Effects of Amlodipine on the Pharmacokinetics of Warfarin after Oral and Intravenous Administration of Warfarin in Rats

( Jin Pil Burm ),( Dong Hyun Choi ),( Yong Ji Piao ),( Eun Joo Choi ),( Jun Shik Choi ) 한국응용약물학회 2011 Biomolecules & Therapeutics(구 응용약물학회지) Vol.19 No.4

The aim of this study was to investigate the effect of amlodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of amlodipine (0.1 or 0.4 mg/kg) in rats. The effect of amlodipine on the P-glycoprotein (P-gp) as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Amlodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration (IC50) of 9.1 μM. Compared to those animals in the oral control group (warfarin without amlodipine), the area under the plasma concentration-time curve (AUC) of warfarin was signifi cantly greater (0.1 mg/kg, p<0.05; 0.4 mg/kg, p<0.01) by 26.5-53.5%, and the peak plasma concentration (Cmax) was signifi cantly higher (0.4 mg/kg, p<0.05) by 26.2% after oral administration of warfarin with amlodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.26- to 1.53-fold and the absolute bioavailability of warfarin with amlodipine was signifi cantly greater by 61.7-72.5% compared to that in the control group (47.4%). In contrast, amlodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver rather than renal elimination and P-gp by amlodipine.

Valsartan/Amlodipine 160/5mg Combination therapy versus Amlodipine 10mg in hypertensive patients with inadequate response to amlodipine 5mg monotherapy

박정의,성지동,정진옥,권성욱,원경헌,김병진,조병렬,김명곤,이삭,김학진,임성훈,박승우 대한심장학회 2016 Korean Circulation Journal Vol.46 No.2

Background and Objectives When monotherapy is inadequate for blood pressure control, the next step is either to continue monotherapy in increased doses or to add another antihypertensive agent. However, direct comparison of double-dose monotherapy versus combination therapy has rarely been done. The objective of this study is to compare 10 mg of amlodipine with an amlodipine/valsartan 5/160 mg combination in patients whose blood pressure control is inadequate with amlodipine 5 mg. Subjects and Methods This study was conducted as a multicenter, open-label, randomized controlled trial. Men and women aged 20-80 who were diagnosed as having hypertension, who had been on amlodipine 5 mg monotherapy for at least 4 weeks, and whose daytime mean systolic blood pressure (SBP) ≥135 mmHg or diastolic blood pressure (DBP) ≥85 mmHg on 24-hour ambulatory blood pressure monitoring (ABPM) were randomized to amlodipine (A) 10 mg or amlodipine/valsartan (AV) 5/160 mg group. Follow-up 24-hour ABPM was done at 8 weeks after randomization. Results Baseline clinical characteristics did not differ between the 2 groups. Ambulatory blood pressure reduction was significantly greater in the AV group compared with the A group (daytime mean SBP change: -14±11 vs. -9±9 mmHg, p<0.001, 24-hour mean SBP change: -13±10 vs. -8±8 mmHg, p<0.0001). Drug-related adverse events also did not differ significantly (A:AV, 6.5 vs. 4.5 %, p=0.56). Conclusion Amlodipine/valsartan 5/160 mg combination was more efficacious than amlodipine 10 mg in hypertensive patients in whom monotherapy of amlodipine 5 mg had failed.

OLETF쥐에서 Amlodipine, Losartan과 비교한 Lithospermic Acid B의 당뇨병성 신증 예방효과

강은석,하헌주,허규연,차봉수,김범석,김철훈,안철우,이현철,서기호,한승진,전성완,정만길 대한당뇨병학회 2008 Diabetes and Metabolism Journal Vol.32 No.1

Background: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Methods: LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Results: None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β1 (TGF-β1). Conclusion: These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartan. (J Kor Diabetes Assoc 32:10~20, 2008) Background: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Methods: LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Results: None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β1 (TGF-β1). Conclusion: These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartan. (J Kor Diabetes Assoc 32:10~20, 2008)

신장 ; 암로디핀 중독 환자의 임상양상

전영우 ( Young Woo Jeon ),김재연 ( Jae Yun Kim ),박재석 ( Jae Seok Park ),박재만 ( Jae Man Park ),길효욱 ( Hyo Wook Gil ),양종오 ( Jong Oh Yang ),이은영 ( Eun Young Lee ),홍세용 ( Sae Yong Hong ) 대한내과학회 2011 대한내과학회지 Vol.81 No.2

