An Improved Lc-Ms/Ms Method Development And Validation For The Determination Of Trandolapril And Verapamil In Human Plasma

Objective: A simple, sensitive and rapid LC-MS/MS technique was developed for the quantitation of trandolapril (TDL) and verapamil (VPL) in a biological matrix and validated. Methods: Sample preparation processed by SPE (Solid Phase extraction) on phenomenex cartridge using Ledipasvir as an internal standard. Two drugs were eluted on waters symmetry-RP18 (5µ, 150 mm×4.0 mm) column with the mobile composition of 10 mmol ammonium formate and ACN(acetonitrile) in the ratio of 70:30 %V/V. Detection and quantitation were processed by electrospray ionization in positive ionization mode. Results: The quantification approach was validated in 5-1500 ng/ml linear concentration range for TDL and 1-2000 ng/ml for VPL. The intraday and inter-day precision and accuracy were found to be 0.58% to 5.69% and 93% to 104% for two drugs. The average recoveries for TDL and VPL were found to be 92.9% and 93.5% respectively. Conclusion: The developed work was validated and can be applicable to the routine analysis of TDL and VPL simultaneously in a biological matrix.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement

PURPOSE: In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. MATERIALS AND METHODS: We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed beta-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. RESULTS: There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). CONCLUSION: In MFS patients who underwent ARR, the addition of RAAS blockade to beta-blocker was associated with reduction of aortic dilatation and clinical events.

The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor / Efeito de esmolol sobre o intervalo QT corrigido e alterações da dispersão do intervalo QT corrigido observadas durante a indução da anestesia em pacientes hipertensos que receberam um inibidor da enzima conversora de angiotensina / Efecto del esmolol sobre el intervalo QT corregido y alteraciones de la dispersión del intervalo QT corregido observadas durante la inducción de la anestesia en pacientes hipertensos que recibieron un inhibidor de la enzima convertidora de la angiotensina

BACKGROUND AND OBJECTIVES: The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. METHODS: 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500 mcg/kg followed by a 100 mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5 min after esmolol and saline administration, 3 min after the induction and 30 s, 2 min and 4 min after intubation. RESULTS: The corrected-QT interval was shorter in the esmolol group (p = 0.012), the corrected-QT interval dispersion interval was longer in the control group (p = 0.034) and the mean heart rate was higher in the control group (p = 0.022) 30 s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p = 0.038). CONCLUSION: Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin ...

JUSTIFICATIVA E OBJETIVO: É óbvia a importância de minimizar as respostas simpatoadrenérgicas exageradas e o intervalo QT e a dispersão do intervalo QT que podem ocorrer por causa de laringoscopia e intubação traqueal durante a indução da anestesia em pacientes hipertensos. Esmolol diminui a resposta hemodinâmica à laringoscopia e à intubação. Porém, o efeito de esmolol sobre a redução do intervalo QT prolongado e a dispersão do intervalo QT induzida pela laringoscopia e intubação é controverso. Pesquisamos o efeito de esmolol sobre a hemodinâmica e o intervalo QT corrigido e as alterações da dispersão do intervalo QT observadas durante a indução da anestesia em pacientes hipertensos que receberam inibidores da enzima conversora de angiotensina (IECA). MÉTODOS: Foram incluídos no estudo 60 pacientes, estado físico ASA I-II, com hipertensão arterial essencial e que receberam IECA. O grupo esmolol recebeu uma dose em bolus de 500 mcg kg-1, seguida por infusão contínua de 100 mcg kg-1 min-1 até o quarto minuto após a intubação. O grupo controle recebeu solução salina a 0,9%, semelhantemente ao grupo esmolol. Os valores da pressão arterial média e da frequência cardíaca e os registros do eletrocardiograma foram obtidos durante a fase inicial pré-anestesia, cinco minutos após a administração de esmolol e solução salina, três minutos após a indução e 30 segundos, dois minutos e quatro minutos após a intubação. RESULTADOS: O intervalo QT corrigido foi menor no grupo esmolol (p = 0,012), o intervalo de dispersão do intervalo QT corrigido foi maior no grupo controle (p = 0,034) e a frequência cardíaca média foi maior no grupo controle (p = 0,022) 30 segundos após a intubação. O risco da frequência de arritmia foi maior no grupo controle no quarto minuto após a intubação (p = 0,038). CONCLUSÃO: Descobrimos que a intubação traqueal prolonga o intervalo e a dispersão do intervalo QT corrigido e aumenta a frequência cardíaca durante a indução da ...

