Broad Safety Research Articles

Uji Toksisitas Akut Kulit Manggis (Garcinia mangostana L.) Kajian Histopatologis Hati

The purpose of research was to examine the toxicity Acute Mangosteen Skin (Garciniamangostana L.) and Histopathologic Study of Liver. Animals in this study was 2 weeks oldchickens with an average weight of 500 grams were divided into the test group; distilled water (blank), doses of 250, 500.1000, 2000.4000 mg / kg weight tubuh.ayam housed in individual cages and given food and drink adlibitum. Acute toxicity tests performed on experimental animals. Giving the toxic dose in the treatment group performed one (single dosage) by intragastric using a stomach sonde. The control group was force-fed with 1 ml physiological saline. Acute toxicity tests performed on experimental animals. Giving the toxic dose in the treatment group performed one (single dosage) by intragastric using a stomach sonde. The control group was force-fed with 1 ml physiological saline. On histopathological examination of liver in the test toksikasi mangosteen rind extract the microscopic changes that occur are cell degeneration and necrosis of hepatocytes. In the treatment group occurred degeneration that occurs in hepatocyte cell degeneration grained and hidrops. Extract of mangosteen rind has a broad safety index and does not cause high mortality in administration. Mangosteen rind extract that does not cause cellular toxicityreaction in the delivery of 100 dosesKeyword: Mangosteen Skin , Acute Toxicit, and Histopathologic

Next steps to evidence-based food safety risk analysis: opportunities for health technology assessment methodology implementation

Food safety risk analysis and health technology assessment (HTA) are two different paradigms sharing multiple common features. Decision makers in both fields have the responsibility to promote the health of society deciding on intervention opportunities based on disease burden, intervention feasibility, effectiveness and cost, equity and ethical considerations. The evolution of HTA in the last two decades has resulted in the establishment and widespread use of quantitative tools to support and justify evidence-based decisions. In contrast, decision making in the food safety domain is still a qualitative process rendering ad hoc weights to all aspects considered. This review evaluates whether HTA methodology is suitable for quantitative decision support in food safety risk analysis. We conclude that cost-utility analysis (CUA) could better serve the priority settings in food safety risk management than the currently (rarely) applied cost-benefit analysis (CBA), considering either broad resource allocation or specific safety measure decisions. Development of multi-criteria decision analysis tools could help the introduction of consistent and explicit weighting among cost and health impacts, equity and all other relevant aspects. Cost-minimisation and cost-effectiveness analyses would be relevant for ‘threshold’ and ‘as low as reasonably achievable’ approaches to single food safety risk assessments, respectively. Assuming a future widespread use of HTA methodology in the food safety paradigm, a vision of integrated healthcare, food safety and nutritional policy emerges, with the re-evaluation of budgets and resources of these large systems in a rational and socially acceptable way.

Next steps to evidence-based food safety risk analysis: opportunities for health technology assessment methodology implementation

Food safety risk analysis and health technology assessment (HTA) are two different paradigms sharing multiple common features. Decision makers in both fields have the responsibility to promote the health of society deciding on intervention opportunities based on disease burden, intervention feasibility, effectiveness and cost, equity and ethical considerations. The evolution of HTA in the last two decades has resulted in the establishment and widespread use of quantitative tools to support and justify evidence-based decisions. In contrast, decision making in the food safety domain is still a qualitative process rendering ad hoc weights to all aspects considered. This review evaluates whether HTA methodology is suitable for quantitative decision support in food safety risk analysis. We conclude that cost-utility analysis (CUA) could better serve the priority settings in food safety risk management than the currently (rarely) applied cost-benefit analysis (CBA), considering either broad resource allocation or specific safety measure decisions. Development of multi-criteria decision analysis tools could help the introduction of consistent and explicit weighting among cost and health impacts, equity and all other relevant aspects. Cost-minimisation and cost-effectiveness analyses would be relevant for ‘threshold’ and ‘as low as reasonably achievable’ approaches to single food safety risk assessments, respectively. Assuming a future widespread use of HTA methodology in the food safety paradigm, a vision of integrated healthcare, food safety and nutritional policy emerges, with the re-evaluation of budgets and resources of these large systems in a rational and socially acceptable way.

