• Journal of Veterinary Clinics
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• v.36 no.3
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• pp.159-165
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• 2019

Pimobendan is an inodilator used to treat canine heart failure, and pentoxifylline is reported to be beneficial for microcirculation and heart disease. The purpose of this study was to evaluate the pharmacokinetic and pharmacodynamic profiles of a novel pimobendan-pentoxifylline liquid mixture after oral administration to dogs. Eight healthy Beagle dogs were included in the study. The dogs were divided into the control group (orally administered water; n = 4) and experimental group (orally administered pimobendan-pentoxifylline liquid mixture [pimobendan 0.25 mg/kg, pentoxifylline 15 mg/kg]; n = 4). Plasma samples were obtained and echocardiographic indices were measured for 24 hours after administration. The concentrations of pimobendan and pentoxifylline were quantified by using a liquid chromatography-mass spectrometer (LC-MS). The elimination half-life ($T_{1/2}$) was $32.96{\pm}9.80mins$ for pimobendan and $29.49{\pm}6.67mins$ for pentoxifylline. The time to reach maximum concentration ($T_{max}$) were $52.50{\pm}31.22mins$ for pimobendan and $41.25{\pm}18.87mins$ for pentoxifylline. The maximum blood concentration ($C_{max}$) was $96.92{\pm}75.64ng/mL$ for pimobendan and $7074.07{\pm}3261.1ng/mL$ for pentoxifylline. Of the echocardiographic indices, fractional shortening (FS) and left ventricular internal diameter at end systole (LVIDs) were significantly altered at 1-3 hours after the administration of pimobendan-pentoxifylline liquid mixture. The pimobendan-pentoxifylline liquid mixture was well tolerated by the dogs, with no adverse effects observed during the study.

• Bulletin of the Korean Chemical Society
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• v.33 no.5
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• pp.1681-1685
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• 2012

A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to determine valproic acid in human red blood cell (RBC). It is important to measure the drug concentration of the RBC as well as that of the plasma because of drug partitioning for pharmacokinetic and pharmacodynamic study. The method was linear over the dynamic range of 1-100 ${\mu}g$/mL with a correlation coefficient $r$ = 0.9997. The linearity of this method was established from 1 to 100 ${\mu}g$/mL for valproic acid in red blood cell with accuracy and precision within 15% at all concentrations. The intra-run and inter-run assay accuracy and coefficient of variations are all within 15% for all QC samples prepared in plasma and red blood human samples. Then, valproic acid amount by protein precipitation in plasma was quantified by LC-MS/MS mass spectrometry. The distribution ratio of VPA in RBC and plasma was analyzed by clinical samples. Based on measurement of the valproic acid in human red blood cell, this method has been applied to clinical research for study of distribution ratio of valproic acid in blood.

• Korean Journal of Clinical Pharmacy
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• v.22 no.3
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• pp.228-233
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• 2012

Purpose: The purpose of this study was to elucidate the effect of dissolved oxygen in alcohol to blood pressure of healthy persons. Methods: Subjects (n=30) were randomized in a double blind crossover study to receive 120 mL, 240 mL, 360 mL of alcohol (Korean spirit, 19.59 v/v%, dissolved oxygen is 8 ppm and 20 ppm). Blood alcohol concentration (BAC) and blood pressure were measured applying Lion SD-400 Alcolmeter$^{(R)}$ Breathalyser and Tensoval duo control. Pharmacokinetic parameters ($C_{max}$, $T_{max}$, $AUC_{last}$, $K_{el}$, $V_d$, Clearance) were calculated using Winnonlin$^{(R)}$ program. The difference of parameters and values were analysed by student t-test using Microsoft$^{(R)}$ Excel program. Results: The $AUC_{last}$ values of 8 ppm group and 20 ppm group in 240 ml administration were $6.15{\pm}2.60cg{\cdot}min/ml$, $5.33{\pm}1.84cg{\cdot}min/ml$ (p<0.05) and those in 360 mL were $11.93{\pm}5.70cg{\cdot}min/ml$, $10.33{\pm}4.60cg{\cdot}min/ml$ (p < 0.01), respectively. Thus, the $AUC_{last}$ was significantly decreased. On the other hands, there was a significant change in systolic blood pressure (SBP) after alcohol administration. All measured value after 360 mL of alcohol administration was significantly decreased (p < 0.01). Conclusions: The dissolved oxygen in alcoholic beverage has no effect on blood pressures but the alcohol administration has an effect on blood pressure. Thus, SBP can be used as a biomarker of alcohol administration and utilized in PK/PD modeling of alcohol.

