Immune tolerance induction in patients with severe hemophilia A with inhibitors

Ji Eun Ryu,박영실,Ki Young Yoo,Kyoo Duck Lee,Yong-Mook Choi 대한혈액학회 2015 Blood Research Vol.50 No.4

BackgroundInhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a use-ful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI.MethodsWe reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life.ResultsIn total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between in-hibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group. ConclusionThis study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about oth-er factors and conditions is needed.

Immune tolerance induction in patients with severe hemophilia A with inhibitors

Ji Eun Ryu,박영실,Ki Young Yoo,Kyoo Duck Lee,Yong-Mook Choi 대한혈액학회 2015 Blood Research Vol.50 No.4

BackgroundInhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a use-ful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI.MethodsWe reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life.ResultsIn total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between in-hibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group. ConclusionThis study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about oth-er factors and conditions is needed.

누룩으로부터 분리된 Pichia farinosa KCTC27753 균주의 발효저해제에 대한 내성

권훈주 ( Kwon H. J. ),윤정아 ( J. A. Yoon ),김명동 ( M. D. Kim ) 강원대학교 농업생명과학연구원(구 농업과학연구소) 2018 강원 농업생명환경연구 Vol.30 No.1

P. farinosa KCTC27753균주의 발효저해제에 대한 내성을 확인하였다. P. farinosa KCTC27753은 누룩으로부터 분리된 균주이며, 46°C, pH 3조건에서 성장이 가능한 스트레스 내성 균주다. KCTC27753균주의 발효저해제에 대한 내성을 확인하기 위해, furfural, phenolic compound, weak acid와 같은 발효저해제가 첨가된 배지를 사용하여 균체의 성장 및 에탄올 생산성을 확인하였다. P. farinosa KCTC27753 균주는 대조구인 P. farinosa KCTC27412, CBS7064 균주에 비하여 HMF, vanillin, 및 phenolic compound가 첨가된 배지에서 우수한 균체성장을 나타내었다. 발효저해제에 혼합물이 1.6% 첨가된 배지에서 P. farinosa KCTC27753 균주는 20 g의 포도당으로부터 8.54 ± 0.51 g/L의 에탄올을 생산하여 소모한 포도당 대비 약 42%의 에탄올 생산수율을 나타냈다. The production of bioethanol from lignocellulosic biomass using yeast will depend, at least in part, on the yeast strain’s tolerance to fermentation inhibitors. Pichia farinosa KCTC27753, which was isolated from nuruk in our laboratory, grows well at 46°C and pH 3.0. To explore the fermentation-inhibitor tolerance profile of this stress-tolerant strain, a cocktail composed of fermentation inhibitors released during biomass pretreatment (e.g., furfurals, phenolic compounds, and weak acids) was tested using a plate growth assay of P. farinosa KCTC27753 and control (KCTC27412, CBS7064) strains. The results of this assay showed that P. farinosa KCTC27753 had relatively higher growth rates than other strains in the presence of HMF, vanillin, and phenolic compounds. During fermentation, KCTC27753 produced 8.54 ± 0.51 g ethanol from 20 g glucose in the presence of an inhibitor cocktail (1.6%). By contrast, CBS7064 did not grow under the test conditions and strain KCTC27412 produced 6.78 ± 0.48 g ethanol from 19.6 g glucose.

아편양 물질의 내약성

신홍기 한양대학교 의과대학 1998 한양의대 학술지 Vol.18 No.1

Morphine and related opioid substances are probably the most widely used analgesics but chronic exposure to them leads to the development of tolerance characterized by their reduced ability to induce analgesic action and dependence. Extensive studies have been made to elucidate the mecahnisms by which toleracne or dependence is produced but their underlying mechanisms are still not clear. Morphine tolerance is characterized by the increases in the sensitivity of NMDA (N-methyl-D-aspartate) receptor, intracellular Ca^2+ level, membrane bound PKC (protein kinase C) and production of NO (nitric oxide), which are also known to be implicated in the development of hyperalgesia. Therefore, the development of tolerance or hyperalgesia is antagonized by the administration of NMDA receptor antagonist, Ca^2+ channel blocker, PKC inhibitor and NO synthase inhibitor. However, cholecystokinin and cAMP aggravate the development of morphine tolerance. These recent findings suggest that the common intracellular mechanisms are implicated in both hyperalgesia and morphine tolerance.