A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys

XMetA is a fully human, allosteric monoclonal antibody that binds the insulin receptor with high affinity and mimics the glucoregulatory, but not the mitogenic, actions of insulin. Here we evaluated the efficacy of both single and repeat s.c. administrations of XMetA in reducing hyperglycemia in obese cynomolgus monkeys with naturally developed type 2 diabetes, a model that shares many features of human diabetes. The data show that a single s.c. administration of XMetA at dose levels ranging from 1.5 to 10 mg/kg markedly reduced fasting hyperglycemia, with a peak effect occurring 1 to 2 days after administration, and sustained for up to 1 week. XMetA's effect on hyperglycemia was observed without elevations in serum insulin and was concomitant with reduced serum C-peptide levels, even at the lowest dose. Subchronic effects were evaluated via once weekly s.c. administration of XMetA, 10 mg/kg, for 6 weeks. XMetA treatment resulted in robust weekly decreases in fasting glucose levels averaging approximately 30% throughout the study, along with a significant absolute reduction from the vehicle control baseline of 1.2% in hemoglobin A1c, a marker of long-term glycemic status. XMetA treatment was well tolerated with no injection-site reactions, no body weight gain, and no episodes of clinical hypoglycemia. Thus, XMetA shows acute and subchronic improvements in glycemic control in spontaneously diabetic cynomolgus monkeys with a broad safety margin. This profile supports the development of XMetA as a novel glucose-lowering therapeutic agent for the management of type 2 diabetes.

Validation of the minimalistic Nodal Drift Method for spatial kinetics on a simple CANDU LOCA benchmark

The recently developed Nodal Drift Method (NDM) provides easy spatial kinetics with a view to broad and coarse safety studies of some promising thorium-fueled High Conversion Water Reactor (HCWR) options. It fills a gap between the extremes of rather loose approximate point kinetics and rather tightly defined and too sophisticated industrial schemes. NDM is based on the 2-group diffusion theory and a lumped parameter model with maximized mesh size. It is validated here on an elementary CANDU-like LOCA benchmark proposed by AECL in the seventies. Chosen for its model simplicity, this design transient allows one to describe NDM principles and to carefully check the accuracy without any need for thermal calculations. Thus precise modeling of the strong coupling between neutronics and thermal–hydraulics is deferred for further developments, and simplified within this framework. Based on a simple transposition of the benchmark, a first application of NDM assesses safety of CANDU with “Th” fuel (Th/233U oxide) compared to “NU” (Natural Uranium oxide).

Safety and efficacy of intraurethral alprostadil in patients with erectile dysfunction refractory to treatment using phosphodiesterase-5 inhibitors

IntroductionPhosphodiesterase-5 inhibitors (PDE5i) are the first choice for treating erectile dysfunction (ED) but are not always effective. The aim of this study was to present our experience in treating patients with ED, refractory to treatment with PDE5i, using intraurethral alprostadil (MUSE). Material and methodsWe conducted a review of 82 patients with ED and no response to PDE5i, from March 2013 to October 2014. Forty-seven patients (57%) had hypertension (AHT), 24 (29%) had diabetes (DM) and 20 (24%) had AHT and DM. Additionally, 19 (23%) had undergone radical prostatic (RP) surgery. The patients were evaluated after the treatment was applied and at 4 weeks using the following validated questionnaires: International Index of Erectile Function (IIEF-5/SHIM), Global Assessment Questionnaire (GAQ), Sexual Encounter Profile (SEP) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). ResultsThe mean patient age was 60.5 years (40–80), and the mean follow-up was 11.3 months (1–20). Sixty-eight percent of the treated patients responded to MUSE® (74% in the AHT group, 65% in the AHT+DM group, 62.5% in the DM group and 58% in the RP group). The mean IIEF-5 score was 11.7±4.7, which increased to 18.6±4.9 after MUSE was administered (P=.027). The mean EDITS score at 4 weeks was 61.6 (6–81.9). The most common adverse effect was urethral burning, which occurred in 24 patients (29%). There were no cases of urinary tract infection, syncope or priapism. ConclusionsIntraurethral alprostadil is an effective treatment and has a broad safety profile for treating patients with erectile dysfunction refractory to oral treatment with PDE5i.

