• Title/Summary/Keyword: Urinary toxicity

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KF-1607, a Novel Pan Src Kinase Inhibitor, Attenuates Obstruction-Induced Tubulointerstitial Fibrosis in Mice

  • Dorotea, Debra;Lee, Seungyeon;Lee, Sun Joo;Lee, Gayoung;Son, Jung Beom;Choi, Hwan Geun;Ahn, Sung-Min;Ha, Hunjoo
    • Biomolecules & Therapeutics
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    • v.29 no.1
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    • pp.41-51
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    • 2021
  • Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury-induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson's trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.

Pharmacological Studies of Cefoperazone(T-1551) (Cefoperazone(T-1551)의 약리학적 연구)

  • Lim J.K.;Hong S.A.;Park C.W.;Kim M.S.;Suh Y.H.;Shin S.G.;Kim Y.S.;Kim H.W.;Lee J.S.;Chang K.C.;Lee S.K.;Chang K.C.;Kim I.S.
    • The Korean Journal of Pharmacology
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    • v.16 no.2 s.27
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    • pp.55-70
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    • 1980
  • The pharmacological and microbiological studies of Cefoperazone (T-1551, Toyama Chemical Co., Japan) were conducted in vitro and in vivo. The studies included stability and physicochemical characteristics, antimicrobial activity, animal and human pharmacokinetics, animal pharmacodynamics and safety evaluation of Cefoperazone sodium for injection. 1) Stability and physicochemical characteristics. Sodium salt of cefoperazone for injection had a general appearance of white crystalline powder which contained 0.5% water, and of which melting point was $187.2^{\circ}C$. The pH's of 10% and 25% aqueous solutions were 5.03 ana 5.16 at $25^{\circ}C$. The preparations of cefoperazone did not contain any pyrogenic substances and did not liberate histamine in cats. The drug was highly compatible with common infusion solutions including 5% Dextrose solution and no significant potency decrease was observed in 5 hours after mixing. Powdered cefoperazone sodium contained in hermetically sealed and ligt-shielded container was highly stable at $4^circ}C{\sim}37^{\circ}C$ for 12 weeks. When stored at $4^{\circ}C$ the potency was retained almost completely for up to one year. 2) Antimicrobial activity against clinical isolates. Among the 230 clinical isolates included, Salmonella typhi was the most susceptible to cefoperazone, with 100% inhibition at MIC of ${\leq}0.5{\mu}g/ml$. Cefoperazone was also highly active against Streptococcus pyogenes(group A), Kletsiella pneumoniae, Staphylococcus aureus and Shigella flexneri, with 100% inhibition at $16{\mu}g/ml$ or less. More than 80% of Escherichia coli, Enterobacter aerogenes and Salmonella paratyphi was inhibited at ${\leq}16{\mu}/ml$, while Enterobacter cloaceae, Serratia marcescens and Pseudomonas aerogenosa were somewhat less sensitive to cefoperagone, with inhibitions of 60%, 55% and 35% respectively at the same MIC. 3) Animal pharmacokinetics Serum concentration, organ distritution and excretion of cefoperazone in rats were observed after single intramuscular injections at doses of 20 mg/kg and 50 mg/kg. The extent of protein binding to human plasma protein was also measured in vitro br equilibrium dialysis method. The mean Peak serum concentrations of $7.4{\mu}g/ml$ and $16.4{\mu}/ml$ were obtained at 30 min. after administration of cefoperazone at doses of 20 mg/kg and 50 mg/kg respectively. The tissue concentrations of cefoperazone measured at 30 and 60 min. were highest in kidney. And the concentrations of the drug in kidney, liver and small intestine were much higher than in blood. Urinary and fecal excretion over 24 hours after injetcion ranged form 12.5% to 15.0% in urine and from 19.6% to 25.0% in feces, indicating that the gastrointestinal system is more important than renal system for the excretion of cefoperazone. The extent of binding to human plasma protein measured by equilibrium dialysis was $76.3%{\sim}76.9%$, which was somewhat lower than the others utilizing centrifugal ultrafiltration method. 