Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 administered by auto-injector or pre-filled syringe: a randomized, open­label, single-dose phase I study.

BACKGROUND: This study compared the pharmacokinetics (PK), immunogenicity, and safety of candidate tocilizumab biosimilar, CT-P47, administered via auto-injector (CT-P47 AI) or pre-filled syringe (CT-P47 PFS), in healthy Asian adults. RESEARCH DESIGN AND METHODS: In this phase I, multicenter, open-label study, participants were randomized 1:1 to receive a single 162 mg/0.9 mL dose of CT-P47 via AI or PFS. Primary endpoints were area under the concentration - time curve from time zero to infinity (AUC0-inf) and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the predefined 80-125% equivalence margin. Secondary PK parameters, immunogenicity, and safety outcomes were also assessed. RESULTS: Of 314 participants randomized (155 CT-P47 AI; 159 CT-P47 PFS), 310 received the study drug (153 CT-P47 AI; 157 CT-P47 PFS). Primary and secondary PK results, immunogenicity and safety were similar between groups. Ninety percent CIs for the ratio of gLSMs were within the predefined equivalence margin for AUC0-inf (85.87-102.94) and Cmax (82.98-98.16). CONCLUSIONS: PK equivalence between CT-P47 AI and CT-P47 PFS was demonstrated in healthy Asian adults, with comparable immunogenicity and safety between the two devices. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05617183.

Tocilizumab is a biologic medicine used to treat inflammatory diseases, such as rheumatoid arthritis. A biosimilar is a drug that is an almost identical copy of an approved original ('reference') biologic medicine; it has identical efficacy and safety to the original medicine but is typically less expensive. CT­P47 is in development as a possible tocilizumab biosimilar.Some patients prefer injections using an auto-injector (AI) rather than a pre-filled syringe (PFS), for reasons including ease of use and convenience. With an AI, medicine is delivered automatically by firmly pressing the device against the skin, whereas, with a PFS, a needle is inserted into the skin and medicine delivered by depressing the plunger. The injection of CT­P47 using a PFS has shown comparable pharmacokinetics (i.e., the uptake, metabolism and excretion of the drug by the body) and safety to tocilizumab. Therefore, if the pharmacokinetics and safety of CT­P47 administered via AI and PFS were shown to be similar, this might expand the choice of administration devices available to patients.In this study, 310 healthy adults received a single injection of CT­P47 via AI or PFS. Blood samples were taken over 43 days to analyze pharmacokinetics. The uptake, metabolism and elimination of CT­P47 by the body was similar when administered by each device, suggesting that CT­P47 can be administered by either AI or PFS.

Rare Columnar Cell Variant of Papillary Thyroid Carcinoma with Cervical Spine Metastasis: A Case Report.

BACKGROUND: Columnar cell carcinoma is a rare subtype of papillary thyroid carcinoma (CCV-PTC) that accounts for only 0.15% to 0.2% of all Papillary Thyroid Carcinomas (PTCs). It has aggressive behavior but a better prognosis than anaplastic thyroid carcinoma. CASE PRESENTATION: A 64-year-old female presented with a huge thyroid mass resulting in compressive myelopathy and was diagnosed as CCV-PTC, not anaplastic carcinoma. After multidisciplinary discussions, we decided to proceed with otolaryngological, thoracic, and orthopaedic surgery. All tumours were unresectable, and we planned to proceed with R2 resection to resolve the gait disturbance and anterior fusion to resolve spinal instability. CONCLUSION: Advanced-stage thyroid cancer is relatively uncommon, but desirable treatment effects can be expected through accurate pathological diagnosis. Immunohistochemical staining and tissue-specific markers can be helpful.

Effectiveness of a dispatcher-assisted CPR using an animated image: Simulation study.

