanolic acid (6) as a major one. Varieties of biological activities exhibited by triterpene acids attracted our attentions, especially from pharmaceutical viewpoints. Cell culture of olive plant was induced and its triterpene constituents were studied. From the cell suspension cultures, six ursane type triterpene acids; ursolic acid (9), pomolic acid (10), rotundic acid (11), tormentic acid (12), 2alpha-hydroxyursolic acid (13) and 19alpha-hydroxyasiatic acid (14), and two oleanane type acids; oleanolic acid and maslinic acid (7), have been isolated. Quantity of ursane type triterpene acids produced by cell cultures was larger than that of oleanane type. Further, a multifunctional oxidosqualene cyclase (OSC) named OEA was cloned by homology based PCRs from the same cultured cells. Major product of OEA is alpha-amyrin (ursane skeleton), showing good accordance to higher content of ursane-type triterpene acids in the cultured cells, and strongly suggesting OEA to be a major contributor OSC for their production.

Dammarenediol-II synthase, the first dedicated enzyme for ginsenoside biosynthesis, in Panax ginseng.

Panax ginseng produces triterpene saponins called ginsenosides, which are classified into two groups by the skeleton of aglycones, namely dammarane type and oleanane type. Dammarane-type ginsenosides dominate over oleanane type not only in amount but also in structural varieties. However, their sapogenin structure is restricted to two aglycones, protopanaxadiol and protopanaxatriol. So far, the genes encoding oxidosqualene cyclase (OSC) responsible for formation of dammarane skeleton have not been cloned, although OSC yielding oleanane skeleton (beta-amyrin synthase) has been successfully cloned from this plant. In this study, cDNA cloning of OSC producing dammmarane triterpene was attempted from hairy root cultures of P. ginseng by homology based PCR method. A new OSC gene (named as PNA) obtained was expressed in a lanosterol synthase deficient (erg7) Saccharomyces cerevisiae strain GIL77. LC-MS and NMR analyses identified the accumulated product in the yeast transformant to be dammarenediol-II, demonstrating PNA to encode dammarenediol-II synthase.