4) Animal pharmacodynamics Central nervous system : Effects of cefoperazone on the spontaneous movement and general behavioral patterns of rats, the pentobarbital sleeping time in mice and the body temperature in rabbits were observed. Single intraperitoneal injections at doses of $500{\sim}2,000mg/kg$ in rats did not affect the spontaneous movement ana the general behavioral patterns of the animal. Doses of $125{\sim}500mg/kg$ of cefoperazone injected intraperitonealy in mice neither increased nor decreased the pentobarbital-induced sleeping time. In rabbits the normal body temperature was maintained following the single intravenous injections of $125{\sim}2,000mg/kg$ dose. Respiratory and circulatory system: Respiration rate, blood pressure, heart rate and ECG of anesthetized rabbits were monitored for 3 hours following single intravenous injections of cefoperazone at doses of $125{\sim}2,000mg/kg$. The respiration rate decreased by $3{\sim}l7%$ at all the doses of cefoperazone administered. Blood pressure did not show any changes but slight decrease from 130/113 to 125/107 by the highest dose(2,000 mg/kg) injected in this experiment. The dosages of 1,000 and 2,000 mg/kg seemed to slightly decrease the heart rate, but it was not significantly different from the normal control. All the doses of cefoperazone injected were not associated with any abnormal changes in ECG findings throughout the monitering period. Autonomic nervous system and smooth muscle: Effects of cefoperazone on the automatic movement of rabbit isolated small intestine, large intestine, stomach and uterus were observed in vitro. The autonomic movement and tonus of intestinal smooth muscle increased at dose of $40{\mu}g/ml$ in small intestine and at 0.4 mg/ml in large intestine. However, in stomach and uterine smooth muscle the autonomic movement was slightly increased by the much higher doses of 5-10 mg/ml. Blood: In vitro osmotic fragility of rabbit RBC suspension was not affected by cefoperazone of $1{\sim}10mg/ml$. Doses of 7.5 and 10 mg/ml were associated with 11.8% and 15.3% prolongation of whole blood coagulation time. Liver and kidney function: When measured at 3 hours after single intravenous injections of cefoperaonze in rabbits, the values of serum GOT, GPT, Bilirubin, TTT, BUN and creatine were not significantly different from the normal control. 5) Safety evaluation Acute toxicity: The acute toxicity of cefoperazone was studied following intraperitoneal and intravenous injections to mice(A strain, 4 week old) and rats(Sprague-Dawler, 6 week old). The LD_(50)'s of intraperitonealy injected cefoperazone were 9.7g/kg in male mice, 9.6g/kg in female mice and over 15g/kg in both male and female rats. And when administered intravenously in rats, LD_(50)'s were 5.1g/kg in male and 5.0g/kg in female. Administrations of the high doses of the drug were associated with slight inhibition of spontaneous movement and convulsion. Atdominal transudate and intestinal hyperemia were observed in animals administered intraperitonealy. In rats receiving high doses of the drug intravenously rhinorrhea and pulmonary congestion and edema were also observed. Renal proximal tubular epithelial degeneration was found in animals dosing in high concentrations of cefoperazone. Subacute toxicity: Rats(Sprague-Dawley, 6 week old) dosing 0.5, 1.0 and 2.0 g/kg/day of cefoperazone intraperitonealy were observed for one month and sacrificed at 24 hours after the last dose. In animals with a high dose, slight inhibition of spontaneous movement was observed during the experimental period. Soft stool or diarrhea appeared at first or second week of the administration in rats receiving 2.0g/kg. Daily food consumption and weekly weight gain were similar to control during the administration. Urinalysis, blood chemistry and hematology after one month administration were not different from control either. Cecal enlargement, which is an expected effect of broad spectrum antibiotic altering the normal intestinal microbial flora, was observed. Intestinal or peritoneal congestion and peritonitis were found. These findings seemed to be attributed to the local irritation following prolonged intraperitoneal injections of hypertonic and acidic cefoperazone solution. Among the histopathologic findings renal proximal tubular epithelial degeneration was characteristic in rats receiving 1 and 2g/kg/day, which were 10 and 20 times higher than the maximal clinical dose (100 mg/kg) of the drug. 6) Human pharmacokinetics Serum concentrations and urinary excretion were determined following a single intravenous injection of 1g cefoperazone in eight healthy, male volunteers. Mean serum concentrations of 89.3, 61.3, 26.6, 12.3, 2.3, and $1.8{\mu}g/ml$ occured at 1,2,4,6,8 and 12 hours after injection respectively, and the biological half-life was 108 minutes. Urinary excretion over 24 hours after injection was up to 43.5% of administered dose.

