Effect of white jade snail secretion on antioxidant capacity and intestinal microbial diversity in mouse model of acute gastric ulcer.

BACKGROUND: In the present work, acute gastric ulcer models were constructed by administering hydrochloric acid/ethanol. The mice ingested white jade snail secretion (WJSS) through gastric infusion. Ulcer areas in gastric tissue were recorded, and malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured. Notably, high-throughput 16S rDNA analysis of intestinal flora and determination of amino acid composition in feces were performed to understand the effect of WJSS on model mice. RESULTS: Compared with the control group, the ulcer area in the WJSS low-, medium- and high-concentration groups declined by 28.02%, 39.57% and 77.85%, respectively. MDA content decreased by 24.71%, 49.58% and 64.25%, and SOD relative enzyme activity fell by 28.19%, 43.37% and 9.60%, respectively. The amounts of amino acids in the low-, medium- and high-concentration groups were slightly lower, and probiotic bacteria such as Bacteroidetes and Lactobacillales increased in different-concentration WJSS groups. Adding WJSS contributes to the establishment of beneficial intestinal flora and the absorption of amino acids. CONCLUSION: Our results showed that WJSS has a beneficial effect on inhibiting hydrochloric acid-ethanolic gastric ulcers, suggesting that WJSS has excellent potential as a novel anti-ulcer agent. Combined with ulcer area, MDA content, SOD content, gut probiotics and other indicators, a high concentration of WJSS had the best protective effect on acute gastric ulcer. © 2023 Society of Chemical Industry.

Metabolomic profiling of five Agave leaf taxa via UHPLC/PDA/ESI-MS inrelation to their anti-inflammatory, immunomodulatory and ulceroprotective activities.

Agave plants are popular for their myriad applications in traditional medicine attributed to their reported anti-inflammatory, immunomodulatory, cytotoxic and antifungal activities. The aim of this study was to examine the anti-inflammatory, immunomodulatory and ulceroprotective activity of Agave species in relation to their metabolite fingerprint via a metabolome based ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) approach coupled to chemometrics. The metabolomic differences among five examined Agave leaves viz. Agave americana L., A. americana var. marginata Trel, A. angustifolia Haw. cv. marginata, A. desmettiana Jacobi, A. pygmaea Gentry were determined via a total of 56 annotated metabolites. Identification based on MSn and UV spectra revealed 25 steroidal saponins and sapogenins, 6 flavonoids, 2 homoisoflavonoids, 7 phenolic acids, 6 fatty acids and 3 fatty acid amides, some of which are reported for the first time in Agave. Metabolites heterogeneity was assessed among leaf taxa via multivariate data analyses for samples classification, showing that saponins is the major metabolite contributing to their classification. The carrageenan induced acute inflammatory rat model was used to assess the anti-inflammatory activity of Agave extracts via monitoring of blood cytokine levels. Additionally, their effects on ethanol-induced gastric ulcer in rats were evaluated. A. pygmaea showed the most significant anti-inflammatory and immunomodulatory activity, while A. angustifolia var. marginata possessed the highest ulceroprotective activity, which could be attributable to the high abundance of various saponins and homoisoflavonoids in those taxa.

Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology.

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.

Drug-drug interactions in patients receiving tyrosine kinase inhibitors.