JUSTIFICACIÓN Y OBJETIVO: Es evidente la importancia que tiene minimizar las respuestas simpatoadrenérgicas exageradas y el intervalo QT y la dispersión del intervalo QT que pueden ocurrir a causa de la laringoscopia e intubación traqueal durante la inducción de la anestesia en pacientes hipertensos. El esmolol disminuye la respuesta hemodinámica a la laringoscopia y a la intubación. Sin embargo, su efecto sobre la reducción del intervalo QT prolongado y la dispersión del intervalo QT inducida por la laringoscopia e intubación es controvertido. Investigamos el efecto del esmolol sobre la hemodinámica y el intervalo QT corregido, y las alteraciones de la dispersión del intervalo QT observadas durante la inducción de la anestesia en pacientes hipertensos que recibieron inhibidores de la enzima convertidora de la angiotensina. MÉTODOS: Fueron incluidos en el estudio 60 pacientes, estado físico ASA I-II, con hipertensión arterial esencial y que recibieron inhibidores de la enzima convertidora de la angiotensina. El grupo esmolol recibió una dosis en bolos de 500 mcg/kg, seguida de infusión continua de 100 mcg/kg/min hasta el cuarto minuto después de la intubación. El grupo control recibió una solución salina al 0,9%, de forma similar al grupo esmolol. Los valores de la presión arterial media y de la frecuencia cardíaca y los registros del electrocardiograma fueron obtenidos durante la fase inicial preanestésica, 5 min después de la administración del esmolol y la solución salina, 3 min después de la inducción, y 30 s, 2 min y 4 min después de la intubación. RESULTADOS: El intervalo QT corregido fue menor en el grupo esmolol (p = 0,012), el intervalo de dispersión del intervalo QT corregido fue mayor en el grupo control (p = 0,034) y la frecuencia cardíaca media fue mayor en el grupo control (p = 0,022) 30 s después de la intubación. El riesgo de la frecuencia de arritmia fue mayor en el grupo control en el cuarto minuto después de la intubación ...

A Randomized, Placebo Controlled, Double Blind, Parallel Group, Multiple Dosing, Dose Escalation Clinical Study to Evaluate Pharmacokinetics/Pharmacodynamics and Tolerability of Zofenopril in Healthy Korean Subjects

BACKGROUND: Zofenopril is a new Angiotensin Converting Enzyme (ACE) inhibitor for the treatment of the patients with hypertension and congestive heart failure. This study aimed to evaluate the pharmacokinetics (PKs)/pharmacodynamics (PDs) and tolerability of zofenopril in healthy Korean subjects. METHODS: A randomized, double blind, placebo-controlled, multiple dosing parallel group study with two dosage groups (zofenopril 30 mg or 60 mg) was conducted in healthy Korean male subjects. Each dosage group consisted of 10 subjects and they were randomly assigned to receive zofenopril or placebo with a ratio of 4:1. PK characteristics of zofenopril and its active metabolite, zofenoprilat, were evaluated after single or multiple dosing. Serum ACE activities and blood pressures were measured for PD evaluation. Adverse events, clinical laboratory tests, electrocardiograms, vital signs and physical examinations were performed for tolerability evaluation. RESULTS: The PK characteristics of zofenopril and zofenoprilat after single dose and multiple doses were similar to one another. The metabolic ratio of zofenoprilat to zofenopril after single dose and multiple doses were 12.4 and 14.9, respectively, in the 30 mg dosage group, and were 6.8 and 6.6, respectively, in the 60 mg dosage group. Complete serum ACE activity inhibition was observed within 1 hour in both doses but it was maintained longer in the 60 mg dosage group compared to the 30 mg dosage group. There were no clinically significant abnormalities in tolerability evaluations. CONCLUSION: The PK/PD characteristics of zofenopril and zofenoprilat after single or multiple administrations were explored. Zofenopril was well tolerated after multiple administrations in healthy Korean subjects.

