Clinical impact of admission hyperglycemia on in-hospital mortality in acute myocardial infarction patients

Kim, Eun Jung,Jeong, Myung Ho,Kim, Ju Han,Ahn, Tae Hoon,Seung, Ki Bae,Oh, Dong Joo,Kim, Hyo-Soo,Gwon, Hyeon Cheol,Seong, In Whan,Hwang, Kyung Kuk,Chae, Shung Chull,Kim, Kwon-Bae,Kim, Young Jo,Cha, Kwa Elsevier 2017 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.236 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Acute hyperglycemia on admission is common in acute myocardial infarction (AMI) patients regardless of diabetic status, and is known as one of prognostic factors. However, the effect of hyperglycemia on non-diabetic patients is still on debate.</P> <P><B>Methods</B></P> <P>A total of 12,625 AMI patients (64.0±12.6years, 26.1% female) who were enrolled in Korea Acute Myocardial Infarction Registry-National Institute of Health between November 2011 and December 2015, were classified into 4367 diabetes (65.4±11.6years, 30.4% female) and 8228 non-diabetes (63.3±13years, 23.9% female). Patients were analyzed for in-hospital clinical outcome according to admission hyperglycemic status.</P> <P><B>Results</B></P> <P>In diabetic patients, independent predictors of in-hospital mortality were old age, high HbA<SUB>1</SUB>C, pre-Thrombolysis In Myocardial Infarction (TIMI) flow 0, left ventricle ejection fraction<40%, cardiogenic shock and ventricular tachycardia. In non-diabetic patients, independent predictors of in-hospital mortality were old age, high admission glucose (≥200mg/dL), pre TIMI flow 0, failed percutaneous coronary intervention, low left ventricle ejection fraction<40%, cardiogenic shock, stent thrombosis and decreased Hb≥5g/dL. In hospital mortality was significantly higher in diabetic patients compared to non-diabetic patients (5.0% vs. 3.4%, <I>p</I> <0.001). However, non-diabetic patients with hyperglycemia have significantly higher mortality compared to diabetic patients (17.4% vs. 7.2%, <I>p</I> <0.001). Comorbidity including cardiogenic shock (<I>p</I> <0.001), cerebral hemorrhage (<I>p</I> =0.012), decreased Hb≥5g/dL (<I>p</I> =0.013), atrioventricular block (<I>p</I> <0.001) and ventricular tachycardia (<I>p</I> =0.007) was higher in non-diabetic with hyperglycemia than in diabetic patients.</P> <P><B>Conclusions</B></P> <P>These findings underscore clinical significance of admission hyperglycemia on in-hospital mortality in non-diabetic AMI patients.</P>

내원시 저혈당이 당뇨병을 동반한 심근경색증 환자의 예후에 미치는 영향

김은정 ( Eun Jung Kim ),정명호 ( Myung Ho Jeong ),정인석 ( In Seok Jeong ),오상기 ( Sang Gi Oh ),김상형 ( Sang Hyung Kim ),안영근 ( Young Keun Ahn ),김주한 ( Ju Han Kim ),김영조 ( Young Jo Kim ),채성철 ( Shung Chull Chae ),홍택종 대한내과학회 2014 대한내과학회지 Vol.87 No.5

Methods: We analyzed 5,249 diabetic patients who enrolled in the Korean Acute Myocardial Infarction Registry from November 2005 to March 2013. The patients were divided into three groups according to their blood glucose level at admission; Group I:hypoglycemia (≤ 70 mg/dL), Group II: normoglycemia (70-140 mg/dL) and Group III: hyperglycemia (≥ 140 mg/dL). We assessed in-hospital mortality and the major adverse cardiac events based on blood glucose levels at admission. Results: The mean age was older in group I at 72.6 ± 11.0 years compared to 71.3 ± 10.7 in group II and 70.3 ± 11.1 in group III (p < 0.006). A total of 344 patients died during hospitalization. In-hospital mortality was higher in group I at 12.9%, compared to 5.2% in group II and 6.8% in group III (p < 0.006). Multivariable logistic regression analysis determined that the independent predictors of 1-month mortality were age, Killip class III-IV, cerebrovascular disease, chronic renal failure, acute renal failure, cardiogenic shock, ventricular tachycardia, ejection fraction < 40% and hypoglycemia in admission. The mortality rate at 1 month was significantly higher in group I compared to group II (odds ratio [OR] 3.571; 95% confidence interval [CI] 1.465-8.705, p = 0.005) compared to group II and group III (OR 4.088; 95% CI 1.757-9.511, p = 0.001). Conclusions: Hypoglycemia on admission was an important predictor of in-hospital and one-month mortality in AMI patients with diabetes mellitus. (Korean J Med 2014;87:565-573)

