• 제목/요약/키워드: New drugs

검색결과 970건 처리시간 0.023초

Effective α-Helix Stabilization via Hexenyl Propionate Cross-Link

  • Yoo, Jiyeon;Kim, Young-Woo
    • Bulletin of the Korean Chemical Society
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    • 제35권12호
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    • pp.3627-3631
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    • 2014
  • In this study we examined two ester-containing cross-links, hex-2-enyl acetate and hex-2-enyl propionate, as new cross-linking systems for helix stabilization of short peptides. We demonstrated that these hexenyl ester cross-links can be readily installed via a ruthenium-mediated ring-closing metathesis reaction of L-aspartic acid 4-allyl ester or L-glutamic acid 5-allyl ester at position i and (S)-2-(4'-pentenyl)alanine at position i+4 using second generation Hoveyda-Grubbs catalyst at $60^{\circ}C$. Between these two cross-links, we found that the hex-2-enyl propionate significantly stabilizes the ${\alpha}$-helical conformations of short model peptides. The helix-stabilizing effects of the hex-2-enyl propionate tether appear to be as powerful as Verdine's i,i+4 all-hydrocarbon stapling system, which is one of the most widely used and the most potent helix-stabilizing cross-linking systems. Furthermore, the hex-2-enyl propionate bridge is reasonably robust against non-enzymatic hydrolytic cleavage at a physiological pH. While extended studies for probing its chemical scopes and biological applications are needed, we believe that this new helix-stabilizing system could serve as a useful chemical tool for understanding protein folding and designing conformationally-constrained peptide drugs.

Molecular and Functional Characterization of Choline Transporter-Like Proteins in Esophageal Cancer Cells and Potential Therapeutic Targets

  • Nagashima, Fumiaki;Nishiyama, Ryohta;Iwao, Beniko;Kawai, Yuiko;Ishii, Chikanao;Yamanaka, Tsuyoshi;Uchino, Hiroyuki;Inazu, Masato
    • Biomolecules & Therapeutics
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    • 제26권4호
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    • pp.399-408
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    • 2018
  • In this study, we examined the molecular and functional characterization of choline uptake in the human esophageal cancer cells. In addition, we examined the influence of various drugs on the transport of [$^3H$]choline, and explored the possible correlation between the inhibition of choline uptake and apoptotic cell death. We found that both choline transporter-like protein 1 (CTL1) and CTL2 mRNAs and proteins were highly expressed in esophageal cancer cell lines (KYSE series). CTL1 and CTL2 were located in the plasma membrane and mitochondria, respectively. Choline uptake was saturable and mediated by a single transport system, which is both $Na^+$-independent and pH-dependent. Choline uptake and cell viability were inhibited by various cationic drugs. Furthermore, a correlation analysis of the potencies of 47 drugs for the inhibition of choline uptake and cell viability showed a strong correlation. Choline uptake inhibitors and choline deficiency each inhibited cell viability and increased caspase-3/7 activity. We conclude that extracellular choline is mainly transported via a CTL1. The functional inhibition of CTL1 by cationic drugs could promote apoptotic cell death. Furthermore, CTL2 may be involved in choline uptake in mitochondria, which is the rate-limiting step in S-adenosylmethionine (SAM) synthesis and DNA methylation. Identification of this CTL1- and CTL2-mediated choline transport system provides a potential new target for esophageal cancer therapy.

Role of Catheter's Position for Final Results in Intrathecal Drug Delivery. Analysis Based on CSF Dynamics and Specific Drugs Profiles

  • De Andres, Jose;Perotti, Luciano;Villanueva, Vicente;Asensio Samper, Juan Marcos;Fabregat-Cid, Gustavo
    • The Korean Journal of Pain
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    • 제26권4호
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    • pp.336-346
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    • 2013
  • Intrathecal drug delivery is an effective and safe option for the treatment of chronic pathology refractory to conventional pain therapies. Typical intrathecal administered drugs are opioids, baclofen, local anesthetics and adjuvant medications. Although knowledge about mechanisms of action of intrathecal drugs are every day more clear many doubt remain respect the correct location of intrathecal catheter in order to achieve the best therapeutic result. We analyze the factors that can affect drug distribution within the cerebrospinal fluid. Three categories of variables were identified: drug features, cerebrospinal fluid (CSF) dynamics and patients features. First category includes physicochemical properties and pharmacological features of intrathecal administered drugs with special attention to drug lipophilicity. In the second category, the variables in CSF flow, are considered that can modify the drug distribution within the CSF with special attention to the new theories of liquoral circulation. Last category try to explain inter-individual difference in baclofen response with difference that are specific for each patients such as the anatomical area to treat, patient posture or reaction to inflammatory stimulus. We conclude that a comprehensive evaluation of the patients, including imaging techniques to study the anatomy and physiology of intrathecal environment and CSF dynamics, could become essential in the future to the purpose of optimize the clinical outcome of intrathecal therapy.

