S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Does planned intravenous sedation affect preoperative anxiety in patients?

Dental surgery generally causes stress and fear, which may affect patient physiology and increase perioperative anxiety. Dental anxiety is considered to be an important factor in determining the need for intravenous sedation. One of the gold standards for measuring preoperative anxiety is Spielberger's State-Trait Anxiety Inventory (STAI). The authors have previously assessed preoperative anxiety using STAI and recommended that intravenous sedation be performed for patients whose anxiety level is high. The intravenous cannulation necessary for sedation and sedation itself may increase anxiety. The authors carried out this study to examine whether planning intravenous sedation before surgery increases preoperative anxiety. The subjects were patients who planned to undergo wisdom teeth extraction under local anaesthesia in the authors' hospital. They were divided into two groups on the basis of the planned intravenous sedation. STAI scores were compared between the initial visit and just before surgery. There were no significant differences in the state and trait anxiety scores between the initial visit and the day of the surgery in the two groups. Planned intravenous sedation based on the evaluation of anxiety levels using STAI is effective for promoting a safe operation without aggravating preoperative anxiety.

Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats.

We orally administered polyphenone-60 (P-60), green tea extract catechins, in the diet (0, 1.25 and 5%) to male rats for 2, 4 and 8 weeks initiated at 5 weeks old. It was found that a 5% dose to male rats for 2-8 weeks induced goiters and decreased weights of the body, testis and prostate gland. Endocrinologically, elevating plasma thyroid stimulating hormone (TSH), luteinizing hormone (LH) and testosterone levels and decreasing tri-iodothyronine (T(3)) and thyroxine (T(4)) levels were induced by this treatment. We also found that P-60 as a whole and some of its constituents exhibited inhibitory effects on human placental aromatase activity by in vitro assay. The concentration of P-60 that required producing 50% inhibition of the aromatase activity (IC(50) value) was 28 microg/ml. The IC(50) values of (-)-catechin gallate (Cg), (-)-epigallocatechin (EGC), (-)-epigallocatechin gallate (EGCg) and (-)-gallocatechin gallate (GCg) were 5.5 x 10(-6), 1.0 x 10(-4), 6.0 x 10(-5) and 1.5 x 10(-5) M, respectively. (-)- Epicatechin gallate (ECg) at 1.0 x 10(-4) M produced 20% inhibition. (-)-Epicatechin (EC) and (+)-catechin (CT) exhibited no effects on aromatase activity. The endocrinological changes observed in vivo were in conformity with antithyroid effects and aromatase inhibition effects of P-60 and its constituents.

Effects of constituents from the bark of Magnolia obovata on nitric oxide production in lipopolysaccharide-activated macrophages.

The methanolic extract from a Japanese herbal medicine, the bark of Magnolia obovata, was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated macrophages. By bioassay-guided separation, three neolignans (magnolol, honokiol, obovatol) and three sesquiterpenes (alpha-eudesmol, beta-eudesmol, gamma-eudesmol) were obtained as active constituents. A trineolignan (magnolianin), a phenylpropanoid glycoside (syringin), lignan glycosides (liriodendrin, (+)-syringaresinol 4'-O-beta-D-glucopyranoside) and a sesquiterpene (caryophyllene oxide) did not show any activity. On the other hand, sesquiterpene-neolignans (eudesmagnolol, clovanemagnolol, caryolanemagnolol, eudeshonokiol A, eudesobovatol A) showed the strong cytotoxic effects. Active constituents (magnolol, honokiol, obovatol) showed weak inhibition for inducible NO synthase (iNOS) enzyme activity, but potent inhibition of iNOS induction and activation of nuclear factor-kappaB.

Goitrogenic effects of green tea extract catechins by dietary administration in rats.