INTRODUCTION: Considering the few studies evaluating bystander cardiopulmonary resuscitation (CPR) performance, we sought to analyze differences in bystander CPR performance with and without the use of our self-developed animated GIFs based on dispatcher-assisted CPR simulation. METHODS: A total of 80 adults who had not received CPR training over the past two years participated in the study. Among them, 40 people were classified into the auditory group (receiving CPR instructions only over the phone), and the other 40 people were classified into the audiovisual group (receiving CPR instructions over the phone after receiving images on a smartphone). All participants were asked to perform adult and infant CPR for 2 min. CPR performance was recorded using two video cameras (front and side) and analyzed by two emergency physicians, whereas CPR quality was measured using Resusci Anne & Baby QCPR Mk II (Laerdal). RESULTS: In the adult CPR study, the audiovisual group had higher performance scores for adequacy of "knee position," "hand posture," "elbow extension," and "vertical compression," as well as higher Standard Posture Completeness and Instruction Performance scores (p < 0.001). No significant difference in CPR quality was observed between the two groups. In the infant CPR study, audiovisual group had higher performance scores in adequacy of "compression site," "finger posture," and "vertical compression," as well as higher Standard Posture Completeness and Instruction Performance scores (p < 0.001). Regarding CPR quality, the audiovisual group had higher scores for "adequate compression rate ratio" (p = 0.047). CONCLUSION: Audiovisual guidance using animated GIFs more effectively improved CPR Standard Posture Completeness and Instruction Performance than did traditional auditory guidance.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study.

BACKGROUND: CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults. RESEARCH DESIGN AND METHODS: This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration - time curve (AUC) from time zero to last quantifiable concentration (AUC0-last), AUC from time zero to infinity (AUC0-inf), and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80-125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated. RESULTS: In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC0-last, AUC0-inf, and Cmax were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80-125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups. CONCLUSIONS: CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05188378.

Tocilizumab is a biologic medicine used to treat inflammatory diseases including rheumatoid arthritis. Biosimilars are drugs that are highly similar to an already approved, 'reference' biologic medicine. This means that they do not have any differences from the reference product in factors including structure, biologic function, efficacy, and safety, that might affect how well they work in patients. Biosimilars are often available at a lower cost than reference drugs, so their use can provide patients with better access to expensive treatments. There are no approved biosimilars of tocilizumab so far: CT-P47 is currently in development as a potential tocilizumab biosimilar.In the main part of this study, 289 healthy Asian volunteers were randomly allocated to receive a single injection of either CT-P47 or the reference drug, European Union-approved tocilizumab (EU-tocilizumab). The main aim of the study was to find out whether CT-P47 and EU-tocilizumab were equivalent in terms of pharmacokinetics (drug absorption, distribution, metabolism, and excretion by the body). This is part of a standard process required by regulatory authorities to ensure that biosimilars work as well as their reference drugs. Analysis of blood samples taken over 43 days showed that the pharmacokinetic profiles of CT-P47 and EU-tocilizumab were equivalent, after the volunteers received a single dose of either drug. Safety and immunogenicity (immune responses made to the drug) were also comparable between CT-P47 and EU-tocilizumab. While only healthy Asian adults were included, further research comparing CT-P47 with reference tocilizumab will help to ensure that the findings from the study can be applied to broader populations.

Effect of Intra- and Post-Operative Fluid and Blood Volume on Postoperative Pulmonary Edema in Patients with Intraoperative Massive Bleeding.

In patients with intraoperative massive bleeding, the effects of fluid and blood volume on postoperative pulmonary edema are uncertain. Patients with intraoperative massive bleeding who had undergone a non-cardiac surgery in five hospitals were enrolled in this study. We evaluated the association of postoperative pulmonary edema risk and intra- and post-operatively administered fluid and blood volumes in patients with intraoperative massive bleeding. In total, 2090 patients were included in the postoperative pulmonary edema analysis, and 300 patients developed pulmonary edema within 72 h of the surgery. The postoperative pulmonary edema with hypoxemia analysis included 1660 patients, and the condition occurred in 161 patients. An increase in the amount of red blood cells transfused per hour after surgery increased the risk of pulmonary edema (hazard ratio: 1.03; 95% confidence interval: 1.01-1.05; p = 0.013) and the risk of pulmonary edema with hypoxemia (hazard ratio: 1.04; 95% confidence interval: 1.01-1.07; p = 0.024). An increase in the red blood cells transfused per hour after surgery increased the risk of developing pulmonary edema. This increase can be considered as a risk factor for pulmonary edema.