Impact of total occlusion of an infarct-related artery on long-term mortality in acute non-ST-elevation myocardial infarction patients who underwent early percutaneous coronary intervention.

Kim, Min Chul,Ahn, Youngkeun,Rhew, Shi Hyun,Jeong, Myung Ho,Kim, Ju Han,Hong, Young Joon,Chae, Shung Chull,Kim, Young Jo,Hur, Seung Ho,Seong, In Whan,Chae, Jei Keon International Heart Journal Association 2012 International heart journal Vol.53 No.3

<P>Some patients with non-ST-elevation myocardial infarction (NSTEMI) have a total occlusive infarct-related artery. However, the long-term prognosis of these patients is uncertain, particularly for those who underwent an early invasive strategy. The aim of this study was to determine the clinical impact of total occlusion (TO) of an infarct-related artery (IRA) in these patients. A total of 2,094 patients with NSTEMI who underwent an early invasive strategy with percutaneous coronary intervention (PCI) in the Korea Acute MI Registry (KAMIR) were analyzed (TO group; 665 patients, and non-TO group; 1,429 patients).In-hospital and one-year clinical outcomes were compared between the two groups. The left circumflex (42.9%) and right coronary artery (31.9%) were the major IRA in the TO group, while the left anterior descending artery was more common as an IRA in the non-TO group (44.1%). In-hospital complications including death and cardiogenic shock occurred frequently in the TO group. Also, the rates of one-month and 12-month adverse cardiac outcomes were higher in the TO group. In the Cox-proportional hazard model, TO in IRA predicted 12-month all-cause death. In conclusion, NSTEMI patients with TO in IRA showed worse short- and long-term clinical outcomes compared with those of non-TO patients.</P>

Decreased Glomerular Filtration Rate is an Independent Predictor of In-Hospital Mortality in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Kim, Joon Young,Jeong, Myung Ho,Ahn, Yong Keun,Moon, Jae Hyun,Chae, Shung Chull,Hur, Seung Ho,Hong, Taek Jong,Kim, Young Jo,Seong, In Whan,Chae, In Ho,Cho, Myeong Chan,Kim, Chong Jin,Jang, Yang Soo,Yo The Korean Society of Cardiology 2011 Korean Circulation Journal Vol.41 No.4

<P><B>Background and Objectives</B></P><P>Patients with renal dysfunction (RD) experience worse prognosis after myocardial infarction (MI). The aim of the present study was to investigate the impact of admission estimated glomerular filtration rate (eGFR) on clinical outcomes of patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI).</P><P><B>Subjects and Methods</B></P><P>We retrospectively evaluated 4,542 eligible patients from the Korea Acute Myocardial Infarction Registry (KAMIR). Patients were divided into three groups according to eGFR (mL/min/1.73 m<SUP>2</SUP>): normal renal function (RF) group (eGFR ≥60, n=3,515), moderate RD group (eGFR between 30 to 59, n=894) and severe RD group (eGFR <30, n=133). Baseline characteristics, angiographic and procedural results, and in-hospital outcomes between the three groups were compared.</P><P><B>Results</B></P><P>Age, gender, Killip class ≥3, hypertension, diabetes, congestive heart failure, peak creatine kinase-MB, high sensitivity C-reactive protein, B-type natriuretic peptide, left ventricle ejection fraction, multivessel disease, infarct-related artery and rate of successful PCI were significantly different between the 3 groups (p<0.05). With decline in RF, in-hospital complications developed with an increasing frequency (14.1% vs. 31.8% vs. 45.5%, p<0.0001). In-hospital mortality rate was significantly higher in the moderate and severe RD groups as compared to the normal RF group (2.3% vs. 13.9% vs. 25.6%, p<0.0001). Using multivariate logistic regression analysis, adjusted odds ratio for in-hospital mortality was 2.67 {95% confidence interval (CI) 1.44-4.93, p=0.002} in the moderate RD group, and 4.09 (95% CI 1.48-11.28, p=0.006) in the severe RD group as compared to the normal RF group.</P><P><B>Conclusion</B></P><P>Decreased admission eGFR was associated with worse clinical courses and it was an independent predictor of in-hospital mortality in STEMI patients undergoing primary PCI.</P>

