• Journal of Microbiology and Biotechnology
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• 제28권11호
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• pp.1771-1781
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• 2018

The emergence of multidrug-resistant microorganisms, as well as fungal infectious diseases that further threaten health, especially in immunodeficient populations, is a major global problem. The development of new antifungal agents in clinical trials is inferior to the incidence of drug resistance, and the available antifungal agents are restricted. Their mechanisms aim at certain characteristics of the fungus in order to avoid biological similarities with the host. Synthesis of the cell wall and ergosterol are mainly targeted in clinical use. The need for new approaches to antifungal therapeutic agents or development alternatives has increased. This review explores new perspectives on mechanisms to effectively combat fungal infections and effective antifungal activity. The clinical drug have a common feature that ultimately causes caspase-dependent cell death. The drugs-induced cell death pathway is associated with mitochondrial dysfunction, including mitochondrial membrane depolarization and cytochrome c release. This mechanism of action also reveals antimicrobial peptides, the primary effector molecules of innate systems, to highlight new alternatives. Furthermore, drug combination therapy is suggested as another strategy to combat fungal infection. The proposal for a new approach to antifungal agents is not only important from a basic scientific point of view, but will also assist in the selection of molecules for combination therapy.

• 약학회지
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• 제25권1호
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• pp.27-35
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• 1981

Etomidoline is a new synthetic atropine-like drug. The present investigation aimed to study the combined effects of etomidoline and neofopam hydrochloride which has an analgesic and muscle relaxant activity, compared with the effects of each drugs. Acute toxicities (ID$_{50}$) in mouse were 132mg/Kg (p.o.) and 49mg/Kg (i.p.) when combination ratio of etomidoline and neofopam was 1:5 and 103 mg/Kg (p.o.) and 30mg/Kg (i.p.) with the ratio of 1:10. Etomidoline showed more potent anticholinergic effects than neofopam in the isolated rat intestine. Whereas, antibarium effects were twice as active with neofopam than with etomidoline. When etomidoline and neofopam were added in combination ratio of 1 : 5, papaverine-like avtivity was increased, but no changes of anticholinergic effect were observed. Analgesic effect was measured by the anti-writhing method of Whittle in mice. Both of the concurrent and single administration of etomidoline and nefopam reduced significantly the writhing number and the effect of the concurrent administration was more active than that of single, and 1 : 5 combination was slightly more potent than 1:10. Each drug or the combined drug was administered to mice and observed the change of the pupil size. Pupil sizes were increased with each drug and with combined drug, although there were no significant differences between the each group of drugs. However, those effects were less than that of atropine sulfate.e.

• Interdisciplinary Bio Central
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• 제5권2호
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• pp.3.1-3.7
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• 2013

Recently, the productivity of drug discovery has gradually decreased as the limitations of single-target-based drugs for various and complex diseases become exposed. To overcome these limitations, drug combinations have been proposed, and great efforts have been made to predict efficacious drug combinations by statistical methods using drug databases. However, previous methods which did not take into account biological networks are insufficient for elaborate predictions. Also, increased evidences to support the fact that drug effects are closely related to metabolic enzymes suggested the possibility for a new approach to the study drug combinations. Therefore, in this paper we suggest a novel approach for analyzing drug combinations using a metabolic network in a systematic manner. The influence of a drug on the metabolic network is described using the distance between the drug target and an enzyme. Target-enzyme distances are converted into influence scores, and from these scores we calculated the correlations between drugs. The result shows that the influence score derived from the targetenzyme distance reflects the mechanism of drug action onto the metabolic network properly. In an analysis of the correlation score distribution, efficacious drug combinations tended to have low correlation scores, and this tendency corresponded to the known properties of the drug combinations. These facts suggest that our approach is useful for prediction drug combinations with an advanced understanding of drug mechanisms.

