Establishment of a Novel Oral Murine Model of Ricin Intoxication and Efficacy Assessment of Ovine Ricin Antitoxins.

Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an area of concern from a public health perspective and no current licensed medical interventions exist to protect from the action of the toxin. Therefore, we examined the oral toxicity of ricin in Balb/C mice and developed a robust food deprivation model of ricin oral intoxication that has enabled the assessment of potential antitoxin treatments. A lethal oral dose was identified and mice were found to succumb to the toxin within 48 h of exposure. We then examined whether a despeciated ovine F(ab')2 antibody fragment, that had previously been demonstrated to protect mice from exposure to aerosolised ricin, could also protect against oral intoxication. Mice were challenged orally with an LD99 of ricin, and 89 and 44% of mice exposed to this otherwise lethal exposure survived after receiving either the parent anti-ricin IgG or F(ab')2, respectively. Combined with our previous work, these results further highlight the benefit of ovine-derived polyclonal antibody antitoxin in providing post-exposure protection against ricin intoxication.

Effects of broiler genetic strain and dietary amino acid reduction on (part I) growth performance and internal organ development.

Genetic selection in broilers has resulted in improved growth performance, meat yield, and feed conversion efficiency. However, consumers have become increasingly concerned about modern broiler welfare that is related to their rapid growth rate, which may be alleviated by nutrient dilution. This study was conducted to investigate the effects of dietary amino acid (AA) reduction on the growth performance and internal organ development of different genetic strains of broilers. A randomized completed block design with a factorial arrangement of 10 treatments (5 strains × 2 AA levels) was used. The 5 different strains of broilers were fed either a control diet, with digestible AA (lysine, total sulfur AA, and threonine) at the highest recommended levels for the 5 strains, or an AA-reduced diet, with the digestible AA being 20% lower than the control diet. Feed conversion ratio was increased by AA reduction in all 5 strains during day 0-14, 14-28, and 28-41 but was not affected from day 41-55. Body weight and feed intake responses to AA reduction varied in the different strains and ages of birds. Liver weight relative to BW on day 40, and weights of the duodenum and jejunum relative to BW on day 60 were increased by decreasing the dietary AA concentration. These results indicate that the birds had adjusted their organ growth and metabolism in response to increases in digestion, absorption, and utilization efficiency to accommodate a decrease in dietary AA content. Surprisingly, the cost of feed required to produce the same BW was decreased in 4 of 5 strains on both day 41 and 55, which was largely because of the lower price of the diets containing reduced AA levels and the later compensatory growth experienced by the birds fed AA-reduced diets. In the future, when dietary AA levels need to be adjusted to control growth rate and improve welfare status, the genetic strain, age of the birds, and targeted goals need to be taken into consideration.

Evaluation of oats with varying hull inclusion in broiler diets up to 35 days.

Use of local feed ingredients in poultry feed, such as oats, can be limited by their perceived less than ideal nutritional content. Dehulling oats is expensive, and it may be that removing hull is detrimental to the bird in terms of gastrointestinal (GI) development, therefore maintaining some of the high-fiber oat hull (OH) might reduce costs and improve potential for inclusion in poultry diets. Male broilers were fed diets with oats replacing 30% of wheat in diets, either dehulled or with graded inclusions of OH from day of hatch until day 35. Each diet was fed to 8 pens of 8 birds and performance recorded weekly. Samples were collected at day 21 and 35 for analysis of ileal amino acid digestibility, apparent metabolizable energy (AME), and gross gut development measures. No detrimental effect was seen on bird weight with hull inclusion, though higher inclusion levels did deleteriously effect feed intake because of increased gut fill from the fiber. Nitrogen corrected AME was also adversely effected in the highest hull inclusion diets. However, amino acid digestibility was improved with hull addition, which may be because of an increase in GI tract length, improving nutrient absorption. Gizzard development was also significantly improved, and thereby, more efficient grinding of diet may also have improved digestibility. At a lower level of hull inclusion (3% total diet) where digestibility is improved without any detrimental effects on gut fill and intake. Oat hull is well known to improve gut development, especially of the gizzard, with resultant increases in digestibility. This is usually attributed to the mechanical effect of fiber in the gizzard having a grinding effect. However in this study, all fiber was finely ground, so the improvements seen cannot be attributed to a physical cause. Oat including diets with some hull remaining are a cost effective way of using oats as a raw material while maximizing bird performance.

