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13-zagrapanSelected parameters of insulin sensitivity in hypertensive patients after the change in
therapy from angiotensin converting enzyme inhibitors to angiotensin II type I receptor
(General Medicine, Year 2)
Supervisors: MUDr. Richard Imrich, PhD., Ing. Štefan Zórad, PhD.
Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava
Candesartan, angiotensin II receptor (AT1) antagonist, has been used as an effective antihypertensive drug for
several years. In addition to the antihypertensive actions, data from animal models showed fat tissue mass
lowering effects, adipose tissue hypotrophy and reduction in adipocyte size of the drug (1). Furthermore, AT1
antagonists have been shown to improve insulin sensitivity and reduce inflammation, the mechanisms implicated
in prevention or retardation of coronary heart disease (2, 3). In the present pilot study, we investigated effects of
candesartan cilexetil therapy on changes in adiposity and glucose metabolism in subjects with primary
Fourteen (N=14) men aged 33-64 years with primary hypertension (European Society of Hypertension/European
Society of Cardiology Grade 1 and 2) treated with angiotensin-converting enzyme inhibitors (ACEI) participated
in the study. The patients were studied before and six months after ACEI were replaced with candesartan
cilexetil in treatment of hypertension, while any other additional antihypertensive medication remained
unchanged. The following procedures were performed before and after the change in hypertension treatment:
• anthropometric measurements including height, weight, body fat % (Omron BF306, Omron Healthcare Europe B.V., The Netherlands), waist/hip ratio), • blood pressure and heart rate measurements, • adipocyte size measurements from subcutaneous adipose tissue biopsy as previously described (1, 4), • the oral glucose tolerance test (OGTT), in which 75g of glucose dissolved in 200ml of liquid were given after an overnight fast; venous blood samples were withdrawn from antecubital vein before and every 15min after the start of OGTT up to 120min; blood samples withdrawn at the start of the examination before any other procedures were conducted were used for determination of fasting levels of glucose, insulin and C-peptide Plasma glucose was measured by glucose oxidase method. Insulin and C-peptide was measured by immunoradiometric assay (Immunotech, France). Plasma samples of one patient were excluded from the study due to poor compliance with overnight fast requirements. The study was approved by the local ethics committee and informed consent was obtained from all participants prior to examination. Statistical analysis Changes in glucose, insulin and C-peptide were analyzed by two-way ANOVA for repeated measurements. Paired Student’s t-test was used to compare mean baseline values for other variables. Results
Six months after change from ACEI to candesartan, the systolic and diastolic blood pressures was lower
(p<0.05) compared to pre-change values; systolic blood pressure decreased by 6.95 ± 4.07 mmHg, diastolic
blood pressure decreased by 5.68 ± 2.35 mmHg. Fasting glycemia was lower (p<0.01) after change from ACEI
to candesartan; the mean fasting plasma glucose decreased by 0.84 ± 0.06 mM. Changes in all other analysed
characteristics were not found to be statistically significant.
Table 1: Measured characteristics before and after the change in prescription to candesartan cilexetil.
after prescription change to
before prescription change
ISI(MATSUDA) [mg-1 x dl x mIU-1 x l] (5) ISI(CEDERHOLM) (5) [mg.l2 x mmol-1 x mIU-1 x min-1] insulin OGTT AUC per 120min [µU x ml-1 x min] Data are expressed as mean ± SD. Quantitative Insulin Sensitivity Check (QUICKI) = 1/log(fasting glucose) + log(fasting insulin), Insulin Resistance Homeostasis Model Assessment (IRHOMA= (fasting insulin x fasting glucose)/22.5), ISI – insulin sensitivity index. SBP – systolic blood pressure, DBP – diastolic blood pressure, m – weight, BMI – body mass index = m/h2, BF – body fat, insulin OGTT AUC – area under curve for insulin 0 to 120min, NS – non-significant. Quantitative statistical assessment of OGTT glucose, insulin and C-peptide curves by ANOVA yielded that any variation among the patients before and after the change of prescription was not statistically significant. Figure 1: Plasma glucose (left) and insulin (right) during the oral glucose tolerance test in primary
hypertension patients before (white circles) and after (black squares) treatment switch from ACEI to
candesartan. Error bars shown as ± SD.