The effects of green tea extract catechins on the rat thyroid were examined in a 13-week feeding study and subsequent 2-,4- and 8-week studies. Commercially available polyphenon-60 (P-60) which contains green tea extract catechins at 66.2% was used as a source of catechins. A basic diet containing different concentrations of P-60 was used for experiments. In the 13-week study, 10 rats of each sex were administered diets containing P-60 at 0 (control), 0.625, 1.25, 2.5 and 5.0%. Goiters were observed in the 13-week test. The mean thyroid weight of rats fed a diet containing 5.0% of P-60 (5.0% group) significantly increased to 444% of the control in males and to 304% of the control in females. Histological examinations of the thyroid of the 5.0% group revealed marked hypertrophy and/or hyperplasia of the follicles, some with depletion of colloid and some with rich colloid, and formation of a fibrous capsule. Slight hypertrophy of follicular cells was observed in male rats fed a diet containing 1.25% of P-60 (1.25% group) and female rats fed a diet containing 2.5% of P-60 (2.5% group). Degree and incidence of thyroid lesions were higher in males than in females in the 1.25, 2.5 and 5.0% groups. In the 2-8-week studies, five rats of each sex were given diets containing 0 (control) and 5.0% of P-60. In the 5.0% group, the mean thyroid weight in males significantly increased to 161% of the control as early as 2 weeks and increased to 357% of the control at 8 weeks. Histologically, these goiters were also associated with follicular cell hypertrophy/hyperplasia as in the 13-week study. The degree and incidence of thyroid lesions were higher in males than in females. These results indicate that dietary administration of the green tea extract catechins at high doses induced goiters in rats, and this may be due to antithyroid effects of catechins. In the 13-week study, the no-observed effect level (NOEL) of green tea extract catechins for F344 rats based on histological changes of the thyroid was considered to be 0.625% in males and 1.25% in females in the diet, respectively.

High hurdle of clinical trials to demonstrate efficacy of anticataractogenic drugs.

Recently, the rapid progression of cataract surgical technique has led cataract patients in industrialized countries to ignore the possibilities of drug therapy. Globally, however, it will be impossible in the near future to treat cataract by surgery alone, mainly due to medicoeconomic reasons. Preventative measures must be sought. As one of the these measures, the development of anticataractogenic drugs has reemerged as a focus in the lens research field. Although clinical trials of newly developed drugs are absolutely necessary before they enter the market, they have been considered to be a rather easy task. However, in order to gain accurate and reproducible data from trials, the trial program must be carefully prepared. The numbers of participants to the trial, the selection criteria of the subjects, the objective judgment of cataractous changes, follow-up period, a high technical level for cataract documentation and image analysis are proposed. Although there still remain some difficulties concerning the methods for objective judgment, a scientifically acceptable examination must be conducted.

Impaired parathyroid hormone action on urinary phosphorus excretion in isolated perfused kidney of streptozotocin-induced diabetic rats.

To study the effects of diabetes on the renal actions of parathyroid hormone (PTH), we observed urinary excretion of cyclic adenosine monophosphate (cAMP) and phosphorus in isolated perfused rat kidney. Diabetic rats were kept for 7 days after an intraperitoneal injection of 70 mg/kg streptozotocin (STZ). STZ-induced diabetic rats were treated with a daily injection of 20 U/kg lente-type insulin for 7 days. Plasma albumin, calcium, phosphorus, and PTH levels were not different among normal control, diabetic and insulin-treated diabetic groups. In the control rat kidney, the addition of PTH increased urinary cAMP excretion from 8 +/- 3 to 190 +/- 49 pmol/5 min and urinary phosphorus excretion from 11.3 +/- 4.4 to 33.6 +/- 10.8 microg/5 min. In the STZ-diabetic rat kidney, basal urinary cAMP was impaired, and PTH altered neither urinary cAMP nor phosphorus excretion (from below 0.7 to below 0.7 pmol/5 min, and from 15.5 +/-4.5 to 13.6 +/- 8.1 microg/5 min, respectively). Insulin treatment completely recovered the PTH actions. These results show that insulinopenic diabetes induces PTH resistance in the kidney.

Rupture of hepatocellular carcinoma after transcatheter arterial embolization: an unusual case.

Rupture of hepatocellular carcinoma (HCC) as a complication of transcatheter arterial embolization (TAE) is very rare. An unusual rupture of HCC after TAE was treated with successful surgical resection. A 65 year-old woman with liver cirrhosis developed multiple HCC in both lobes of the liver. TAE was attempted for the HCCs, but the original left hepatic artery, obliterated due to the previous repeated TAEs, was replaced by the left gastric artery. Right hepatic arteries were embolized while preserving the replaced left hepatic artery. Nine days after TAE, the patient presented a rupture of HCC in the left lateral segment of the liver, in which no deposit of Lipiodol was recognized. Since additional TAE to achieve hemostasis failed, left lateral segmentectomy was carried out with concern for the poor hepatic functional reserve. The patient was discharged 3 weeks after surgery without any complication. This is the first case of ruptured HCC in the non-embolized part of the liver after TAE, which was resected successfully.