Rationale Tyrosine kinase inhibitors are increasingly used in the treatment of cancer. Drug interactions involving tyrosine kinase inhibitors are commonly encountered in clinical practice. The objective of this study was to describe the frequency of tyrosine kinase inhibitor-associated drug interactions among a cohort of oncology patients. Methods Adult patients were included who presented to either of two outpatient oncology practices and were prescribed a tyrosine kinase inhibitor during 2 January 2013 to 1 January 2015. Demographic and medication data were abstracted from electronic medical records. Lexicomp®, Micromedex Solutions®, and medication labeling were utilized to identify potential interactions between tyrosine kinase inhibitors and concomitant medications. Interactions were then assessed by the investigators for clinical significance. The primary outcome was the frequency of significant drug interactions involving tyrosine kinase inhibitors and concomitant medications. Secondary outcomes included describing the nature and clinical impact of interactions, and describing interactions by medication class. Results A total of 356 patients were identified for analysis, in whom 244 potential interactions were identified, and 109 (44.7%) of which were considered severe. Decreased tyrosine kinase inhibitor absorption due to acid suppressive therapy and CYP3A4 interactions were the most frequent mechanisms of potential subtherapeutic and supratherapeutic concentrations, respectively. Potential clinical consequences included QTc prolongation ( n = 53, 48.6%), decreased tyrosine kinase inhibitor concentration ( n = 53, 48.6%), and increased tyrosine kinase inhibitor concentration ( n = 3, 2.8%). Conclusions Safer alternative therapy and/or more frequent clinical monitoring should be considered if an interaction poses a significant risk of increased tyrosine kinase inhibitor toxicity or decreased tyrosine kinase inhibitor efficacy. Oncology pharmacists can play a role in screening for tyrosine kinase inhibitor-associated interactions, recommending alternative therapies or dosing strategies, and monitoring tyrosine kinase inhibitor efficacy and toxicity.

Formulation and Evaluation of Naringenin Nanosuspensions for Bioavailability Enhancement.

The clinical potential of naringenin (NRG) is compromised due to its poor aqueous solubility and low oral bioavailability. The study is aimed at addressing these issues by means of naringenin nanosuspensions (NRG-NS) formulated using polyvinylpyrrolidone (PVP K-90) as stabiliser via antisolvent sonoprecipitation method. Optimisation of sonication time, drug concentration and stabilisers was done based on particle size. Characterisation of pure NRG and NRG-NS was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), x-ray powder diffractometry (XRD) and Fourier transform infrared spectroscopy (FTIR). In vitro dissolution, intestinal absorption by non-everted rat intestinal sac model and in situ single pass intestinal perfusion techniques were performed for further investigation. Nanosuspensions prepared using PVP K-90 lead to minimum particle size (117 ± 5 nm) with zeta potential of -14.6 ± 5.6 mV. The particle size was affected by increasing sonication time, concentration of stabiliser and drug. Nanosizing process converted the crystalline drug into amorphous form as predicted from DSC and XRD patterns. FTIR demonstrated the formation of hydrogen bonds between drug and polymer. NRG-NS displayed a higher dissolution amount (91 ± 4.4% during 60 min) compared to NRG powder (42 ± 0.41%). The apparent and effective permeability of NRG-NS was increased as compared to the pure NRG. The in vivo pharmacokinetics demonstrated that the C max and AUC0-24 h values of NRG-NS were approximately 2- and 1.8-fold superior than the pure drug. Hence, overall results confirmed nanosuspensions as promising approach for NRG delivery with high absorption in gastrointestinal tract, improved dissolution and oral bioavailability.

Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum.

CONTEXT: Ostericum koreanum (Maxim.) Kitagawa (Apiaceae) roots are traditionally used as an analgesic and antiulcer agent. However, the antiulcer potential of isoimperatorin isolated from O. koreanum has not yet been explored. AIM: To evaluate the antiulcer activity of isoimperatorin isolated from the roots of O. koreanum. MATERIALS AND METHODS: Isoimperatorin was isolated as cubic crystals by repeated column chromatography of the ethyl acetate fraction and structure was verified with 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS-FAB). The crystals obtained were analyzed with the single crystal X-ray method. The MTT assay was used to determine its cytotoxicity against chondrocytes at different concentrations (0.0-737.74 µM, 24 h). The in vivo antiulcer activity of isoimperatorin (40 mg/kg) was determined against ethanol-, indomethacin- and pyloric ligation-induced ulcers in Sprague-Dawley rats. Furthermore, the effect of isoimperatorin (0.0-737.74 µM, 24 h) on the expression of type II collagen in chondrocytes was determined using western blot method. The in vitro urease inhibitory activity of isoimperatorin (0-80 µM) and molecular docking was also performed against urease. RESULTS AND DISCUSSION: Isoimperatorin demonstrated significant inhibitory activity (IC50 36.43 µM) against urease as compared to the standard drug thiourea (IC50 33.57 µM) without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Isoimperatorin showed the highest expression level of type II collagen at 368.87 µM. The docking results confirmed strong binding affinity with the target protein. CONCLUSION: Isoimperatorin may be used to develop antiulcer drugs with decreased side effects.