18th Annual Meeting of the Safety Pharmacology Society: drug safety assessment on gastrointestinal system functions.

Introduction: The 18th Annual Meeting of the Safety Pharmacology Society included a session dedicated to the assessment of drug safety on the gastrointestinal (GI) system.Areas covered: GI anatomy, physiology, adverse effects (AEs) of chemical and biological therapies, and approaches to mitigate them.Expert opinion: GI AEs, albeit common and generally of minor intensity, may prolong clinical development time and reduce patient compliance.

Insecticide activity of Curcuma longa (leaves) essential oil and its major compound α-phellandrene against Lucilia cuprina larvae (Diptera: Calliphoridae): Histological and ultrastructural biomarkers assessment.

Lucilia cuprina, known as the Australian blowfly, is of high medico-sanitary and veterinary importance due to its ability to induce myiasis. Synthetic products are the most frequent form of fly control, but their indiscriminate use has selected for resistant populations and accounted for high levels of residues in animal products. This study aimed to assess the effect of essential oil from leaves of Curcuma longa (CLLEO), and its major compound α-phellandrene against L. cuprina L3. An additional goal was to determine the morphological alterations in target organs/tissues through ultrastructural assessment (SEM) and light microscopy, as well as macroscopic damage to cuticle induced by CLLEO. Groups of 20 L3 were placed on filter paper impregnated with increasing concentrations of CLLEO (0.15 to 2.86 µL/cm2) and α-phellandrene (0.29 to 1.47 µL/cm2). Efficacy was determined by quantifying L3 mortality 6, 24 and 48 h after contact with CLLEO and by measuring the structural damage to L3. CLLEO and α-phellandrene inhibited adult emergence by 96.22 and 100%, respectively. Macroscopic cuticle damage, appeared as diffuse pigment and darkening of larval body, was caused by both extracts. The SEM revealed dryness on the cuticle surface, distortion of the sensorial structures and general degeneration in treated L3. Furthermore, alterations in target organs (digestive tract, fat body and brain) were noticed and shall be used as biomarkers in future attempts to elucidate the mechanism of action of these compounds. The vacuolar degeneration and pyknotic profiles observed in the brain tissue of treated larvae with both extracts and the decreased motility within <6 h after treatment leads us to suggest a neurotoxic activity of the products. This work demonstrates the potential use of CLLEO and α-phellandrene as bioinsecticides to be used against L. cuprina, representing an ecofriendly alternative for myiasis control in humans and animals.

Preclinical safety assessment of antipyrine combined with lidocaine hydrochloride as ear drops.

This study was designed to assess the preclinical toxicity of antipyrine combined with lidocaine hydrochloride ear drops (ALED) and support the clinical trials of ALED in clinical settings in China. All the experiments including acute toxicity in rodents, skin sensitization toxicity in guinea pigs, skin irritation toxicity in rabbits and chronic toxicity in rats were performed according to China Food and Drug Administration guidelines. The maximum tolerated dose (MTD) of ALED administration for mice and rats was over (400 g antipyrine plus 100 g lidocaine hydrochloride)/kg and (240 g andtipyrine plus 60 g lidocaine hydrochloride)/kg, respectively. No obvious skin sensitization toxicity and skin irritation toxicity were observed. The main changes concentrated in chronic toxicity study in rats. For the chronic toxicity, rats were administrated once a day for 28 consecutive days, and a 14-day recovery period was followed. The side effects of ALED included decreased dietary intake in male rats, increased proportion of reticulocytes, decreased or even inversed granulocyte:erythrocyte ratio, fluctuated alanine aminotransferase and aspartate aminotransferase, and slightly increased relative weight of liver. Conclusively, blood system (especially erythrocyte system) and digestive system, including liver and gastrointestinal tract, might be the toxic targets of ALED.

Enteric nervous system analyses: New biomarkers for environmental quality assessment.

