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PubMed1998

Thiazide-induced vasodilation in humans is mediated by potassium channel activation.

-Hydrochlorothiazide and indapamide are thought to exert their hypotensive efficacy through a combined vasodilator and diuretic effect, but in vivo evidence for a direct vascular effect is lacking. The presence and mechanism of a direct vascular action of hydrochlorothiazide in vivo in humans were examined and compared with those of the thiazide-like drug indapamide. Forearm vasodilator responses to infusion of placebo and increasing doses of hydrochlorothiazide (8, 25, and 75 microg. min-1. dL-1) into the brachial artery were recorded by venous occlusion plethysmography. Dose-response curves were repeated after local tetraethylammonium (TEA) administration to determine the role of potassium channel activation and, in patients with the Gitelman syndrome, to determine the role of the thiazide-sensitive Na-Cl cotransporter in the vasodilator effect of hydrochlorothiazide. Vascular effects of hydrochlorothiazide were compared with those of indapamide in both normotensive (mean arterial pressure, 85+/-7 mm Hg) and hypertensive (mean arterial pressure, 124+/-16 mm Hg) subjects. At the highest infusion rate, local plasma concentrations of hydrochlorothiazide averaged 11.0+/-1.6 microg/mL, and those of indapamide averaged 7. 2+/-1.5 microg/mL. In contrast to indapamide, hydrochlorothiazide showed a direct vascular effect (maximal vasodilation, 55+/-14%; P=0. 013), which was inhibited by TEA (maximal vasodilation after TEA, 13+/-10%; P=0.02). The response was not dependent on blood pressure and was similar in patients with Gitelman syndrome, indicating that absence of the Na-Cl cotransporter does not alter the vasodilatory effect of hydrochlorothiazide. The vasodilator effect of hydrochlorothiazide in the human forearm is small and only occurs at high concentrations. The mechanism of action is not mediated by inhibition of vascular Na-Cl cotransport but involves vascular potassium channel activation. In contrast, indapamide does not exert any direct vasoactivity in the forearm vascular bed.

Antihypertensive Agents↗
PubMed1994

Lower dose diuretic therapy in the treatment of patients with mild to moderate hypertension.

Indapamide (Lozol), an indoline antihypertensive drug with diuretic and vasodilating activities, was evaluated in 195 patients with mild to moderate essential hypertension (sitting DBP between 95 and 110 mmHg) in a multicentre, randomised, double-blind, parallel-group design trial. A four week single-blind placebo wash-out period was followed by an eight week double-blind period. Patients were randomised to indapamide 1.25 mg/day or to placebo. The primary efficacy endpoint was the mean change in sitting DBP from baseline to week 8. Ninety patients in the placebo group (93%) and 82 patients (84%) in the indapamide group completed the eight weeks of double-blind therapy. Indapamide produced a mean (SE) decrease in sitting DBP of 7.4 (0.63) mmHg (from 100.1 to 92.8 mmHg) compared with a decrease of 3.6 (0.75) mmHg (from 99.6 to 95.8 mmHg) produced by placebo (p < 0.0001). Indapamide and placebo also produced mean decreases in standing DBP of 6.8 (0.75) and 2.8 (0.77) mmHg, respectively (p = 0.0002), in sitting SBP of 11.1 (1.18) and 3.2 (1.35) mmHg, respectively (p = 0.0001) and in standing SBP of 11.4 (1.29) and 4.0 (1.43) mmHg, respectively (P = 0.0002). Reduction in BP of > or = 10 mmHg or to a DBP of < or = 90 mmHg was more frequent (P = 0.0005) among indapamide (46.6%) compared with placebo (23.7%) treated patients. During the eight week double-blind treatment period, incidence rates for all adverse experiences and for drug-related adverse experiences were similar between the two treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

The effect of treatment with low dose ACE inhibitor and/or diuretic on coronary microvasculature in stroke-prone spontaneously hypertensive rats.

Angiotensin II is considered to have angiogenic properties. Nevertheless, several authors reported an increase in coronary capillary density after treatment with ACE inhibitors. The aim of the present study was to evaluate the effect of treatment with low doses of ACE inhibitor perindopril, low doses of the diuretic indapamide, or a combination of the two on microvascular structure in hearts from stroke-prone spontaneously hypertensive rats (SHR-sp). Young adult male SHR treated with indapamide (0.24 mg/kg/day), perindopril (0.76 mg/kg/day), or both were compared with untreated animals after 8 or 14 weeks of treatment. Survival of SHR-sp was significantly increased after treatment. Only perindopril alone or in combination with indapamide significantly decreased blood pressure and cardiac mass. Treatment also significantly increased capillary and myocyte densities but arteriolar density tended to decrease. External and internal diameters significantly increased in treated animals while arteriolar thickness remained the same. Thus, thickness in vessels of the same size was the greatest in untreated animals, followed by indapamide- and perindopril-treated rats with the thinnest walls in rats with combined treatment, and the treatment resulted in a significant increase in the lumen to wall ratio. Capillary and arteriolar growth responses in treated animals seem to indicate that the two are independently regulated processes. Treatment with indapamide alone at this dosage did not significantly influence most responses but in combination with perindopril it strengthened the effect of perindopril.