ATPS-12RE-EVALUATION OF THE USEFULNESS OF INTRAOPERATIVE COMPUTED TOMOGRAPHY FOR NEUROSURGICAL PROCEDURES IN INTRAOPERATIVE MAGNETIC RESONANCE IMAGING ERA

PURPOSE: Our hospital introduced an intraoperative computed tomography (CT) for reasons such as its broad utility, safety and economy, despite an increase in intraoperative magnetic resonance imaging (MRI). We would like to verify existence value of our intraoperative CT system for neurosurgical procedures. MATERIALS AND METHODS: We performed intraoperative CT scans for the patients with 16 gliomas and 1 anterior cerebral artery partially thrombosed large aneurysm, which was treated by A2 side to side anastomosis and proximal occlusion, using a CT with 900mm opening size, radiolucent skull clamp and three types of pin made by stainless, titan, and sapphire, respectively. We assessed the residual tumors with plain and enhanced CT scans. In the cases of non-contrast tumors, small titan clips were applied on the wall of resection cavity to clarify the residual tumors. We also use 3-dementional CT angiography (3DCTA) for evaluating the hemodynamics. The time from the preparation to take images to restarting operation, image quality including the amount of halation caused by pins, and incidence during these procedures, were evaluated. RESULT: We could obtain CT scans all of these cases, regardless of the patients' position. All the surgical instruments were just put on the table below the breast. The amount of halation with sapphire pins was minimum, however even with them, it was difficult to evaluate the detailed residual tumors just beneath the location of pins. CTA was useful, especially for demonstrating the hemodynamics after resection of insulo-opercular gliomas and bypass/clipping. Total time to take CT scans was 15–40 (mean, 27) minutes. There had occurred no incidence including anesthesia. CONCLUSION: MRI is better than CT at the point of spatial resolution, but CT can be defined as an useful system in its easy-to-use, safety, and vascular evaluation.

A systems thinking approach of occupational safety and health applied in the micro-, meso- and macro-levels: A Finnish survey

The aim of this study was also to explore the interconnected frameworks of the systems thinking approach between the micro-, meso- and macro-levels within occupational safety and health (OSH). The goal of this study was to analyze different entities through different types of aggregation. The aggregated variables of micro-, meso- and macro-levels of the systems thinking approach were found to exert an effect on each other in the regression analysis. For OSH managers and workers’ OSH representatives, the Hypotheses were supported with the aggregated variables as follows: Hypothesis 1 – OSH management & collaboration was positively related to training, measuring and monitoring, quality of OHC services and quality of OSH legislation; Hypothesis 2 – technical processes were positively related to training, measuring and monitoring, OSH management & collaboration and quality of OSH legislation; Hypothesis 3 – measuring and monitoring were positively related to training, OSH management & collaboration, quality of OHC services and quality of OSH legislation; Hypothesis 4 – instructions were positively related to training, measuring and monitoring, OSH management & collaboration and quality of OHC services; and Hypothesis 5 – use of personal protective equipment was positively related to training, measuring and monitoring, OSH management & collaboration, quality of OHC services and quality of OSH legislation. The functional specification related micro-, meso- and macro-levels revealed how one can apply a system approach model to demonstrate how the human, safety management, and organizational factors fit together in the broad safety context (e.g., OSH legislation).

Eficacia y seguridad del alprostadil intrauretral en pacientes con disfunción eréctil refractarios al tratamiento mediante inhibidores de la 5-fosfodiesterasa

IntroductionPhosphodiesterase-5 inhibitors (PDE5i) are the first choice for treating erectile dysfunction (ED) but are not always effective. The aim of this study was to present our experience in treating patients with ED, refractory to treatment with PDE5i, using intraurethral alprostadil (MUSE). Material and methodsWe conducted a review of 82 patients with ED and no response to PDE5i, from March 2013 to October 2014. Forty-seven patients (57%) had hypertension (AHT), 24 (29%) had diabetes (DM) and 20 (24%) had AHT and DM. Additionally, 19 (23%) had undergone radical prostatic (RP) surgery. The patients were evaluated after the treatment was applied and at 4 weeks using the following validated questionnaires: International Index of Erectile Function (IIEF-5/SHIM), Global Assessment Questionnaire (GAQ), Sexual Encounter Profile (SEP) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). ResultsThe mean patient age was 60.5 years (40–80), and the mean follow-up was 11.3 months (1–20). Sixty-eight percent of the treated patients responded to MUSE® (74% in the AHT group, 65% in the AHT+DM group, 62.5% in the DM group and 58% in the RP group). The mean IIEF-5 score was 11.7±4.7, which increased to 18.6±4.9 after MUSE was administered (P=.027). The mean EDITS score at 4 weeks was 61.6 (6–81.9). The most common adverse effect was urethral burning, which occurred in 24 patients (29%). There were no cases of urinary tract infection, syncope or priapism. ConclusionsIntraurethral alprostadil is an effective treatment and has a broad safety profile for treating patients with erectile dysfunction refractory to oral treatment with PDE5i.