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Effects of Aqueous Azadirachta indica Extract on Hepatotoxicity in Rats (수용성 님추출물이 랫드의 간 독성에 미치는 영향)

  • Park, Kyung-Hun;Yoon, Hyunjoo;Han, Beom Seok;Lee, Je-Bong;Jeong, Mi Hye;Cho, Namjun;Om, Ae Son;Paik, Min-Kyoung
    • Korean Journal of Environmental Agriculture
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    • v.33 no.4
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    • pp.395-402
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    • 2014
  • BACKGROUND: Azadirachta indica Extract(AIE) containing azadirachtin as active ingredient have been used worldwide as environment-friendly organic material having pest control properties. However, the extracts prepared with different solvent and from different plant site is very diverse and have different toxicity. METHODS AND RESULTS: In this study, the four week repeated oral dose toxicity test of aqueous AIE in Sprague-Dawley rats was carried out to investigate the toxic effect of liver, main toxicity target organ of AIE. The male and female rats were divided into 4 groups, respectively; control(0 g/Kg bw), low-dose group(0.5 g/Kg bw), middle-dose(1.0 g/Kg bw) and high-dose group(2.0 g/Kg bw). As a results, relative liver weight increased with dose-dependent of AIE(p<0.05). Serum LDH in all AIE-treated groups were significantly lower than the control in male rats(p<0.05). However, serum GOT and GPT were significantly increased in all male AIE-treated groups in male rats(p<0.05) and, in particular, increase of serum GPT in dose-dependent manner raise the possibility of liver damage. Even through serum GLU was increased significantly in high-dose group in male rats compared to control, there were no significant differences of urinary GLU among all groups(p<0.05). In addition, histopathological examination of the liver did not reveal any lesions in all AIE-treated groups. CONCLUSION: In conclusion, 4 weeks of the repeated oral administration of AIE 2.0 g/Kg to rats has resulted no toxic response in liver. Therefore, AIE was no indicated to have any toxic effect in the SD rats, when it was orally administrated below the dosage 2.0 g/Kg/day for 4weeks.

Effect of Elemental Sulfur Supplementation on Rumen Environment Parameters and Utilization Efficiency of Fresh Cassava Foliage and Cassava Hay in Dairy Cattle