목적: 칼슘 통로 차단제는 흔히 사용되는 항고혈압 약제이다. 전세계적으로 사용량 증가에 따른 과량 복용에 대한 보고가 증가 하고 있지만 국내 보고는 미흡하다. 칼슘 통로 차단제 중 암로디핀은 매우 흔히 사용되는 약제이나 과량복용에 대해서는 임상의에게는 익숙하지 않다. 따라서 본 연구는 암로디핀을 과다 복용한 환자들의 임상양상, 치료 경과, 합병증 및 예후에 대해 조사하였다. 방법: 2002년 1월부터 2010년 12월까지 순천향대학교 천안병원에 약물중독으로 내원한 환자 중 암로디핀을 과량복용한 환자를 대상으로 후향적 조사를 하였다. 약물 복용량은 환자나 보호자 진술에 근거하여 체표면적당 약물 복용량(Billy`s BSA formula)으로 계산하였고, 응급실 내원 당시의 초기 생징후, 혈액 검사, 심전도 검사 등을 조사하였으며, 심전도 이상은 서맥, 방실 전도장애, QT, QRS 간격의 증가 중1개 이상의 변화가 있을 경우로 정의하였다. 결과: 총 9명의 환자(남자 2명, 여자 7명)가 포함되었고, 체표면적당 암로디핀 복용량은 197.78±128.37 mg이었으며, 모든 환자에서 다른 종류의 약물을 같이 과량 복용했다. 9명의 환자 중 2명이 사망했고, 사망한 환자의 체표면적당 약물복용량은 343.5 mg/m2와 225.6 mg/m2이었고, 생존 환자 모두에서는 200 mg/m2 이하였다. 3명의 환자에서 glimepride를 같이 과량 복용했지만, 200 mg/dL 이상의 혈당 수치를 보였고, 이중에서 1명은 고혈당이 조절되지 않아 대사성 케톤산증이 진행되어 다장기 부전으로 사망하였다. 심전도 이상을 보인 환자의 평균 체표면적당 약물 복용량은 197.1±92.3 mg/m2이었고, 심전도 이상이 없는 환자에서는 58.5±27.1 mg/m2이었다. 결론: 비교적 안전하다고 알려진 non-dihydropyridine계인 암로디핀도 과량 복용 시 고혈당과 대사성 케톤산증 및 심장 전도이상이 유발되어 치명적인 결과를 보일 수 있다. 고혈당 발생은 나쁜 예후를 시사하므로 이에 대한 주의가 필요하다. Background/Aims: Calcium channel blockers (CCBs) are anti-hypertensive medications that are used worldwide. CCB overdose has increased in proportion to the use of these drugs. Although amlodipine is the most widely used CCB, many physicians are not familiar with amlodipine overdose. We report the clinical outcome in patients with an intentional amlodipine overdose. Methods: We retrospectively reviewed the medical records of the patients who visited Soonchunhyang University Cheonan Hospital with an amlodipine overdose from January 2002 through December 2010. We recorded the initial vital signs, blood chemistry, electrocardiography, and estimated amount of amlodipine ingested. Results: Nine patients were enrolled, of whom two patients died. Both patients who died had ingested more than 200 mg/m2 of amlodipine, while all of the patients who ingested less than 200 mg/m2 of amlodipine survived. Three patients had blood sugar levels exceeding 200 mg/dL and two of these died despite high-dose insulin therapy in combination with glucose infusion (hyperinsulinemia/euglycemia therapy). Although three patients also took a glimepiride overdose, none had hypoglycemia. The amount of amlodipine ingested relative to the body surfaced area (BSA) was 197.1±92.3 mg/m2 in patients with an abnormal ECG and 58.5±27.1 mg/m2 in patients with a normal ECG. Conclusions: Amlodipine overdose can induce hyperglycemia, resulting in lethal cardiogenic shock owing to the decreased calcium influx, inappropriate energy production, and weakened inotropic effect. Therefore, amlodipine-induced hyperglycemia indicates a poor prognosis. (Korean J Med 2011;81:208-214)

Coated dextrin microcapsules of amlodipine incorporable into orally disintegrating tablets for geriatric patients

