Treatment Of Various Gastrointestinal Disorders Research Articles

A recent update on gastro retentive drug delivery systems

Gastro retentive drug delivery systems (GRDDS) have garnered significant attention in recent years due to their potential to enhance therapeutic efficacy and patient compliance by prolonging gastric residence time and optimizing drug release kinetics. This review provides a comprehensive overview of the latest advancements in GRDDS, focusing on formulation strategies, design principles, and evaluation methodologies. Various approaches such as floating systems, mucoadhesive systems, expandable systems, and magnetic systems are discussed in detail, highlighting their mechanisms of action and applications in targeted drug delivery. Furthermore, recent innovations in materials science and formulation technologies have enabled the development of novel GRDDS with improved biocompatibility, stability, and controlled release profiles. The review also addresses challenges associated with GRDDS, including physiological variability, drug stability, and regulatory considerations, and proposes potential strategies to overcome these obstacles. Additionally, the clinical relevance of GRDDS in the treatment of various gastrointestinal disorders and their future prospects in personalized medicine and targeted therapy are explored. Overall, this review aims to provide valuable insights into the current state-of-the-art in GRDDS research and its implications for the advancement of drug delivery science.

Leucaena leucocephala succinate based polyelectrolyte complexes for colon delivery of synbiotic in management of inflammatory bowel disease

Polyelectrolyte complexes (PECs) formed by the interaction between oppositely charged polymers have emerged as promising carriers for accomplishing colon-specific release. In this study, we have explored the potential of polyelectrolyte complexes between a succinate derivative of Leucaena leucocephala galactomannan and cationic guar gum for colon delivery of synbiotic. The PECs were prepared using a polyelectrolyte complexation method and characterized. The PECs exhibited excellent stability, with high encapsulation efficiency for both probiotics (95.53 %) and prebiotics (83.33 %). In vitro studies demonstrated enhanced survivability and proliferation of the encapsulated probiotics in the presence of prebiotics (93.29 %). The SEM images revealed a smooth and firm structure with reduced number of pores when both prebiotic and probiotic were encapsulated together. The treatment with synbiotic PECs in acetic acid induced IBD rats significantly relieves colitis symptoms as was evident from colon/body ratio, DAI score and histopathology studies. An increase in the protein and reduced glutathione levels and reduction in superoxide dismutase activity was observed in colitic rats that received synbiotic treatment as compared to colitic rats. Overall, this study highlights the potential of Leucaena leucocephala succinate-cationic guar gum PECs as a promising system for colon-specific synbiotic delivery, with implications for improved gut health and the treatment of various gastrointestinal disorders.

Variability in the volatile constituents and biological activities of Achillea millefolium L. essential oils obtained from different plant parts and by different solvents

Achillea millefolium Linn. is an aromatic edible plant used traditionally for the remediation of wounds, liver disorders, and as an herbal tea for the treatment of various gastrointestinal disorders. The plant's volatile oils have economical value in cosmetic preparation and as an insect repellant. The essential oils obtained from different plant parts, i.e., leaves, stems, and aerial portions, by hydrodistillation and by non-polar solvents, i.e., n-hexane and diethyl ether, were phytochemically analyzed and biologically investigated from the plant species cultivated in Saudi Arabia for their potential antioxidant and anticancer activities. The GC-analysis revealed substantial variations among the major constituents and classes of volatile oils in all batches of the plant, characterized by the significant high percentages of monoterpenes, e.g., myrcene, 1,8 cineole, camphor, α-thujone, and β-thujone, in the distilled oils and sesquiterpenes in the non-polar extracts of the plant. Furthermore, the ketonic monoterpenes α-thujone and β-thujone were found to be the most representative compounds in the distilled and extracted batches of the plant. Variable antioxidant activity of different batches of the plant was recognized; however, distilled batches of leaves, stems, and aerial parts exhibited better total antioxidant activity (TAA) compared to the plant’s non-polar extracts. With the little cytotoxic activity of distilled batches, the non-polar extracts exhibited remarkable cytotoxic effects against Panc-1 and MCF-7-Adr (35 and 43.3 μg/mL and 41.3 and 57.1, respectively, in the n-hexane and diethyl ether extracts), which were attributed to their comparatively higher contents of germacrene D, viridiflorol, and caryophyllene oxide. The n-hexane extract induced a concentration- and time-dependent apoptotic effect in Panc-1 and MCF-7 Adr cells, as observed by staining with FITC/PI and flow cytometry analysis. The docking simulation of the major n-hexane extract constituents indicated the prospective mechanism behind the ability of the extract to inhibit MCF-7-Adr cells by inhibiting P-glycoprotein/multidrug resistance 1/adenosine triphosphate-binding cassette.

