Single Administration Group Research Articles

Development of two step liquid-liquid extraction tandem UHPLC-MS/MS method for the simultaneous determination of Ginkgo flavonoids, terpene lactones and nimodipine in rat plasma: Application to the pharmacokinetic study of the combination of Ginkgo biloba dispersible tablets and Nimodipine tablets.

A sensitive, reliable and accurate UHPLC-MS/MS method has been firstly established and validated for the simultaneous quantification of ginkgo flavonoids, terpene lactones and nimodipine in rat plasma after oral administration of Ginkgo biloba dispersible tablets, Nimodipine tablets and the combination of the both, respectively. The plasma samples were extracted by two step liquid-liquid extraction, nimodipine was extracted by hexane-ether (3:1, v/v) at the first step, after that ginkgo flavonoids and terpene lactones were extracted by ethyl acetate. Then the analytes were successfully separated by running gradient elution with the mobile phase consisting of 0.1% formic acid in water and methanol at a flow rate of 0.6mL/min. The detection of the analytes was performed on a UHPLC-MS/MS system with turbo ion spray source in the negative ion and multiple reaction monitoring (MRM) mode. The calibration curves for the determination of all the analytes showed good linearity (R(2)>0.99), and the lower limits of quantification were 0.50-4.00ng/mL. Intra-day and inter-day precisions were in the range of 3.6%-9.2% and 3.2%-13.1% for all the analytes. The mean extraction recoveries of the analytes were within 69.82%-103.5% and the matrix were within 82.8%-110.0%. The validated method had been successfully applied to compare the pharmacokinetic parameters of ginkgo flavonoids, terpene lactones and nimodipine in rat plasma after oral administration of Ginkgo biloba dispersible tablets, Nimodipine tablets with the combination of the both. There were no statistically significant differences on the pharmacokinetic behaviors of all the analytes between the combined and single administration groups. Results showed that the combination of the two agents may avoid dosage adjustments in clinic and the combination is more convenient as well as efficient on different pathogenesis of cerebral ischemia.

Evaluation of the effects of single or multiple dose methotrexate administration, salpingectomy on ovarian reserve of rat with the measurement of anti-Müllerian hormone (AMH) levels and histological analysis

ObjectiveTo evaluate the effects of single, multiple dose methotrexate (MTX) administration and salpingectomy on ovarian reserve in a rat model. Study designIn this prospective controlled experimental study, forty female Wistar-albino rats were randomly divided into four groups; healthy control group (group 1), one month after single dose (50mg/m2) MTX administration group (group 2), multiple (1mg/kg, 1, 3, 5, 7 days) dose MTX administration group (group 3), and unilateral salpingectomy applied group (group 4). Ovarian reserves were assessed with anti-Müllerian hormone (AMH) and ovarian follicles including primordial, primary, secondary, tertiary and total follicle counts. SettingKobay and Duzen experimental research laboratory. ResultsSerum AMH levels decreased significantly in the single and multiple dose MTX administration group and salpingectomy group compared with control group. Primordial follicle counts were comparable between single dose MTX group and control group whereas all type of follicle counts in single and multiple dose MTX and salpingectomy group were significantly reduced compared with control. The least affected ovarian reserve in the treatment groups was single dose MTX group. ConclusionsOvarian reserve markers including follicle counts and AMH levels were decreased after single, multiple dose MTX administration, and salpingectomy. Single dose MTX was the least detrimental method on ovarian reserve for the treatment of ectopic pregnancy.