[Successful combination chemotherapy for a case of small cell carcinoma of the rectum with multiple liver metastasis].

A 69-year-old-man with small cell carcinoma of the rectum and multiple liver metastases was admitted in December 1996. Poorly differentiated adenocarcinoma was preoperatively diagnosed in a biopsy specimen from the rectum. Chemolipiodolization using 50 mg DXR and 6 ml lipiodol was performed for the multiple liver metastases. Ten days later, he underwent rectal amputation including lymph node dissection combined with the implantation of reservoir for hepatic arterial infusion chemotherapy. After operation 5-FU (500 mg, days 1-5) and CDDP (10 mg, days 1-5) were injected for 3 weeks through hepatic arterial route. The metastatic lesions in the liver represented a good response to the chemolipiodolization, though the metastatic tumor in the liver S4 region did not disappear on CT scan. The histological diagnosis of the resected rectum revealed small cell carcinoma so we attempted additional chemotherapy according to the regimen for treatment of small cell lung cancer. ETP + CDDP therapy was performed, in which ETP (100 mg, days 1-3) and CDDP (80 mg, day 1) were intraarterially infused. After three courses of this therapy, he achieved a complete response (CR) for the liver metastasis. Two courses of ETP + CDDP therapy were additionally performed in the outpatient department, and treatment is currently continued by oral administration of ETP (75 mg/day). He has been free of the disease for 16 months with few side effects. The combination therapy of chemolipiodolization and hepatic arterial infusion chemotherapy with ETP and CDDP may assure a good prognosis for multiple liver metastases of small cell rectal cancer.

A novel fungal endo-beta-N-acetylglucosaminidase that specifically acts on plant glycoproteins.

An endo-beta-N-acetylglucosaminidase specific for plant glycoprotein oligosaccharides was purified from the culture fluid of a fungus. The Mr of the purified enzyme was 89,000. This enzyme was stable at pH 5.5-7.0, up to 30 degrees C, and showed the highest activity at pH 6.0. Among sugar chains tested, xylose-containing sugar chains (M3X, M3FX, and M2FX) were the most favored substrates. Oligomannose type (M3, M5, and M9) and hybrid type (GNM3) sugar chains were hydrolyzed much more slowly than xylose-containing sugar chains, and a complex type sugar chain (GN2M3) was not hydrolyzed at all by the enzyme. Moreover, the enzyme released sugar chains from native horseradish peroxidase and stem bromelain, which were not hydrolyzed by other endo-beta-N-acetylglucosaminidases (Endo H, D, and F). The enzyme could transfer the xylose-containing sugar chain from bromelain to DNS-Asn-GlcNAc-Fuc.

Evidence that folliculo-stellate cells mediate the inhibitory effect of Japanese kampo medicine, unkei-to, on growth hormone secretion in rat anterior pituitary cell cultures.

PROBLEM: Cytokine-induced neutrophil chemoattractant (CINC) was reported to influence anterior pituitary hormone release. We recently found that Unkei-to, one of the Japanese Kampo medicines, stimulated CINC secretion by rat anterior pituitary cells and the pituitary folliculo-stellate (FS)-like cell line (TtT/GF). Therefore, the effect of Unkei-to on growth hormone (GH) secretion by rat anterior pituitary cells was investigated. METHOD OF STUDY: Dispersed normal anterior pituitary cells, the folliculo-stellate-like cell line TtT/GF, and the GH3 cell were used to test the effect of Unkei-to on GH secretion. In reconstitutive coculture experiments, TtT/GF cells were mixed with GH3 cells at a ratio (TtT/GF cells: GH3 cells) of 1:99. From this mixture, cells were seeded onto plates at a density of 10(4) cells/well and were cultured for 5 days. The cells were then used in the experiments. RESULTS: Unkei-to at 20 micrograms/ml significantly inhibited GH secretion by normal anterior pituitary cells within 12 hr of incubation. In contrast Unkei-to stimulated GH secretion by GH3 cells in a time- and dose-dependent manner, suggesting that an accessory cell type was involved. To assess the contribution of CINC as a paracrine factor, an experiment using a reconstitutive coculture system was performed, and Unkei-to was found to inhibit GH secretion when GH3 cells were cocultured with TtT/GF cells. The addition of anti-CINC antibody to the reconstitutive coculture system antagonized Unkei-to-inhibited GH secretion. CONCLUSION: CINC, which was secreted from FS cells by Unkei-to, may be responsible for mediating the inhibitory effect of Unkei-to on GH secretion by rat anterior pituitary cells.