Acute and subchronic toxicity assessment model of Ferula assa-foetida gum in rodents.

Aim:The present study was performed to investigate acute and subchronic oral toxicity of Ferula assa-foetida gum (28 days) in Sprague Dawley rats.Materials and Methods:Acute oral administration of F. assa-foetida was done as a single bolus dose up to 5 g/kg in mice and subchronic toxicity study for 28 days was done by oral administration at doses of 0 (control) and 250 mg/kg in Sprague Dawley rats.Results:The obtained data revealed that oral administration of F. assa-foetida extract in rats for 28 successive days had no significant changes on body weight, body weight gain, the hematological parameters in rats all over the period of the experiment, and there are no significant increases in the activity of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine and urea. Liver of treated rats showed mild changes as thrombosis and sinusoidal leukocytosis. It also showed portal infiltration with inflammatory cells, while kidney of treated rat showed an atrophy of glomerular tuft, thickening of parietal layer of Bowman capsule, and focal tubular necrosis. It also showed dilatation and congestion of renal blood vessels.Conclusion:We concluded that F. assa-foetida gum had broad safety and little toxicity for short term use in dose of 250 mg/kg.

Selective targeting of FAK–Pyk2 axis by alpha-naphthoflavone abrogates doxorubicin resistance in breast cancer cells

Despite an initial positive response, breast cancer cells inevitably acquire resistance to doxorubicin (Dox). Alpha-naphthoflavone (ANF) is a well-known chemopreventive agent; however, its anti-cancer properties have not been established. We examined the therapeutic efficacy of ANF in doxorubicin-resistant MCF-7 (MCF-7/Dox) breast cancer cells and investigated its underlying molecular mechanisms of action. MCF-7/Dox cells expressed constitutively active forms of the tyrosine kinases: focal adhesion kinase (FAK-Y397) and protein tyrosine kinase 2 beta (Pyk2- Y579/580) compared with parental MCF-7 cells. ANF significantly enhanced the sensitivity of MCF-7/Dox cells to Dox cytotoxicity in vitro and when co-administered in vivo. This ANF-mediated chemosensitization has dual mechanisms of action: (a) intracellular Dox retention via suppression of P-glycoprotein pump activity, and (b) inhibition of clonogenic cell survival via de-phosphorylation of FAK, Pyk2, and EGF-induced Akt in MCF-7/Dox cells and tumor xenografts. Because of its strong chemosensitization action, broad safety profile, and health benefits, ANF is an attractive anti-cancer drug with therapeutic implications to circumvent drug resistance in breast cancer patients.

Early mobilization after stroke: early adoption but limited evidence.

In the last decade, increasing attention has been paid to understanding the components of care that might contribute to the stroke unit effect. Early mobilization, in its many guises, is one component of care proposed to contribute to the survival and recovery benefits of stroke unit care.1 This topical review provides an overview of the current evidence, research, and practice recommendations for early mobilization after stroke. As a term, early mobilization is problematic. There is no common understanding of the meaning of early (eg, hours, days, weeks, months) or mobilization (movement of, eg, cells, joints, limbs, people). A recurring theme in this review, inadequate definition currently limits our ability to synthesize information on the topic. For example, in some clinical trials of mobility interventions started soon after stroke, mobilization is used to describe a program of task-specific standing and walking retraining (rehabilitation) delivered by therapists or nurses and continued throughout the acute hospital stay.2,3 In other cases, mobilization refers simply to moving a patients’ limbs in bed or sitting them out of bed. The timing of commencement of activity is also highly variable and often hard to determine. As both what we do (intervention type, intensity, frequency, amount), and when we do it, may confer benefit or harm, we highlight variations in definition where relevant. We have focused our review on out-of-bed interventions commencing in the first 24 to 72 hours after stroke, as this is the period of greatest clinical uncertainty. Early mobilization was first discussed at a Swedish consensus conference on stroke care in the mid-1980s (Bo Norving and Bent Indredavik, personal communication, 2014) with several local guidelines in Norway and Sweden recommending the practice. Early mobilization became more prominent in the literature in the early 1990s when Indredavik and colleagues reported their clinical …