Proteomic study on effect of Tangcao pill on microsome CYP450

Tangcao pill is commonly applied in adjuvant and even alternative therapy for patients with AIDS. However, the herb contains complex ingredients, but with unknown effect against anti-HIV drug and unknown function. Because CYP450 emzyme is the main metabolic enzymes of the drug, it is of important significance to study the regulation of CYP450 enzymes before and after the combined administration of Tangcao pill and EFV. Proteomics, due to its high throughout and high sensitivity, has been widely applied in CYP450 enzyme study. In this paper, liver microsomes were separated through differential centrifugation. Their proteins were separated through SDS-PAGE. The three protein bands that CYP450 enzymes were located were cut and identified by liquid chromatography tandem mass spectrometry. Totally 16 CYP450 isoenzymes were identified. Furthermore, in order to make a quantitative analysis on the effect of tang herb on CYP450 emzyme, the multiple reaction monitoring (MRM) technology based on MS was adopted. The CYP2C11 was selected based on the results of the mass spectrum identification of proteins. The characteristic polypeptides were obtained through searching Expasy blast database. The m/z of the fragment ions was less than 800. In the paper, the m/z of ion pairs of CYP2C11 were 711.5/232.1, 711.5/319.2, 711.5/466.2 and 711.5/595.3, and the m/z of ESAT-6 (internal standard, IS) were 735.5/215.3, 735.5/389.3, 735.5/460.3 and 735.5/524.3. The relative peak (analyte/IS) area was adopted for the relative quantitative analysis. Compared with the EFV single administration group, the EFV and Tangcao pill combined administration group showed a 1.6-fold increase in CYP2C11. The results of the paper indicated that Tangcao pill may affect drug metabolism by regulating metabolic enzymes such as CYP2C11, but the specific mechanism still unknown.

Tolerability and Pharmacokinetics of a New P-Glycoprotein Inhibitor, HM30181, in Healthy Korean Male Volunteers: Single- and Multiple-Dose Randomized, Placebo-Controlled Studies

BackgroundHM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs. ObjectiveThe objective of this study was to investigate the tolerability and pharmacokinetic properties of HM30181 after single and multiple oral administrations to healthy Korean male volunteers. The study was performed to meet regulatory criteria for marketing the test product in South Korea. MethodsA dose-block–randomized, double-blind, placebo-controlled, dose-escalation study was performed in 180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose study, blood and urine samples were collected for up to 120 hours after drug administration. In the multiple-dose study, subjects received the study drug or placebo orally once daily for 5 days. Blood samples were collected up to 624 hours after the last dose, and up to 24 hours after the first dose to evaluate the accumulation index. Urine samples were collected up to 120 hours after the last dose. Pharmacokinetic analysis was performed using noncompartmental methods. Adverse events were collected by the spontaneous reporting of the subjects or when subjects were asked general health-related questions. ResultsThirty and 70 healthy male volunteers completed the single- and multiple-dose studies, respectively. Mean (SD) age and body weight of subjects in the single administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7) kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined with t½ of 75.7 to 169.3 hours after single administration, and peaked at 5.5 to 8.0 hours and declined with t½ of 153.5 to 215.2 hours after multiple administrations. Cmax and area under the concentration curve within dosing intervals (AUCτ) increased dose dependently after single administration; however, dose-dependent increases in Cmax and AUCτ were not observed after multiple administrations. The fraction of drug excreted unchanged in urine was minimal, with values <0.01% in all dose groups. HM30181 accumulated after multiple administrations with an accumulation index of 4.0 to 7.4. All adverse events reported were mild in intensity; there were no serious adverse events reported. The most frequently reported adverse event was gastrointestinal disorder. ConclusionsHM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.

Evaluation of the Toxicity of Eugenol at Anesthetic Doses in African Clawed Frogs (Xenopus laevis)

Eugenol has been shown to induce anesthesia in African clawed frogs (Xenopus laevis). The toxicity of eugenol, administered at anesthetic doses, was evaluated in Xenopus frogs with an average body weight of 28.2 ± 13.7 g. Frogs were immersed in 250 mL of an aqueous solution containing 350 µl/L of eugenol for ten minutes and received a single administration (group 1, twelve animals) or three consecutive daily administrations (group 2, twelve animals). In each group, six frogs were scheduled to be euthanized the following day (subgroup A) and the other six were scheduled to be euthanized after a one-week recovery period (subgroup B). Morphologic changes consistent with renal tubular apoptosis affecting distal tubules in the medulla were observed in all subgroup A animals, ranging from mild to moderate in group 1, and from mild to severe in group 2. In subgroup B, renal tubular regeneration was present in all but one animal examined. These findings suggest that eugenol toxicity in amphibians is first manifested by renal tubular apoptosis. Other eugenol-related lesions were massive hepatic necrosis in group 2 (n = 6), hyaline membranes in the lung (n = 5), and adipose tissue hemorrhages in group/subgroup 2B (n = 4).

