Improved knowledge of the time course of antimicrobial activity should provide useful information for designing optimal dosage regimen. In contrast to $\beta$-lactam, aminoglycosides tend to induce a prolonged postantibiotic effect against aerobic or facultative gram negative rods and clinical outcome was significantly correlated with achieving peak serum concentrations. The objective of this study was to compare the efficacy, safety of e same total daily dose of amikacin and gentamicin given either twice or thrice daily in the treatment of patients. Consecutive patients over 20 years old with a suspected or confirmed infection for which an aminoglycosides was indicated were eligible. Exclusion criteria were known allergy to aminoglycosides, renal impairment, granulocytopenia and pregnancy. Patients were treated with intravenous amikacin 15 mg/kg/day or gentamicin 4.5 mg/kg/day either in two devided or in three devided. Seventy-four patients with infection were enrolled in this study of amikacin twice daily (A2, n=29), gentamicin twice daily (G2, n=8) vs amikacin thrice daily (A3, n=30), gentamicin thrice daily (G3, n=7). Baseline characteristics were comparable in G2 and G3. The clinical cure rate (including partial improve) were $89.0\%\;and\;86.0\%$ in A2 group and A3 group respectively. The bacteriologic cure rate were $99.0\%\;and\;85.7\%$ in A2 group and in A3 group respectively. The clinical and bacteriologic effects were difficult to compare G2 with G3, because of the small numbers of patients. The serum creatinin rose in $3.44\%$ (1 in 29) of patients in the A2 group compared to $13.3\%$ (4 in 30) in e A3 group. Although audiometry was not performed, there was no clinical evidence of ototoxicity in any of the patients. In our opinion, twice-daily regimen of aminoglycosides is more effective and less nephrotoxic than thrice-daily regimen.

Seasonal rhythmic changes in gentamicin pharmacokinetics was evaluated in 10 healthy male volunteers after single intravenous 80 mg administration of gentamicin at 9:00 a.m. during summer and winter. The mean terminal half-life and AUC of gentamicin were $3.56\pm0.14\;hr\;and\;25.03\pm2.84\;{\mu}g/ml{\cdot}hr$ in winter and $3.08\pm0.41\;hr\;and\;21.84\pm2.51\;{\mu}g/ml{\cdot}hr$ in summer. The mean total body clearance $(CL_t)$ and elimination rate constant $(k_{10})$ of gentamicin was $3.17\pm0.43\;L/hr,\;0.458\pm0.06\;hr^{-1}\;in\;winter\;and\;3.66\pm0.45\;L/hr,\;0.561\pm0.07\;hr^{-1}$ in summer, The mean volumn of distribution $(V_{dss})$ of gentamicin at steady state was $12.65\pm1.09$L in winter and $12.39\pm1.25$ L in summer. Serum concentrations of gentamicin in winter were increased significantly during 4-8 hr (p<0.05) compared to those of gentamicin in summer. The elimination rate constant $(k_{10})$ of gentamicin in winter was decreased significantly $(p<0.05)$ compared to that of gentamicin in summer. The mean volume of distribution at steady state $(V_{dss})$, AUC, mean total body clearance ($CL_t$) and terminal half-life of gentamicin in the winter were increased but were not significant. The mean intrasubject fluctuations in terminal half-life, AUC and $CL_t$ between winter and summer were 8.2, 11.0 and $6.0\%$ respectively.