  • Promkot, C.;Wanapat, Metha
    • Asian-Australasian Journal of Animal Sciences
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    • v.22 no.10
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    • pp.1366-1376
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    • 2009
  • Effect of sulfur (S) on utilization efficiency of fresh cassava foliage and cassava hay in dairy cows was evaluated using thirty-two $1^{st}-2^{nd}$ lactation Holstein-Friesian crossbred dairy cows. The experimental treatment was a 2${\times}$2 factorial arrangement in a randomized complete block design (RCBD) using two roughages (rice straw+fresh cassava foliage (FCF) and rice straw+cassava hay (CH)) and two elemental sulfur (S) levels (0.15 and 0.4% S of dry matter (DM)), respectively. Four dietary treatments (FCF+0.15, FCF+0.4, CH+0.15 and CH+0.4) were offered ad libitum in the form of a total mixed ration (TMR) with concentrate to roughage (chopped rice straw+chopped cassava foliage) ratio at 60:40. Fresh cassava foliage or cassava hay resulted in similar dry mater intake, rumen ecology parameters, total tract digestibility, blood chemistry, milk production and composition. However, HCN intake, blood and milk thiocyanate concentration were significantly higher (p<0.01) in cows fed fresh cassava foliage with no sign of potential toxicity. Dry matter intake, body weight changes, molar percentage of propionate in rumen, neutral detergent fiber (NDF) digestibility and nitrogen (N) retention of cows tended to be increased while DM digestibility (65.6, 72.7, 68.6 and 72.1% of total DM intake for the respective treatments), rumen bacteria population (1.4, 1.7, 1.6 and $1.7{\times}10^{11}$ cell/ml for respective treatments), fungal zoospore population (0.4, 0.6, 0.4 and $0.5{\times}10^{6}$ cell/ml for respective treatments), urinary allantoin (25.3, 28.0, 26.3 and 27.6 g/d for respective treatments), microbial N yield (136.0, 154.6, 142.8 and 151.3 g N/d for respective treatments) and milk protein content (3.4, 3.5, 3.2 and 3.5% for respective treatments) were significantly (p<0.05) higher in cows fed on supplemented sulfur at 0.4% of DM in comparison with 0.15% S-supplemented diets. Based on these results, it is concluded that cassava foliage could be used as a portion of roughage for dairy cows and supplementation of S would be nutritionally beneficial.

The Indian Magical Herb 'Sanjeevni' (Selaginella bryopteris L.) - A Promising Anti-inflammatory Phytomedicine for the Treatment of Patients with Inflammatory Skin Diseases

  • Paswan, Shravan Kumar;Gautam, Arti;Verma, Pritt;Rao, Chandana Venkateswara;Sidhu, Om Prakash;Singh, Ajeet Pratap;Srivastava, Sajal
    • Journal of Pharmacopuncture
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    • v.20 no.2
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    • pp.93-99
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    • 2017
  • Objectives: Selaginella bryopteris L. (family: Selaginaceae), is often used in traditional Indian systems of medicine for the prevention and cure of several disorders and for the treatment of patient with spermatorrhoea, venereal disease, constipation, colitis, urinary tract infections, fever, epilepsy, leucorrhoea, beri-beri and cancer. It is also used as a strength tonic. This study aimed to evaluate the mechanisms underlying the anti-inflammatory effects of topically administered aqueous, polar and non-polar methanolic fractions ($10mg/20{\mu}L$) of Selaginella bryopteris. Methods: An acute oral toxicity study of Selaginella bryopteris at doses from 250 to 2,000 mg/kg body weight (bw) was performed. Aqueous, polar and non-polar methanolic extracts ($10mg/20{\mu}L$) applied topically for 5 days were evaluated for their anti-inflammatory effects against 12-tetra-O-decanoyl phorbol acetate (TPA)- induced inflammation by using the redness in the ear, the ear's weight (edema), oxidative stress parameters, such as lipid-peroxide (LPO) and nitric oxide (NO), and the pro-inflammatory cytokines involved in inflammation, such as tumour necrosis factor $(TNF)-{\alpha}$, interleukin $(IL)-1{\beta}$ and IL-6. Indomethacine ($0.5mg/20{\mu}L$) was used for the positive control. Results: Selaginella bryopteris produced no mortalities when administered orally at doses from 250 to 2,000 mg/kg bw. Topical treatment with the non-polar methanolic fraction ($10mg/20{\mu}L$) significantly suppressed redness ($2.4{\pm}0.5$) and edema ($30.4{\pm}1$) and effectively reduced the LPO level ($32.3{\pm}3.3$). The NO level was ($8.07{\pm}0.55$), and the $TNF-{\alpha}$, $IL-1{\beta}$, and IL-6 levels were decreased to $69.6{\pm}15.5$, $7.7{\pm}4.8$ and $82.6{\pm}5.9$, respectively. Conclusion: This study demonstrated for the first time the mechanisms underlying the anti-inflammatory effect of medicinal plants like Selaginella bryopteris and quantified the pharmacological interactions between them. The present study showed this herbal product to be a promising anti-inflammatory phytomedicine for the treatment of patients with inflammatory skin diseases.