Safety and toxicological evaluation of Meratrim®: An herbal formulation for weight management

Meratrim is a unique dietary ingredient consisting of extracts from Sphaeranthus indicus flower heads and Garcinia mangostana fruit rind. Clinical studies have demonstrated that Meratrim is effective and well-tolerated in weight management. Herein we assessed the broad spectrum safety of Meratrim in a battery of in vitro and animal toxicological studies including a sub-chronic repeated-dose 13-week oral toxicity study to determine the no-observable-adverse-effect-level (NOAEL). The LD50 levels of Meratrim in Sprague-Dawley (SD) rats, as determined by the acute oral and dermal toxicity studies, were >5000 and >2000 mg/kg body weight, respectively. The primary skin and eye irritation tests classified Meratrim as non-irritating to the skin and mildly irritating to the eye. Genotoxicity studies showed that Meratrim is non-mutagenic. In the repeated-dose 13-week oral toxicity study, SD rats were orally gavaged with Meratrim at 0, 250, 500 or 1000 mg/kg/day. No morbidity, mortality, or significant adverse events were observed either during the course of the study or on the 13th week. The NOAEL of Meratrim was concluded to be 1000 mg/kg of body weight/day in male and female SD rats. These results, combined with the tolerability of Meratrim in the human clinical trials, demonstrate the broad spectrum safety of Meratrim.

Cell-permeable inhibitors of neuronal nitric oxide synthase open new prospects for the treatment of neurological disorders.

The disubstituted pyrimidines based SAR study by Silverman et al. ( J. Med. Chem. 2014 , DOI: 10.1021/jm501719e ) was focused on improving bioavailability and physicochemical properties of the designed inhibitors while retaining the potency for neural nitric oxide synthase (nNOS) and selectivity over the other two nitric oxide synthase (NOS) isoforms (endothelial NOS and inducible NOS). One of the new promising lead compounds, compound 7, displayed nanomolar potency for nNOS (Ki = 19 nM), good selectivity over endothelial (260-fold), and inducible (41-fold) NOS isoforms and also showed potential for oral bioavailability (good cell permeability with efflux ratio of 1.8) and broad safety profile with minimal off-target activities at 50 CNS based receptors. This remarkable achievement not only serves as a template for next generation selective NOS inhibitor design but also opens new prospects for the treatment of neurological disorders.

Magnetic resonance imaging in cochlear implant recipients: pros and cons.

The article by Kim et al1 brings to light a larger topic— namely, how does one “prove” safety, either in general or specificallywithin themagnetic resonance imaging (MRI) environment?For example, in the caseof cochlear implants, several studieshavedocumented the “safety” ofMRI exposure by numerous patients with various cochlear implants. Why, then, did the patients in the study by Kim et al experience adverse events or pain, even to the point of terminating the examination? It is important to recognize that it is a mathematical impossibility to prove something to be safe, per se. All that can be done is to document that when specifically tested, some stimulus, agent, process, orother influencing factorwas found to not be associated with any recognized adverse events to a specifically tested threshold of detectability or statistical significance. For example, if 100 patients were studied following exposure to a specific drug, one might claim that following 100 exposures, the incidence of hives or other recognized cutaneous allergic reactionswas0.Clearly this is not the same as proving safety—it merely documents that in their experience, the recorded incidence of a specifically studied adverse event was 0. This might provide a statistical window of confidence to safety, but it is far from proving that this agent is, per se, safe. For example, it is entirely possible that the 101st patient exposedmight experience a severe anaphylactic reaction from exposure to that same drug. Additionally, it may be that allergic reactionswere not observed, but perhaps the patient did experience a severe but clinically asymptomatic hypokalemiaor thrombocytopenia—adverseevents thatmaynot have been anticipated, specifically prospectively studied, or clinically recognized in the study cohort. Not having observed that which one did not study is exceedingly common andmust be consideredbeforebroadlypainting the testedhypothesis itself as entirely safe. Furthermore, many studies purport to document safety merely by exposing a finite number of patients to a specific stimulus, environment, or situation and failing to observe—or recognize?—any adverse reactions. The current literature is repletewith such cases: for example,MRI exposure andpatients with cardiac pacemakers. What remains unrecognized, however, is that failing to identify an adverse reaction or event is not the same as proving safety. Yet a single publication documenting a life-threatening adverse event on a single patient with a cardiac pacemaker exposed to MRI successfully disproves the entire inappropriately broad safety claim. As has beenpreviously noted, “...failing to identify an adverse event isnotequivalent todemonstratingsafety—especiallywhenonly a limitednumberofpatientsare studied.”2(p1326)This solidprinciple is the basis of theUSFood andDrugAdministration’s rejectionof the“wesawnoproblems”methodologyand for their having required far more rigorous science before they would approve the first truly MRI conditionally safe cardiac pacemaker.3 Finally, while MRI scanners operating at magnetic fields of 1.5 T to 3.0 T raise concerns of potential translational and rotational forces, as detailed by Kim et al,1 scanners operatRelated article page 45 Research Original Investigation Adverse Events DuringMRIWith Cochlear Implants