The herbal medicine unkei-to stimulates cytokine-induced neutrophil chemoattractant production in the pituitary folliculo-stellate-like cell line (TtT/GF).

PROBLEM: We previously reported that a cytokine-induced neutrophil chemoattractant (CINC) was produced in the pituitary gland and that it influenced anterior pituitary hormone release. In this study we investigated the effect of Unkei-to, a Japanese herbal medicine, on CINC production in the rat anterior pituitary gland and the pituitary folliculo-stellate-like cell line (TtT/GF). METHOD OF STUDY: Dispersed normal anterior pituitary cells and the folliculo-stellate-like cell line TtT/GF were used to test the effect of Unkei-to on CINC secretion and CINC mRNA accumulation. Concentrations of CINC in the conditioned media were measured by an enzyme-linked immunosorbent assay, and levels of CINC mRNA were analyzed by Northern blot analysis. RESULTS: Unkei-to (20 micrograms/ml) significantly increased the secretion of CINC by normal anterior pituitary cells within 12 hr of incubation. Unkei-to also stimulated CINC secretion from TtT/GF cells in a time- and dose-dependent manner. Unkei-to (20 micrograms/ml) increased CINC mRNA accumulation in TtT/GF cells within 3 hr of incubation and also caused a 13-fold increase in the secretion of CINC from TtT/GF cells compared with the vehicle group within 24 hr of incubation. Finally, we found that some of the Unkei-to's ingredients, Evodiae fructus and Pinelliae tuber, markedly stimulated CINC secretion from TtT/GF cells. CONCLUSIONS: Our results will help to elucidate the mechanism behind the clinical effect of Unkei-to on the anterior pituitary gland. They also suggested the presence of special substances, which stimulate CINC secretion, within Unkei-to's ingredients such as E. fructus and P. tuber.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects.

To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N-acetylaspartate/creatine-phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Cytokine-induced neutrophil chemoattractant gene expression in the rat hypothalamus by osmotic stimulation.

Cytokine-induced neutrophil chemoattractant (CINC) is one of the chemokines and has chemotaxity for neutrophils. Recently, we found the presence of stress-sensitive CINC expression in the hypothalamic nuclei such as the paraventricular nucleus. Since CINC was predominantly co-localized with vasopressin in the supraoptic nucleus (SON), we investigated the effect of hyperosmotic challenge on CINC mRNA in the hypothalamus. We found that CINC mRNA expression in the hypothalamus was augmented within 30 min following osmotic stimulation and immediately returned to the basal level. The suckling, which is a stimulation to oxytocin neurons in the SON, has no effect on CINC mRNA expression in the hypothalamus. This is the first evidence that the chemokine in the brain is activated by osmotic stimulation.

Local delivery of antithrombotic drug prevents restenosis after balloon angioplasty in atherosclerotic rabbit artery.

We investigated the ability of various antithrombotic drugs, delivered locally, to prevent restenosis after angioplasty in hypercholesterolemic rabbits. After dilating atherosclerotic iliac stenoses by balloon angioplasty, a low dose of heparin or a new antithrombotic drug, such as low molecular weight heparin (fragmin), argatroban, or batroxobin, was delivered locally using the balloon double-occlusion technique. In 1 group, high-dose heparin was administered intravenously. Animals that received no drugs served as a control group. After angioplasty, the stenotic segment was dilated and the mean percentage luminal stenosis fell from 89% to 9% in the group that received locally delivered heparin, from 88% to 7% in the group that received locally delivered argatroban, from 87% to 11% in the group that received locally delivered fragmin, from 88% to 15% in the group that received locally delivered batroxobin, from 82% to 18% in the group that received i.v. heparin (p < 0.0001 compared with before angioplasty in each case), and from 84% to 17% in the control group (p < 0.005 compared with before angioplasty). Twenty-eight days after angioplasty, the percentage luminal stenosis remained at 14% in the group that received locally delivered argatroban, 15% in the group that received locally delivered fragmin, and 28% in the group that received locally delivered batroxobin, whereas it increased to 45% in the group that received i.v. heparin, 30% in the group that received locally delivered heparin and 72% in the control group (p < 0.05 compared with after angioplasty in each case). Thus, local delivery low doses of new antithrombotic drugs prevents restenosis after angioplasty without affecting systemic coagulability; heparin, whether administered locally or intravenously, was less effective than the new drugs in preventing restenosis.