• Biomolecules & Therapeutics
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• v.15 no.3
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• pp.156-161
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• 2007

Rapid advances in pharmacogenomic research have provided important information to improve drug selection, to maximize drug efficacy, and to minimize drug adverse reaction. The SNPs that are the most abundant type of genetic variants have been proven as valid biomarkers to give information on the prediction of pharmacokinetic/pharmacodynamic properties of drugs based on genotype. In order to elucidate a correlation between SNPs of calcium channel encoding gene and adverse reactions of calcium channel blockers, we investigated SNPs in CACNA1C gene known as a binding site of calcium channel blocker. 96 patients with hypertension who had taken or are taking an antihypertensive drug, 1,4-dihydropyridine (DHP) were included for analysis. These patients were composed of 47 patients with adverse drug reactions (ADR) such as edema from calcium channel blockers and 49 patients without ADR as a control group. The exons encoding the drug binding sites were amplified by PCR using specific primers, and SNPs were analyzed by direct sequencing. We found that there was no SNP in the exons encoding DHP binding site, but four novel SNPs in the exon-intron junction region. However, four novel SNPs were not associated with the ADR of calcium channel blockers. In conclusion, this study showed that ADR from calcium channel blockers may not be caused by SNPs of the binding sites of calcium channel blockers in CACNA1C gene.

• The Korea Journal of Herbology
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• v.23 no.1
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• pp.117-125
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• 2008

Objectives : This study was to verify the Attributive Channel theory of herbal medicine. Methods : [$^{131}I$]iodohesperetin was synthesized, separated, and refined from hesperetin, the major component of Citrus species, followed by observing the biodistribution in an organism of C57 BL/6 mice with and without Lewis Lung Carcinoma. Results : Iodohesperetin 27.5 mg was obtained through column cliromatography after a reaction with 50 mg of Hesperitin and 8 mg of Nal. The radiochemical yield of [$^{131}I$]iodohesperetin synthesis was 25 % when checked with Radio TLC chromatography. [131I]iodohesperetin was most largely distributed in the stomach, lung and liver of C57BL/6 mouse. The highest %ID/g in stomach was 40 min, in lung and liver was 20 min after injection. The % ID/g of tumor tissue was comparable with that of blood. Conclusions : The fact that [$^{131}I$]iodocurcumin was most largely distributed in the stomach, lung and liver was related with the Attributive Channel theory. And there was no significant finding related to tumor cells.

• Korean Journal of Clinical Pharmacy
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• v.21 no.4
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• pp.339-346
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• 2011

Over the past few decades, drug regulatory agencies in advanced countries have been emphasizing pharmacometrics as a tool for an effective and efficient drug evaluation. Despite this international movement, the value of pharmacometrics is still poorly recognized by the Korean drug evaluation system. This study aimed to analyze the current state of utilization of pharmacometrics by foreign drug regulatory agencies and develop a road map to guide the implementation pharmacometrics into the Korean drug evaluation system. MEDLINE and foreign drug regulatory agency database were extensively searched to obtain scientific research articles, guidance, regulations and pharmacometric review reports on foreign pharmacometric drug evaluation system. A systematic roadmap comprised of 3 stages to implement pharmacometrics in Korean drug evaluation system was formulated after analyzing the collected data in tune with the current evaluation system. Pharmacometrics is an urgently required tool to achieve an efficient drug evaluation and review in Korea. The road map developed by this study is expected to aid in setting up a policy to implement and utilize pharmacometrics in Korea.

• Journal of Ginseng Research
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• v.26 no.3
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• pp.111-131
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• 2002