Biphasic anaphylaxis to gemifloxacin

Anaphylaxis have been documented as adverse effects of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, and moxifloxacin. However resistant and biphasic anaphlylactic reactions to gemifloxacin have not been reported to date. Management of severe anaphylaxis in the elderly can be complicated by concurrent medications such as beta (β) adrenergic, alpha (α) adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors. We report here in the case of a 60-year-old male who was taking on ACE inhibitor, α and β blockers and experienced a severe, resistant and biphasic anaphlylactic reaction to gemifloxacin mesylate.

A Case of Angiotensin Converting Enzyme Inhibitor-Induced Systemic Lupus Erythematosus

Drug-induced lupus erythematosus is defined as a lupus-like syndrome related to continuous drug exposure which resolves after discontinuation of the offending drug. Here we report a case of a 70-year-old man who developed drug-induced lupus erythematosus after receiving angiotensin converting enzyme inhibitor medication for unstable angina pectoris, for 5 years. He was hospitalized with arthralgia, edema, and newly developed pleural effusion. The serum analysis revealed an elevated level of antinuclear antibody and antihistone antibody. After discontinuation of angiotensin converting enzyme inhibitor and receiving a course of prednisolone treatment, his symptoms and pleural effusion improved. To the best of our knowledge, this is, the first case report of angiotensin converting enzyme inhibitor-induced systemic lupus erythematosus in Korea.

The causes of chronic cough: Chronic cough due to extrapulmonary etiologies / 대한내과학회지

Cough is one of the most common symptoms leading to referral to medical institutions, and can be triggered by various causes. Since chronic cough does not respond well to antitussives that are generally prescribed in outpatient clinics, it is most important to seek the underlying cause and provide appropriate treatment rather than to just simply relieve symptoms. Although chronic cough is induced by various causes, it is one of difficult symptoms to deal with in clinical settings, having no specific symptom for diagnosis or definitive diagnostic tool. While taking patient's history, however, physicians can take a step closer to the treatment of chronic cough by asking more details about the character, frequency, onset, duration, and aggravating factor of cough, if any; the type of medication and time of its application; the response to previous treatment, etc. Underlying causes of chronic cough often require a long term treatment. Therefore, when treating patients, the physician must inform and discuss with the patient about the duration of treatment and what specifically he or she needs to do at home to maintain satisfactory compliance and expect good outcomes.

Incrementos continuos de las hospitalizacionesdebidas a angioedema / Continued increases in hospitalizations due to angioedema

Es posible que las hospitalizaciones y las consultas a lasala de emergencias debidas a angioedema estén enaumento. En este estudio se determinó el patrón de losingresos hospitalarios por angioedema en el estado deNueva York para los años 1990 a 2005...

Hospitalizations and emergency visits due to angioedemamay be on the rise. In this study, the pattern of hospital admissions for angioedema in New York state were profiled for the years 1990 through 2005...

Effect of Preoperative Omitting Angiotensin-converting Enzyme Inhibitor on Hemodynamics in Patients Undergoing Off Pump Coronary Artery Bypass Surgery / 대한마취과학회지

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACE-I) have been widely used for cardiac patients. This study investigated the effect of omitting ACE-I medication on hemodynamics during induction of anaesthesia and operation in patients chronically treated with ACE-I undergoing off pump coronary artery bypass graft surgery (OPCAB). METHODS: Sixty patients scheduled for OPCAB were included in this study. Patients not treated with ACE-I were included in control group (Group 1, n = 20). And then, patients treated with ACE-I more than 4 weeks were randomly divided into two groups: continuing group including patients who continued ACE-I medication until the morning of surgery (Group 2, n = 20) and discontinuing group including patients who discontinued ACE-I one day before the surgery (Group 3, n = 20). Norepinephrine (8microgram/ml) was infused when systolic blood pressure decreased below 90 mmHg during induction and operation. Amount of norepinephrine infused and hemodynamic data were recorded. RESULTS: Significantly larger amount of norepinephrine was infused in Group 2 than in other two groups during obtuse marginal artery anastomosis. Total amount of norepinephrine infused during the all coronary anatsomosis was significantly larger in Group 2 than those values in other two groups. CONCLUSIONS: Continuing ACE-I treatment until the morning of surgery significantly increased the use of norepinephrine during the anastomosis. In contrast, there was no significant difference in the use of norepinephrine between Group 1 and Group 3. Discontinuing ACE-I before the surgery may helpful to maintain hemodynamics stable during coronary anastomosis in OPCAB.