In-hospital mortality in patients with STEMI admitted during off hours

( Sung-Soo Kim ),( Myung Ho Jeong ),( Jeong Gwan Cho ),( Young Keun Ahn ),( Jong Hyun Kim ),( Shung Chull Chae ),( Young Jo Kim ),( Seung Ho Hur ),( In Whan Seong ),( Taek Jong Hong ),( Dong-hoon Choi 대한내과학회 2013 대한내과학회 추계학술발표논문집 Vol.2013 No.1

Conflicting results exist on the outcome of off hours PCI in ST elevation myocardial infarction (STEMI). However, there were only a few studies that have focused on the clinical characteristics and outcomes of off hours PCI in STEMI. So, we studied the clinical characteristics and hospital mortality in STEMI patients treated with primary PCI during regular hours (weekdays 9:00 AM to 6:00 PM) versus off hours Weekdays 6:01 PM to 8:59 AM, weekends, and holidays) in Korea Acute Myocardial Infarction Registry. We analyzed in hospital and one year mortality among 5,665 consecutive ST segment elevation myocardial infarction patients treated with primary PCI between November 2005 to January 2008. Total 2,848 (50.2%) patients were treated during off hours. Baseline finding were similar, although regular hours patients were older. Median symptom to balloon time (304 min, IQR 175 to 750 vs. 270 min, IQR 145 to 551, p=0.001) were longer for regular hours primary PCI. Median door to balloon time (71min, IQR: 48 to 132 vs. 59 min, IQR 39 to 110 min, p=0.001) were longer for off hours pPCI. Also, Cardiac enzyme such as Max CK-MB (212.1±299.3 vs 194.7±303.4, p=0.031) and max TnI (72.6±239.5 vs. 58.9±94.4, p=0.013) were increased in off hours pPCI. However, unadjusted in hospital (6.0% off hours vs. 6.0% regular hours, p=0.946) and one year cardiac mortality (11.3% off hours vs. 11.7% regular hours, p=0.661) were comparable. In multivariate analysis, off hours primary PCI did not predict an adverse outcome. In conclusion, when primary PCI was performed within an appropriate reperfusion strategy, the clinical effectiveness of either off hours or regular hours pPCI is comparable.

Temporal trends and in-hospital outcomes of primary percutaneous coronary intervention in nonagenarians with ST-segment elevation myocardial infarction

( Joon Young Kim ),( Myung Ho Jeong ),( Yong Woo Choi ),( Yong Keun Ahn ),( Shung Chull Chae ),( Seung Ho Hur ),( Taek Jong Hong ),( Young Jo Kim ),( In Whan Seong ),( In Ho Chae ),( Myeong Chan Cho ) 대한내과학회 2015 The Korean Journal of Internal Medicine Vol.30 No.6

Background/Aims: Data regarding the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in nonagenarians are very limited. The aim of the present study was to evaluate the temporal trends and in-hospital outcomes of primary PCI in nonagenarian STEMI patients. Methods: We retrospectively reviewed data from the Korea Acute Myocardial Infarction Registry (KAMIR) from November 2005 to January 2008, and from the Korea Working Group on Myocardial Infarction (KorMI) from February 2008 to May 2010. Results: During this period, the proportion of nonagenarians among STEMI patients more than doubled (0.59% in KAMIR vs. 1.35% in KorMI), and the rate of use of primary PCI also increased (from 62.5% in KAMIR to 81.0% in KorMI). We identified 84 eligible study patients for which the overall in-hospital mortality rate was 21.4% (25.0% in KAMIR vs. 20.3% in KorMI, p = 0.919). Multivariate analysis identified two independent predictors of in-hospital mortality, namely a final Thrombolysis in Myocardial Infarction (TIMI) flow < 3 (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.2 to 59.0; p < 0.001) and cardiogenic shock during hospitalization (OR, 6.7; 95% CI, 1.5 to 30.3; p = 0.013). Conclusions: The number of nonagenarian STEMI patients who have undergone primary PCI has increased. Although a final TIMI flow < 3 and cardiogenic shock are independent predictors of in-hospital mortality, primary PCI can be performed with a high success rate and an acceptable in-hospital mortality rate.