• 한국임상약학회지
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• 제25권3호
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• pp.138-144
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• 2015

Objective: It is to evaluate the drug interaction monitoring program as a pilot project to develop a pharmaceutical care model in a medical intensive care unit and to analyze the influencing factors of drug interactions. Method: Electronic medical records were retrospectively investigated for 116 patients who had been hospitalized in a medical intensive care unit from October to December in 2014. The prevalence of adverse reaction with risk rating higher than 'D' was investigated by Lexi-$Comp^{(R)}$ Online database. The factors related with potential drug interaction and with treatment outcomes were analyzed. Results: The number of patients with a potential interaction of drug combination was 92 (79.3%). Average ages, the length of stay in the intensive care unit and the numbers of prescription drugs showed significant differences between drug interaction group and non-drug interaction group. Opioids (14.4%), antibiotics (7.2%), and diuretics (7.2%) were most responsible drug classes for drug interactions and the individual medications included furosemide (6.4%), tramadol (4.9%), and remifentanil (4.5%). There were 950 cases with a risk rating of 'C' (84.6%), 142 cases with a risk rating of 'D' (12.6%), and 31 cases with a risk rating of 'X' (avoid combination) (2.8%). The factors affecting drug interactions were the number of drugs prescribed (p < 0.0001) and the length of stay at intensive care unit (p < 0.01). The patients in intensive care unit showed a high incidence of adverse reactions related to potential drug interaction. Therefore, drug interaction monitoring program as a one of pharmaceutical care services was successfully piloted and it showed to prevent adverse reaction and to improve therapeutic outcomes. Conclusion: Active participation of a pharmacist in the drug management at the intensive care unit should be considered.

• 한국임상약학회지
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• 제23권3호
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• pp.239-247
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• 2013

Background: Fixed drug combinations are formulations containing two or more active ingredients in a single dosage form. Such combination therapies are commonly applied to improve efficacy, reduce adverse events and replace co-administration, etc. National and international guidelines for hypertension treatment recommend addition of other classes of antihypertensive drugs rather than incremental dose of mono-therapy, when blood pressure is not adequately controlled. Thus, many dual combinations of antihypertensive drugs have been approved and pharmaceutical companies are recently interested in developing antihypertensive triple combinations. Clinical trial designs for the fixed combinations are various depending on the target patients, dosage and clinical endpoints. Thereby, further discussions for the clinical trials of antihypertensive triple therapies are required regarding the indication claimed. Conclusion: This article provides a review for the assessment of the label and medical reports of the clinical trials on antihypertensive triple therapies in advanced foreign countries.

• 생물정신의학
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• 제7권1호
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• pp.34-45
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• 2000

Pharmacotherapy of bipolar disorder is a rapidly evolving field. Mood stabilizers and anticonvulsants have varying biochemical profiles which may predispose them to different adverse effects and drug-drug interactions. Several of the new anticonvulsants appear less likely to have the problems with drug-drug interaction. To provide more effective combination pharmacotherapies, clinicians should be allowed to anticipate and avoid pharmacokinetic and pharmacodynamic drug-drug interactions. We reviewed the role of cytochrome P450 isozymes in the metabolism of the drugs and their interactions. The drug-drug interactions of several classes of drugs which used as mood stabilizers and new anticonvulsants, some of which may have psychotropic profiles, are discussed mainly in this article. Finally, potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs are discussed briefly.

• 대한약침학회지
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• 제21권3호
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• pp.203-206
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• 2018