T2 shortening in the motor cortex: effect of aging and cerebrovascular diseases.

PURPOSE: To evaluate the effect of aging and cerebrovascular diseases on T2 shortening in the motor cortex at magnetic resonance (MR) imaging. MATERIALS AND METHODS: High-field-strength (1.5-T) MR images of 298 neurologically normal patients (157 male patients, 141 female patients; age range, 2-86 years) and 107 patients with cerebrovascular diseases (66 men, 41 women; age range, 41-86 years) were evaluated retrospectively. On T2-weighted spin-echo images, the signal intensities of the motor, sensory, parietal, temporal, and prefrontal cortices were divided into three grades compared with the signal intensity of the frontal subcortical white matter. RESULTS: Decreased signal intensity (grade III) was not seen in any region in the neurologically normal patients younger than 60 years. After the age of 60 years, however, the signal intensity of the motor cortex decreased, and 43 (66%) of 65 neurologically normal patients reached grade III by age 80 years. In patients with cerebrovascular disease, grade III was seen in 12 (34%) of the 35 patients younger than 60 years (5th and 6th decades). CONCLUSION: T2 shortening of the motor cortex was seen frequently in the older neurologically normal individuals and in patients with cerebrovascular diseases. These findings are compatible with those of a previously reported histochemical study of normal iron deposition in the motor cortex.

Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter.

The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.

Local treatment with an antithrombotic drug reduces thrombus size in coronary and peripheral thrombosed arteries.

Since the treatment of thrombotic disease by antithrombotic drugs may be associated with bleeding complications, a local delivery technique for administration of the drug may be useful. The efficacy of low-dose local delivery of an antithrombotic drug on thrombosis was investigated in 73 dogs. The antithrombotic drug (heparin, 25 U/kg, antithrombin: argatroban, 0.05 mg/kg, or defibrinogenating agent: batroxobin, 0.05 U/kg) was infused locally to a 1-h-old thrombus, and no drug was given in controls. The effect of the local delivery on the thrombus was evaluated. Low- and high-dose systemic drug delivery was also evaluated. The mean reduction in thrombotic coronary stenosis observed by angiography was 30.3% with argatroban, 22% with heparin, and 20.8% with batroxobin (P < 0.005 vs controls). Systemic delivery of low-dose heparin or argatroban did not induce any change in thrombus size. With high-dose systemic drug delivery (heparin 250 U/kg, argatroban 0.5 mg/kg), the mean reduction of thrombotic stenosis was 15.2% with heparin and 32.8% with argatroban (P < 0.005 vs controls). In the iliac arterial thrombosis, after local delivery of the drugs, the mean reduction of thrombotic stenosis observed by angiography was 24.4% in the argatroban group, and 19.2% in the heparin group (P < 0.05 vs controls, respectively). With high-dose systemic heparin delivery, the mean reduction of the thrombotic stenosis was 13.2% (P < 0.01 vs control). Angioscopy also demonstrated a similar trend. The high-dose drug delivery reduced systemic coagulability. Thus, local delivery of an antithrombotic agent can reduce the thrombus size in the coronary and iliac arteries without having any significant influence on coagulability.

Effect of ebselen on renal scarring in rats following renal infection.

Renal scarring, which occurs following refluxing pyelonephritis, is considered to be involved in the development of reflux nephropathy. Prevention of renal scar formation requires immediate initiation of antimicrobial treatment; treatment delay results in renal scarring. We demonstrate that Ebselen, an antioxidant agent, given at a dose of 15 mg/kg twice a day prevents renal scarring in rats following direct renal parenchymal bacterial inoculation. In addition, using an ascending pyelonephritis model, which clinically resembles refluxing pyelonephritis in humans, we show that when initiation of antimicrobial treatment was delayed, coadministration of Ebselen prevents renal scar formation. These results show that Ebselen is effective in preventing renal scarring and suggest that the clinical use of this drug may prevent renal scar formation following pyelonephritis and progression to reflux nephropathy.