In vivo gastroprotective effect along with pharmacokinetics, tissue distribution and metabolism of isoliquiritigenin in mice.

As numerous herbal products have been used as dietary supplements or functional foods, the demands of the pharmacokinetic and pharmacodynamic characteristics of active compounds are increasing in order to secure a consistent outcome (i.e., efficiency and safety). In this study, the pharmacokinetics including tissue distribution, metabolism, and protein binding of isoliquiritigenin, a chalcone found in Glycyrrhiza glabra, and its metabolite, liquiritigenin, at various doses in mice are reported. Also, correlations between the preferential tissue distribution and pharmacological effect of isoliquiritigenin in certain organs were investigated using the in vivo gastroprotective effect of isoliquiritigenin in mice with indomethacin-induced ulcer. The absorbed fraction of isoliquiritigenin was high, but the absolute bioavailability was low mainly due to its metabolism. In spite of the low bioavailability, the gastroprotective effect of isoliquiritigenin was attributed to its high distribution in the stomach. Isoliquiritigenin prevented the occurrence of gastric ulcers by indomethacin, which is associated with increased gastric mucous secretion because the pretreatment with isoliquiritigenin presumably counteracted the decreased cyclooxygenase 2 by indomethacin. This may suggest that the pharmacokinetic properties of isoliquiritigenin are useful to predict its efficacy as a gastroprotective agent in a target organ such as the stomach.

Safety and anti-ulcerogenic activity of a novel polyphenol-rich extract of clove buds (Syzygium aromaticum L).

Despite the various reports on the pharmacology of Clove bud [Syzygium aromaticum]-derived essential oil and its major component eugenol, systematic information on the bioactivity of clove polyphenols is very limited. Clove buds being one of the richest sources of dietary polyphenols with many traditional medicinal uses, the present contribution attempted to derive their standardized polyphenol-rich extracts as a water soluble free flowing powder (Clovinol) suitable for functional food applications, without the issues of its characteristic pungency and aroma. The extract was characterized by electrospray ionization-time of flight mass spectrometry (ESI-TOF-MS), and investigated for in vivo antioxidant, anti-inflammatory and anti-ulcerogenic activities. Clovinol showed significant antioxidant and anti-inflammatory effects as measured by cellular antioxidant levels, and the ability to inhibit carrageenan-induced paw swelling in mice. Further investigations revealed its significant anti-ulcerogenic activity (>97% inhibition of ethanol-induced stomach ulcers in Wistar rats when orally administered at 100 mg per kg b.w.) and up regulation of in vivo antioxidants such as superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Clovinol also reduced the extent of lipid peroxidation among ulcer induced rats, indicating its usefulness in ameliorating oxidative stress and improving gastrointestinal health, especially upon chronic alcohol consumption. The extract was also shown to be safe and suitable for further investigations and development upon acute toxicity studies at 5 g per kg body weight and 28 days of repeated dose toxicity studies at 2.5 g per kg b.w.

Coenzyme Q10: a novel gastroprotective effect via modulation of vascular permeability, prostaglandin E2, nitric oxide and redox status in indomethacin-induced gastric ulcer model.