Objectives: There is an increasing number of complex diseases that are progressively more difficult to be controlled using the conventional "single compound, single target" approach as demonstrated in our current modern drug development. TCM might be the new cornerstone of treatment alternative when the current treatment option is no longer as effective or that we have exhausted it as an option. Orthogonal stimulus-response compatibility group study is one of the most frequently employed formulas to produce optimal herbal combination for treatment of multi-syndromic diseases. This approach could solve the relatively low efficacy single drug therapy usage and chronic adverse effects caused by long terms administration of drugs that has been reported in the field of pharmacology and medicine Methods: The present review was based on the Science Direct database search for those related to the TCM and the development of antihypertensive TCM herbal combination using orthogonal stimulus-response compatibility group studies approach. Results: Recent studies have demonstrated that the orthogonal stimulus-response compatibility group study approach was most frequently used to formulate TCM herbal combination based on the TCM principles upon the selection of herbs, and the resulting formulated TCM formula exhibited desired outcomes in treating one of global concerned complex multi-syndromic diseases, the hypertension. These promising therapeutic effects were claimed to have been attributed by the holistic signaling mechanism pathways employed by the crude combination of herbs. Conclusion: The present review could serve as a guide and prove the feasibility of TCM principles to be used for future pharmacological drug research development.

• Journal of Microbiology and Biotechnology
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• 제15권3호
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• pp.595-602
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• 2005

A one-step real-time quantitative RT-PCR assay in combination with automated RNA extraction was evaluated for routine testing of HCV RNA in the laboratory. Specific primers and probes were developed to detect 302 bp on 5'-UTR of HCV RNA. The assay was able to quantitate a dynamic linear range of $10^7-10^1$ HCV RNA copies/reaction ($R^2=0.997$). The synthetic HCV RNA standard of $1.84{\pm}0.1\;(mean{\pm}SD)$ copies developed in this study corresponded to 1 international unit (IU) of WHO International Standard for HCV RNA (96/790 I). The detection limit of the assay was 3 RNA copies/reaction (81 IU/ml) in plasma samples. The assay was comparable to the Amplicor HCV Monitor (Monitor) assay with correlation coefficient r=0.985, but was more sensitive than the Monitor assay. The assay could be completed within 3 h from RNA extraction to detection and data analysis for up to 32 samples. It allowed rapid RNA extraction, detection, and quantitation of HCV RNA in plasma samples. The method provided sufficient sensitivity and reproducibility and proved to be fast and labor-saving, so that it was suitable for high throughput HCV RNA test.

• Asian Pacific Journal of Cancer Prevention
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• 제16권13호
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• pp.5191-5197
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• 2015

A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatment of patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvant or combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a molecule activated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repair molecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in response to this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applying increasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPI staining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis was also applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applying arsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest that arsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1D dependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1299-1308
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• 2016

Our previous studies clearly demonstrated that a combination of WP 631 and Epo B has higher activity against ovarian cancer cells than either of these compounds used separately. In order to fully understand the exact mechanism of action in combination, we assessed effects on the cell cycle of SKOV-3 cells. We evaluated three control points essential for WP 631 and Epo B action to determine which cell cycle-regulating proteins (CDK1/cyclin B complex, EpCAM or HMGB1) mediate activity. The effects of the drug on the cell cycle were measured based on the nuclear DNA content using flow cytometry. Expression of cell cycle-regulating genes was analyzed using real-time PCR. It was discovered that WP 631, at the tested concentration, did not affect the SKOV-3 cell cycle. Epo B caused significant G2/M arrest, whereas the drug combination induced stronger apoptosis and lower mitotic arrest than Epo B alone. This is very important information from the point of view of the fight against cancer, as, while mitotic arrest in Epo B-treated cells could be overcame after DNA damage repair, apoptosis which occurs after mitotic slippage in combination-treated cells is irreversible. It clearly explains the higher activity of the drug combination in comparison to Epo B alone. Epo B acts via the CDK1/cyclin B complex and has the ability to inhibit CDK1, which may be a promising strategy for ovarian cancer treatment in the future. The drug combination diminishes EpCAM and HMGB1 expression to a greater degree than either WP 631 and Epo B alone. Owing to the fact that the high expression of these two proteins is a poor prognostic factor for ovarian cancer, a decrease in their expression, observed in our studies, may result in improved efficacy of cancer therapy. The presented findings show that the combination of WP 631 and Epo B is a better therapeutic option than either of these drugs alone.