Erratum: The effect of first nocturnal ejaculation timing on risk and sexual behaviors of Korean male adolescents.

[This corrects the article on p. 43 in vol. 22.].

The effect of first nocturnal ejaculation timing on risk and sexual behaviors of Korean male adolescents.

PURPOSE: This study evaluated the effect of first nocturnal ejaculation timing on risk and sexual behaviors of Korean male adolescents. METHODS: We analyzed data from the 10th edition of the Korea Youth Risk Behavior Web-based survey that was conducted with male high school adolescents in grades 10-12. The survey included 17,907 adolescents, and 10,326 responded their experience of first nocturnal ejaculation. Of these, 595 had their first nocturnal ejaculation in ≤grade 4 ("early puberty") and 9,731 had their first nocturnal ejaculation in ≥grade 5 ("normal puberty"). We analyzed differences between these 2 groups in risk and sexual behaviors. RESULTS: Early first nocturnal ejaculation showed a positive association with sexual intercourse (odds ratio [OR], 3.27; 95% confidence interval [CI], 2.56-4.17), sexual debut at elementary school age (OR, 7.45; 95% CI, 5.00-11.10), and having had a sexually transmitted disease (OR, 6.60; 95% CI, 3.94-11.08). After a multiple logistic regression to adjust for socio-demographic variables, early first nocturnal ejaculation was still positively associated with sexual intercourse (OR, 2.73; 95% CI, 2.03-3.69), sexual debut at elementary school age (OR, 5.96; 95% CI, 3.47-10.22), and having had a sexually transmitted disease (OR, 5.17; 95% CI, 2.52-10.20). Early first nocturnal ejaculation was positively associated with alcohol consumption, smoking, and substance use. However, this was not statistically significant after adjusting for several socio-demographic variables. CONCLUSION: There is a positive association between early nocturnal ejaculation and sexual behaviors in male adolescents. Proactive education about sexual behaviors is required for adolescents who reach sexual maturity early.

Comparative Effects of Human Neural Stem Cells and Oligodendrocyte Progenitor Cells on the Neurobehavioral Disorders of Experimental Autoimmune Encephalomyelitis Mice.

Since multiple sclerosis (MS) is featured with widespread demyelination caused by autoimmune response, we investigated the recovery effects of F3.olig2 progenitors, established by transducing human neural stem cells (F3 NSCs) with Olig2 transcription factor, in myelin oligodendrocyte glycoprotein- (MOG-) induced experimental autoimmune encephalomyelitis (EAE) model mice. Six days after EAE induction, F3 or F3.olig2 cells (1 × 10(6)/mouse) were intravenously transplanted. MOG-injected mice displayed severe neurobehavioral deficits which were remarkably attenuated and restored by cell transplantation, in which F3.olig2 cells were superior to its parental F3 cells. Transplanted cells migrated to the injured spinal cord, matured to oligodendrocytes, and produced myelin basic proteins (MBP). The F3.olig2 cells expressed growth and neurotrophic factors including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF). In addition, the transplanted cells markedly attenuated inflammatory cell infiltration, reduced cytokine levels in the spinal cord and lymph nodes, and protected host myelins. The results indicate that F3.olig2 cells restore neurobehavioral symptoms of EAE mice by regulating autoimmune inflammatory responses as well as by stimulating remyelination and that F3.olig2 progenitors could be a candidate for the cell therapy of demyelinating diseases including MS.

Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase.