Piroxicam-$\beta$-cyclodextrin은 piroxicam을 $\beta$-cyclodextrin으로 포접시킨 비스테로이드성 항염증약물이다. 이러한 포접형 약물은 위장관에서의 흡수속도가 증가하는 것으로 외국자료에서 보고되고 있으며 이는 이 약물의 위장관 내성에 보다 나은 영향을 끼칠 수 있음을 시사하고 있다. 본 연구는 정상성인 한국인을 대상으로 randomized, crossover design에 의해 piroxicam-$\beta-cyclodextrin(Brexin^{(R)})$과 piroxicam 확산정$(Feldene^{(R)})$ 흡수속도를 비교하고자 하였다. 건강한 성인 8명의 피험자를 2군으로 나누어 시험약 또는 대조약을 각각 20 mg씩 20일의 휴약 기간을 두고 이중 맹검으로 교차 투여하였다. 시험약 또는 대조약의 투여 후 24시간 동안 일정 간격으로 채혈하여 HPLC 방법으로 혈장 내 piroxicam 농도를 측정하였다. $AUC_{0-24}\;({\mu}g/mL)$는 piroxicam-$\beta$-cyclodextrin군에서 $56.1\pm4.9$, piroxicam군에서 $57.3\pm5.6$으로 통계적인 유의성이 없었으나, 투여 후 0.5시간에서의 혈중농도는 piroxicam-$\beta$-cyclodextrin군 $2.9\pm0.4\;{\mu}g/mL$, piroxicam군 $1.6\pm0.3\;{\mu}g/mL$으로 통계적인 유의성을 보였다(p<0.05). 또한 최고혈중농도는 piroxicam-$\beta$-cyclodextrin$(4.3\pm0.5\;{\mu} g/mL)\;piroxicam(3.5\pm0.3\l{\mu}g/mL)$,으로 유의성이 있었으며(p<0.05), 흡수 속도상수는 piroxicam-$\beta$-cyclodextrin$(3.00\pm0.49\;h^{-1}), \;piroxicam(1.80\pm0.21\;h^{-1})$이었다(p<0.1). 이상의 결과에서, piroxicam-$\beta$-cyclodextrin정은 piroxicam 확산정과 비교하여 흡수되는 정도는 서로 비슷하지만 흡수 초기의 혈장농도 및 흡수속도상수에서 보다 빠른 약동학적 특성을 나타내었다.

A bioequivalence study of the Kerola tablets (Dongkwang Pharmaceutical Co., Korea) to the Tarasyn tablets (Roche Co., Korea), formulations of ketorolac trometamine(KTR), was conducted. Sixteen healthy Korean male subjects received each formulation at the dose of 10 mg as KTR in a $2\times2$ crossover study. There was a 1-week washout period between the dose. Plasma concentrations of KTR were monitored by an HPLC method for over a period of 12 hr after each administration. AUC (area under the plasma concentration-time curve) was calculated by the linear trapezoidal method. $C_{max}$ (maximum plasma drug concentration) and $T_{max}$ (time to reach $C_{max}$) were compiled from the plasma drug concentration-time data. Analysis of variance (ANOVA) revealed that there are no differences in AUC, $C_{max}\;and\;T_{max}$ between the formulations. The apparent differences between the formulations in these parameters were all far less than $20\%$ (i.e., 2.31, 8.19 and $0\%$ for AUC, $C_{max}\;and\;T_{max}$, respectively). Minimum detectable differences $(\%)\;at\;\alpha=0.1\;and\;1-\beta=0.8$ were all less than $20\%$ difference in these parameters between the formulations were all over 0.8. The $90\%$ confidence intervals for these parameters were also within $20\%$. These results satisfy the bioequivalence criteria of the Korea Food and Drug Administration (KFDA) guidelines (No. 1998-86). Therefore, these results indicate that the 2 formulations of KTR are bioequivalent and, thus, may be prescribed interchangeably.

Lovastatin is a lipid lowering agent for the treatment of hypercholesterolemia and belongs to a new class of pharmacologic compounds called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. By competitively inhibiting HMG CoA reductase, lovastatin disrupts the biosynthesis of cholesterol in hepatic and peripheral cells and increases the synthesis of high-density-lipoprotein HDL) receptors. Following oral administration, the lactone ring of lovastatin is hydrolysed to the active inhibitor of HMG CoA reductase, lovastatin acid. Lovastatin is known to have poor oral absorption and wide individual variation. In this study, bioequivalence test of two lovastatin formulations, the test drug ($Lovaload^{TM}$, Chong Kun Dang Pharmaceutical Co.) and the reference drug ($Mevacor^{TM}$, Chung Wae Pharmaceutical Co.) were conducted according to the guidelines of Korea Food and Drug Administration (KFDA). A total of 18 healthy male volunteers, $31.90\pm3.60$ years old and $72.17\;7.88$ kg of body weight in average, were evaluated in a randomized crossover manner with a 2-week washout period. Concentrations of lovastatin acid in plasma were measured upto 12 hours following a single oral administration of eight tablets (20 mg of lovastatin per tablet) by high-performance liquid chromatography with UV detection at 238 nm. The area under the concentration-vs-time curve from 0 to 12 hours $(AUC_{0-12h})$ was calculated by the trapezoidal summation method. The statistical analysis showed that there are no significant differences in $AUC_{0-12h),\;C_{max}\;and\;T_{max}$ between the two formulations ($6.72\%,\;1.52\%,\;and\;0.88\$, respectively). The least significant differences between the formulations at $\alpha$=0.05 were less than $20\%\;(11.65\%,\;19.73\%,\;and\;14.81\%\;for\;AUC_{0-12h},\;C_{max}\;and\;T_{max}$, respectively). The $90\%$ confidence intervals for these parameters were also within $\pm20\%\;(-1.50{\leq}{\delta}{\leq}15.00$, $-12.50{\leq}{\delta}{\leq}15.50,\;and\;-9.64{\leq}{\delta]{\leq}11.40{\leq}\;for\;\;AUC_{0-12h}$ ,$C_{max}\;and\;T_{max}$, respectively). In conclusion, the new generic product $Lovaload^{TM}$ was proven to be bioequivalent with the reference drug.