The Therapeutic Effects of Angiotensin-Converting Enzyme Inhibitors in Severe Non-proliferative Diabetic Retinopathy

PURPOSE: To evaluate the effects of angiotensin-converting enzyme inhibitors (ACE-I) in retarding progression of severe non-proliferative diabetic retinopathy (NPDR) in normotensive type 2 diabetic patients. METHODS: This was a retrospective case control study of 128 patients with normotensive type 2 diabetes with lower than +1 dipstick proteinuria and severe NPDR who were classified into either an ACE-I treated group (Enalapril maleate 10 mg, n=12 , Ramipril 5 mg, n=17) or an ACE-I untreated group (n=99). Medical records were reviewed for endpoints of (a) occurrence of proliferative diabetic retinopathy (PDR) or macular edema (ME) for which laser phototherapy was necessary or (b) development of proteinuria of higher than +1 level requiring medication of ACE-I. RESULTS: From the total of 128 patients, there were 29 ACE-I treated patients and 99 ACE-I untreated patients. There were no differences in the average age, duration of diabetes, body mass indices, blood pressure and levels of hyperglycemia or HbA1C between the two groups. Blood pressure and HbA1C levels in both groups remained unchanged during the study. The mean follow-up period was 41.6 months. In the ACE-I group, 6 patients progressed to PDR, 5 to ME and 6 developed proteinuria of greater than +1 over the follow-up period. In the control group, 30 patients progressed to PDR, 6 to ME and 9 developed proteinuria of greater than +1 over the follow-up period. CONCLUSIONS: Small doses of ACE-I did not yield any beneficial effects in retarding the progression of severe NPDR.

IGF-1 is an Independent Risk Factor for Anemia in Diabetic Pre-dialysis Patients

BACKGROUND: We investigated whether the presence of diabetes mellitus (DM) was related to the degree of the anemia in predialytic patients with renal failure and what was the most relevant factor for anemia in patients with chronic kidney disease (CKD) from DM (DM-CKD). METHODS: Seventy seven patients (47 predialytic patients with long-term type 2 DM (DM-CKD) and 30 predialytic patients whose disease was due to other causes (non DM-CKD)) were enrolled in this study. The blood hemoglobin (Hb) and hematocrit, and the creatinine, ferritin, vitamin B12, folate, iron, LDH, albumin, hs-CRP, intact-PTH, erythropoietin, leptin and Insulin-like growth factor I (IGF-1) levels were measured using standard methods. The estimated GFR was calculated using the abbreviated MDRD equation. RESULTS: The two groups did not significantly differ as to age, gender, the serum creatinine level and the inflammatory status. The Hb level was significantly lower in the DM-CKD patients than that in the non DM-CKD patients (8.5+/-1.7 g/dL vs 9.6+/-1.6 g/dL, respectively, p=0.01). The Hb level was significantly lower in the DM-CKD patients who were being treated with ACE inhibitors (the DM-ACE patients) than that in the non DM-CKD patients who were being treated with ACE inhibitors (the non DM-ACE patients) (8.5+/-1.5 g/dL vs 10.8+/-1.6 g/dL, respectively, p=0.001). Multiple regression analysis indicated that serum IGF-1 concentration was independently associated with the Hb level (beta=0.425, p=0.02) in the DM-CKD patients. CONCLUSIONS: The Hb concentration was significantly lower in the DM-CKD patients than that in the non DM-CKD patients. It was independently associated with the serum IGF-1 concentration in the DM-CKD patients.