Aging is characterized by progressive loss of cognitive and memory functions as well as decrease in physical activities. In the present study, a human neural stem cell line (F3 NSC) over-expressing choline acetyltransferase (F3.ChAT), an enzyme responsible for acetylcholine synthesis, was generated and transplanted in the brain of 18-month-old male ICR mice. Four weeks post-transplantation, neurobehavioral functions, expression of ChAT enzyme, production of acetylcholine and neurotrophic factors, and expression of cholinergic nervous system markers in transplanted animals were investigated. F3.ChAT NSCs markedly improved both the cognitive function and physical activity of aging animals, in parallel with the elevation of brain acetylcholine level. Transplanted F3 and F3.ChAT cells were found to differentiate into neurons and astrocytes, and to produce ChAT proteins. Transplantation of the stem cells increased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), enhanced expression of Trk B, and restored host microtubule-associated protein 2 and cholinergic nervous system. The results demonstrate that human NSCs over-expressing ChAT improve cognitive function and physical activity of aging mice, not only by producing ACh directly but also by restoring cholinergic neuronal integrity, which might be mediated by neurotrophins BDNF and NGF.

Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice.

Brain ageing leads to atrophy and degeneration of the cholinergic nervous system, resulting in profound neurobehavioral and cognitive dysfunction from decreased acetylcholine biosynthesis and reduced secretion of growth and neurotrophic factors. Human adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously (1 × 10(6) cells) or intracerebroventricularly (4 × 10(5) cells) transplanted into the brains of 18-month-old mice once or four times at 2-week intervals. Transplantation of ADMSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with recovery of acetylcholine levels in brain tissues. Transplanted cells differentiated into neurons and, in part, into astrocytes and produced choline acetyltransferase proteins. Transplantation of ADMSCs restored microtubule-associated protein 2 in brain tissue and enhanced Trk B expression and the concentrations of brain-derived neurotrophic factor and nerve growth factor. These results indicate that human ADMSCs differentiate into neural cells in the brain microenvironment and can restore physical and cognitive functions of aged mice not only by increasing acetylcholine synthesis but also by restoring neuronal integrity that may be mediated by growth/neurotrophic factors. © 2013 Wiley Periodicals, Inc.

Transplantation of Human Adipose Tissue-Derived Mesenchymal Stem Cells Restores the Neurobehavioral Disorders of Rats With Neonatal Hypoxic-Ischemic Encephalopathy.

Improving the effects of human adipose tissue-derived mesenchymal stem cells (ASCs) on the demyelination and neurobehavioral function was investigated in an experimental model of neonatal hypoxic-ischemic encephalopathy (HIE). Seven-day-old male rats were subjected to hypoxia-ischemia-lipopolysaccharide and intracerebroventricularly transplanted with human ASCs (4 × 10(5) cells/rat) once at postnatal day 10 (PND10) or repeatedly at PND10, 17, 27, and 37. Neurobehavioral abnormalities (at PND20, 30, and 40) and cognitive functions (at PND41-44) were evaluated using multiple test systems. Human ASCs recovered the using ratio of forelimb contralateral to the injured brain, improved locomotor activity, and restored rota-rod performance of HIE animals, in addition to showing a marked improvement of cognitive functions. It was confirmed that transplanted human ASCs migrated to injured areas and differentiated into oligodendrocytes expressing myelin basic protein (MBP). Moreover, transplanted ASCs restored production of growth and neurotrophic factors and expression of decreased inflammatory cytokines, leading to attenuation of host MBP loss. The results indicate that transplanted ASCs restored neurobehavioral functions by producing MBP as well as by preserving host myelins, which might be mediated by ASCs' anti-inflammatory activity and release of growth and neurotrophic factors.

Neuroprotective Effects of a Butanol Fraction of Rosa hybrida Petals in a Middle Cerebral Artery Occlusion Model.