Prophylactic Protective Action of Aqueous Extract of Green Oak Acorns on Ethanol-Induced Acute Injury to Rat Gastroduodenal Mucosa.

Quercus ilex fruit is widely used in the treatment of various gastrointestinal disorders, including diarrhea, for its bioactive compounds and astringent property. The current study focuses on the phytochemical characterization of the Q. ilex-aqueous extract (QIAE) and its protective effect against gastroduodenal (GD) ulcer (GDU) produced by absolute ethanol (EtOH) intoxication in adult male Wistar rats. Experimental rats were divided into six groups (n = 6): control, EtOH [95%, 4 g/kg body weight (b.w.)], EtOH + different doses of QIAE (100, 200, and 400 mg/kg, b.w.), and EtOH + Famotidine (FAM, 10 mg/kg, b.w.). Animals were orally pretreated (p.o.) with QIAE for 15 days and intoxicated with a single oral administration of EtOH for 2 h. The findings showed that the QIAE is rich in phenolic-astringent compounds and fibers, and it exhibited a significant scavenging activity on DPPH/ABTS free-radicals with half maximal inhibitory concentration (IC50) values of 177.00 ± 5.11 and 203.9 ± 2.23 μg/mL, respectively. In vivo part, QIAE significantly reduced the GD mucosal injury revealed by edema and leukocyte infiltration of the submucosal layer. GD mucosal homogenates revealed a remarkable increase in endogenous antioxidant enzyme activities (catalase, superoxide dismutase, and glutathione peroxidase) and a decrease in the lipid peroxidation levels (malondialdehyde) in animals pretreated with QIAE compared with the ulcer control group. QIAE exerted significant and dose-dependent anti-GDU protection in the rat model with a more effective action than FAM. The GD protective effect of the QIAE might be related to a direct radical scavenging activity, increased antioxidant enzymes, and depression of lipid peroxidation.

Inonotus obliquus Aqueous Extract Suppresses Carbon Tetrachloride-induced Hepatic Injury through Modulation of Antioxidant Enzyme System and Anti-inflammatory Mechanism

Background: Chaga mushroom (Inonotus obliquus) is an edible macrofungus used in traditional and folk medicine for the treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies, including anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-κB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The diverse inflammatory and carcinogenic agents, like carbon tetrachloride (CCl4), a potent hepatotoxic chemical, cause liver damage by inducing lipid peroxidation and other oxidative damages. Aims: The study aimed to analyze the biochemical, cellular and molecular mechanisms of CCl4 induced chronic liver inflammation and carcinoma, and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms. Method: Physiological, histological and immunohistochemical analyses of the physiological functions and cellular functions were performed. Biochemical assays were conducted for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for the evaluation of the molecular interaction. Results: CCl4-exposed mice exhibited a significant decrease in body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored the normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level increased to 447 IU/L in CCl4 treated mice as compared to control (236 IU/L). Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control (52 μM), and induced the catalase enzyme activity up to 259 U/mL as compared to control (124 U/L). These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions, which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide exerted an inhibitory effect on these critical proinflammatory signaling proteins. Conclusions: The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanisms, which can be utilized for natural prevention of liver toxicity.