Comparison of single high-dose streptozotocin with partial pancreatectomy combined with low-dose streptozotocin for diabetes induction in rhesus monkeys

Monkeys with insulin-dependent diabetes are important experimental models for islet xenotransplantation. However, with regard to diabetes induction, total pancreatectomy is a difficult operation with a high complication rate, while streptozotocin (STZ) administration may cause serious toxic effects and individual difference in metabolism. We compared two strategies involving pancreatectomy and STZ to successfully and safely induce diabetes in rhesus monkeys. Thirteen rhesus monkeys were divided into two groups: single high-dose STZ administration (80, 100 and 120 mg/kg, n = 3 for each dose) (group 1) and partial pancreatectomy (70-75%) combined with low-dose STZ (15 mg/kg, n = 4) (group 2). Induction of diabetes was evaluated by blood glucose, insulin, C-peptide, intravenous glucose tolerance test (IVGTT) and arginine stimulation test (AST). Detection of hematological and serum biochemical parameters and biopsies of pancreas, liver and kidney were periodically performed. In our study, animals in both groups developed diabetes. Serum C-peptide levels in groups 1 and 2 decreased to 0.08 +/- 0.07 and 0.35 +/- 0.06 nmol/L, respectively. IVGTT and AST indicated severely impaired glucose tolerance. Immunohistochemistry demonstrated that rare insulin-positive cells remained in the pancreas. In terms of STZ toxicity, four monkeys died 8-14 days after STZ administration (3 with 120 mg/kg STZ and 1 with 100 mg/kg STZ). Group 1 animals developed liver and kidney injury evidenced by increased alanine aminotransferase, aspartate aminotransferase, total cholesterol, LDL, triglyceride and blood urea nitrogen for one month, and histological abnormality including hepatic steatosis, renal glomerulus and tubular injury. Nevertheless, moderate histological injuries were seen in animals with 80 mg/kg STZ, with subsequent recovery. In contrast, group 2 animals displayed normal biochemical parameters and histology, with generally less risk of postoperative complications. We conclude that injection of 80 mg/kg STZ could induce diabetes with moderate injuries. Partial pancreatectomy with low-dose STZ is a safer and more reproducible method for inducing diabetes in rhesus monkeys.

Repeated edaravone treatment reduces oxidative cell damage in rat brain induced by middle cerebral artery occlusion

The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) has been used to treat acute brain infarction in Japan since 2001. To obtain direct evidence that edaravone serves as an antioxidant in vivo, four groups of rats were prepared: (i) an ischemia/reperfusion (I/R) group receiving 2 h occlusion-reperfusion of the middle cerebral artery; (ii) a single administration group treated by intravenous infusion of edaravone (3 mg/kg) immediately after I/R; (iii) a repeated treatment group receiving twice daily edaravone administration for 14 days; and (iv) a sham operation group without occlusion. Repeated treatment with edaravone significantly improved the neurological symptoms and impairment of motor function as compared to the I/R group, while single administration demonstrated limited efficacy. No significant differences in plasma antioxidants such as ascorbate, urate, and vitamin E, or in redox status of coenzyme Q9 were observed among the four groups. In contrast, the plasma content of oleic acid in the total free fatty acids (percentage 18:1) was significantly increased in the I/R group for 7 days as compared to the sham operation group. Oleic acid was produced from stearic acid by the action of stearoyl-CoA desaturase to compensate for the oxidative loss of polyunsaturated fatty acids. The above results suggest that cellular oxidative damage in the rat brain is evident for at least 7 days after I/R. Repeated treatment suppressed the percentage 18:1 increment, while the single administration did not, which is consistent with the limited efficacy of single administration.