Poster Session : PS 0033 ; Cardiology : Impact of Metabolic Syndrome and Obesity on Clinical Outcomes After Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

( Uh Jin KIM ),( Seunghun LEE ),( Myung Ho JEONG ),( Ju Han KIM ),( HyukJin PARK ),( Ji Eun KIM ),( Youngkeun AHN ),( Jong Hyun KIM ),( Shung Chull CHAE ),( Young Jo KIM ),( Seung Ho HUR ),( In Whan S 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1

Background: The correlation between obesity and metabolic syndrome (MetS) remains unclear. This study aims to investigate impact of obesity phenotype on clinical outcomes with ST-segment elevation myocardial infarction (STEMI). Methods: We analyzed in-hospital mortality and major adverse cardiac events (MACE) of 2,606 obese patients who underwent primary percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry from November 2005 to October 2010. Patients were divided into two groups: unhealthy (any of the Mets components) obesity (BMI =25 kg/m2) and healthy (none of the Mets components) obesity. Results: The unhealthy obesity group was composed of 703 patients (27%) and healthy obesity group 1,903 patients (73%). Unhealthy obesity was more frequent in female (25.9% vs. 10.1%, P<0.001) and multi-vessel disease (53.1% vs. 47.6%, P=0.012). There were no signifi cant differences in other baseline characteristics, angiographic and procedural fi ndings, and prescribed medications between two groups. The overall incidence of complications after PCI (13.1% vs. 10.7%, P=0.097) and in-hospital mortality (1.9% vs. 1.6%, P=0.521) were similar in unhealthy obesity group compared with healthy obesity group. By the multivariate Cox regression analyses, the presence of Mets in obese patients was not an independent factor for predicting the adjusted MACE rate at one-month (HR 1.19, 95% CI 0.56-2.54, P=0.645), six-month (HR 1.48, 95% CI 0.94-2.32, P=0.088), and twelve-month (HR 1.10, 95% CI 0.75-1.61, P=0.622). Conclusions: Obesity phenotype is not an independent prognostic factor for patients with STEMI who undergoing primary PCI. The risk stratifi cation by presence or absence of Mets is not useful in these patients.

Comparison of prasugrel versus clopidogrel in Korean patients with acute myocardial infarction undergoing successful revascularization

Park, Keun-Ho,Jeong, Myung Ho,Kim, Hyun Kuk,Ahn, Tae Hoon,Seung, Ki Bae,Oh, Dong Joo,Choi, Dong-Joo,Kim, Hyo-Soo,Gwon, Hyeon Cheol,Seong, In Whan,Hwang, Kyung Kuk,Chae, Shung Chull,Kim, Kwon-Bae,Kim, Elsevier 2018 Journal of cardiology Vol.71 No.1