To clarify whether nizatidine, a $H_2$ receptor antagonist, has the cholinergic activity, the effects of nizatidine on the guinea pig ileum and on the acetylcholinesterase in human serum were studied. And, the mechanism of excitatory effect of nizatidine on the cholinergic system in ileum was also studied. Nizatidine caused a concentration-dependent contractile response by the guinea pig ileum. The $EC_{50}\;was\;53\;{\mu}M$ and the maximum response was at $300\;{\mu}M$. Ranitidine also caused a contractile response by the guinea pig ileum, but cimetidine and famotidine did not. The pretreatment with $H_1$ receptor antagonist did not affect the actions of nizatidine on the guinea pig ileum, but the pretreatment with atropine completely blocked them. Nizatidine significantly enhanced the acetylcholine-induced response of the guinea pig ileum, but not the pilocarpine-induced response. Nizatidine did not affect the histamine-induced response of the guinea pig ileum. Nizatidine still exerted the small excitatory effect on the guinea pig ileum pretreated with the high concentration of physostigmine. Nizatidine significantly inhibited the acetylcholinesterase in human serum. These results suggest that nizatidine exerts an excitatory effect on guinea pig ileum which seems to be associated with the cholinergic system, probably through an indirect mechanism, inhibition of acetylcholinesterase and/or increased release of acetylcholine.

SB-31 which contains Pursatilla, Licoris and Ginseng extracts was recently proved as an anticancer agent. In a preclinical effort to be applied this drug to human, pharmacokinetics of SB-31 was carried out in rats and rabbits. Glycyrrhizin(GZ), a saponin of Licoris was used as a standard ingradient for the pharmacokinetics of SB-31. The rat's blood, bile and urine samples were serially collected in femoral vein, common bile duct and bladder, respectively, after bolus i.v. injection at a dose of 1 or 1/5 ampul/rat and rabbit's blood samples from the marginal ear vein at a dose of 1 or 3 amp./rabbit. GZ and glycyrrhetic acid(GA), a major metabolite of GZ in the physiological samples were analysed by HPLC with UV detection. The decline of GZ in plasma concentration was generally biexponential at each dose. GZ was almost completely recovered in bile within 18 hour. GA wasn't detected in the samples with UV detector. In the rat, Vss and Kel at a dose of 1 and 1/5 ampul of SB-31 were $98.06\pm6.07\;ml,\;0.33\pm0.05\;hr^{-1}\;and\;65.46\pm11.19\;ml,\;0.68\pm0.25\;hr^{-1}$, respectively. Those in rabbits at a dose of 3 and 1 ampul of SB-31 were $235.24\pm30.72\;ml,\;0.13\pm0.36\;hr^{-1}\;and\;341.32\pm28.58\;ml,\;0.27\pm0.04\;hr^{-1}$, respectively. 'WinNonlin' was utilized for the compartmental analysis. A two-compartment model was chosen as the most appropriate pbarmaco-kinetic model. The data were best described by using a weighting factor of $1/y^2$. To evaluate the effect of SB-31 on cardiovascular system, serially diluted SB-31 was directly injected into coronary artery in the isolated perfused rat heart and the effect of PSF, PSH, saponins of Pursatilla, and SB-31 on PT, APTT of healthy human plasma was examined. Except the positive inotropic effect of ten times diluted solution of SB-31, there was no significant effect on LVDP, (- dp/dt)/(+dp/dt), heart rate and coronary flow in comparision with that of vehicle. SB-31 had no effect on PT but slightly delayed APTT about $6.9{\sim}11.5\%$. There was no significant effect of PSF and PSH on PT & APTT. Conclusively, SB-31 did not show any notable toxic effects on cardiovascular system.