Korean ginseng (Panax ginseng C.A. Meyer) received a great deal of attention from the Orient and West as a tonic agent, health food and/or alternative herbal therapeutic agent. However, controversy with respect to scientific evidence on pharmacological effects especially, evaluation of clinical efficacy and the methodological approach still remains to be solved. Author reviewed those articles published since 1980 when pharmacodynamic studies on ginseng have intensively started. Special concern was paid on metabolic disorders including diabetes mellitus, circulatory disorders, malignant tumor, sexual dysfunction, and physical and mental performance to give clear information to those who are interested in pharmacological study of ginseng and to promote its clinical use. With respect to chronic diseases such as diabetes mellitus, atherosclerosis, high blood pressure, malignant disorders, and sexual disorders, it seems that ginseng plays preventive and restorative role rather than therapeutics. Particularly, ginseng plays a significant role in ameliorating subjective symptoms and preventing quality of life from deteriorating by long term exposure of chemical therapeutic agents. Also it seems that the potency of ginseng is mild, therefore it could be more effective when used concomitantly with conventional therapy. Clinical studies on the tonic effect of ginseng on work performance demonstrated that physical and mental dysfunction induced by various stresses are improved by increasing adaptability of physical condition. However, the results obtained from clinical studies cannot be mentioned in the indication, which are variable upon the scientist who performed those studies. In this respect, standardized ginseng product and providing planning of the systematic clinical research in double-blind randomized controlled trials are needed to assess the real efficacy for proposing ginseng indication. Pharmacological mode of action of ginseng has not yet been fully elucidated. Pharmacodynamic and pharmacokinetic researches reveal that the role of ginseng not seem to be confined to a given single organ. It has been known that ginseng plays a beneficial role in such general organs as central nervous, endocrine, metabolic, immune systems, which means ginseng improves general physical and mental conditons. Such multivalent effect of ginseng can be attributed to the main active component of ginseng,ginsenosides or non-saponin compounds which are also recently suggested to be another active ingredients. As is generally the similar case with other herbal medicines, effects of ginseng cannot be attributed as a given single compound or group of components. Diversified ingredients play synergistic or antagonistic role each other and act in harmonized manner. A few cases of adverse effect in clinical uses are reported, however, it is not observed when standardized ginseng products are used and recommended dose was administered. Unfavorable interaction with other drugs has also been suggested, which the information on the products and administered dosage are not available. However, efficacy, safety, interaction or contraindication with other medicines has to be more intensively investigated in order to promote clinical application of ginseng. For example, daily recommended doses per day are not agreement as 1-2g in the West and 3-6 g in the Orient. Duration of administration also seems variable according to the purpose. Two to three months are generally recommended to feel the benefit but time- and dose-dependent effects of ginseng still need to be solved from now on. Furthermore, the effect of ginsenosides transformed by the intestinal microflora, and differential effect associated with ginsenosides content and its composition also should be clinically evaluated in the future. In conclusion, the more wide-spread use of ginseng as a herbal medicine or nutraceutical supplement warrants the more rigorous investigations to assess its effacy and safety. In addition, a careful quality control of ginseng preparations should be done to ensure an acceptable standardization of commercial products.

• Korean Journal of Clinical Pharmacy
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• v.25 no.2
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• pp.120-129
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• 2015

Objectives: Drug utilization review program in Korea has provided 'drug combinations to avoid (DCA)' alerts to physicians and pharmacists to prevent potential adverse drug events or inappropriate drug use. Seven hundred and six DCA pairs have been announced officially by the Ministry of Food and Drug Safety (MFDS) by March, 2015. Some DCA pairs could be grouped based on the drug interaction mechanism and its consequences. This study aimed to investigate the drug-drug interaction (DDI) pairs, which may be potential DCAs, generated by the drug class-drug class interaction method. Methods: Eleven additive/synergistic and one antagonistic drug class-drug class interaction groups were identified. By combining drugs of two interacting drug class groups, numerous DDI pairs were made. The status and severity of DDI pairs were examined using Lexicomp and Micromedex. Also, the DCA listing rate was calculated. Results: Among 258 DDI pairs generated by the drug class-drug class interaction method, only 142 pairs were identified as official DCA pairs by the MFDS. One hundred and four pairs were identified as potential DCA pairs to be listed. QT prolonging agents-QT prolonging agents, triptans-ergot alkaloids, tricyclic antidepressants-monoamine oxidase inhibitors, and dopamine agonists-dopamine antagonists were identified as drug class-drug class interaction groups which have less than 50 % DCA listing rate. Conclusion: To improve the clinicians' adaptability to DCA alerts, the list of DCA pairs needs to be continuously updated.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7089-7095
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• 2015

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC- 0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.

• Journal of Pharmaceutical Investigation
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• v.37 no.6
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• pp.369-376
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• 2007

Cyclosporine (CsA) and tacrolimus (FK506) have a narrow therapeutic range, and their pharmacokinetic (PK) characteristic varies among individual. They are also substrates for cytochrome P450 (CYP) 3A4, 3A5 genes, and P-glycoprotein, the product of the multidrug resistance 1 (MDR1). The aims were to investigate the relationship between CYP3A and MDR1 genotypes and their PK parameters among healthy subjects. We investigated the genotype for CYP3A and MDR1 gene in human using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After oral administration of CsA and FK506 (100 mg and 1 mg, respectively), whole blood samples were taken up to 24 hours. Blood CsA and FK506 concentrations were measured by LC/MS/MS. Each PK parameters were compared using Kruskal-Wallis test according to the CYP3A and MDR1 genotype. We found that the values of AVC for CsA were significantly different among CYP3A5 and MDR1 exon 26 (C3435T) genotypes (P=0.037 and P=0.049). On the other hand, the AUC for FK506 was significantly different only among CYP3A5 genotypes (P=0.013). The results clearly demonstrate the effects of CYP3A5 and MDR1 exon 26 on Cys and FK506 disposition.