The gastrointestinal tract (GIT) of fish is a target of contaminants since it can absorb these substances. We evaluated the morphophysiological alterations in the GIT of Sphoeroides testudineus collected in two estuaries presenting differences in their environmental quality (NIA and IA). The intestine was analyzed for histological and neuronal changes; liver and gills for biochemical markers; muscle tissues for neurotoxicity and peripheral blood for genotoxic damage. The results showed alterations in the GIT of the animals collected in the IA, such as muscle tunica and goblet cell density reduction, increased intraepithelial lymphocytes density and changes in neuronal density. Furthermore, changes were observed in MTs and LPO in the gills. Thus, we suggest that TGI is functioning as a barrier that responds to ingested contaminants, in order to reduce their absorption and translocation. Thus, alterations in morphophysiological and enteric neurons in S. testudineus can be used as biomarkers of environmental contamination.

High precision microfluidic microencapsulation of bacteriophages for enteric delivery.

A Salmonella specific bacteriophage Felix O1 (Myoviridae) was microencapsulated in a pH responsive polymer formulation. The formulation incorporated a pH responsive methacrylic acid copolymer Eudragit® S100 (10% (w/v)) with the addition of the biopolymer sodium alginate, the composition of which was varied in the range (0.5% (w/v)-2% (w/v)). The microencapsulation process employed commercially available microfluidic droplet generation devices. We have used readily available low cost microfluidic chips instead of bespoke in-house fabricated glass capillary devices which are accessible only in specialist research facilities. We show that these co-flow microfluidic devices can easily be used to prepare phage encapsulated microparticles making them suitable for use by both the phage research community and industry in order to evaluate and optimise phage compatible formulations for microencapsulation. A novelty of the work reported here is that the size of the generated monodispersed droplets could be precisely controlled in the range 50 µm-200 µm by varying the flow rates of the dispersed and continuous phases. Consequently, alginate concentration and microparticle size were shown to influence the phage release profile and the degree of acid protection afforded to phages upon exposure to simulated gastric fluid (SGF). Bigger microparticles (∼100 µm) showed better acid protection compared with smaller beads (∼50 µm) made from the same formulation. Increasing the alginate composition resulted in improved acid protection of phages for similar particle sizes. The high viscosity formulations containing higher amounts of alginate (e.g. 2% (w/v)) negatively affected ease of droplet generation in the microfluidic device thereby posing a limitation in terms of process scale-up. Felix O1 encapsulated in the formulation containing 10% (w/v) ES100 and 1% (w/v) alginate showed excellent protection upon exposure of the gelled microparticles to SGF (pH 1 for 2 h) without the use of any antacids in the encapsulation matrix. Encapsulated phages previously exposed to SGF (pH 1 for 2 h) were released at elevated pH in simulated intestinal fluid (SIF) and were shown to arrest bacterial growth in the log growth phase. We have therefore demonstrated the microencapsulation of phages using readily available microfluidic chips to produce solid dosage microcapsule forms with a rapid pH triggered release profile suitable for targeted delivery and controlled release in the gastrointestinal tract.

Nonclinical Safety Assessment of the γ-Secretase Inhibitor Avagacestat.

The toxicity of avagacestat, a sulfonamide-based gamma (γ)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed. Gastrointestinal (GI) findings, including goblet cell metaplasia, dilatation of intestinal crypts/glands, mucosal epithelial necrosis and regeneration, and villous atrophy, were limited to dogs that had clinical evidence of GI toxicity. Other avagacestat-related findings attributed to interference with Notch signaling included decreases in peripheral lymphocytes (T and/or B cells) and lymphoid depletion in lymph nodes and the spleen in both species, as well as epiphyseal cartilage and trabecular bone changes in rats. Pharmacologically mediated decreases in brain and cerebrospinal fluid levels of ß-amyloid (Aß) peptides Aß40 and Aß42 and decreased expression of white blood cell mRNA levels of the Notch-regulated gene hairy and enhancer of split-1 confirmed target engagement at all doses. Reductions in brain Aß peptide levels (22 to 34%) in dogs after 1 year at exposures up to the no-observed-effect level for GI toxicity of 1.1× the human plasma exposure, and reversible GI changes at a 3.2× multiple, indicated that a sustained pharmacodynamic effect was attained at exposures without dose-limiting toxicity.

Citrus aurantium (bitter orange) extract: Safety assessment by acute and 14-day oral toxicity studies in rats and the Ames Test for mutagenicity.