Toxicity study of GC-100X in rats and beagles (랫드와 비글에서 GC-100X 세정제의 독성에 대한 연구)

  • Kang, Kyung-Sun;Cho, Sung-Dae;Ahn, Nam-Shik;Jung, Ji-Won;Yang, Se-Ran;Park, Joon-Suk;Park, Ki-Soo;Hong, In-Sun;Seo, Min-Soo;Jo, Eun-Hye;Nguyen, Ba Tiep;Lee, Yong-Soon
    • Korean Journal of Veterinary Research
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    • v.44 no.1
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    • pp.29-40
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    • 2004
  • Because cleaning products are part of our everyday lives, it is essential that they should not present significant risks to health. However, many petrochemicals in most soaps and detergents can be absorbed through the scalp and skin and, over time, accumulate in the organs and tissues. This accumulation may result in brain, nerve, and liver damage. Therefore, it is interested in developing non-harmful detergent. According to Korea Research Institute of Chemical Technology, GC-100X may be non-harmful and non-corrosive alkaline ionic water (pH 12). It is composed of hydroxyl radicals and supplemented with xylitol. To evaluate influence of GC-100X on rats and beagles, GC-100X was diluted with distilled water (25%, 50%, and 100% solution respectively). Each of diluted GC-100X was daily treated per oral. In body weight analysis, urinary analysis, ophthalmological test and autopsy, we did not find any significance, but in serum biochemical analysis and hematological analysis, we found some significances in middle dose group compared with control group. These significances in serum biochemical analysis and hematological analysis may be not induced by GC-100X, because it was not found to be significant from control group in histopathological examination. Thus, it is concluded that NOEL(No Observed Effect Level) of GC-100X may be higher than all treatment doses used in this study, and GC-100X may be a non-toxic detergent.

Effect of Dietary Selenium on $\delta$-Aminolevulinic Acid Dehydratase Activity in Lead Poisoned Rats (식품 Selenium이 납중독된 흰쥐에 있어서 $\delta$-Aminolevulinic Acid Dehydratase 활성에 미치는 영향)

  • 방진숙
    • Journal of Nutrition and Health
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    • v.24 no.6
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    • pp.526-533
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    • 1991
  • The effect of dietary selenium on the activity of $\delta$-aminolevulinic acid dehydratase (ALAD) inhibited by the administration of lead were investigated in rats. The levels of dietary lead in the acetate form were 0(contro)200, 1, 000, 2, 000 and 5, 000ppm. Except control group four-level of lead diet groups were again subdivided into two depending on with and without 0.5ppm selenium supplementation. Sixty-three 40-day-old male Sprague-Dawley rats weighing 141$\pm$5g were distributed into total of nine diet groups according to RCB design and fed ad libidum for 4 weeks. Lead dietary groups did not show any significnat difference in food intake from the control group. Food efficiency and weight gain were lower in 2.000ppm and 5, 000ppm lead groups but not found in selenium supplemented ones. Hemoglobin contents hematocrit values ALAD activities in blood were significantly decreased and urinary aminolevulinic acid(ALA) excretion increa-sed with increasing dietary lead levels but partly restored by selenium supplementation. however only in 200, 1, 000 and 2, 000ppm dietary lead groups. On the other hand the hepatic ALAD activites of all four lead groups were recovered 19-30% from suppression by selenium supplementation. It was concluded that selenium administration alleviated lead toxicity in rats.