Gastroprotective Activity Of Methanol Extract Of Mesocarp Of Unripe Carica Papaya Linn. Fruit On Experimentally-induced Gastric Ulcer In Wistar Rats

Background: Peptic ulcer affects up to 10 % of the world’s population. There has been renewed interest in identifying natural drug sources with gastroprotective activity. Unripe Carica papaya fruit is used traditionally for the treatment of various gastrointestinal disorders including peptic ulcer which may have not been well explored. Objective: The aim of this study was to determine the gastroprotective activity of methanol extract of mesocarp of unripe Carica papaya fruit (MECP) on experimentally-induced gastric ulcer in Wistar rats. Methodology: Forty-six (46) wistar rats (150 g to 170 g) were used for the studies. Six (6) were used for acute toxicity testing using OECD method no.423. Graded doses of MECP (500, 1000 and 1500 mg/kg) were administered as gastroprotective agents, omeprazole and cimetidine were standard drugs used for ethanol-induced and acetic acid-induced ulcer models respectively. Thereafter, 20 rats each were used for ethanol-induced and acetic acid-induced ulcer models to induce gastric ulcers. All drugs and extracts administration were via oral route. Subsequently, animals were euthanized; stomachs excised, cut open and measured to examine the extent of ulceration and level of protection by the MECP. Results: Phytochemical screening showed MECP contains alkaloids, flavonoids, saponins, glycosides, tannins and terpenoids. Anthraquinones were absent. Results of acute toxicity test indicated that MECP is relatively safe with LD50 > 5000 mg/kg. In ethanol-induced ulcer model, rats administered with 1000 mg/kg MECP had the least mean ulcer index (0.917 cm2 ± 0.086) with the highest ulcer protection percentage (76.95 %) of all the extract doses, relative to the standard (omeprazole) with 77.93 % protection. Reduction in mean ulcer index was recorded across the MECP groups for analysis of variance, using Dunnetts post-hoc test for multiple comparison, but showed no statistically significant difference between them. For acetic acid-induced ulcer model, MECP at the lowest dose (500 mg/kg) elicited the least mean ulcer index (0.678 cm2± 0.102) with 87.54 % ulcer protection in a similar manner to cimetidine (20 mg/kg) which had 0.600 cm2 + 0.144 mean ulcer index with 88.97 % ulcer protection. All doses of MECP showed reduction in mean ulcer index when compared to (5.442 cm2 ± 0.511) of the untreated group (normal saline) with no statistically significant difference recorded. Conclusion: MECP has gastroprotective and ulcer healing effects on ethanol-induced ulcer and acetic acid-induced ulcer in Wistar rats. This confirms scientifically, the traditional use of mesocarp of unripe Carica papaya fruit in treatment of peptic ulcer

Drug Induced Cutaneous Manifestations due to Treatment of Gastrointestinal Disorders.

Cutaneous manifestations due to drugs used in the treatment of gastrointestinal disorders are multiple and common. Adequate diagnosis is of great importance, bearing in mind that the therapeutic regimen depends on its diagnosis. In this review, we provided an overview of the most common drug-induced skin lesions with a detailed explanation of the disease course, presentation and treatment, having in mind that in recent years, novel therapeutic modalities have been introduced in the treatment of various gastrointestinal disorders, and that incidence of cutaneous adverse reactions has been on the rise.

Gut Microbiota is the Key to the Antidepressant Effect of Chaihu-Shu-Gan-San.

Accumulating evidence highlights the link between gut microbiota and depression. As an antidepressant herbal drug in clinic, Chaihu-Shu-Gan-San (CSGS) has also been used in China for the treatment of various gastrointestinal disorders. Therefore, we hypothesize that the gut microbiota might be involved in the effect of CSGS. Here, we investigated the antidepressant effects of CSGS against chronic variable stress (CVS)-induced depression rats with and without antibiotic treatment using 16S rRNA gene sequencing and ultra-performance liquid chromatography coupled with time of flight mass spectrometry (UPLC-Q-TOF/MS) based metabolomics approaches. As a result, the prominent effects of CSGS against the depression-like behavioral disorder of CVS-induced rats were significantly weakened when the gut microbiota was changed after oral administration of the broad-spectrum antibiotic. The mediation of CSGS on hippocampal levels of serotonin (5-HT) and glutamic acid (Glu) was also receded with the antibiotic treatment. Further investigation on the diversity of microbiome indicated that the improvement effect of CSGS on gut microbiota dysbiosis—especially the phylum level of Firmicutes—was attenuated after the CSGS combined antibiotic treatment. Moreover, 3-hydroxypicolinic acid (H4) and inosine (H8) in the hippocampus were considered as important biomarkers for depression and are also associated with gut microbiota mediated CSGS efficacy. Taken together, our current study indicated that gut microbiota is a critical factor in the antidepressant effect of CSGS, which improve depression-related metabolic disturbance partly through gut microbiota.