The primary active constituent in bitter orange extract (BOE) is p-synephrine. This study assessed the safety of a BOE standardized to 50% p-synephrine following short-term exposure to rats and by the Ames Test. Following 5000 mg/kg of the extract orally to female rats all animals survived. Administration at 2000 mg/kg to female rats for four days yielded no signs of toxicity. Five male and five female rats were administered the BOE at 0, 250, 500, 1000 and 2000 mg/kg/day for 14 days. No significant effects were observed at any dose with respect to body weights, food intake, absolute and relative organ weights, hematology, clinical chemistry, and pathology. Two male rats died after 2000 mg/kg with gastrointestinal impaction at necropsy. During week two of 1000 mg/kg and 2000 mg/kg/day, rats exhibited transient signs of repetitive burrowing of heads in the bedding material (hypoactivity) for about 15 and 45 min, respectively. The no-observed-effect-level (NOEL) was 500 mg/kg/day. The mutagenic potential was assessed at and up to the limit dose of 5000 µg/plate in a Salmonella typhimurium reverse mutation (Ames) test, performed in duplicate as a pre-incubation assay in the presence and absence of metabolic activation (S9). The BOE did not induce an increase in the frequency of revertant colonies at any dose in the five tester strains, and was therefore non-mutagenic.

Food contact materials and gut health: Implications for toxicity assessment and relevance of high molecular weight migrants.

Gut health is determined by an intact epithelial barrier and balanced gut microbiota, both involved in the regulation of immune responses in the gut. Disruption of this system contributes to the etiology of various non-communicable diseases, including intestinal, metabolic, and autoimmune disorders. Studies suggest that some direct food additives, but also some food contaminants, such as pesticide residues and substances migrating from food contact materials (FCMs), may adversely affect the gut barrier or gut microbiota. Here, we focus on gut-related effects of FCM-relevant substances (e.g. surfactants, N-ring containing substances, nanoparticles, and antimicrobials) and show that gut health is an underappreciated target in the toxicity assessment of FCMs. Understanding FCMs' impact on gut health requires more attention to ensure safety and prevent gut-related chronic diseases. Our review further points to the existence of large population subgroups with an increased intestinal permeability; this may lead to higher uptake of compounds of not only low (<1000 Da) but also high (>1000 Da) molecular weight. We discuss the potential toxicological relevance of high molecular weight compounds in the gut and suggest that the scientific justification for the application of a molecular weight-based cut-off in risk assessment of FCMs should be reevaluated.

Toxicity assessment of ZnO-decorated Au nanoparticles in the Mediterranean clam Ruditapes decussatus.

The synthesis of hybrid nanomaterials has greatly increased in recent years due to their special physical and chemical properties. However, information regarding the environmental toxicity associated with these chemicals is limited, in particular in the aquatic environment. In the present study, an experiment was performed in which the marine bivalve (Ruditapes decussatus) was exposed for 14days to 2 concentrations of zinc oxide-decorated Au nanoparticles (Au-ZnONPs: Au-ZnONP50=50µg/L; Au-ZnONP100=100µg/L). The stability and resistance of Au-ZnONPs in the natural seawater were assessed by combining transmission electron microscopy and dynamic light scattering. Inductively coupled plasma-atomic emission spectroscopy revealed uptake of these nanoparticles within clams and their ability to induce metallic deregulation. The results obtained indicate that Au-ZnONPs induce biochemical and histological alterations within either the digestive gland or gill tissues at high concentration. This was deduced from the significant increase in H2O2 level, superoxide dismutase and catalase activities and malondialdehyde content. Furthermore, the toxicity of Au-ZnO nanoparticles was linked with the increase of intracellular iron and calcium levels in both tissues. Histological alterations in gill and digestive gland were more pronounced with Au-ZnONP100 and this is likely related to oxidative mechanisms. Gill and digestive gland are differentially sensitive to Au-ZnONPs if the exposure concentration is higher than 50µg/L. In conclusion, the parameters considered here could constitute reliable biomarkers for evaluation of hybrid nanoparticles toxicity in environmental model organisms. In addition, based on the results obtained, gill and digestive gland of R. decussatus could be proposed as models to detect harmful effects of hybrid nanoparticles.

Critical review of the safety assessment of nano-structured silica additives in food.

