• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.39-45
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• 2000

We have investigated the efficacy of liposome encapsulated N-(phosphonacetyl)-L-aspartic acid (PALA) for the treatment of the C-26 murine colon tumor in Balb/c mice, and have compared it in this regard to free PALA. Healthy female Balb/c mice and C-26 tumor inoculated mice were randomized for the maximum tolerated dose (MTD) study and the in vivo therapy study, and the survival was measured after a single intraperitoneal injection of the drug. The maximum tolerated dose for intraperitoneally administered drug was found to be 750 mg/Kg for free PALA, and was greater than the maximum dose possible (150 mg/Kg) for PALA encapsulated in both DSPC and DSPG liposomes. When drug was administered one day after tumor implantation, 150 mg/Kg of PALA in DSPG liposomes increased the percentage of tumor bearing mice surviving at day 36 from 8% (buffer control) to 88%. In contrast, 150 mg/Kg free PALA increased the day 36 surviving percentage to only 25%. A 150 mg/Kg dose of PALA in DSPC liposomes increased the surviving percentage to 50%, while a 75 mg/Kg dose of PALA in sterically stabilized liposomes increased the surviving percentage to 78%. These results show that PALA in negatively charged or sterically stabilized liposomes can exhibit considerably greater potency than free PALA in C-26 tumor bearing mice.

• Archives of Pharmacal Research
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• v.18 no.3
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• pp.141-145
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• 1995

Omeprazole, a proton pump inhibitor, was given intravenously (iv), orally (po), intraperitoneally (ip), hepatoportalvenously (pv), and intrarectally (ir) to rats at a dose of 72mg/kg in order to investigate the bioavailability of the drug, The extent of bioavailabilities of omeprazole administered through pv, ip, po, and ir routes were 88.5, 79.4, 40,8, and 38.7%, respectively. Pharmacokinetic analysis in this study and literatures (Regardh et al., 1985 : Watanabe et al., 1994) implied significant dose-dependency in hepatic first-pass metabolism, clearance and distribution, and acidic degradation in gastric fluid. The high bioavailability from the pv administration (88.5%) means that only 11.5% of dose was extracted by the first-pass metabolism through the liver at this dose (72 mg/kg). The low bioavailability from the oral administration (40.8%) in spite of minor hepatic first-pass extraction indicates low transport of the drug from GI lumen to portal vein. From the literature (Pilbrant and Cederberg, 1985), acidic degradation in gastric fluid was considered to be the major cause of the low transport. Thus, enteric coating of oral preparations would enhance the oral bioavailability substantially. The bioavailability of the drug from the rectal route, in which acidic degradation and hepatic first-pass metabolism may not occur, was low (38.7%) but comparable to that from the oral route (40.8 %) indicating poor transport across the rectal membrane. In this case, addition of an appropriate absorption enhancer would improve the bioavailability. Rectal route seems to be an possible alternative to the conventional oral route for omeprazole administration.

• Journal of Veterinary Science
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• v.22 no.6
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• pp.41.1-41.14
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• 2021

Background: Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine Streptococcus suis infections, while the irrational dose has not been formulated. Objectives: The rational dose regimens of CEF oily suspension against S. suis were systematically studied using a pharmacokinetic-pharmacodynamic model method. Methods: The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC_0-24h/MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating in vivo pharmacokinetic data of the infected pigs and ex vivo pharmacodynamic data using the sigmoid E_max (Hill) equation. The dose was calculated based on the AUC_0-24h/MIC values for bacteriostatic action, bactericidal action, and bacterial elimination. Results: The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 ㎍/mL, 811.99 ± 54.70 ㎍·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 ㎍/mL, 735.85 ± 26.20 ㎍·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against S. suis strain was 0.25 ㎍/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC_0-24h/MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity. Conclusions: A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against S. Suis infections.

• Journal of Pharmaceutical Investigation
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• v.39 no.5
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• pp.373-379
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• 2009

This study was conducted to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of a direct thrombin inhibitor, argatroban to predict the concentration-effect profiles in rats. Argatroban was i.v. injected to rats at 0. 2, 0.8 and 3.2 mg/kg doses (n = 4-5 per dose), and plasma drug levels were determined by a validated LC/MS/MS assay. The pharmacokinetics of argatroban was linear over the i.v. dose range studied. The thrombin time (TT) and the activated partial thromboplastin time (aPTT) were measured in rat plasma and they were found to linearly increase with increasing the dose. A 2-compartment pharmacokinetic model linked with an indirect response pharmacodynamic model was successfully utilized to evaluate the drug concentration-response relationship.

• YAKHAK HOEJI
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• v.31 no.4
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• pp.204-212
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• 1987

Rifampicin is an indispensable drug along with isoniazid for the control of tuberculosis and is usually prescribed as the combination of rifampicin and isoniazid. This paper is attemtped to investigate the interaction of rifampicin and isoniazid. Isoniazid was administered orally at a dose of 30mg/kg of rabbits pretreated with rifampicin 7.5mg/kg, 15mg/kg, and 30mg/kg, respectively twice daily for 9 days. The results are as follows: The blood level and relative bioavailability of isoniazid were decreased significantly (p<0.05) by rifampicin at a dose of 15mg/kg and 30mg/kg. The renal clearance of total isoniazid and ratio of its metabolites to isoniazid were increased significantly (p<0.05) by rifampicin at a dose of 15mg/kg and 30mg/kg. It seemed to be due to enzyme induction by rifampicin. Elimination rate constant ($\beta$) of isoniazid was increased and half life ($t_{1/2$\beta}$) was decreased by rifampicin pretreatment. Dosage regimen of isoniazid after long term administration of rifampicin should be adjusted carefully.