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Although there have been several reports that prasugrel can improve clinical outcomes, the efficacy and safety of prasugrel is unknown in Korean patients with acute myocardial infarction (AMI) undergoing successful revascularization.</P> <P><B>Methods</B></P> <P>A total of 4421 patients [637 patients were prescribed prasugrel (60/10 or 5mg, loading/maintenance dose) and 3784 patients clopidogrel (600 or 300/75mg)] with AMI undergoing successful revascularization were enrolled from the core clinical cohort of Korea Acute Myocardial Infarction Registry-National Institute of Health.</P> <P><B>Results</B></P> <P>After propensity score matching (637 pairs), there were no significant differences in baseline clinical and procedural characteristics and in-hospital medications between the two groups. The primary efficacy endpoint, defined as the composite of cardiac death, MI, stroke, or target vessel revascularization at 6 months showed no significant difference between prasugrel and clopidogrel (2.4% vs. 2.9%, <I>p</I> =0.593). Also, no difference was observed in the composite of cardiac death, MI, or stroke during hospitalization between two groups (0.8% vs. 0.9%, <I>p</I> =0.762). However, the incidence of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding was significantly higher in prasugrel compared with clopidogrel (5.3% vs. 2.7%, <I>p</I> =0.015). In multivariate linear regression analysis, trans-femoral intervention, use of glycoprotein IIb/IIIa inhibitors, use of calcium channel blocker, and use of prasugrel were independent predictors of in-hospital TIMI major or minor bleeding [odds ratio (OR)=6.918; 95% confidence interval (CI)=2.453–19.510, OR=2.577; 95% CI=1.406–4.724, OR=4.016; 95% CI=1.382–11.668, OR=2.022; 95% CI=1.101–3.714].</P> <P><B>Conclusions</B></P> <P>Our study shows that the recommended dose of prasugrel had significantly higher in-hospital bleeding complications without reducing ischemic events compared with clopidogrel. However, further large-scale, long-term, randomized clinical trials are required to accurately assess the efficacy and safety of prasgurel and to find out the optimal dose for Korean AMI patients.</P>

Early Valuable Risk Stratification with Hemoglobin Level and Neutrophil to Lymphocyte Ratio in Patients with Non-ST-Elevation Myocardial Infarction Having an Early Invasive Strategy

Seung Jin Jun,,정명호,Kyung Hoon Cho,,안영근,김주한,조정관,Shung Chull Chae,Young Jo Kim,In Whan Seong,채제건,Hyo-Soo Kim,KAMIR-NIH 한국지질동맥경화학회 2018 지질·동맥경화학회지 Vol.7 No.1

Objective: The complete blood count is the most widely available laboratory data in the early in-hospital period after acute myocardial infarction. We assessed the clinical utility of the combined use of hemoglobin (Hb) level and neutrophil to lymphocyte ratio (N/L) for early risk stratification in patients with non-ST-elevation myocardial infarction (STEMI). Methods: We analyzed 6,157 consecutive patients with non-STEMI (65±12.4 years, male 69%) were included in the final analysis. Patients were categorized into 3 groups by using the median value of N/L (4.42) and the presence of anemia (Hb <13 mg/dL in men and <12 mg/dL in women): group I, low N/L & no anemia (n=3,170); group II, no group I or III (n=2,168); group III, high N/L & anemia (n=819). Results: There were significant differences on clinical outcomes during 180-day follow-up among 3 groups. The prognostic discriminatory capacity of the combined use of Hb level and N/L was also significant in high-risk subgroups, such as patients with a renal dysfunction, multivessel coronary disease, low ejection fraction, and even in those having higher mortality risk based on the thrombolysis in myocardial infarction risk score. In a multi-variate logistic regression, after adjusting for multiple covariates, group III had higher incidence of major adverse cardiac events at 180-day (hazard ratio, 2.4; 95% confidence interval, 1.5–4.0;p≤0.001) compared with group I. Conclusions: The combined use of Hb level and N/L provides valuable timely information for early risk stratification in patients with non-STEMI.

151종 생약제 추출물이 B형 간염 바이러스 표면 항원(HBsAg)과 항체(HBsAb)의 결합반응 그리고 HBV DNA polymerase 활성에 미치는 효과 : 한국산 각종 생약제를 이용한 B형 간염치료제의 개발