Quercetin a major biomarker of Psidium guajava L. inhibits SepA protease activity of Shigella flexneri in treatment of infectious diarrhoea

The leaves of the plant Psidium guajava L. (Myrtaceae) has been traditionally used in treatment of various gastrointestinal disorders including diarrhoea and have also been reported for its potent antidiarrhoeal activity on various chemical induced diarrhoea models. The objective of our present study was to evaluate the potency of the leaf extract of the plant Psidium guajava (PGE) along with its major biomarker quercetin against Shigella flexneri-induced sub chronic model of infectious diarrhoea. PGE at 100, 200 and 400 mg/kg, p.o. and quercetin at 50 mg/kg, p.o. were administered to Shigella flexneri-induced diarrhoeal rats for five days and various behavioural parameters were evaluated on 1st, 3rd and 5th day of treatment. This was followed by assessment of stool water content, density of Shigella flexneri in stools and blood parameters examination. After treatment, colon and small intestine of rats was dissected and subjected to biochemical estimations, cytokine profiling, antioxidant evaluations, ion concentration determination, Na+/K+–ATPase activity and histopathology. Molecular docking studies on crystal structure of Secreted Extracellular Protein A (SepA) from Shigella flexneri with biomarker quercetin was also performed. PGE at 200 mg/kg followed by quercetin depicted maximum antidiarrhoeal potential, which was confirmed through diarrhoea score and % protection, while PGE at 400 mg/kg showed similar effect to PGE 200 mg/kg thus, the later may have ceiling effect. PGE and quercetin also significantly reduced the density of Shigella flexneri in stools, water content of stools and restored the alterations observed in blood parameters, antioxidant status and pro-inflammatory cytokines (IL-6 and TNF-α) expression. These parameters contributed in normalization of electrolyte balance, reactivation of Na+/K+–ATPase activity and repairing of epithelial tissue damage, confirmed through histopathology. Docking simulation studies revealed the role of quercetin in inactivating the protease activity of SepA, a protein secreted by Shigella, which disrupts epithelial barrier integrity during infection and also manages its signal production. Thus, the overall results confirmed the role of quercetin as a major biomarker for the observed antidiarrhoeal potential of P. guajava against Shigella flexneri induced infectious diarrhoea.

Phytochemical screening and anti-implantation activity of Asparagus africanus root extract in female Sprague–Dawley rats

Asparagus africanus Lam., Asparagaceae, is used traditionally as medicinal plant for treatment of various gastrointestinal disorders and for birth related applications. This study aimed to evaluate anti-implantation potential, screening for bioactive phytochemicals and to determine its toxicity. Thirty healthy rats were distributed into five groups (n = 6). Pregnant rats were orally administered vehicle and aqueous extract A. africanus at three different doses thrice daily for seven days. Misoprostol 300 µg/kg bw was used as positive control. All rats were laparotomized 24 h after the last dose and number of live fetuses, implantations and resorption sites were enumerated, and ovaries were harvested for histopathology. The phytochemical analysis was carried out using LC/MS. Acute toxicity was investigated, the animals were randomly grouped into five groups (n = 3); control, four different doses of aqueous extract A. africanus at a single dose treatment and rats were observed for 14 days. Prenatal study demonstrated that 300 mg/kg bw of extract and misoprostol were significantly increased the percentage of anti-implantation as compared to untreated rats. Histopathology of ovaries showed a dose dependent toxicity. LC/MS revealed the presence of steroidal saponins; asparasaponin II, sarsasapogenin, spirostans, and stigmasterol. The mean weight gain of rats treated with 2000 mg/kg bw of aqueous extract was significantly reduced (p = 0.032) compared to control group. In conclusion, the aqueous extract A. africanus has anti-implantation effect in female rats and is safe up to 2000 mg/kg bw. In addition, it contains some potential steroidal saponins, which could be used to explain its anti-implantation activity, however this finding needs further pharmacological studies to confirm the antifertility activities.