The neuroprotective effects of a butanol fraction of white rose petal extract (WRPE-BF) were investigated in a middle cerebral artery occlusion (MCAO) model. Seven week-old male rats were orally administered WRPE-BF for 2 weeks and subjected to MCAO for 2 h, followed by reperfusion. Twenty-four h later, MCAO-induced behavioral dysfunctions were markedly improved in a dose-dependent manner by pretreatment with WRPE-BF. Moreover, higher dose of WRPE-BF not only decreased infarction area but also effectively reduced astrogliosis. The expression of inducible nitric oxide synthase, cyclooxygenase-2, and glial fibrillary acidic protein in MCAO model were markedly inhibited by WRPE-BF treatment. Notably, WRPE-BF decreased nitric oxide and malondialdehyde levels in the striatum and subventricular zone of stroke-challenged brains. These data suggested that WRPE-BF may exert its neuroprotective effects via anti-oxidative and anti-inflammatory activities against ischemia-reperfusion brain injury and could be a good candidate as a therapeutic target for ischemic stroke.

Anti-Helicobacter pylori effects of IgY from egg york of immunized hens.

Effects of egg york containing IgY specific for Helicobacter pylori on the bacterial growth and intragastric infection were investigated in comparison with a proton-pump inhibitor pantoprazole. For in vitro anti-bacterial activity test, H. pylori (1×10(8) CFU/mL) was incubated with a serially diluted IgY for 3 days. As a result, IgY fully inhibited the bacterial growth at 16 mg/mL, which was determined to a minimal inhibitory concentration. In vivo elimination study, male C57BL/6 mice were infected with the bacteria by intragastric inoculation (1×10(8) CFU/mouse) 3 times at 2-day intervals, and 2 weeks later, orally treated twice a day with 50, 100, 200 or 500 mg/kg IgY for 18 days. After the final administration, biopsy sample of the gastric mucosa was assayed for the bacterial identification via urease, oxidase, catalase, nitrate reduction and H(2)S tests in addition to microscopic examination for mucosal inflammation. In CLO kit test, 75, 50, 12.5 and 12.5% of the animals revealed positive reaction following treatment with 50, 100, 200 and 500 mg/kg IgY, respectively, resulting in a superior efficacy at 200 mg/kg than 30 mg/kg pantoprazole that displayed 75% elimination. The CLO test results were confirmed by bacterial identification. Microscopic examination revealed that H. pylori infection caused severe gastric mucosal inflammation, which were not observed in the CLO-negative mice following treatment with IgY or pantoprazole. Taken together, IgY inhibited the growth of H. pylori, and improved gastritis and villi injuries by eliminating the bacteria from the stomach. The results indicate that IgY could be a good candidate overcoming tolerance of antibiotics for the treatment of H. pylori-mediated gastric ulcers.

Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction.

A human neural stem cell (NSC) line over-expressing human choline acetyltransferase (ChAT) gene was generated and these F3.ChAT NSCs were transplanted into the brain of rat Alzheimer disease (AD) model which was induced by application of ethylcholine mustard aziridinium ion (AF64A) that specifically denatures cholinergic nerves and thereby leads to memory deficit as a salient feature of AD. Transplantation of F3.ChAT human NSCs fully recovered the learning and memory function of AF64A animals, and induced elevated levels of acetylcholine (ACh) in cerebrospinal fluid (CSF). Transplanted F3.ChAT human NSCs were found to migrate to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and astrocytes. The present study demonstrates that brain transplantation of human NSCs over-expressing ChAT ameliorates complex learning and memory deficits in AF64A-cholinotoxin-induced AD rat model.

Neurobehavioural deficits correlate with the cerebral infarction volume of stroke animals: a comparative study on ischaemia-reperfusion and photothrombosis models.