• Toxicological Research
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• v.20 no.2
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• pp.123-129
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• 2004

The present study was conducted to investigate the single and 2-week repeated dose toxicity of DHP2, a hydrophobic drug delivery vehicle, in ICR mice. The test article was administered orally to mice at the dose levels of 2.5, 12.5 and 37.5 g/kg for single dose toxicity study and at the dose levels of 0, 2.5, 5, and 10 g/kg for repeated dose toxicity study. In both studies, there were no treatment-related effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights of all animals treated DHP2. Based on these results, it was concluded that the 2-week repeated oral dose of DHP2 may have no toxic effect in mice at a dose level of 10 g/kg. In the condition of this study, the no-observed-adverse-effect level (NOAEL) was considered to be 10 g/kg/day for both sexes.

• The Korean Journal of Applied Statistics
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• v.22 no.5
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• pp.1033-1046
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• 2009

In new drug development studies or clinical trials, zero-dose control is needed in general to determine the lowest dose level for a new drug which can act with our bodies. When the lowest dose level compared with zero-dose control has significant difference in effect, it is referred as minimum effective dose(MED). We propose, in this paper, parametric sequential test using updated control to identify the minimum effective dose(MED) level. Monte Carlo Simulation is adapted to examine the power and experimental significance levels of the proposed method with other methods.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10413-10420
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• 2015

Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place. The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) against the hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel (DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups ($DTX_L$, $CTX_L$, $EPI_L$ or $DTX_H$, $CTX_H$, $EPI_H$), and low or high dose chemotherapeutics+APS groups ($DTX_L$+APS, $CTX_L$+APS, $EPI_L$+APS or $DTX_H$+APS, $CTX_H$+APS, $EPI_H$+APS). Controls were treated with equivalent normal saline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or high doses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group were separately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS (100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructure morphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points. With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and AST were significantly increased. Sections of liver tissue showed massive hepatotoxicity in $CTX_H$ group compared to the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis in hepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatin aggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that the protein levels of caspase-3 increased in $CTX_H$ group. The low dose groups exhibited trivial hepatotoxicity. More interestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities (low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes and the protein levels of caspase-3 ($CTX_H$+APS group). In conclusion, DTX, CTX and EPI induce liver damage in a dose dependent manner, whereas APS exerted protective effects.

• Journal of Pharmaceutical Investigation
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• v.5 no.2
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• pp.51-56
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• 1975

In the course of the investigations on drug metabolism and drug disposition in man, it has been noted that there are often rather striking individual differences in the response to drugs and in the ability to metabolize and dispose of drugs. Some of the person-to-person differences are due to environmental factors, but some have clearly demonstrated to be genetically determined. This report determined the rate of acetylation and some constants of sulfa-methizole to korean. The results are as follows: The overall removal rate of drug from the body is 0.572(k, $hr^{-1}$) the rate constant for acetylation, 0.222($k_2$, $hr^{-1}$) the rate constant for excretion of unchanged drug, 0.350($k_3$, $hr^{-1}$) and the faction of a dose ultimately excreted in the urine as unchanged drug is 0.677. And this report determined the optimal time to make a single blood level determination after an oral dose of the drug and obtain a reasonable index of the rate of sulfamethizole metabolism. The resulting data(sulfamethizole levels at 5 hours after drug administration) clearly established bimodality even though only about 106 subjects were tested.

• YAKHAK HOEJI
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• v.38 no.5
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• pp.483-487
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• 1994

The pharmacokinetic characteristics of an 1% flurbiprofen gel were evaluated using rats in reference to IV bolus and oral administration of the drug using rats. Following the transdermal application of the gel at the dose of 2 mg/kg as flurbiprofen, the $C_{max}$ and $T_{max}$ of the drug were $2.14\;{\mu}g/ml$ and 2 hr, respectively, whereas those after the oral administration of the drug as a suspension were $9.90\;{\mu}g/ml$ and 0.25 hr, respectively. These results indicate that, by the transdermal administration fo flubiprofen as the gel, the absorption of the drug was much slowed down and the lower $C_{max}$ compared to the oral administration may reduce the systemic side effects of the drug. The relative bioavailability of the flurbiprofen gel in reference to the oral dose was 48.5%. Tissue levels of flurbiprofen following the application of 50 mg of the 1% flurbiprofen gel onto ventral skin of rats showed that the maximum drug concentrations in the skin $(8.52\;{\mu}g/g)$ and the muscle $(2.06\;{\mu}g/g)$ occurred at 2 hrs postdose. The drug concentration in the both tissues remained relatively constant over the next 6 hrs following the peak concentration.