Resistance levels and fitness of protoporphyrinogen oxidase (PROTOX) inhibitor-resistant transgenic rice in paddy fields

Jung, H.I.,Kuk, Y.I.,Kim, H.Y.,Back, K.,Lee, D.J.,Lee, S.,Burgos, N.R. Elsevier 2010 Field crops research Vol.115 No.2

<P><B>Abstract</B></P><P>We previously confirmed that the transgenic rice line, M4, was about 200-fold more resistant to oxyfluorfen than the wild-type (WT) rice in whole-plant bioassays in pots. The transgenic rice line was also cross-resistant to other protoporphyrinogen oxidase (PROTOX)-inhibiting herbicides, acifluorfen, carfentrazone, and oxadiazon. The objectives of this research were to (a) verify the resistance of transgenic rice plants to commercial doses of PROTOX-inhibiting herbicides under paddy field conditions, (b) compare the growth, yield, and grain quality of transgenic and WT rice under weed-free conditions in a paddy field, and (c) determine the responses of transgenic and WT rice plants to chilling and drought stress. In the field, M4 was resistant to PROTOX inhibitors oxyfluorfen, acifluorfen, carfentrazone, pyraflufen, and oxadiazon in transplanted and direct-seeded rice culture. The transgenic and WT plants had similar plant heights and number of tillers. However, the yield of M4 at T<SUB>4</SUB> and T<SUB>5</SUB> generations was 7–8% less than that of WT plants. This was due to reduced number of spikelets per panicle and reduced grain weight. Head rice yield, immature kernels, damaged kernels, palatability, and protein and amylose contents were similar between M4 and WT rice. There was no difference in chilling injury between WT and M4, but M4 was more tolerant to drought stress than WT plants. PROTOX inhibitor-resistant rice is agronomically viable. It will expand the herbicide options in rice production. Follow-up research is required to elucidate the mechanisms underlying the slight yield difference and differential drought response between WT and transgenic rice.</P>

The Use of Rituximab with Immune Tolerance Induction Therapy for Hemophilia A with Inhibitors

김채영,이금노,박영실 대한소아혈액종양학회 2015 Clinical Pediatric Hematology-Oncology Vol.22 No.1

Inhibitor development is one of the major adverse events associated with increased morbidity and mortality in patients with congenital hemophilia. Recent treatment for them is immune tolerance induction (ITI), which involves the administration of high doses of factor concentrates over a prolonged period, sometimes combined with immunosuppressive agents. We report a case of inhibitor elimination with Rituximab, and high-dose factor VIII concentrates in a 5-year-old boy with hemophilia A. The patient improved clinically, with fewer bleeding episodes. However, he continued to have low immunoglobulin levels, which led to recurrent infections. After an infusion of intravenous immunoglobulin, inhibitor titers increased rapidly and his ITI was deemed a failure. In conclusion, even though it failed in the present study, Rituximab may be an alternative adjuvant therapy to eliminate the inhibitor in patients with hemophilia. The appropriate schedule and long-term side effects need further investigation.

Rates of Chlorimuron Applied in Glyphosate-Tolerant and Sulfonylurea-Tolerant Soybean

Leandro Paiola Albrecht,Alfredo Junior Paiola Albrecht,André Felipe Moreira Silva,Fábio Henrique Krenchinski,Henrique Fabrício Placido,Ricardo Victoria Filho 한국작물학회 2018 Journal of crop science and biotechnology Vol.21 No.3

Susceptibility to chlorimuron varies according to soybean genotype. STS® (sulfonylurea-tolerant soybean) presents a high tolerance to some sulfonylureas; this feature is determined by semi-dominants alleles, Als1 and Als2. Experiments were conducted in the field for four seasons with two cultivars for season to evaluate the selectivity of chlorimuron rates in post-emergency (V4) of glyphosate-tolerant and sulfonylurea-tolerant soybean. Data analysis made it possible to infer that there was no significant effect on the productivity of the cultivars when they received application in post-emergency, of chlorimuron at the doses used (0, 15, 30, 45, 60, 75, and 90 g ai ha-1). The maximum recommended rate for non-STS cultivars of chlorimuron is 20 g ai ha-1, or 4.5 times less than the maximum rate employed in this study. The soybean cultivars CD 250 RR/STS, CD 236 RR/STS, CD 2630 RR/STS, and BMX Turbo RR/STS were tolerant to the application, in post-emergency (V4) of the herbicide chlorimuron, until the rate of 90 g ai ha-1.

Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects

Cha, Yu-Jung,Lim, Kyoung Soo,Park, Min-Kyu,Schneider, Stephen,Bray, Brian,Kang, Myung-Chol,Chung, Jae-Yong,Yoon, Seo Hyun,Cho, Joo-Youn,Yu, Kyung-Sang Dove Medical Press 2014 Drug design, development and therapy Vol.8 No.-

<P><B>Background</B></P><P>KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection.</P><P><B>Objective</B></P><P>This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects.</P><P><B>Materials and methods</B></P><P>A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography–tandem mass spectrometry.</P><P><B>Results</B></P><P>The average maximum concentration (C<SUB>max</SUB>) and area under the concentration–time curve from time 0 to infinity (AUC<SUB>∞</SUB>) values of KM-023 for the 75–600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng · h/mL to 33,705.6 ng · h/mL, respectively. Values of the mean C<SUB>max</SUB> at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng · h/mL to 10,232.6 ng · h/mL, respectively, following 75–600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events.</P><P><B>Conclusion</B></P><P>KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75–600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection.</P>

Effects of 6-Month Sitagliptin Treatment on Insulin and Glucagon Responses in Korean Patients with Type 2 Diabetes Mellitus

양혜경,강보라미,이승환,김헌성,윤건호,차봉연,조재형 대한당뇨병학회 2015 Diabetes and Metabolism Journal Vol.39 No.4

Background: This study aimed to evaluate the effect of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, on insulin secretion and glucagon suppression in Korean subjects with type 2 diabetes mellitus. Methods: Twenty-four subjects underwent a 75-g oral glucose tolerance test (OGTT) before and after 6 months of sitagliptin treatment. Sitagliptin, insulin, and sulfonylurea were withdrawn for 3 days before OGTT to eliminate any acute effects on β-cell insulin or α-cell glucagon secretion. Venous samples were drawn five times during each OGTT to measure plasma glucose, insulin, and glucagon. Indices on insulin secretion and resistance were calculated. Results: Early phase insulin secretion, measured by the insulinogenic index significantly increased after 6 months of sitagliptin treatment, especially in the higher baseline body mass index group and higher baseline glycosylated hemoglobin (HbA1c) group. There were no significant differences in the insulin resistance indices before and after sitagliptin treatment. Although no significant differences were observed in the absolute levels of glucagon and the glucagon-to-insulin ratio, there was a significant reduction in the percentile change of glucagon-to-insulin ratio at 30- and 120-minute during the OGTT. Conclusion: Although the HbA1c level did not decrease significantly after 6 months of sitagliptin treatment, an increase in insulin secretion and reduction in early phase postprandial plasma glucagon-to-insulin ratio excursion was confirmed in Korean subjects with type 2 diabetes.

Growth and Fermentation Characteristics of Saccharomyces cerevisiae NK28 Isolated from Kiwi Fruit

( Jong Sub Lee ),( Eun Hee Park ),( Jung Wan Kim ),( Soo Hwan Yeo ),( Myoung Dong Kim ) 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.9

The influences of glucose concentration, initial medium acidity (pH), and temperature on the growth and ethanol production of Saccharomyces cerevisiae NK28, which was isolated from kiwi fruit, were examined in shake flask cultures. The optimal glucose concentration, initial medium pH, and temperature for ethanol production were 200 g/l, pH 6.0, and 35oC, respectively. Under this growth condition, S. cerevisiae NK28 produced 98.9 ± 5.67 g/l ethanol in 24 h with a volumetric ethanol production rate of 4.12 ± 0.24 g/l?h. S. cerevisiae NK28 was more tolerant to heat and ethanol than laboratory strain S. cerevisiae BY4742, and its tolerance to ethanol and fermentation inhibitors was comparable to that of an ethanologen, S. cerevisiae D5A.