Coenzyme Q10 is an essential cofactor in the mitochondrial electron transport pathway, and is endowed for its potent antioxidant capacity; characters that endorse its implication in several clinical practices and as a food supplement. Nevertheless, its potential gastro-protective effect, in acute models, has never been assessed, which is the objective of this study. Since indomethacin mediated gastropathy is multifaceted, including mitochondrial dysfunction and generation of reactive oxygen species, thus, the indomethacin-induced gastric injury serves as a convenient animal model for this work. Rats treated with indomethacin revealed mucosal hemorrhagic lesions, increased microvascular permeability and inhibited prostaglandin E2 and mucus content. Redox imbalance was reflected by decreased mucosal glutathione (GSH), nitric oxide and glutathione peroxidase contents/activity, along with elevated lipid peroxides. Pretreatment with CoQ10 caused discernible decrease in indomethacin-induced gastric lesions, vascular permeability and lipid peroxide content. In addition, prostaglandin E2 and GSH levels were restored, while those of nitric oxide and glutathione peroxidase were elevated significantly above normal; however, mucus formation was not altered significantly. The positive effects were comparable to those of sucralfate, the standard drug used herein, except for the mucus and prostaglandin E2 levels that were increased above normal by sucralfate. CoQ10-mediated gastroprotective effect involves preservation of microvascular permeability, elevation of prostaglandin E2, improvement of redox status, as well as boosting of nitric oxide. Nevertheless, maintaining gastric mucus content is ruled out.

Herbal medicine yin zhi huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole.

AIM: To explore the potential interactions between yin zhi huang (YZH) and omeprazole, a substrate of CYP3A4 and CYP2C19. METHODS: Eighteen healthy volunteers, including 6 CYP2C19*1/*1, 6 CYP2C19*1/*2 or *3 and 6 CYP2C19*2/*2 were enrolled in a 2-phase, randomized, crossover clinical trial. In each phase, the volunteers received either placebo or 10 mL YZH oral liquid, 3 times daily for 14 d. Then all the patients took a 20 mg omeprazole capsule orally. Blood samples were collected up to 12 h after omeprazole administration. Plasma concentrations of omeprazole and its metabolites were quantified by HPLC with UV detection. RESULTS: After 14 d of treatment of YZH, plasma omeprazole significantly decreased and those of omeprazole sulfone and 5-hydroxyomeprazole significantly increased. The ratios of the area under the plasma concentration-time curves from time 0 to infinity (AUC(0-infinity) of omeprazole to 5-hydroxyomprazole and those of omeprazole to omeprazole sulfone decreased by 64.80%+/-12.51% (P=0.001) and 63.31%+/-18.45% (P=0.004) in CYP2C19*1/*1, 57.98%+/-14.80% (P=0.002) and 54.87%+/-18.42% (P=0.003) in CYP2C19*1/*2 or *3, and 37.74%+/-16.07% (P=0.004) and 45.16%+/-15.54% (P=0.003) in CYP2C19*2/*2, respectively. The decrease of the AUC(0-infinity) ratio of omeprazole to 5-hydroxyomprazole in CYP2C19*1/*1 and CYP2C19*1/*2 or *3 was greater than those in CYP2C19*2/*2 (P=0.047 and P=0.009). CONCLUSION: YZH induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole leading to decreases in plasma omeprazole concentrations.

Diet-derived nutrients modulate the effects of amylin on c-Fos expression in the area postrema and on food intake.