An experimental design for judging synergism on consideration to endocrine disruptor animal experiments

AbstractThis paper investigates an appropriate statistical design for an animal experiment to evaluate synergism of two test chemicals. It assumes a certain number of animals are divided into groups, each of which is treated with a combination of dose levels of two chemicals. A design is identified by the set of group size for each combination of doses, including the case where the dose of either one chemical is zero. The power of t‐test to detect synergism by positive surplus of response on a simultaneous administration group from the additivity plane composed of the responses on single administration groups is adopted as the criterion for the appropriate design. The applicable design is investigated for the application to real cases of endocrine disrupter study conducted at the National Institute of Health Sciences of Japan.It revealed that the dose level of the simultaneous administration group should be located inside or on the boundary of a triangular region and that the total number of animals should be the same as those for single administration groups. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Neutralizing activity of bovine colostral antibody against verotoxin derived from enterohemorrhagic Escherichia coli O157:H7 in mice

The neutralization efficacy of bovine colostral antibody against verotoxin (VT) 1 and 2 was investigated. Cows were immunized with VT1 or VT2 fourteen times at 7-day intervals. A colostral antibody exhibiting high titers was obtained from immunized cows. Survival rates were evaluated in mice administered VT1 or VT2, and those infected with Escherichia coli (E. coli) O157:H7 producing VT1 or VT2. Survival rates after VT1 administration were 100% in the single-administration group, 90% in the repeat-administration group, and 78.6% in the control group. Survival rates after VT2 were 75.0% in the single-administration group, and 100% in the repeat-administration group. All mice in the control group died. Colostral antibody and fosfomycin (FOM) in the colostral antibody group and FOM and skim milk in the control group were administered three times per day for 5 days to mice infected with E. coli O157:H7 producing VT1 or VT2. Survival rates after inoculation with E. coli O157:H7 producing VT1 were 80.0% in the colostral antibody group, and 63.6% in the control group. Survival rates after inoculation with E. coli O157:H7 producing VT2 were 83.3% in the colostral antibody group, and 20.0% in the control group. The survival rate in mice without treatment following inoculation with E. coli O157:H7 producing VT2 was 88.2%. The survival rates in mice infected with E. coli O157:H7 strains producing VT1 or VT2 improved after administration of this colostral antibody, which exhibited neutralization efficacy against VT.

Effects of keishi-ka-jutsubu-to (traditional herbal medicine: Gui-zhi-jia-shu-fu-tang) on in vivo insulin action in streptozotocin-induced diabetic rats

This study investigated the effects of the traditional herbal medicine, Keishi-ka-jutsubu-to (KJT) on insulin action in vivo and insulin signaling in skeletal muscle in STZ-induced diabetes. Rats were divided into single and 7-days oral administration groups. Euglycemic clamp (insulin infusion rates: 3 and 30 mU/kg/min) was used in awaked rats and the insulin signaling in skeletal muscle was evaluated. At low-dose insulin infusion, the decreased metabolic clearance rates of glucose (MCR) in diabetic rats were improved by a single and 7-days administration of KJT (800 mg/kg BW, p.o.; acute effect: 6.7 ± 0.6 vs. 12.3 ± 1.2, and 7-days effect: 6.3 ± 0.5 vs. 13.9 ± 1.0 ml/kg/min, P < 0.001, respectively). During high-dose insulin infusion, the MCR was increased in 7-days KJT treated diabetes compared with saline diabetes, but, these changes were not observed after a single KJT treatment. About 90% of the increasing effect in MCR induced by the 7-days KJT treatment was blocked by l-NMMA. However, no further additive effects were seen in KJT + SNP treatment. IRβ protein increase and decreased IRS-1 protein expression in diabetes were significantly improved by KJT treatment. KJT had no effect on the GLUT4 protein content. The increased tyrosine phosphorylation level of IRβ, IRS-1, and IRS-1 associated with PI 3-kinase were significantly inhibited in KJT treated diabetes. The present study suggests that the improvement of impaired insulin action in STZ-diabetes by administration of KJT may be due, at least in part, to enhanced insulin signaling, which may be involved with production of nitric oxide (NO).