Development of a physiologically based pharmacokinetic model to predict the effects of flavin-containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure.

Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CLint of 9μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69l/h, which was comparable to those observed (55 to 88l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.

Medico-ethnobotanical Claims used against Gastrointestinal Disorders by Different Tribes of Assam, India

ABSTRACT Aim The present communication deals with some newly reported Medico-ethnobotanical claims used for the treatment of various gastrointestinal disorders like blood dysentery, chronic dysentery, diarrhea, and cholera by using medicinal plants documented during field survey since last 3 years. Materials and methods Field surveys were conducted in different locations of Assam where many folk healers were interviewed for documentation of Medico-ethnobotanical information. The reported plants are collected, identified, and specimens are preserved. Results Nine different tribes and communities of Assam are newly recorded to use 30 medico-ethnobotanical claims for the concerned purpose, while use of similar claims is already reported elsewhere by other tribes of different regions; the other tribes using similar claim are highlighted. Out of total 47 medicinal plant specimens documented, 10 medicinal plants were recorded for 11 single formulations, 39 medicinal plants for 19 compound formulations, and among these 2 medicinal plants are repeated for both compound and single formulations. Conclusion Ethnic societies are still depending upon the medicinal plants for the treatment of various diseases including gastrointestinal disorders. Further scientific investigations are needed for validation of these folk claims. Clinical significance Cross-cultural study along with other tribes was done and highlighted against enumeration for further validation of folk claims. How to cite this article Bora D, Mehmud S, Baruah D, Bharali BK, Rath C, Mangal AK, Joseph GVR. Medico-ethnobotanical Claims used against Gastrointestinal Disorders by Different Tribes of Assam, India. J Drug Res Ayurvedic Sci 2017; 2(3):175-182.

Potential benefits of colostrum in gastrointestinal diseases.

This paper reviews the composition of colostrum and the potential preventive and therapeutic use of this "first milk" for treating various gastrointestinal disorders in humans. Colostrum is a complex biological liquid that is richer in antimicrobial peptides, immune-regulating compounds and growth factors than the subsequent mature milk. The main functions of colostrum are to provide essential nutritional components, strengthen the natural defense system, modulate immune response, balance intestinal microbiota and enhance the growth and repair of several tissues. Several studies and clinical trials carried out both in vitro and in vivo on humans and animals suggest the clinical benefits of bovine colostrum (BC) supplementation in gastro-intestinal diseases. Despite the encouraging results, further well-designed studies are required in order to confirm these effects, the dose and duration of treatment. Colostrum is safe since there are no contraindications regarding high dose levels and few side effects of clinical relevance have been reported. In conclusion, in the near future, colostrum-based supplements may play a complementary role to synthetic drugs in the prevention and treatment of various gastrointestinal disorders.

Corticotropin-releasing Hormone and Its Biological Diversity toward Angiogenesis.

Angiogenesis is the formation of new blood vessels from existing ones and an underlying cause of numerous human diseases, including cancer and inflammation. A large body of evidence indicates that angiogenic inhibitors have therapeutic potential in the treatment of vascular diseases. However, detrimental side effects and low efficacy hinder their use in clinical practice. Members of the corticotropin-releasing hormone (CRH) family, which comprises CRH, urocortin I-III, and CRH receptors (CRHR) 1 and 2, are broadly expressed in the brain and peripheral tissues, including the intestine and cardiovascular system. The CRH family regulates stress-related responses through the hypothalamic-pituitary-adrenal axis. Therapeutic agents that target CRH family members offer a new approach to the treatment of various gastrointestinal disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer. Since the discovery that CRHR 2 has anti-angiogenic activity during postnatal development in mice, studies have focused on the role of the CRH system in the modulation of blood vessel formation and cardiovascular function. This review will outline the basic biological functions of the CRH family members and the implications for the development of novel anti-angiogenic therapies.