Fabrication of Compound K-loaded Polymeric Micelle System and its Characterization in vitro and Oral Absorption Enhancement in vivo

  • Hong, Sun-Mi;Jeon, Sang-Ok;Seo, Jo-Eun;Chun, Kyeung-Hwa;Oh, Dong-Ho;Choi, Young Wook;Lee, Do Ik;Jeong, Seong Hoon;Kang, Jae Seon;Lee, Sangkil
    • Bulletin of the Korean Chemical Society
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    • 제35권11호
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    • pp.3188-3194
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    • 2014
  • Compound K (CK) was formulated as polymeric micelles (PM) using Pluronic$^{(R)}$ F-127 to enhance the oral absorption of CK, an intestinal bacterial metabolite of ginseng protopanaxadiol saponin. The physicochemical properties of Ck-loaded PM were characterized and an in vitro transport study using the Caco-2 cell system as well as an in vivo pharmacokinetic study using SD rats was carried out. The hydrodynamic mean particle size of CK-loaded PM (CK-PM) was $254{\pm}23.45nm$ after rehydration and the drug loading efficiency was ca. 99.9%. The FT-IR spectroscopy, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy data supported the presence of a new solid phase in the PM. The $P_{app}$ value of in vitro Caco-2 cell permeation of CK-PM and the oral absorption of CK was enhanced about 1.2-fold and 2.6-fold compared to CK suspension, respectively, showing that the present PM formulation enabled an enhancement of oral CK absorption.

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

  • Kobet, Robert A.;Pan, Xiaoping;Zhang, Baohong;Pak, Stephen C.;Asch, Adam S.;Lee, Myon-Hee
    • Biomolecules & Therapeutics
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    • 제22권5호
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    • pp.371-383
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    • 2014
  • The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.

생약의 류코트리엔 $B_4$ 수용체결합 저해작용 검색 (Screening of Leukotriene $B_4$ Receptor Antagonist Activity from the Herbal Drugs)

  • 이화진;류재하
    • 생약학회지
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    • 제31권3호
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    • pp.273-279
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    • 2000
  • Leukotriene $B_4\;(LTB_4)$ is a pro-inflammatory mediator synthesized in myeloid cells from arachidonic acid. Elevated levels of $LTB_4$ have been found in a number of inflammatory diseases and levels are related to disease activity in some of these. Because $LTB_4$ interacts with cells through specific cell surface receptors, $LTB_4$ receptor blockade is the most specific approach to reduce the pathogenic role of $LTB_4$. In order to find $LTB_4$ receptor antagonist from plants, we screened the $LTB_4$ receptor antagonistic activity of the methanol extract and solvent fractions of herbal drugs. The ability of samples to inhibit specific binding of $[^3H]-LTB_4$ to human peripheral neutrophils was used as assay to evaluate the antagonistic activity of plant materials. Among the tested methanol extracts of herbal drugs, Mori Radicis Cortex, Perillae Semen, Armeniacae Semen and Sophorae subprostratae Radix showed potent inhibitory activity above 70% at the concentration of $100\;{mu}g/ml$. The inhibitory activities of $LTB_4$ binding to human neutrophils were evaluated for several solvent fractions at three different concentrations. Especially, hexane soluble fractions of Anemarrhenae Rhizoma and Embeliae Radix, and ethyl acetate soluble fractions of Aristolochiae Fructus, Magnoliae Cortex and Zingiberis Rhizoma crudus showed moderate activity at $25\;{mu}g/ml$. These fractions were promising candidates for the study of the activity-guided chromatographic purification of active compounds. Silica gel column chromatography of hexane soluble fractions of Anemarrhenae Rhizoma and Embeliae Radix gave very active sub-fractions, AA-4 and ES-4, and their inhibition activities of $LTB_4$ binding to human neutrophil at $30\;{mu}g/ml$ were 78% and 62%, respectively. From these results we could anticipate new $LTB_4$ receptor antagonist from herbal drugs, and the block of $LTB_4$ effects may provide beneficial in neutrophil mediated diseases such as inflammation and bronchial asthma.

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녹용 물추출물과 항암제의 병용투여에 관한 연구(제 1보) -녹용 물추출물과 cis-Platin 및 Mitomycin C 병용투여에 의한 항암제 부작용 경감효과- (Studies on Combined Usage of Velvet Antler Water Extract and Anti-neoplastic Drugs (I) -Reducing Effect of Velvet Antler Water Extract to the Adverse Actions of cis-Platin and Mitomycin C-)

  • 심상범;김재근;원도희;홍남두;김남재
    • 생약학회지
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    • 제29권2호
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    • pp.93-103
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    • 1998
  • In order to investigate the reducing effect of velvet antler water extract (VAWE) on the toxicity of anti-cancer drug, cis-platin (CDDP) and mitomycin C (MMC), we examined effects of co-administration with VAWE and anti-cancer drugs on their toxicities. We recognized that $LD_{50}$ of CDDP/MMC were increased by co-administration with VAWE and them in mice. It was found that co-administration of VAWE and MMC increased the survival rate in mice treated by lethal dose of MMC. Also, co-administration of VAWE and CDDP/MMC inhibited decrease of the body weight and organ weight in mice intoxificated by CDDP/MMC. The increase of serum blood urea and serum creatinine levels in rats intoxicated by CDDP were significantly inhibited by the co-administrationin with VAWE and CDDP. The decrease of RBC and WBC in rats intoxificated by MMC were significantly inhibited by the co-administration with VAWE and MMC. These results suggest that the combined usage of VAWE and CDDP/MMC drugs may be a new method for prevented or minimized the toxicity of them.