The development of nano-materials is viewed as one of the most important technological advances of the 21st century and new applications of nano-sized particles in the production, processing, packaging or storage of food are expected to emerge soon. This trend of growing commercialization of engineered nano-particles as part of modern diet will substantially increase oral exposure. Contrary to the proven benefits of nano-materials, however, possible adverse health effects have generally received less attention. This problem is very well illustrated by nano-structured synthetic amorphous silica (SAS), which is a common food additive since several decades although the relevant risk assessment has never been satisfactorily completed. A no observed adverse effect level of 2500 mg SAS particles/kg body weight per day was derived from the only available long-term administration study in rodents. However, extrapolation to a safe daily intake for humans is problematic due to limitations of this chronic animal study and knowledge gaps as to possible local intestinal effects of SAS particles, primarily on the gut-associated lymphoid system. This uncertainty is aggravated by digestion experiments indicating that dietary SAS particles preserve their nano-sized structure when reaching the intestinal lumen. An important aspect is whether food-borne particles like SAS alter the function of dendritic cells that, embedded in the intestinal mucosa, act as first-line sentinels of foreign materials. We conclude that nano-particles do not represent a completely new threat and that most potential risks can be assessed following procedures established for conventional chemical hazards. However, specific properties of food-borne nano-particles should be further examined and, for that purpose, in vitro tests with decision-making cells of the immune system are needed to complement existing in vivo studies.

Precision Medicine in Gastrointestinal Pathology.

CONTEXT: -Precision medicine is the promise of individualized therapy and management of patients based on their personal biology. There are now multiple global initiatives to perform whole-genome sequencing on millions of individuals. In the United States, an early program was the Million Veteran Program, and a more recent proposal in 2015 by the president of the United States is the Precision Medicine Initiative. To implement precision medicine in routine oncology care, genetic variants present in tumors need to be matched with effective clinical therapeutics. When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. OBJECTIVE: -To present the current state of precision medicine using gastrointestinal oncology as a model. We will present currently available targeted therapeutics, promising new findings in clinical genomic oncology, remaining quality issues in genomic testing, and emerging oncology clinical trial designs. DATA SOURCES: -Review of the literature including clinical genomic studies on gastrointestinal malignancies, clinical oncology trials on therapeutics targeted to molecular alterations, and emerging clinical oncology study designs. CONCLUSIONS: -Translating our ability to sequence thousands of genes into meaningful improvements in patient survival will be the challenge for the next decade.

The role of vitamin D in reducing gastrointestinal disease risk and assessment of individual dietary intake needs: Focus on genetic and genomic technologies.

With the endogenous formation of vitamin D being significantly curtailed because of public awareness of skin cancer dangers, attention is turning to dietary sources. Cumulative evidence has implicated vitamin D deficiency in increasing susceptibility to various gastrointestinal disorders, including colorectal cancer, inflammatory bowel diseases, diverticulitis, and irritable bowel syndrome. There is also reason to suggest adjunct vitamin D therapy for such diseases. Although there is justification for increasing vitamin D intake overall, optimal intakes will vary among individuals. Genomic technologies have revealed several hundreds of genes associated with vitamin D actions. The nature of these genes emphasizes the potentially negative implications of modulating vitamin D intakes in the absence of complementary human genetic and genomic data, including information on the gut microbiome. However, we are not yet in a position to apply this information. Genomic data (transcriptomics, metabolomics, proteomics, and metagenomics) could provide evidence that vitamin D sufficiency has been achieved. We suggest that there is an increasingly strong case for considering the more widespread use of vitamin D fortified foods and/or dietary supplements to benefit gastrointestinal health. However, intake levels might beneficially be informed by personalized genetic and genomic information, for optimal disease prevention and maintenance of remission.

Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential.