정태호,김정철,김문규,이인선,채성철,김승래,정준모,이인수,김승호,함경수 慶北大學校 醫科大學 1992 慶北醫大誌 Vol.33 No.3

세계인구 43억명 중 B형 간염 바이러스 보균자는 2억 1천 5백만명이며 이중 78%인 1억 6천만명 이상이 아시아 대륙에 집중되어 있다. 한국도 B형 바이러스 간염의 침윤지대이다. 본 연구는 B형 바이러스 보균자 혹은 만성간염을 치료할 수 있는 생약제를 탐색할 목적의 일환으로 한국에서 시판하는 생약제 151종을 구입하여 증류수로 추출하고 여과한 후 냉동건조하여 HBs 항원에 대한 결합능, HBV DNA polymerase억제능, tumor necrosis factor(TNF) 유리에 미치는 영향, 그리고 galactosamine 유발 간염에 대한간장보호 작용을 조사하였다. 151종의 생약제중 0.16㎍/㎖ 농도에서 간염 vaccine 내에 함유된 HBs 항원과 결합하는 생약제는 지유, 가자, 복분자, 대황, 정향, 빈량, 산수유, 소목, 마황, 쇄양, 후박, 목과, 양강, 오약, 산사, 목단피 등 16종이었다. 이들 생약제중 대황(Rheum palmatum L. 大黃), 가자(Terminalia chebula R. 訶子), 지유(Sanguisorba officinalis L. 地楡), 복분자(Rubus coreanus M. 覆盆子)는 HBV DNA polymerase 활성도를 비교적 강하게 억제하였으며 빈량(Areca catechu L. 빈랑), 정향(Eugenia caryophyllata T. 丁香), 목과(Chaenomeles japonica L. 木瓜), 산수유(Cornus officinalis S. 山茱萸)는 약하게나마 HBV DNA polymerase 활성을 억제하였다. 또한 HBV DNA polymerase를 억제한 대황, 가자, 지유, 복분자, 빈량, 정향, 마황, 소목, 산수유를 대상으로 TNF 유리에 미치는 영향을 조사한 결과 소목을 제외한 8종의 생약제 모두가 대식세포를 자극하여 TNF를 유리시켰다. 그리고 장차 임상에 사용함을 전제로 HBV DNA polymerase를 억제한 대황, 가자, 지유, 복분자, 빈량, 정향, 마황, 소목, 산수유를 galactosamine 유발 간염(백서)에 투여하여 간기능 검사에 미치는 효과를 조사하였으나 간기능 검사상으로는 특별한 보호작용을 나타내지 못하였으며 생약제 단독 투여로서는 간기능에 대하여 나쁜 영향을 주지 않았다. Hepatitis B virus infection is major cause of acute and chrome hepatitis, cirrhosis of liver, and hepatocellular carcinoma. There are over 200 million carriers of hepatitis B virus in the world, nearly 80 % of whom live in the South East Asia, Korea is also highly endemic area of hepatitis B virus infection. This study was performed to evaluate the effect of extracts of traditional Korean herbal medicines on hepatitis B virus. 151 traditional herbs were extracted, filtered and lyophilized. Using 151 herbal extracts we tested binding capability to the HBs Ag, inhibition of HBV DNA polymerase, release of tumor necrosis factor (TNF), and protection against galactosamine induced liver damage. Among 151 herbs, 16 herbs (Sanguisorba officinalis L., Terminalia chebula R., rubus coreanus M., Rheum palmatum L., Eugenia caryophyllata T., Areca catechu L., Cornus officinalis S., Caesalpinia sappan L, Ephedra sinica S., Cynomorium songaricum R., Machilus thunbergii S., Chaenomeles japonica L., Alpinia officinarum H., Lindera strychnifolia V., Crataegus pinnatifida B., Paeonia suffruticasa A. ) had binding capability to HBs Ag which contained in the commercial hepatitis vaccine, at 16 ug/㎖ of concentratioa Among the above 16 herbs, Rheum palmatum L., Terminalia chebula R., Sanguisorba officinalis L., Rubus coreanus M. significantly inhibited the HBV DNA polymerase activity, and Areca catechu L., Eugenia caryophyllata T., Ephedra sinica S., Caesalpinia sappan L., Chaenomeles Japonica L., Cornus officinalis S. also inibited the HBV DNA polymerase activity but less effective. All of the herbs, except Caesalpinia sappan L., which inhibited the HBV DNA polymerase activity, actively stimulated the mononuclear cells to release tumor necrosis factor(TNF) in whole blood culture system. The herbs which inhibited the HBV DNA polymerase activity, did not show any protective effect in galactosamine-induced hepatitis in rats, but there was no direct toxic effect when herbs were administered alone.