Jang, D.J.,Bae, S.K.,Oh, E. Masson Pub. USA, Inc 2014 BIOMEDICINE AND PHARMACOTHERAPY Vol.68 No.8

To improve oral absorption and patient compliance when using amlodipine, novel coated dextrin microcapsules incorporable into orally disintegrating tablets (ODT's) were investigated. Amlodipine-loaded dextrin microcapsules (ADM) were prepared by spray-drying a mixture of amlodipine free base dissolved in ethanol and aqueous dextrin solution. The ADM were suspended in Eudragit<SUP>®</SUP> EPO solution in ethanol and subsequently spray-dried to collect coated ADM (CADM). The ADM or CADM were blended with ODT excipients and then directly compressed into ODTs. The ADM and CADM used were both spherical with smooth surfaces and had mean particle sizes of 13.3 and 18.5μm, respectively. Amlodipine was dispersed in an amorphous state and was readily encapsulated within ADM or CADM. Unlike the ADM, the tableted CADM remained intact without rupture during tableting, which was consistent with no loss of ethanol (0.82%) entrapped in the ODTs containing the CADM (ODTs-CADM). The amlodipine content appeared to be uniformly maintained as designed in all the dextrin microcapsules and ODTs. The ODTs-CADM compressed with 3kp of hardness showed acceptable ODT characteristics: fast disintegration time (29.8s) and low friability (0.1%). Drug dissolution from the ODTs-CADM was much faster than that of amlodipine free base itself at both pH 1.2 and 6.8 over the tested time. CADM demonstrated significantly higher plasma concentrations (2.7 fold in AUC<SUB>0-24h</SUB> and 2.5 fold in C<SUB>max</SUB>) in SD rats than did amlodipine free base. These results indicate that CADM substantially increased the oral absorption of amlodipine and can be incorporated into ODTs while maintaining their original physicochemical features. The dextrin microcapsules coated using Eudragit<SUP>®</SUP> EPO may be applied to the development of an amlodipine ODT formulation for improving geriatric patient compliance.

ORIGINALARTICLE : Amlodipine and cardiovascular outcomes in hypertensive patients: meta-analysis comparing amlodipine-based versus other antihypertensive therapy

( Seung Ah Lee ),( Hong Mi Choi ),( Hye Jin Park ),( Su Kyoung Ko ),( Hae Young Lee ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.3

Background/Aims: This meta-analysis compared the effects of amlodipine besylate,a charged dihydropyridine-type calcium channel blocker (CCB), with othernon-CCB antihypertensive therapies regarding the cardiovascular outcome. Methods: Data from seven long-term outcome trials comparing the cardiovascularoutcomes of an amlodipine-based regimen with other active regimens werepooled and analyzed. Results: The risk of myocardial infarction was significantly decreased with anamlodipine-based regimen compared with a non-CCB-based regimen (odds ratio[OR], 0.91; 95% confidence interval [CI], 0.84 to 0.99; p = 0.03). The risk of strokewas also significantly decreased (OR, 0.84; 95% CI, 0.79 to 0.90; p < 0.00001). The risk of heart failure increased slightly with marginal significance for anamlodipine-based regimen compared with a non-CCB-based regimen (OR, 1.14;95% CI, 0.98 to 1.31; p = 0.08). However, when compared overall with ß-blockersand diuretics, amlodipine showed a comparable risk. Amlodipine-based regimensdemonstrated a 10% risk reduction in overall cardiovascular events (OR, 0.90;95% CI, 0.82 to 0.99; p = 0.02) and total mortality (OR, 0.95; 95% CI, 0.91 to 0.99; p= 0.01). Conclusions: Amlodipine reduced the risk of total cardiovascular events as wellas all-cause mortality compared with non-CCB-based regimens, indicating itsbenefit for high-risk cardiac patients.