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천연물화학(天然物化學)에서 보는 동의약(東醫藥) (The Oriental Materia Medica in viewpoint of natural products chem)

  • 안병준
    • 혜화의학회지
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    • 제4권2호
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    • pp.309-329
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    • 1996
  • There are the Seven Effect of Drugs and unique processing methods in Chinese traditional medicine. The Seven Effects are single effrect(單行), additive effect(相加, 相須), synergic effect(上乘, 相使), antagonistic effect(相畏, 拮抗), inhibitory effect(相惡), neutralizing effect(相殺) and opposite effect(相反). We are interested in synergic effects of some drugs and components ; Addition of OLDENLANDIA DIFFUSA to Kilkyungtang combanation enhanced the cytotoxic activity of Kilkyungtang against A549 and B16-Fo eells by 20% and 50%, respectively. The Oldenlandia-added kilkyungtang also potentiated the cytotoxicities of mitomycine Cand 5-fluorouracil. ar-tunnerone. isolated from the root of Curcuma longa, potentiated the cytotoxic activity of sesquiphellandrene(isolated from the same root), aurapten(isolated from Aurantii semen)or cyclophosphamide by 10 times. The purpose of the processing(修治) of Chinese grugs is to remove unusable parts of plants and to eliminate toxicities as well as to produse new active components in drugs. On a occasion of study on the anthelmintic drugs against the chinese fluke(Clonorchis sinesis, (肝디스토마), we have observed that the processed mume fruit(鳥梅) possessed a very very potent clonorchicidal effect, while the methanol extract of the non-processed fruit inactive. The active component was isolated from the processed mume and identified as 5-hydroxymethylfurfuryl aldehyde. This substance dose not occur in the immature fruit and was found only in the processed one. Wehave heated the immature fruit in an oven at $90^{\circ}C$ for 52 hrs and found that the heated fruit eame clonorchidal. As demonstrated in these and other example cited in this presentation, the natural products chemistry is contributory to univeiling the drug effect ensued from the processing and the synergic effect of Oriental medical drug combinations, and to rationalization or modernization of the traditional medicine.

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지역약사의 시리즈형 OTC 약물에 대한 약사의 직능 수행에 대한 평가 (Relationship between the Series named OTC Products and Pharmacist's Professional Workloads in Community Pharmacy)

  • 김정은;임성실
    • 한국임상약학회지
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    • 제30권4호
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    • pp.226-233
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    • 2020
  • Background: Currently, the over-the-counter (OTC) drug market is flooded with series OTC products. The pharmacist must follow the OTC product's indication, given that the most critical role of a pharmacist is the right selection and recommendation of an OTC drug for a patient's symptoms in a dynamic pharmacy environment. Therefore, pharmacists must know each OTC product information precisely to avoid any ambiguity due to several OTC series brand names. Objective: We evaluated the risk and effectiveness of OTC series medicines. Methods: From December 5 to December 18, 2019, an online survey was conducted among 145 community pharmacists. Results: A total of 51.0% of pharmacists knew the difference between products named in a series and could explain it spontaneously. Only 0.7% of the pharmacists admitted to not knowing the difference between products named in a series. While 42.9% of pharmacists who owned a pharmacy opined that the OTC medicines named in a series have health benefits for patients, 50.0% of employee pharmacists admitted that they were rather confused because there are several OTC series medicines. In contrast, 69.2% of pharmacists who owned pharmacies and 72.2% of employee pharmacists admitted that OTC series drugs with names similar to popular OTC drugs sell better. Conclusion: While pharmacists had different opinions regarding OTC series drugs per employment status, they opined that OTC series are more helpful in pharmacy management than completely new brand names. Further studies in this regard are needed.

Detergent and Phospholipid Mixed Micelles as Proliposomes for an Intravenous Delivery of Water-Insoluble Drugs

  • Son, Kyong-Hee
    • Journal of Pharmaceutical Investigation
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    • 제22권3호spc1호
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    • pp.17-34
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    • 1992
  • A novel drug delivery system, detergent-phospholipid mixed micelles as proliposomes, for water-insoluble compounds was developed by investigating (i) spontaneous formation of small unilamellar vesicles (SUV) from bile salt-egg phosphatidylcholine mixed micelles, (ii) the molecular mechanism of micelle-to-vesicle transition in aqueous mixtures of detergent-phospholipid, (iii) preparation and screening of a suitable liposomal formulation for a lipophilic drug: solubilization of the drug within the lipid bilayer, evaluation of the solubility limit, and characterization of the resulting product with respect to the physical properties and stability of the drug in the system, and (iv) testing antitumor activity in vitro. The results showed that the new carrier had a strong possibility to be a biocompatible universal formulation for water-insoluble drugs.

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