Gross mismatch between thermal tolerances and environmental temperatures in a tropical freshwater snail: Climate warming and evolutionary implications

The relationship between acute thermal tolerance and habitat temperature in ectotherm animals informs about their thermal adaptation and is used to assess thermal safety margins and sensitivity to climate warming. We studied this relationship in an equatorial freshwater snail (Clea nigricans), belonging to a predominantly marine gastropod lineage (Neogastropoda, Buccinidae). We found that tolerance of heating and cooling exceeded average daily maximum and minimum temperatures, by roughly 20°C in each case. Because habitat temperature is generally assumed to be the main selective factor acting on the fundamental thermal niche, the discordance between thermal tolerance and environmental temperature implies trait conservation following ‘in situ’ environmental change, or following novel colonisation of a thermally less-variable habitat. Whereas heat tolerance could relate to an historical association with the thermally variable and extreme marine intertidal fringe zone, cold tolerance could associate with either an ancestral life at higher latitudes, or represent adaptation to cooler, higher-altitudinal, tropical lotic systems. The broad upper thermal safety margin (difference between heat tolerance and maximum environmental temperature) observed in this snail is grossly incompatible with the very narrow safety margins typically found in most terrestrial tropical ectotherms (insects and lizards), and hence with the emerging prediction that tropical ectotherms, are especially vulnerable to environmental warming. A more comprehensive understanding of climatic vulnerability of animal ectotherms thus requires greater consideration of taxonomic diversity, ecological transition and evolutionary history.

Safety and toxicological evaluation of a novel, fermented, peptide-enriched, hydrolyzed swine placenta extract powder

Placenta is an important organ that connects the developing fetus to allow nutrient uptake, antibody provisions and gas exchange via the blood supply of the mother. We developed a novel, standardized, stable, water-soluble, peptide-enriched hydrolyzed, Horus fermented placenta powder (HFPEP) from healthy, pathogen-free, swine placenta. Earlier studies demonstrated that HFPEP significantly improves physical fatigue, hepatic functions and repair of muscle fibers. We examined the broad safety of HFPEP in various toxicology models in Good Laboratory Practices-approved laboratories. The acute oral toxicity study was conducted in female Sprague-Dawley rats, and the acute oral LD50 was found to be greater than 5000 mg/kg body weight. Ames’ bacterial reverse mutation assay was conducted to determine the ability of HFPEP to induce reverse mutation at selected histidine loci in five tester strains of Salmonella typhimurium viz. TA1535, TA1537, TA98, TA100 and TA102 in the presence and absence of a metabolic activation system (S9) at the doses of 50, 15, 4.5, 1.35 and 0.41 mg/ml. No mutagenic potential was observed. Mutagenic potential was also evaluated using in vivo micronucleus test, and no mutagenic potential of HFPEP was observed. Repeated dose 28-d oral toxicity study was performed in male and female rats with 14-d recovery period at the dose levels of 250, 500 or 1000 mg/kg. No abnormal clinical signs or toxicity were detected. No observed adverse effect level of HFPEP was found to be greater than 1000 mg/kg body weight. These studies affirm that HFPEP has broad spectrum safety for human consumption.