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Accumulation and Depletion of Melamine Through Experimental Feeding in Catfish Silurus asotus (메기(Silurus asotus)에 투여한 멜라민의 체내함량 변화)

  • Kim, Poong-Ho;Jo, Mi-Ra;Lee, Hee-Jung;Kim, Kyoung-Duck;Ha, Kwang-Soo;Yoo, Hyun-Duk;Lee, Hong-Sik;Lee, Doo-Seog;Yoon, Ho-Dong
    • Korean Journal of Fisheries and Aquatic Sciences
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    • v.44 no.6
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    • pp.577-583
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    • 2011
  • In 2007, pet food contaminated with melamine caused hundreds of dogs and cats to develop renal failure all over the world. In 2008, over 294,000 infants consumed infant formula and developed kidney stones in China. Further investigation revealed that fish feed also contained melamine; this raised concerns about melamine residues in edible fish tissues, which could have caused the urinary tract stone epidemic. In Korea, catfish fed with assorted feed that included cuttlefish organs that contained melamine developed whitening syndrome and fell dead in some populations in 2008. This event raised suspicions about the toxicity of melamine and all feeds containing melamine were immediately recalled. In this study, we investigated the rates of melamine accumulation and depletion in muscle and viscera of catfish to propose proper withdrawal periods. One group of catfish was fed a commercially available diet that contained 30, 100 and 300 mg melamine per kg diet for 14 days. To investigate residual melamine contents in muscle and viscera, other experimental groups were fed a melamine free diet after being fed melamine for 7 days. The residual amount of melamine was analyzed by LC-MS/MS. The melamine concentration in muscle was estimated to be 3.7 mg/kg after 6 days of feeding with a diet containing 300 mg melamine/kg. After 2 days of culture with a melamine free diet, the residual melamine was depleted and the concentration had decreased from 1.15 mg/kg to 0.19 mg/kg in the muscle of catfish fed a diet containing 300 mg melamine/kg for 7 days. The residual amount of melamine was reduced to 0.03 mg/kg in muscle after 7 days of culture with a melamine free diet and was undetectable after a prolonged culture period of 14 days. Catfish tend to excrete melamine rapidly after oral administration and changes in body color were not observed during the short dosing period.

Potential Reproductive Toxicity Study of p53 Expressing Adenoviral Vector in Mice (아데노바이러스 유전자치료벡터의 생식독성 연구)

  • Rhee, Gyu-Seek;Kwack, Seung-Jun;Kim, Soon-Sun;Lee, Rhee-Da;Seok, Ji-Hyun;Chae, Soo-Young;Chung, Soo-Youn;Kim, Seung-Hee;Lee, Seung-Hoon;Park, Kui-Lea
    • Korean Journal of Microbiology
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    • v.43 no.3
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    • pp.151-158
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    • 2007
  • The possibility of inadvertent introduction of therapeutic gene expressing viral vectors has raised safety concerns about germ-line infection. Particularly, for indications such as prostate cancer and ovarian cancer, the proximity of the point of viral administration to organs of the reproductive system raises concerns regarding inadvertent germ-line transmission of genes carried by the virus vector. To evaluate the safety of in vivo adenovirus mediated gene transfer, we explored the biodistribution, persistance and potential germ-line transmission of p53-expressing adenovirus (Ad-CMV-p53). Both male and female Balb/c mice were injected with $1{\times}10^9$ PFU of Ad-CMV-p53. The PCR analysis showed that there were detectable vector sequences in liver, kidney, spleen, seminal vesicle, epididymis, prostate, ovary, and uterus. The RT-PCR analysis for detecting inserted gene, p53 showed that Ad-CMV-p53 viral RNA were present in spleen, prostate and ovary. Direct injected male and female mice of adenovirus vector into testis and ovary were mated and their of offspring were evaluated for germ-line transmission of the adenoviral vector. The PCR and RT-PCR analysis showed no evidence of germline transmission, although vector sequences were detected in DNA extracted from gonadal tissues. Real-time PCR result confirmed a significant decrease of adenovirus in gonad tissues 1 week after injection. We have also analysed the cell specific localization of viral DNA in gonad tissues by using in-situ PCR. Positive signals were detected in interstitial tissue but not in seminiferous tubule in sperm. In the case of ovary, adenovirus signal were localized to the stromal tissue, but no follicular signals were observed. Together, these data provide strong evidence that the risk of the Inadvertent germ-line transmission of vector sequences following intraperitoneal or direct injection into genito-urinary system of adenovirus is extremely low.