Protective effects of Aegle marmelos fruit pulp on 2,4,6-trinitrobenzene sulfonic acid-induced experimental colitis.

Background:Aegle marmelos (AM) fruit has been advocated in indigenous system of medicine for the treatment of various gastrointestinal disorders, fever, asthma, inflammations, febrile delirium, acute bronchitis, snakebite, epilepsy, leprosy, myalgia, smallpox, leucoderma, mental illnesses, sores, swelling, thirst, thyroid disorders, tumours and upper respiratory tract infections.Objective:The objective of this study was to study the curative effect of 50% ethanol extract of dried fruit pulp of AM (AME) against 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis.Materials and Methods:AME (200 mg/kg) was administered orally, once daily for 14 days after TNBS-induced colitis. Rats were given intracolonic normal saline or TNBS alone or TNBS plus oral AME. AME was studied for its in vitro antibacterial activity against Gram-negative intestinal bacteria and on TNBS-induced changes in colonic damage, weight and adhesions (macroscopic and microscopic), diarrhea, body weight and colonic levels of free radicals (nitric oxide and lipid peroxidation), antioxidants (superoxide dismutase, catalase and reduced glutathione) and pro-inflammatory marker (myeloperoxidase [MPO]) in rats.Results:AME showed antibacterial activity against intestinal pathogens and decreased colonic mucosal damage and inflammation, diarrhea, colonic free radicals and MPO and enhanced body weight and colonic antioxidants level affected by TNBS. The effects of AME on the above parameters were comparable with sulfasalazine, a known colitis protective drug (100 mg/kg, oral).Conclusion:AME shows curative effects against TNBS-induced colitis by its antibacterial activity and promoting colonic antioxidants and reducing free radicals and MPO-induced colonic damage.

Naringin Exhibits in vivo Prokinetic Activity via Activation of Ghrelin Receptor in Gastrointestinal Motility Dysfunction Rats

Background and Purpose: Poncirus fructus (PF), also known as the dried immature fruit of Poncirus trifoliata (L.) Raf., has long been used as a cure for the treatment of various gastrointestinal disorders in eastern Asia. Recently, it was reported that naringin, a flavonoid constituent of the PF extract, causes the activation of ghrelin receptor in vitro. Although the ghrelin receptor is involved in the enhancement of intestinal motility, there are no studies as yet involving in vivo action of naringin. Therefore, the purpose of the present study is to investigate whether naringin exhibits a prokinetic effect in vivo. Methods: We measured the intestinal transit rate in rats with gastrointestinal motility dysfunction (GMD) and performed a pharmacokinetic analysis of naringin to investigate the effect of naringin on prokinetic activity in vivo. Results: The results of this study show that the aqueous extract of PF and its constituent naringin have a strong prokinetic activity in GMD rats via activation of the ghrelin receptor. Surprisingly, pharmacokinetic analysis revealed that naringin has low bioavailability (11%), implying that the prokinetic effect of naringin was largely due to the local activation of ghrelin receptor in the intestine rather than a systemic effect after absorption. Indeed, it turned out that intravenous administration of naringin led to a lower prokinetic effect than when administrated orally to rats, indicating that naringin prefers to act on the intestinal wall rather than getting absorbed into the systemic circuit. This local mode of action might be advantageous for preventing possible systemic side effects since naringin is not well absorbed into the system circuit. Conclusions: Naringin exhibits an in vivo prokinetic activity by a preferable local activation of ghrelin receptor. Moreover, we propose that naringin could play a role as a leading compound for the development of ghrelin receptor-based prokinetic agents.