Left Ventricle Myocardium Volume Densities in Spontaneously Hypertensive Rats (SHR) Following Combination of Exercise and ACE Inhibitor Treatment: A Stereological Study / Densidad de Volumen del Miocardio del Ventrículo Izquierdo en Ratas Espontáneamente Hipertensas (REH) Posterior a la Combinación de Ejercicios y Tratamiento Inhibidor de la ACE: Estudio Estereológico

This study was designed to test the possible effects of a combination of physical and pharmacological therapy intervention on myocardial structure of the left ventricle in spontaneously hypertensive rats (SHR). Twelve weeks old spontaneously hypertensive rats (n = 40) were divided into four groups of sedentary, (Sed) as controls, exercise only (Exer), lisinopril only 20mg/kg/day (Lis), and exercise + lisinopril (LisExer). Exercise training was performed on a treadmill (5m/min.) for 60 minutes/day, 5 days/week for 10 weeks. At the end of 10 weeks, all the rats were terminally anaesthetised, the heart was arrested in diastole by intravenous procaine and whole animal perfusion fixation through the abdominal aorta was carried out using Karnovsky's fixative (pH 7.24). The heart was removed and left ventricle plus the interventricular septum was serially sectioned at a thickness of 3 mm. One piece was randomly chosen, and embedded in JB4 resin. Six sections were obtained from each block, stained with toluidine blue:acid fucin. Measurement of volume fraction (Vf), of myocardium, capillaries and interstitium were carried out using a stereology software (Histometrix MIL6 Kinetic imaging Ltd.). Mean Vf of capillaries in Sed group was 0.114 ± 0.01 (SEM). This was significantly increased in LisExer group. The Vf of muscle in Sed group was 0.795 ± 0.02 (SEM). This was significantly decreased in Lis but unchanged in Exer group. Capillaries Vf was significantly higher in LisExer as compared to Lis or Exer groups (p<0.05). Muscle Vf was not different betweenLisExer and Lis groups. The outcome of these changes could well be a better enhancement of cardiac performance in hypertension by combined exercise and ACE inhibitor treatment than either of the interventions alone.

Este estudio fue diseñado para probar los posibles efectos de una combinación de ejercicios y una intervención de terapia farmacológica en las estructuras del miocardio del ventrículo izquierdo, en ratas espontaneamente hipertensivas (SHR). Ratas de 20 semanas espontáneamente hipertensas (n = 40) fueron divididas en cuatro grupos: sedentarias (Sed) y controles, solamente con ejercicio (Ejer), solamente con lisinopril con 20mg/kg/día (Lis), y ejercicios + lisinopril (LisEjer). Los ejercicios fueron ejecutados en una máquina de entrenamiento (5m/min.) por 60 minutos/día, 5 días/semana por 10 semanas. Al término de las 10 semanas, las ratas fueron sacrificadas bajo anestesia, el corazón fue detenido en diástole usando procaina intravenosa. Los animales fueron perfundidos a través de la parte abdominal de la aorta, usando solución de Karnovsky (pH 7.24). El corazón fue removido y tanto al ventrículo izquierdo como al septo interventricular se les realizaron cortes seriados de 3 µm. Una pieza fue seleccionados al azar, y sumergida en resina JB4. Fueron obtenidas 6 secciones de cada bloque y luego teñidas con azul de toluidina:fucsina ácida. Las mediciones de fracción volumétrica (Vf) del miocardio, capilares, e intersticio fueron obtenidas usando un software de estereología (Histometrix MIL6 Kinetic imaging Ltd.). El promedio Vf de capilares en el grupo Sed, fue 0.114 ± 0.01 (SEM). Éste fue significativamente mayor en el grupo LisExer. El Vf de músculo en Sed fue 0.795 ± 0.02 (SEM). Éste fue significativamente menor en Lis pero no varió en el grupo Ejer. Vf capilares fue significativamente alto en LisExjr, si es comparado con los grupos Lis o Ejer (p<0.05). En Vf músculo no hubo diferencias entre los grupos LisEjer y Lis. El resultado de estos cambios pudo deberse a un mejor funcionamiento cardiaco en ratas hipertensa,s producto de ejercicios combinados y tratamiento con inhibidor ACE, que en aquellos en que se efectó un solo procedimiento.