The study investigated the correlation between infarction areas and behavioural deficits in middle cerebral artery occlusion (MCAO) and photothrombosis stroke models. In the MCAO model, a 0.38 mm-diameter silicone-coated thread was introduced through the left external carotid artery and advanced 18 mm via the internal carotid artery to the origin of middle cerebral artery of male Sprague-Dawley rats weighing 300-350 g. The thread was removed for reperfusion after occlusion for 0.5, 1 or 2h. In the photothrombosis model, after a midline incision on the scalp, a focused light (10,000 lux, 6 mm-diameter) was delivered 1mm anterior to the bregma and 3mm left of the midline for 5, 10 or 20 min. During the first 2 min of irradiation, Rose Bengal dye (30 mg/kg) was injected intravenously. Twenty four hours post-surgery, the animals were subjected to neurological scoring and behavioural performances, and were sacrificed for macroscopic and microscopic examinations of brain injury. Total infarction volumes in the MCAO model rats increased in an occlusion time-dependent manner, while the infarction volumes in photothrombosis model rats plateaued relatively quickly with no time-dependent increase. The MCAO model displayed neurological scores and behavioural deficits that correlated well with infarction volumes, while relatively poor correlation between infarction volume and neurobehavioural abnormalities was evident in the photothrombosis model. The results indicate the suitability of the MCAO model for studies on preventive or therapeutic compounds related to functional recovery, although the photothrombosis model might be useful to generate focused lesions leading to the location-related behavioural changes.

Silk and silkworm pupa peptides suppress adipogenesis in preadipocytes and fat accumulation in rats fed a high-fat diet.

PURPOSE: The objective was to confirm the anti-obesity activity of a silk peptide (SP) and a silkworm pupa peptide (SPP) in rats fed a high-fat diet (HFD) and to elucidate their action mechanism(s) in a preadipocyte culture system. METHODS: In an in vitro mechanistic study, the differentiation and maturation of 3T3-L1 preadipocytes were stimulated with insulin (5 µg/mL), and effects of SP and SPP on the adipogenesis of mature adipocytes were assessed. In an in vivo anti-obesity study, male C57BL/6 mice were fed an HFD containing SP or SPP (0.3, 1.0, or 3.0%) for 8 weeks, and blood and tissue parameters of obesity were analyzed. RESULTS: Hormonal stimulation of preadipocytes led to a 50-70% increase in adipogenesis. Polymerase chain reaction and Western blot analyses revealed increases in adipogenesis-specific genes (leptin and Acrp30) and proteins (peroxisome proliferator-activated receptor-γ and Acrp30). The hormone-induced adipogenesis and activated gene expression was substantially inhibited by treatment with SP and SPP (1-50 µg/mL). The HFD markedly increased body weight gain by increasing the weight of epididymal and mesenteric fat. Body and fat weights were significantly reduced by SP and SPP, in which decreases in the area of abdominal adipose tissue and the size of epididymal adipocytes were confirmed by magnetic resonance imaging and microscopic examination, respectively. Long-term HFD caused hepatic lipid accumulation and increased blood triglycerides and cholesterol, in addition to their regulatory factors Acrp30 and leptin. However, SP and SPP recovered the concentrations of Acrp30 and leptin, and attenuated steatosis. CONCLUSIONS: SP and SPP inhibit the differentiation of preadipocytes and adipogenesis by modulating signal transduction pathways and improve HFD-induced obesity by reducing lipid accumulation and the size of adipocytes.

Increased nephrotoxicity after combined administration of melamine and cyanuric Acid in rats.

Renal toxicity by melamine in combination with cyanuric acid (1:1) was investigated. Male rats were orally administered melamine plus cyanuric acid (5, 50 or 400 mg/kg each) for 3 days. In contrast to a negligible effect by melamine alone (50 mg/kg, a no-observed-adverse-effect-level: NOAEL), co-administration with cyanuric acid markedly increased the concentrations of blood urea nitrogen and creatinine, as well as kidney weight. A high dose (400 mg/kg) of melamine plus cyanuric acid induced more severe kidney toxicity. The increased blood parameters for kidney toxicity and organ weight lasted longer than 4 days. Combined treatment with melamine and cyanuric acid (50-400 mg/kg each) resulted in many gold-brown crystals and toxic lesions in renal tubules, which were not observed in animals treated with melamine alone (50 mg/kg). These results indicate that only a 3-day exposure to melamine in combination with cyanuric acid causes severe renal damage, even at a NOAEL for melamine found in a 13-week toxicity study. Therefore, it is suggested that the tolerable daily intake or regulatory/management levels of melamine need to be re-considered for cases of co-exposure with cyanuric acid.