A statistical method for judging synergism: application to an endocrine disruptor animal experiment

AbstractThis article proposes a statistical method for judging whether or not the combined action of chemicals is synergistic, being focused on the case in which two or more endocrine disruptors are made to act simultaneously. After defining synergism, the synergistic relation of two chemicals is formulated for a higher response than that expected under an exchangeable relation between them. Using this formulation as a basis, we then rationalize the triangular design for an animal experiment in which all dose settings are controlled within a triangle domain that prescribes the sum of doses of simultaneously applied chemicals less than a certain level. In addition, a statistical test is proposed for judging the synergism among chemicals used in animal experiments, i.e. the test evaluates the discrepancy between the observed mean response from simultaneous administration groups of chemicals and an estimated response under the null hypothesis of zero interaction based on data from single administration groups. Finally, test performance is examined using a simulation study and a case study—the rodent uterotrophic assay. The simulation study revealed that the test is not superior in power to the standard analysis of variance test based on a linear model with interaction term, yet robust in the sense that type I errors under variance heterogeneity were better controlled using Welch correction than the analysis of variance test. The application of the proposed statistical test to an animal experiment is considered acceptable based on results. Copyright © 2003 John Wiley &amp; Sons, Ltd.

喉頭アレルギーに対するＩＰＤの効果

Twenty-three patients with an allergy of the larynx, who complained of a foreign body sensation in the throat or a persistent cough, inclusive of eight suspected patients, were treated with suplatast tosilate (IPD) for an average of 36.3-24.0 days between January 1997 and December 1999. The final subjective efficacy of IPD (300 mg/day) in twenty evaluable patients were as follows: excellent, 50.0%; good, 40.0% ; and poor, 10.0%, with an efficacy rate of 90.0%. The final subjective effectiveness rates inclusive of excellent and good efficacy were 90.9% for the IPD® single administration group, and 88.9% for the combined administration (IPD®+concomitant drugs) group. No statistical differences in efficacy were noted between the two groups. Mild nausea appeared as an adverse effect in one patient (4.8%) in the IPD single administration group. It was speculated that the efficacy of IPD therapy for the allergy of the larynx is mainly attributable to suppression of chemical mediators derived from mast cells of the laryngeal mucosa or suppression of IL-4 or IL-5 production from The type cells.

Studies on penetration of peroral new quinolone, levofloxacin to rabbit oral soft tissues with influence of stomachics sankyo magen mittel

It is a well-known fact that theoretically the absorption of new quinolones in the intestinal tract is significantly inhibited as a result of their interaction with metal cations. In order to study the effects of S. M powder, which is frequently used in the department of dentistry, on the tissue transfer of new quinolones, we administered S. M powder in combination with levofloxacin (LVFX) to rabbits and made comparative studies of soft tissue transfer rates. Prior to the initiation of the present study, we confirmed that there is a significant difference in tissue transfer rates of ofloxacin (OFLX) and LVFX, based upon the fact that LVFX is an optical activator of the OFLX. We obtained the following results in this study: 1) All the samples including the serum and tissue specimens collected from the LVFX single administration group reached Tmax 0.33–0.82 hours later than those collected from the OFLX single administration groups showed 2) Although the serum samples collected from the LVFX and OFLX single administration groups showed nearly the equivalent Cmax, all tissue samples collected from the LVFX single administration group showed higher transfer rates than those collected from the OFLX single administration group. 3) All the samples including the serum and tissue specimens collected from the S. M powder combination group showed lower values of Cmax and AUC than those collected from the LVFX single administration group.

An experimental study on the effects of selected drugs on pancreatic regeneration after partial pancreatectomy.

This study was undertaken to determine the effect of the single and combined administration of caerulein, hydrocortisone, and FOY-305 (camostat) on the regeneration of the remnant pancreas after a 90% pancreatectomy in rats. After undergoing either a sham operation or a 90% pancreatectomy, the rats were administered the three drugs either singly or in combination. After the rats were killed, the pancreas was weighed and examined for tissue amylase activity, tissue protein content and total DNA content. The results were as follows: In the sham operation group, the caerulein among three drugs produced a significant trophic effect. The trophic effect in the combined administration group was greater than that in the single administration group. In the 90% pancreatectomy group, of the three drugs administered, hydrocortisone produced the most significant trophic effect. The trophic effect in the combined administration group was greater than that in the single administration group. These data suggest that the trophic effect of caerulein is significant in mature pancreatic cells while that of hydrocortisone is an immature one and that an additive effect of the three drugs was observed.

Regulation of intestinal immunoglobulin production in response to dietary ovalbumin.