증례 : 신장 ; 장기간 Amlodipine 복용 후 발생한 심한 잇몸 과증식 1예

이성진 ( Sung Jin Lee ),정영국 ( Young Kuk Chung ),이해림 ( Hae Lim Lee ),최수진 ( Su Jin Choi ),조성연 ( Sung Yeon Cho ),최현주 ( Hyun Joo Choi ),김형욱 ( Hyung Wook Kim ) 대한내과학회 2012 대한내과학회지 Vol.82 No.5

Amlodipine is one of the most commonly used calcium-channel blockers for the management of hypertension in Korea. Gingival overgrowth is an infrequent complication in patients receiving amlodipine treatment. A 52-year-old man on an amlodipine regimen of 10 mg/day for 25 months sought medical attention because of gradually progressive gingival enlargement. Examination of the oral cavity revealed severe gingival overgrowth. We stopped the amlodipine treatment and recommended the maintenance of good oral hygiene and a gingivectomy. Histological findings of the gingivectomy were typical of drug-induced gingival overgrowth, including epithelial thickening with proliferation, acanthosis with elongated rete ridges, and focal parakeratosis. A marked reduction in gingival overgrowth was evident 1 month after the gingivectomy and cessation of amlodipine. This report describes the case of a 52-year-old man who developed severe and histologically confirmed amlodipine-induced gingival overgrowth. (Korean J Med 2012;82:623-627)

만성 신부전으로 인한 고혈압 환자에서 Amlodipine(Norvasc^(�))의 감압효과에 대한 임상적 관찰

박광기,문경협,조정관,최기철,강영준 최신의학사 1992 最新醫學 Vol.35 No.5

Losartan과 Amlodipine의 병용투여에 의한 고혈압 및 혈관재협착 보호효과

한주희,정상혁,명창선 충남대학교 약학대학 의약품개발연구소 2014 藥學論文集 Vol.29 No.-

Abstract - To examine the protective effect of combination treatment of angiotensin II AT1-receptor blockers (ARBs) with Ca2+ channel blockers (CCBs) for high blood pressure and neointima hyperplasia, losartan and amlodipine were orally injected into telemetered-spontaneous hypertensive rats and vascular injury induced by cuff-inserted neointimal formation model in vivo. For the measurement of blood pressure, random orders of losartan 0, 4.79, 9.58 mg/kg/day, amlodipine 0, 0.48, 0.96 mg/kg/day, or higher/lower doses in combination were administered in spontaneous hypertensive rats (SHRs; n=10). For the measurement of neointimal hyperplasia, 9.58 mg/kg/day of losartan or 0.96 mg/kg/day of amlodipine in alone or combination were given for 2 weeks to cuffed C57BL/6 mice (n=6). Our results suggest that the combination therapy of high doses of losartan and amlodipine are effective in lowering systolic blood pressure (SBP) and mean arterial pressure (MAP) as compared with monotherapy of each drug, but not in combined therapy of low doses of two drugs. In protection for vascular remodeling, the combination therapy of losartan with amlodipine synergistically decreased BrdU-positive cells in neointima and DNA synthesis in [3H]-thymidine incorporation by reducing cell proliferation. Therefore, present study implies that combination of losartan with amlodipine may be effective for the treatment of hypertension and vascular remodeling such as restenosis.

Valsartan과 Amlodipine의 병용투여에 의한 혈압하강 상승 및 혈관손상 보호효과

한주희,명창선 충남대학교 약학대학 의약품개발연구소 2013 藥學論文集 Vol.28 No.-

This study was aimed to investigate the synergistic effect of valsartan combined with amlodipine on the anti-hypertensive effect and protective action in vascular injury mediated by cuff-induced neointimal formation model in vivo. For the measurement of blood pressure, spontaneous hypertensive rats (SHRs) were given in that random orders valsartan 0, 7.65, 15.3 mg/kg, amlodipine 0, 0.48, 0.96 mg/kg, or the higher/lower doses in combination. For the measurement of neointimal hyperplasia, 15.3 mg/kg of valsartan or 0.96 mg/kg of amlodipine in alone or combination were given for 2 weeks to cuffed C57BL/6 mice. The results showed that the combination therapy of high doses of valsartan and amlodipine significantly decreased in systolic blood pressure (SBP) and mean arterial pressure (MAP) as compared with monotherapy of each drug, but not in combined therapy of low doses of two drugs. In protection for vascular remodeling, valsartan 15.3 mg/kg and amlodipine 0.96 mg/kg in combination significantly decreased BrdU-positive cells in neointima and [3H]-thymidine, indicating the inhibition of cell proliferation including a progress of DNA synthesis comparing to respective effects. Therefore, present study implies that combination of valsartan and amlodipine may be fully effective for the treatment of hypertension and vascular remodeling.