The pancreatic hormone amylin decreases food intake via activation of area postrema (AP) neurons. We investigated whether amylin's potency to reduce food intake and to induce c-Fos expression in the AP/nucleus of the solitary tract region is affected by the feeding conditions and specifically by the macronutrient composition of the diet. Whereas a low dose of amylin (5 microg/kg s.c.) induced very little c-Fos expression in ad libitum chow fed rats, it caused a strong c-Fos expression in 24-hour food-deprived rats and in rats that received a nutrient-deficient non-caloric mash (NCM; vanilla-flavoured cellulose) 24 h before injection. To reveal the contribution of single nutrients to the low c-Fos expression after chow feeding, amylin-induced c-Fos was analyzed after feeding NCM that was selectively supplemented with glucose, fat (lard), or protein (casein), matching the intake of these nutrients of chow-fed rats. While the rats fed NCM supplemented with glucose or fat displayed an equally strong amylin-induced activation as fasted rats or rats fed plain NCM, a significantly lower c-Fos expression was observed in rats fed a protein-supplemented NCM or a NCM containing all three nutrients. In line with this lower activation, the same dose of amylin failed to reduce food intake in NCM/protein-fed rats, while amylin caused a reduction in feeding when animals received NCM, NCM/glucose, or NCM/fat. Interestingly, amylin effectively reduced food intake in ad libitum chow fed rats despite the low level of amylin-induced c-Fos expression in the AP under these conditions. We conclude that the anorectic potential of amylin may be attenuated by diet-derived proteins, whereas this effect appears to be overridden when the amount of carbohydrates/fat is high relative to the protein content, such as, e.g., in standard chow.

Hyperthermia ameliorates 2,4,6-trinitrobenzene sulphonic acid-induced colitis in rats: the role of heat shock proteins.

PURPOSE: Hyperthermia is known to protect against cellular injury through the expression of heat shock proteins. In this study, the therapeutic effects of hyperthermia on experimental colitis in the rat were evaluated. MATERIALS AND METHODS: Male Wistar rats were given a single intracolonic injection of 2,4,6-trinitrobenzene sulphonic acid (TNBS). Hyperthermia was induced in anesthetized rats by placing them in a temperature-controlled water bath. We started the hyperthermic treatment on the day after the enema. The severity of colitis was evaluated pathologically, and the activities of tissue myeloperoxidase were measured 6 days after the induction of colitis. Furthermore, cytokines, and hyperthermia-induced heat shock proteins in colonic mucosa were detected by enzyme-linked immunosorbent assay and Western blotting. We also investigated the effects of geranylgeranylacetone and zinc protoporphyrin IX on the therapeutic effect of hyperthermia. RESULTS: Hyperthermia significantly improved the macroscopic scores of colitis. The TNBS-induced increases in the activities of myeloperoxidase in the colonic tissue were blunted significantly in hyperthermia-treated animals. Furthermore, hyperthermia attenuated increases in cytokine-induced neutrophil chemoattractants-1 and tumor necrosis factor-alpha in the colon. Furthermore, hyperthermia induced the production of heat shock proteins in rat colonic mucosa, and the combination of geranylgeranylacetone with hyperthermia further induced the heat shock protein HSP70, which resulted in further improvement of TNBS-induced colitis. On the other hand, the combination of zinc protoporphyrin IX with hyperthermia attenuated the therapeutic effect of hyperthermia. CONCLUSIONS: Hyperthermia ameliorates TNBS-induced colitis in rats through the expression of HSP70 and HO-1. It is postulated that hyperthermia may be useful for the treatment of inflammatory bowel diseases.

Assessment of DNA damage by extracts and fractions of Strychnos pseudoquina, a Brazilian medicinal plant with antiulcerogenic activity.

Strychnos pseudoquina St. Hil. is a native plant of the Brazilian Savannah, used in popular medicine to treat a number of conditions. Since it contains large quantities of alkaloids with proven antiulcer activity, we tested the genotoxic potential of crude extracts and fractions containing alkaloids and flavonoids from the leaves of this plant, on Salmonella typhimurium and performed the micronucleus test on peripheral blood cells of mice treated in vivo. The results showed that the methanol extract of the leaves of S. pseudoquina is mutagenic to the TA98 (-S9) and TA100 (+S9, -S9) strains of Salmonella. The dichloromethane extract was not mutagenic to any of the tested strains. Fractions enriched with alkaloids or flavonoids were not mutagenic. In vivo tests were done on the crude methanol extract in albino Swiss mice, which were treated, by gavage, with three different doses of the extract. The highest dose tested (1800 mg/kgb.w.) induced micronuclei after acute treatment, confirming the mutagenic potential of the methanol extract of the leaves of S. pseudoquina. In high doses, constituents of S. pseudoquina compounds act on DNA, causing breaks and giving rise to micronuclei in the blood cells of treated animals.