Effect of Preoperative Angiotensin-Converting Enzyme Inhibitor on Hemodynamics and Vasoconstrictor Requirements in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery / 대한마취과학회지

BACKGROUND: This study examined the effect of chronic preoperative ACEI treatment on hemodynamics and the amount of vasoconstrictor used to maintain mean arterial pressure (MAP) during off-pump coronary artery bypass surgery (OPCAB) METHODS: Sixty patients undergoing OPCAB were divided into two groups: ACEI group, in which patients were treated with ACEI preoperatively (n = 30) and control group, in which patients were not treated with ACEI preoperatively (n = 30). Norepinephrine was infused when MAP decreased below 70 mmHg during operation. Hemodynamic variables and amount of norepinephrine infused were obtained during pericardiotomy and during the anastomosis of each coronary artery including left anterior descending artery (LAD), obtuse marginal artery (OM) of left circumflex coronary artery, and posterior descending artery (PDA) of right coronary artery. RESULTS: During LAD, OM, and PDA anastomosis, cardiac index and mixed venous oxygen saturation were decreased and central venous pressure and systemic vascular resistance index were increased significantly in both group. There was no significant difference in hemodynamic variables, including MAP, between two groups during all study period. During OM anastomosis, amount of norepinephrine infused to maintain MAP was significantly greater in ACEI group than in control group CONCLUSIONS: Preoperative treatment with ACEI significantly increased amount of vasoconstrictor used to maintain target MAP during OM anastomosis, which has been known as hemodynamically unstable period during OPCAB, and cautious management is required to maintain MAP.

Effects of Enalapril on Synthesis of Collagen TypeI, II, III in Incomplete Ureteral Obstruction with Uninephrectomized Rat / 대한비뇨기과학회지

PURPOSE: Unilateral ureteral obstruction results in tubulointerstitial fibrosis of the affected kidney which is driven by increased levels of angiotensin II. In this study, we examed the fibrotic changes in un inephrectomized rats with incomplete urteral obstruction and explored the effect of an angiotensin converting enzyme(ACE)inhibitor, enalapril on the tubulointerstitial fibrosis of obstructive uropathy. MATERIALS AND METHODS: 130 Rats were sacrificed at 1, 2, 4 weeks after nephrectomy or obstruction. Collagen type I, II, and III were localized by immunohistochemical staining. And the distribution of each collagen type was analyzed using differences of their staining densities. RESULTS: There is no difference in total collagen amount and immunohistochemical staining between control and uninephrectomized group. After 2weeks in incomplete ureteral obstruction in uninephretomized rat, the total amount of collagen in affected kidney was significantly increased compared to control (p<0.05), and immunohistochemical staining for all type of collagen was gradually increased by increased duration of incomplete ureteral obstruction. Enalapril did not affect the total collagen amount and immunohistochemical staining in the kidney of uninephrectomized rat. Enalapril significantly decreased the collagen amount in affected kidneys of collagen was not significantly changed compaired to control group. CONCLUSIONS: the incomplete ureteral obstruction in uninephrectomized rat induces progressive increase of amount of collagen according to the duration of obstruction, especially 2 weeks, and enalapril administration after incomplete unilateral obstruction of tubulointerstitial fibrosis of obstructive uropathy.

The Effect of ACE Inhibitors on The Gene Expression of TGF-beta and TNF-alpha in Renal Tissues from Patients with IgA Nephropathy / 대한신장학회잡지

Progressive nephropathies are characterized by the enhanced accmulation of extracellular matrix in the kidney. Overproduction of transforming growth factor-beta(TGF-beta) was shown to result in pathological fibrosis of tissue via the accumulation of extracellular matrix proteins. It has been proposed that angiotensin II stimulates the production of TGF-beta. Despite accumulating volume of data supporting the effects of angiotensin converting enzyme(ACE) inhibitors in the attenuation of TGF-beta in vitro and in rats, studies in humans are absolutely lacking. There is evidence that TNF-alpha expression is increased in various glomerulonephritis. The present study sought to determine the effects of ACE inhibitors on TGF-beta1 and TNF-alpha in patients with IgA nephropathy. Using competitive polymerase chain reaction, TGF-beta1 and TNF-alpha mRNA abundance were measured. Patients taking ACE inhibitors showed significantly lower renal TGF-beta1 gene expression compared with patients not on these medications(ratios of TGF-beta1/beta-actin, 4.27+/-0.62 versus 14.81+/-3.87, p<0.05), whereas no difference was noted between patients on ACE inhibitors and normal controls(4.27+/-0.62 versus 2.78+/-0.71). ACE inhibitor therapy did not affect the TNF-alpha mRNA expres- sion in renal tissue. In conclusion, we observed a significant reduction of the TGF-beta1 expression in the kidney by ACE inhibitors, and this suggests that the effects of ACE inhibitors observed in animals can be extrapolated to patients with chronic renal disease.