Phthalimidyl ester of ceftezole (CFZ-PT) was synthesized as a prodrug by esterification of ceftezole (CFZ) with N-bromophthalimide. CFZ-PT was more lipophilic than CFZ when the lipophilicity was assessed by partition coefficients between n-octanol and water at various pH. The pharmacokinetic characteristic of CFZ-PT and CFZ preparations were compared following oral administrations of these compounds to rabbits. CFZ-PT is expected to be metabolized rapidly to CFZ in the body. The metabolism process appears to be hydrolysis of the ester to CFZ, the parent drug of CFZ-PT. In vivo metabolism of CFZ-PT to CFZ was confirmed in rabbit by HPLC analysis. CFZ concentration in the serum samples taken after oral administration of CFZ-PT(equivalent amount of CFZ) were released and higher than those of CFZ. Oral bioavailability of CFZ-PT was 1.9 fold higher than at of CFZ in rabbits because of enhanced lipophilicity and absorption. Finally, it was concluded that CFZ-PT appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.

The effects of MeOH extracts from 28 herbal medicines on monoamine oxidase (MAO) activity were investigated. MAO was purified from mouse brain and its activity was determined by fluoro-photometry using kynuramine as a substrate. Three MeOH extracts, Coptis japonica, Cinnamomum cassia and Poncirus trifoliate from the herbal medicines showed a strong inhibitory effect with less than $100\;{\mu}g/ml$ in their inhibitory amounts of $50\%$ ($IC_{50}$ values) on MAO activity. Four MeOH extracts including Evodia officinalis exhibited a mild inhibition of MAO activity with $100-200\;{\mu}g/ml$ in their $IC_{50}$ values.

Acetaminophen (APAP) suppositories with active ingredients, i.e., polyethylene glycol (PEG), Witepsol H-15 (WH), were prepared for hospital use and investigated on their drug release characteristics and pharmacokinetics. WH was employed as oil-soluble base with an aim of reducing fragility and mucosa irritancy that are common drawbacks found in PEG suppositories. Also hollow type suppository was tried as compared with conventional type suppository. Drug release tests revealed that in most formulations, more than $80\%$ of loaded APAP were released within 20 minutes, except for APAP-WH hollow type suppositories. Significant differences in the plasma concentration profile were observed among four type suppositories. $T_{max}$ of APAP-PEG and APAP-WH suppositories were 90 and 60 minutes, respectively, in hollow types. APAP-WH hollow type suppositories demonstrated fast absorption rates of APAP as compared with those of APAP-PEG suppositories. No burst effect was observed from APAP-WH suppository in contrast to APAP conventional type suppository, whereas AUCs of all the suppositories were similar. APAP-WH hollow type suppository may be an useful dosage form for hospital use.

The purpose of this study was to test the stability of TPN basic solutions containing amino acids and dextrose. Test solutions containing $4.25\%$ amino acids in $25\%$ dextrose (central TPN basic solution) or $4.25\%$ amino acids in $10\%$ dextrose (peripheral TPN basic solution) were prepared. Two different amino acids solutions $(Fravasol^{(R)}\;vs\;Freamine^{(R)})$ were tested. The samples were taken from each admixture and stored in the evacuated, sterile containers at $2{\sim}8^{\circ}C$ and ambient room temperature. Each sample was analyzed at 0, 3, 7, 14 and 30 days of storage. Each amino acid was analyzed by amino acid analyzer. Dextrose content was measured by polarimeter. The pH and chromagen formation were also monitored. The decomposition was measured by the changes in concentration of amino acids and dextroser TPN basic $solution-Freamine^{(R)}$ admixture stored at $2\sim8^{\circ}C$ were stable for 30 days. Central and peripheral TPN basic solutions stored at room temperature were stable for 7 days and 14 days, respectively. There were no changes in color for 30 days by naked eye. Amino acid concentrations in TPN basic $solution-Fravasol^{(R)}$ admixture stored at $2\sim8^{\circ}C$ or room temperature were stable for 30 days. But, significant color change was detected according to passing time. In conclusion, Peripheral TPN basic $solution-Fravasol^{(R)}$ admixture stored at room temperature and in refrigerator were stable for 3 days and 7 days, respectively. However, central TPN basic solution-Fravasol admixtures were unstable. Therefore, it is recommended that it should be admixed right before use.