Air embolism complicating gastrointestinal endoscopy: A systematic review

Gastrointestinal endoscopy has become an important modality for the diagnosis and treatment of various gastrointestinal disorders. One of its major advantages is that it is minimally invasive and has an excellent safety record. Nevertheless, some complications do occur, and endoscopists are well aware and prepared to deal with the commonly recognized ones including bleeding, perforation, infection, and adverse effects from the sedative medications. Air embolism is a very rare endoscopic complication but possesses the potential to be severe and fatal. It can present with cardiopulmonary instability and neurologic symptoms. The diagnosis may be difficult because of its clinical presentation, which can overlap with sedation-related cardiopulmonary problems or neurologic symptoms possibly attributed to an ischemic or hemorrhagic central nervous system event. Increased awareness is essential for prompt recognition of the air embolism, which can allow potentially life-saving therapy to be provided. Therefore, we wanted to review the risk factors, the clinical presentation, and the therapy of an air embolism from the perspective of the practicing endoscopist.

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161-170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.

Profiling of the Compounds Absorbed in Human Plasma and Urine after Oral Administration of a Traditional Japanese (Kampo) Medicine, Daikenchuto

Daikenchuto (DKT), a pharmaceutical-grade traditional Japanese (Kampo) medicine, has been widely used for the treatment of various gastrointestinal disorders including postoperative ileus and has been integrated into the modern medical care system in Japan as a prescription drug. DKT is a multiherbal medicine consisting of Japanese pepper (zanthoxylum fruit), processed ginger, and ginseng with maltose as an additive. Despite substantial research on the pharmacological activities of DKT and its ingredients, the lack of studies on absorption, distribution, metabolism, and excretion of DKT has made it difficult to obtain a consistent picture of its mechanism of action. In the present study, we constructed an analysis procedure consisting of seven conditions of liquid chromatography and mass spectrometric analysis, which enabled the identification of 44 ingredients of DKT component herbs. We investigated the plasma and urine profiles of these ingredients 0.5 to 8 h after oral administration of 15.0 g of DKT in four healthy volunteers. The results indicated that 1) hydroxy-α-sanshool and [6]-shogaol, the prominent peaks in plasma derived from Japanese pepper and ginger, respectively, were detected at 0.5 h and thereafter decreased throughout the sampling period; 2) ginsenoside Rb(1), a prominent peak derived from ginseng, increased gradually during the sampling period; 3) glucuronide conjugates of hydroxy-sanshools, shogaols, and gingerols were detected in plasma and urine; and 4) no obvious differences between samples from the two male and the two female individuals were observed. These results provide a strong basis for future studies on pharmacokinetics and pharmacology of DKT.

Compatibility studies between mannitol and omeprazole sodium isomers

Omeprazole, commonly used in the treatment of various gastrointestinal disorders degrades rapidly in acidic pHs and results in inter-individual variability due to different rates of metabolism amongst patients. Since S-omeprazole shows more predictable bioavailability and excipients have been known to interact with active pharmaceutical ingredients to produce altered bioavailability, it was decided to investigate the compatibility of omeprazole sodium isomers with mannitol, the major excipient in omeprazole formulations using differential scanning calorimetry (DSC) for bulk drug, attenuated total reflectance (ATR) infrared (IR) spectroscopy in a powder mixture and localized thermal analysis (LTA) from a drug disk. DSC results clearly indicate an interaction between mannitol and R-omeprazole sodium due to decreased melting temperatures and broadening peaks. The DSC of S-omeprazole sodium does not show melting temperature although the drug was crystalline. Because of the accelerated temperature conditions during DSC experiments applied in this work, ATR-IR was undertaken to determine whether these results occurred at room temperature for the solid dosage form. The ATR-IR results show a difference between R- and S-omeprazole sodium with mannitol by the appearance of both the amino (N–H) and imino ( N–H) stretching frequencies for R-omeprazole and only the N–H for the S-omeprazole sodium. It may thus be concluded that different ratios for the tautomeric forms for S- and R-omeprazole sodium result in changes in the degree of crystallinity and are responsible for the interaction with mannitol, common excipient in formulation. These interactions may be directly related to the difference in terms of bioavailability.