Clinical Study of Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Antagonist Combination Therapy in Renal Patients / 대한신장학회잡지

BACKGROUND: Angiotensin-converting enzyme inhibitors(ACEi) do not decrease plasma angiotensin II levels in chronic use to the same extent as in acute use. this reincrease in angiotensin II level is explained either by a renin-mediated reactive rise in plasma angiotensin I or by non-ACE dependent angiotensin II generation. The aim of this study was to compare the additive effects of an ACEi and angiotensin II receptor antagonist(AT1a) in antiproteinuric effect, hyperkalemia, and hypotension. METHODS: 58 outpatients with chronic renal insufficiency were included and they were randomly classified into two groups : Group I(prescribed AT1a only), Group II(AT1a and ACEi combination therapy), and the changes of serum creatinine, the amount of proteinuria, the developement of hyperkalemia, and hypotension were evaluated. RESULTS: In group I, the amount of proteinuria decreased to 92.8% of initial amount at 1 month after the start of drugs. 2 of 28 patients(7.1%) developed hyperkalemia, and serum creatinine did not change (1.686+/-1.415mg/dL 1.821+/-1.301mg/dL, p=0.289). But in combination therapy group, serum creatinine level increased from baseline value of 1.466+/-0.619mg/dL to 1.800+/-0.881mg/dL(p=0.05), proteinuria did not change (101% of initial amount), and 7 of 30 patients(23.3%) developed hyperkalemia. CONCLUSION: Combination therapy seems to have no additive antiproteinuric effect, but serum creatinine and potassium levels should be closely monitered during the combination therapy.

Effect of High Glucose, Angiotensin ll and Aniotenisn Converting Enzyme Inhibitor on the Expression of PC alpha1(IV) mRNA in Cultured Human Mesangial Cells / 대한신장학회잡지

OBJECTIVE: Diverse glomerular disorders leadsing to progressive glomerulosclerosis share the common features of increased mRNA expression for extra- cellular matrix protein and growth factors. The precise role of angiotensin II in contributing to these disturbances is currently unknown. ACE inhibitors have been proved to be beneficial in protecting against glomerular injury in animal models and many of human glomerular diseases. Type IV collagen is a main component of extracellular matrix in the mesangium : its increased accumulation is a common pathologic finding in the glomerulosclerosis. There are some evidences that the beneficial effect of ACE inhibitor does not solely depend on the hemodynamic effect, but may be mediated by other effect. The purpose of this study is to evaluate the effects of high glucose, angiotensin II and angiotensin converting enzyme inhibitor on the expression of PC alpha1(lV) in mesansial cells(MCs). METHODS: Human mesangial cells were cultured with standard method. To investigate the effect of each drug and high glucose condition, MCs were cultured in the normal-glucose medium(100mg/dl) and high-glucose medium(450mg/dl), respectively. An- giotensin II and angiotensin converting enzyme inhibitor(captopril) were added to culture medium at final concentration of 10 M which is the physiologic dose in vivo. MCs were cultured in each condition for 3days, when the maximal effect of high glucose on MCs, and harvested for mesurement of the expression of PC alpha1(IV) mRNA. To quantitate the PC alpha(1V) mRNA levels in each condition, semiquantitatine RT-PCR was done with co-amplification of house keeping gene. RESULTS: PCa1(IV) mRNA expression was significantly increased in high-glucose medium(30mM) compared to normal-glucose medium(5.5mM)(2.28+/-0.34 vs 0.96+/-0.08, p(IV) mRNA expression to 4.64+/-0.28(p<0.05). Angiotensin II in the normal-glucose medium increased the PC alpha1(lV) mHNA expression as 2.69+/-0.23 control(p<0.05). Addition of angiotensin converting enzyme inhibitor(Capopril, 10(-6)M) in high- glucose culture medium significantly suppressed the PC alpha1(IV) mRNA expression as 0.690.11(p<0.05). CONCLUSION: High glucose concentration in culture medium significantly increases the mRNA expression of procollagen alphal(IV) than normal glucose concentration. Angiotensin II increases the collagen mRNA expression directly and this effect was significantly prevented by ACE inhibitor. This result suggests that hyperglycemia in diabetic millieu can directly increase collagen production, and ACE inhibitor may inhibit progressive glomerulosclerosis by decreasing collagen production as well as reducing intraglomerular pressure.