PO-0358 Concomitant Ceftriaxone-induced Nephrolithiasis And Biliary Pseudolithiasis In A Small Toddler

<h3>Introduction</h3> Ceftriaxone is a frequent choice in Romanian hospitals for empiric antimicrobial therapy because of its broad spectrum, long half-life, safety and tolerability. However, some relatively rare side effects as renal lithiasis and biliary pseudolithiasis may occur. <h3>Case report</h3> A 5 month male toddler was admitted into our unit with extreme agitation and mild respiratory symptoms. The child had interstitial pneumonia and received ceftriaxone intravenously for 7 days in a county hospital. Clinical examination showed productive cough, fine crackles, mild systolic murmur and small crystals in the in diaper. Ultrasound examination of the kidneys revealed the presence of sediment in the bladder and a hyperechoic image of 4 mm in the gallbladder. Complete blood count, urea, creatinine, creatinine clearance, serum glucose, calcium (total and ionised), serum phosphorus, bilirubinemia, alkaline phosphatase were within normal limits. Urinalysis showed calcium carbonate deposit and increased calcium/creatinine ratio. Chest X-Ray revealed discrete bilateral interstitial infiltrate. The echocardiography found permeable foramen ovale and moderate left ventricular diastolic dysfunction. Treatment consist in suspending ceftriaxone administration, antispasmodics, hydrochlorothiazide 6,25 mg/daily and adequate hydration. The child was dismissed after 3 days in good general condition, disappearance of bladder sediment but persistant gallbladder image that disappeared within 3 weeks. <h3>Conclusions</h3> This is a particular case of a very young patient with renal and vesicular pseudolithiasis induced by ceftriaxone; the negative family history of kidney stones, a normal intake of vitamin D3 and normal liver and renal function excluded any other cause of lithiasis except the antibiotic itself.

Toxicological evaluation of hydroethanolic extract of Helicteres sacarolha A. St.- Hil. et al.

Ethnopharmacological relevanceHelicteres sacarolha, popularly known in Brazil as ‘rosquinha’, ‘sacarolhas’, ‘semente-de-macaco’, is widely distributed in different phytogeographic zones in Brazil. Preparations from its roots and leaves are employed in popular Brazilian medicine in the treatments of ailments such as peptic ulcer, hypertension among others. Cytotoxicity, acute oral and subchronic toxicity of the hydroethanolic extract of Helicteres sacrolha was investigated as well as the classes of phytochemical present in the extract. Materials and methodsHydroethanolic (70%) extract of Helicteres sacarolha (HEHs) was prepared by maceration. Potential cytotoxicity was evaluated in CHO-k1 cells. Acute administration of HEHs was done in mice as a single dose up to 5000mg/kg and subchronic oral toxicity study for 30 days in Wistar rats at daily oral doses of 0, 250 and 750mg/kg b.w. Clinical observations and toxicological related parameters were determined every 6 days. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Selected secondary metabolites detected were quantified by UV-spectrophotometry and high performance liquid chromatography (HPLC). ResultsThe extract was non-cytotoxic to CHO-k1 cells. In acute oral toxicity, there was no mortality or clinical alterations in the female mice, at all doses, except for the transient diarrhea observed at 5000mg/kg acute. Doses up to 2000mg/kg caused no mortality or treatment-related clinical manifestations in the male mice, but treatment-related alterations were however observed at 4000mg/kg, with mortalities recorded at 5000mg/kg. During the subchronic oral toxicity study, no mortality or treatment-related clinical signs were observed. Differences in relative organ weight, hematological parameters and histopathology observations between the treated and the control groups were considered not to be treatment-related. Spectrophotometric analysis revealed the presence of relatively high content of phenolics and flavonoids in HEHs. HPLC analysis confirmed the presence of the quantified compounds and demonstrated the presence of ellagic acid, morin and naringin. ConclusionOur results confirmed that HEHs have a broad safety margin for therapeutic use.

67. The AMP-kinase inhibitor metformin inhibits chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. There are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin inhibits pathological pain following nerve injury in mice and rats. We tested the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits in mice. Mice were treated with cisplatin together with metformin or saline. Co-administration of metformin almost completely prevented the cisplatin- and paclitaxel-induced mechanical allodynia. Cisplatin decreased the time to detect an adhesive patch on the hind paw, a novel indicator of sensory deficits. Reduced sensory function was prevented by co-administration of metformin. Moreover, metformin prevented cisplatin-induced loss of IENFs in the hind paw. In the spinal cord, metformin treatment altered glial activation, indicating a contribution of regulation of neuroinflammation to the protective effect. In conclusion, metformin protects against pain and loss of sensory function in a mouse model of CIPN. The mechanism involves reduced peripheral nerve damage and changes in neuroinflammation, strongly suggesting that metformin exerts a neuroprotective effect. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.