The effects of oral administration of ovalbumin (OVA) on intestinal immunoglobulin production was examined. Balb/c mice, bred and reared on an OVA-free diet, received either one dose or 14 consecutive daily intragastric doses of 25 mg OVA/dose. Single dose administration of OVA resulted in significant suppression of total immunoglobulins in the intestinal mucosa, particularly of the IgA isotype, although a very low titre anti-OVA IgG class antibody response was induced. After multiple peroral immunisations, there was more intestinal anti-OVA antibody induction and less suppression of total immunoglobulins. However, all the anti-OVA antibody was of the IgG isotype. In vitro production of mucosal immunoglobulins was not significantly reduced over 5 days, compared with controls, in either single or multiple administration groups, suggestive of a loss of T suppressor cell function in culture. Prior adoptive transfer of splenic and lymph node cells from mice preimmunised with OVA was capable of abrogating the local suppression of immunoglobulin production in vivo. Although adoptive transfer of bovine serum albumin-sensitised cells could also overcome some of the local suppression, complete restoration of normal immunoglobulin levels was not achieved. These data suggest that single oral administration of a novel dietary antigen induces a transient, non-specific suppression of intestinal immunoglobulin production, which can be overcome by antigen-specific T cells.

Distribution of thiabendazole (TBZ) in pregnant mice.

Thiabendazole (TBZ) suspended in olive oil or 3% gum arabic was given orally to pregnant ICR mice on day 15 (a single administration group) or during days 6 to 15 (repetitive administration group) of gestation at dose levels of 700, 350 and 100 mg/kg/d and TBZ in the liver, placenta and fetus of mice was analyzed by means of gas chromatography with FPD at 12 and 24 h after final administration. TBZ was transferred to the fetus from the placenta in maternal mice treated with TBZ and the concentration of TBZ in the organs increased with an increase in dose level. TBZ and its metabolite, 5-hydroxythiabendazole (5-OH TBZ, including glucuronide and sulfate of it), in the blood, liver, kidney, placenta and fetus of mice treated with 700 mg/kg/d of TBZ were analyzed by means of fluorometry at 1, 2, 6, 12, 24, 48 and 120 h after final dose. The time course of concentration of TBZ and 5-OH TBZ in the liver, kidney, placenta and fetus showed a similar pattern to that in the blood. The maximum concentration of TBZ in repetitive administration group was observed at 1 h after final dose and was no difference between those in two vehicles, whereas in a single administration group the maximum concentration in TBZ-olive oil group at 1 h was higher than that in TBZ-gum arabic group at 1 or 2 h. The concentration of 5-OH TBZ in repetitive administration group was higer than that in a single administration group within 12 h after final dose in both different vehicles.

Experimental study on cystitis as a risk factor in urinary bladder carcinoma--effect of inflammation on N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat urinary bladder carcinogenesis

Administrations of 0.01% and 0.005% BBN were undertaken in female Sprague Dawley rats (aged 12 weeks) and female Wistar rats (aged 16 weeks) for 4 and 8 weeks, respectively. Escherichia coli isolated from the urine of patients with urinary tract infections, which invade the rat tunica mucosa vesicae urinariae to varying degrees, were transurethrally inoculated into the bladder.When 0.1ml of 103/ml bacteria of a highly invasive strain was inoculated twice at intervals of 2 weeks before, during and after the administration of 0.01% BBN, the incidences of tumors were 64.3% (9/14), 57.1% (8/14) and 46.7% (7/15), respectively. Administration of BBN alone resulted in a tumor incidence of 33.3% (5/15). Transitional cell carcinoma was observed in only two animals in which inflammation was induced after BBN administration.Among the animals given 0.005% BBN after the induction of inflammation, 69.2% (9/13) of those inoculated twice with 0.1ml of 103/ml bacteria of the highly invasive strain at intervals of 4 weeks had tumors (papilloma in one and hyperplasia in eight). The incidence of tumors in animals which had the combined treatment was lower than the 77.8% (14/18) found in the animals which received only a single administration of BBN (hyperplasia in 14), but the tumors were larger in the latter group. The incidence was highest in animals inoculated four times with 0.1ml of 105/ml bacteria of a moderately invasive strain at intervals of three weeks, 87.6% (14/16). Half of them had transitional cell carcinoma or squamous cell carcinoma. There were significant differences (p<0.01) in both the number of tumors occurring in one animal and the sizes of the tumors in the single administration group and the combined treatment group. In contrast, the incidence was lowest, 43.8% (7/16), in animals inoculated four times with 0.1ml of 108/ml bacteria of a moderately invasive strain at intervals of three weeks. All the animals with tumors showed simple hyperplasia of less than 1mm in diameter, indicating a decrease in carcinogenesis.From these results, it was concluded that tissues with inflammatory changes are more likely to be initiated by a carcinogenic substance than are normal tissues, in so far as the inflammatory changes induce no separation or destruction of basal cells even if superficial cells are separated. When inflammatory changes occurred in the tissues during the promotive stage, the inflammation stimuli also exerted a promoting effect on tumor formation.