INTRODUCTION: The purpose of this study was (i) to evaluate the gastrointestinal behavior of micro- and nanosized fenofibrate in humans and (ii) to develop a simple yet qualitatively predictive in vitro setup that simulates the observed absorption-determining factors. MATERIALS AND METHODS: Commercially available micro- and nanoparticles of fenofibrate (Lipanthyl® and Lipanthylnano®, respectively) were administered orally to five healthy volunteers in fasting and postprandial conditions. Intraluminal and systemic drug concentrations were determined as reference data for the development of a predictive in vitro setup. To capture the observed solubility/permeability interplay, in vitro dissolution testing was performed in the presence of a permeation bag with sink conditions. RESULTS: In fasting conditions, intake of nanosized fenofibrate generated increased duodenal concentrations compared to microsized fenofibrate, which was reflected in an improved systemic exposure. In postprandial conditions, duodenal concentrations were greatly enhanced for both formulations, however without an accompanying increase in systemic exposure. It appeared that micellar encapsulation of the highly lipohilic fenofibrate limited its potential to permeate from fed state intestinal fluids. To capture these in vivo observations in an in vitro setup, classic dissolution testing was combined with permeation assessment into a permeation bag with sink conditions. In case of fasting conditions, the dissolution/permeation approach allowed for an improved discriminative power between micro- and nanosized fenofibrate by better simulating the dynamic interplay of dissolution and absorption. In case of postprandial conditions, the observed solubility-permeability interplay could be simulated using the dissolution/permeation approach in combination with biorelevant media (FeSSGFFortimel and FeSSIF-V2) to mimic micellar entrapment and reduced permeation potential of fenofibrate. CONCLUSION: For the first time, reduced permeation of a lipophilic drug despite increased intraluminal concentrations, was demonstrated in humans. Dissolution testing using biorelevant media in combination with permeation assessment into a sink permeation bag appeared to be a simple yet pragmatic approach to capture this solubility-permeability interplay in early formulation evaluation.

In vitro assessment of the prebiotic potential of Aloe vera mucilage and its impact on the human microbiota.

Aloe vera mucilage is reported to be rich in acemannan that is a polysaccharide with a backbone of ß-(1→4)-D-mannose residues acetylated at the C-2 and C-3 positions and contains some side chains of galactose and arabinose attached to the C-6 carbon. The evaluation of the prebiotic potential of Aloe vera mucilage was carried out by in vitro fermentation using intestinal microbiota from six healthy donors as the inoculum. The prebiotic activity was assessed through the quantification of short chain fatty acids (SCFA) and the evaluation of dynamic bacterial population in mixed faecal cultures by fluorescence in situ hybridization (FISH). Our findings support the possible incorporation of the Aloe vera mucilage in the development of a variety of food products known as prebiotics aimed at improving gastrointestinal health.

Experimental assessment of antidiarrheal and antisecretory activity of 80% methanolic leaf extract of Zehneria scabra in mice.

BACKGROUND: The leaf of Zehneria scabra is traditionally used for the management of diarrhea in Ethiopia. Its use, however, has not been scientifically validated for safety and efficacy. The aim of this study was to investigate antidiarrheal and antisecretory effects of hydroalcolic leaf extract of Z. scabra in mice models. METHODS: For each of antidiarrheal, gastrointestinal motility and antisecretory activity study Swiss albino mice were divided in to five groups. Group I was treated as control group and received 10 ml/kg of 2% Tween-80 orally; Group II served as a positive control and took standard drug in each of the experiments orally; Group III, IV and V were test groups which received the methanolic extract orally at 100, 200 and 400 mg/kg, respectively. Depending on the model total weight of fecal output, total weight of wet feces, total number of fecal output, number of wet faeces, length of intestinal transit and intestinal weight were collected. Finally, data were analyzed using one-way ANOVA followed by Tukey's post test. RESULT: In castor oil induced diarrhea model, the extract dose produced a significant reduction in mean stool score (1.94 ± 0.102) at 200 mg/kg. Moreover, the 100, 200, and 400 mg/kg doses inhibited stool frequency by 40, 45 and 55%, respectively. All test doses of extract and loperamide (3mg/kg) reduced fecal fluid content significantly (p<0.01). The 100 mg/kg dose of extract produced 25.74% reduction of fluid content (p<0.001) while both 200 and 400 mg/kg showed 29.70 % (p<0.001) compared to negative control group. CONCLUSION: The extract of Zehineria scabra showed antidiarrheal and antisecretory activity in mice model. Moreover, the extract found to be safe at dose of 2000mg/kg in mice model. The findings suggest the validity of the acclaimed effect of Zehineria scabra as antidiarrheal agent in Ethiopian traditional herbal medicine.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009-2013 French PharmacoVigilance assessment.

BACKGROUND: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS: This study suggests different ADR patterns between romiplostim and eltrombopag.