Primary hypertension (HT) as the risk factor for stroke, cardiovascular diseases and renal insufficiency is among
the most frequently medically treated conditions (6). It appears that lowering of blood pressure per se
irrespective of pharmacotherapy, has a direct positive effect in decreasing the risk of HT-related problems (7). A
meta-analysis comparing effects of different antihypertensive regimens found a possible decrease in the risk of
stroke, coronary heart disease, heart failure and cardiovascular death by 28-38%, 20%, 16% and 22%,
respectively (8). Nevertheless, the risk lowering potential varies among first-line antihypertensives. These effects
seem to be largely due to variation among antihypertensives in clinical efficacy of blood pressure control.
However, blood pressure-independent factors such as different modes of action, pharmacokinetics and the degree
of end organ protection (kidney, heart, vascular system and brain) probably also play a role (8). Furthermore,
tolerability and potential side-effects are considered when it comes to the choice of treatment for the individual
As expected, our results showed that candesartan had blood pressure lowering effects, which were comparable to
those of ACEI. This result is in line with other larger studies comparing ACEI or ARB efficacy in primary
hypertension treatment (9, 10). Although the change from ACEI to candesartan resulted in lowering of fasting
plasma glucose, there were no other signs of improvement in insulin sensitivity observed in our study. Six
months of candesartan treatment had only modest effect on adipocyte size with no change in the anthropometric
markers of body fat quantity used in our study.
The study was supported by grant of Slovak Ministry of Health MZ2007/27-SAV-02.
AT1 - Angiotensin II receptor type I
ACEI – angiotensin converting enzyme inhibitor
ARB – angiotensin receptor blockers
HT – hypertension
OGTT – oral glucose tolerance test
1. Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J, Saavedra JM: Long-term angiotensin II
AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of
adiponectin and PPARgamma. Eur J Pharmacol. 2006 Dec 15; 552(1-3): 112-22.
2. Higashiura K, Ura N, Miyazaki Y, Shimamoto K: Effect of an angiotensin II receptor antagonist,
candesartan, on insulin resistance and pressor mechanisms in essential hypertension. J Hum Hypertens. 1999
Jan; 13 Suppl 1: S71-4
3. Koh KK, Quon MJ, Han SH, Chung WJ, Lee Y, Shin EK: Anti-inflammatory and metabolic effects of
candesartan in hypertensive patients. Int J Cardiol. 2006 Mar 22; 108(1): 96-100
4. Skopkova M, Penesova A, Sell H, Radikova Z, Vlcek M, Imrich R, Koska J, Ukropec J, Eckel J, Klimes I,
Gasperikova D: Protein array reveals differentially expressed proteins in subcutaneous adipose tissue in obesity.
Obesity (Silver Spring). 2007 Oct ; 15(10): 2396-406
5. Radikova Z: Assessment of insulin sensitivity/resistance in epidemiological studies. Endocr Regul. 2003 Sep;
6. Mancia G, Grassi G: Management of essential hypertension. Br Med Bull. 2010 Feb 8; 1-11
7. Mancia G: Blood pressure reduction and cardiovascular outcomes: past, present, and future. Am J Cardiol.
2007 Aug 6; 100(3A): 3J-9J
8. Turnbull F, Blood Pressure Lowering Treatment Trialists' Collaboration: Effects of different blood-pressure-
lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised
trials. Lancet. 2003 Nov 8; 362(9395): 1527-35
9. Ong HT: Are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers especially useful for
cardiovascular protection? J Am Board Fam Med. 2009 Nov-Dec ; 22(6): 686-97
10. Uchiyama-Tanaka Y, Mori Y, Kishimoto N, Fukui M, Nose A, Kijima Y, Yamahara H, Hasegawa T,
Kosaki A, Matsubara H, Iwasaka T: Comparison of the effects of quinapril and losartan on carotid artery
intima-media thickness in patients with mild-to-moderate arterial hypertension. Kidney Blood Press Res. 2005;
Does Mental Illness Exist? By Dr. Edward Watke Jr. I. Mental Illness -- Becomes a New Theory A . Historical aspects 1 . Historically, illness was referred to as a bodily disorder. 2 . Altered bodily structure constituted illness. B. A new criterion for determining illness came on the scene. When man began to label illness on the basis of observing behavior a new criterion was