Antihypertensive effect and safety of imidapril on the patient with essential hypertension / 영남의대학술지

Imidapril(Tanatril(R)), a newly developed ACE inhibitor, has been used to treat hypertension and congestive heart failure. This study was designed to assess the antihypertensive effect and safety of Imidapril(Tanatril(R)) in patient with essential hypertension. 5-10mg of imidapril(Tanatril(R)) was administered once day in 30 patients with essential hypertension and followed up to 8 weeks. We tested the drug's effectiveness, safety, and the incidence of imidapril induced dry coughs. After 8 weeks of treatment with Imidapril, 76.2%(16/21) of patient showed lowered blood pressure and 47.6% showed normal blood pressure. The overall incidence of adverse effects was 33.3%(7/21). and among these adverse effects. dry cough was shown in only 9.5%. Thus, concluded that imidapril(Tanatril(R)) is as safe and effective as other ACE inhibitors. especially with imidapril showing very little incidence of dry cough compared to other ACE inhibitors.

A case of "scleroderma renal crisis" developed from diffuse scleroderma / 대한내과학회지

Polymyositis is an inflammatory, autoimmune disease of the skeletal muscle characterized by symmetrical, proximal muscle weakness, elevated muscle enzymes, and characteristic features on electromyogram and muscle biopsy. The kidneys are generally spared and myoglobinuric renal failure is very rare in polymyositis. There have been infrequent reports of polymyositis developing myoglobinuric renal failure secondary to rhabdomyolysis. The flare-up may occur in polymyositis, usually manifest within several weeks to months of achieving a remission. But, rhabdomyolysis and myoglobinuric renal failure was a very rare feature of the relapse of polymyositis. We present a case report of patient with polymyositis who initially presented and relapsed as rhabodomyolysis that lead to myoglobinuric, oliguric renal failure and required transient dialytic support.

The Effect of ACE Inhibitors on the Gene Expression of Various Cytokines in Peripheral Blood Mononuclear Cells from Patients with Glomerular Diseases: TGF-beta, IL-6, IL-10 and TNF-alpha / 대한신장학회잡지

Angiotensin II(ANG II) has been known to induce systemic and glomerular hypertension, which leads to renal tissue injury and progressive fibrosis of kidney. Some effects of ANG II may be mediated by its effect on the cytokine synthesis. In the present study, we investigated the effect of ANG II inhibition on the expression of various cytokines implicated in the pathogenesis and progression of the kidney disease. Blood samples of 11 patients with glomerulonephritis were obtained before the ACE inhibitor therapy and then while they were taking ACE inhibitors. Using peripheral blood mononuclear cells(PBMC) harvested from the samples, RT-PCR was performed to evaluate the changes in mRNA expression of TGF-beta1, IL-6, TNF-alpha and IL-10. The ratios of target cytokines and beta-actin were calculated. TGF-beta1 mRNA expression was decreased in five pat ients after ANG II inhibition with ACE inhibitors, while it was increased in the remaining six patients. ACE inhibitors consistently decreased IL-6 mRNA expression in all 11 patients. IL-10 expression was decreased in 4 patients, and increased in 3 patients after ANG II inhibition. It was not expressed in 4 patients. TNF-alpha expression was increased in 8 patients, and decreased in only 1 patient. In two patients, it was not changed while on ACE inhibitors. Conclusion: ACE inhibitors attenuate IL-6 expression consistently in all 11 patients. This is the first-time demonstration of the in vivo inhibitory effect of ACE inhibitors on IL-6 mRNA expression in humans. The lack of significant suppression of TGF-beta1 in PBMC suggests that the in vivo attenuating effect of ACE inhibitors on TGF-beta1 may be derived from renal hemodynamic changes. The tendency of heightened expression of TNF-alpha confirms the previous investigations in which IL-6 was shown to down regulate TNF-alpha expression