新しい経口抗不整脈薬Ｐｒｏｐａｆｅｎｏｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ（ＹＭ‐１３４００）の第１相臨床試験

A phase I study on propafenone hydrochloride (YM-13400), a new antiarrhythmic agent, was carried out in 12 healthy Japanese male volunteers . The safety, tolerance and pharmacokinetic profile of the drug were studied by single oral administration (group 1) and continuous administration (group 2). The six men of group 1 received 100, 200, and 300mg doses and the remaining six were given doses of 100 tid for 2 days, 200mg tid for 2days, and finally 200mg tid for 7days. Each dose were increased step by step at intervals of 2weeks or more after the safety of the drug was confirmed.No pronounced change was noted in vital signs (blood pressure, pulse rate), subjective symptoms, or clinical laboratory test data. Prolongation of PR, QRS and QTc interval was found at 2 to 4 hours after each administration.The maximum concentration (Cmax) and the area under the time-concentration curve (AUC) increased nonlinearly, increasing with each dosage. The biological half life in the elimination phase was about 2 to 3hours. In the continuous administration study, steady state was reached at about the 5 th day after administration. The amount of twenty-four hour cumulative urinary excretion of unchanged propafenone was 1% or less.The above results confirmed the safety of propafenone in healthy male volunteers.less.

Cerebrospinal fluid penetration after combined administration of cefotaxime and ampicillin to rabbits with staphylococcal meningitis.

The pharmacokinetics of cefotaxime and ampicillin in the cerebrospinal fluid (CSF) were studied by a HPLC method after administering each of the antibiotics singly or as a mixture to rabbits with experimental meningitis caused by Staphylococcus aureus. The half-lives of cefotaxime and desacetyl-cefotaxime in the serum and of ampicillin in the CSF were found to be significantly shorter in the mixture group than in the respective single administration groups. No other statistically significant differences were observed between the mixture and single administration groups with respect to the maximum concentrations (Cmax) of the antibiotics in the serum and the CSF, to the relative percentage of the Cmax of each antibiotic in the CSF to the Cmax in the serum, and to the relative percentage of the AUC of each antibiotic in the CSF to that in the serum. These results differ from earlier findings that the concentration of ampicillin in the CSF of rabbits was significantly lower in animals concomitantly dosed with latamoxef (moxalactam) and ampicillin than in a group dosed only with ampicillin.

Effects of dimercaprol or thioctic acid on the distribution and excretion of Na374AsO3 injected subcutaneously in rats.

This report dealt with the effects of dimercaprol (BAL) and thiotic acid (TA), antidotes against arsenical, on the distribution and the excretion of 74As in several organs of the rat. Each organ was removed and served for quantitative analysis of 74As five days after subcutaneous injection of Na374AsO3 5 microCi/100 g. Administration of BAL or TA was performed intraperitoneally with a single administration or five consecutive administrations for five days before animals were sacrificed. 74As content in each organ of the rat decreased to a greater extent in the five consecutive administration group of BAL or TA than in the non-treated or single administration groups. Moreover, the excretion of 74As in a digestive tract increased more remarkably in the five consecutive administration group than in the non-treated or single administration groups. There were no differences in the excretion or the content of 74As in each organ between the single administration group and the non-treated group.