Different antiulcer activities of pantoprazole in stress, alcohol and pylorus ligation-induced ulcer models.

Antiulcer effects of pantoprazole, a proton-pump inhibitor, on water-immersion restraint stress (WIRS)-, alcohol (ethanol)- and pylorus ligation-induced gastric ulcers were investigated in male rats. Rats were orally administered with pantoprazole 30 min prior to exposure to various types of ulcer inducers. In stress-induced ulcer model, rats were subjected to WIRS at 22℃ for 4 hours, and the degree of ulcer (in mm) was evaluated. In alcohol-induced ulcer model, rats were orally administered with pure (100%) ethanol (1 mL/kg), and the ulcer lesions were measured 1 hour after ethanol challenge. In pylorus ligation-induced ulcer model, rats were subjected to pylorus ligation, and the degree of erosions and ulcers was scored 17 hours after the operation. Pantoprazole attenuated the ulcer lesions induced by WIRS in a dose-dependent manner, exhibiting a median effective dose (ED(50)) value of 0.78 mg/kg. By comparison, pantoprazole was effective at relatively-high doses for the improvement of ethanol-induced ulcers, showing an ED(50) value of 20.5 mg/kg. Notably, pantoprazole was practically ineffective (ED(50)>50.0) in pylorus ligation model. Taken together, it was confirmed that pantoprazole showed inhibitory activity on gastric ulcers induced by stress and alcohol, but was ineffective on pylorus ligation-induced ulcer. Therefore, the results indicate that proton-pump inhibitors including pantoprazole might reveal highly-different effects according to the type of ulcer inducers, and that the prescription of antiulcer agents should be carefully selected.

Animal models of periventricular leukomalacia.

Periventricular leukomalacia, specifically characterized as white matter injury, in neonates is strongly associated with the damage of pre-myelinating oligodendrocytes. Clinical data suggest that hypoxia-ischemia during delivery and intrauterine or neonatal infection-inflammation are important factors in the etiology of periventricular leukomalacia including cerebral palsy, a serious case exhibiting neurobehavioral deficits of periventricular leukomalacia. In order to explore the pathophysiological mechanisms of white matter injury and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, novel animal models have been developed using hypoperfusion, microbes or bacterial products (lipopolysaccharide) and excitotoxins. Such efforts have developed rat models that produce predominantly white matter lesions by adopting combined hypoxia-ischemia technique on postnatal days 1-7, in which unilateral or bilateral carotid arteries of animals are occluded (ischemia) followed by 1-2 hour exposure to 6-8% oxygen environment (hypoxia). Furthermore, low doses of lipopolysaccharide that by themselves have no adverse-effects in 7-day-old rats, dramatically increase brain injury to hypoxic-ischemic challenge, implying that inflammation sensitizes the immature central nervous system. Therefore, among numerous models of periventricular leukomalacia, combination of hypoxia-ischemia-lipopolysaccharide might be one of the most-acceptable rodent models to induce extensive white matter injury and ensuing neurobehavioral deficits for the evaluation of candidate therapeutics.

Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA.

BACKGROUND: Since cyclophosphamide is metabolically activated to teratogenic acrolein and cytotoxic phosphoramide mustard by cytochrome P-450 type 2B (CYP2B), we assessed the effects of licorice, a CYP2B inducer, on the fetal defects induced by cyclophosphamide. METHODS: Pregnant Sprague-Dawley rats were daily administered with licorice (100 mg/kg) by gavage for 7 days, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11 mg/kg) 1 hr after the final licorice treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. RESULTS: Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 93.8, 41.1, and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. When pre-treated with licorice, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with licorice greatly increased mRNA expression and activity of hepatic CYP2B. CONCLUSIONS: The results indicate that repeated intake of licorice may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by upregulating CYP2B.