Inducers and co-inducers of molecular chaperones.

Molecular chaperones, which are mostly heat- or stress-induced proteins (HSPs), not only regulate various cellular functions such as protein folding, refolding of partially denatured proteins, protein transport across membranes, cytoskeletal organization, degradation of disabled proteins, and apoptosis, but also act as cytoprotective factors against deleterious environmental stresses. Recent studies indicated that moderate overexpression of molecular chaperones could confer cells and tissues stress tolerance and provide beneficial effects on various pathological states associated with protein misfolding and protein aggregation. Mild heat shock, transfection of HSP genes, and some chemical compounds are the major means of overexpression of molecular chaperones. In this review, we summarize recent studies of chemical compounds that could induce or enhance the expression of molecular chaperones or HSPs.

Gastroprotective activity of the diterpene solidagenone and its derivatives on experimentally induced gastric lesions in mice.

The labdane diterpene solidagenone 1 and its semisynthetic and biotransformations products 2-7 were assessed for gastroprotective effect in the HCl.EtOH-induced lesions in mice. At 100 mg/kg, solidagenone presented a statistically significant gastroprotective effect (P<0.05) comparable to lansoprazole at 20 mg/kg. The presence of the furan ring was required for the activity of solidagenone while hydroxylation at C-3 or C-6 afforded products with different activity associated with the stereochemistry. Solidagen-6beta-ol 7 and 3alpha-hydroxysolidagenone 2 presented higher activity than solidagenone itself, while its epimers were inactive.

Effect of honey and sugars on the metabolism and disposition of naringin in rabbits.

To investigate the effect of honey and sugars on the metabolism and disposition of naringin, rabbits were administered naringin alone and naringin with honey or its component sugars - fructose, glucose and sucrose in crossover designs. An HPLC method was developed to determine naringenin in serum after enzymatic hydrolysis. Our results indicate that honey, fructose and sucrose significantly reduced AUC(0-t) of naringenin by 41 %, 61 % and 45 %, respectively. In vitro studies using a rabbit feces suspension to incubate naringin without or with honey or the respective sugars were employed to investigate the mechanism of this interaction. The results indicated that honey and its component sugars did not affect the rate and extent of naringin hydrolysis, whereas the degradation of naringenin was significantly enhanced in the presence of honey and fructose. It could be concluded that concomitant intake of honey, fructose and sucrose resulted in the reduction of naringin absorption which could be attributable in part to the enhanced preabsorption degradation of absorbable naringenin in the large intestine.

Liquorice and its health implications.

This article presents an overview of the health implications of liquorice. Liquorice has beneficial applications in the medicinal and the confectionery sectors; the substance, therefore, is both widely available and commercially attractive. However, the ingestion of liquorice, and/or its active metabolites, can sometimes produce an acquired form of apparent mineralocorticoid excess (AME) syndrome, expressed as sodium retention, potassium loss and suppression of the renin-angiotensin-aldosterone system, in addition to clinical consequences such as raised blood pressure and oedema. Moreover, these metabolic changes, the mechanisms underlying which are highlighted in the accompanying text, are associated with a number of additional clinical symptoms. Considering the easy availability of liquorice itself and also of other products containing its active metabolites, it is quite possible that the health burden of liquorice-induced morbidity could be substantial. Healthcare practitioners need to be fully aware of the risks in view of a large number of reports in the literature concerning its toxicity.

Soft drugs. 21. Design and evaluation of soft analogs of propantheline.

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.