Angiotensin II↗
PubMedDate not supplied

Bioavailability and pharmacokinetics of a fixed combination of delapril/indapamide following single and multiple dosing in healthy volunteers.

The study objective was to obtain detailed information on the bioavailability and pharmacokinetics of the new fixed combination of delapril and indapamide following single and multiple dosing. For this reason, the study was performed in two parts, separated by a medication-free period of at least 7 days. In the single dose part, one tablet, containing 30 mg delapril and 2.5 mg indapamide, was administered to 12 male volunteers; in the multiple dose part, the volunteers received one tablet of the test preparation, once daily over 7 days. Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods. In addition, urine samples were collected following single and multiple dosing for evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine. For the area under the curve, calculated from time 0 to infinity (AUC(0-infinity)) the study revealed, following single dosing, mean values of delapril and its metabolites M1, M2 and M3 of 281, 2178, 739 and 716 h.ng/ml, respectively; for indapamide the mean value was 1597 h.ng/ml. The corresponding mean values found after multiple dose administration were 272, 2071, 857 and 598 h.ng/ml for delapril and its metabolites, respectively and 1536 h.ng/ml for indapamide. Evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine (Ae) demonstrated mean values following single dosing (observation period 36 h) of 705, 4521, 454 and 4203 micrograms, respectively; the corresponding values after multiple dose administration (observation period 24 h) of the test preparation were 655, 4679, 469 and 4801 micrograms, respectively. The most important pharmacokinetic parameters AUC(0-infinity) and Ae were statistically compared by analysis of variance (ANOVA) and 90% confidence intervals were calculated. It may be concluded from the results of this study, that the bioavailability and pharmacokinetic parameters of the test preparation after single dosing and after multiple doses correspond well. The undesired side effects observed are known to occur after administration of the test preparation. The occurrence was a little more frequent after multiple dose application in comparison with the single dose administration.

Adult↗
PubMed1995

Carotid artery mechanical properties of Dahl salt-sensitive rats.

We evaluated the mechanical properties of the carotid artery in anesthetized Dahl rats with or without long-term treatment with the diuretic compound indapamide. The mechanical properties of the carotid artery were evaluated by establishing pressure-volume curves in situ in vivo before and after total relaxation of arterial smooth muscle by potassium cyanide. Dahl salt-sensitive and salt-resistant rats were fed either a low (0.4%) or high (7%) NaCl diet for 5 weeks. In each group, half the rats received for the same period of time oral treatment with indapamide (3 mg/kg per day). Blood pressure, heart rate, and pressure-volume curves were studied at the end of the 5-week period. In untreated Dahl salt-sensitive rats, the pressure-volume curve of the carotid artery was shifted to the right compared with that in untreated Dahl salt-resistant rats. The finding was observed even after potassium cyanide and regardless of the NaCl diet (P < .01 between Dahl salt-sensitive and -resistant rats). Indapamide was able to prevent the development of hypertension in Dahl salt-sensitive rats receiving a high NaCl diet (185 +/- 7 versus 146 +/- 8 mm Hg in untreated and treated Dahl salt-sensitive rats with a high NaCl diet, P < .0005). In the other groups, indapamide had no effect on blood pressure. Indapamide treatment increased carotid arterial static compliance in Dahl salt-sensitive rats with a high or low NaCl diet and to a lesser extent in Dahl salt-resistant rats. The increase was observed even after total relaxation of carotid arterial smooth muscle by potassium cyanide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of antihypertensive drugs on renal function and atrial natriuretic polypeptide in spontaneously hypertensive rats with renal ablation.

To determine whether pharmacological control of blood pressure could affect the renal function and levels of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) with renal ablation, and to ascertain the benefits of antihypertensive drugs, we studied effects of oral administration of captopril (50 mg/kg/day), an inhibitor of angiotensin converting enzyme, benidipine (3 mg/kg/day) and nilvadipine (10 mg/kg/day), newly developed blockers of calcium channel, and indapamide (10 mg/kg/day) for 14 days on systolic blood pressure, serum creatinine, blood urea nitrogen, and plasma ANP concentration in SHR subjected to surgical removal of the left kidney and infarction of two-thirds of the right kidney (5/6 nephrectomy) a week before. Three weeks after the surgery, systolic blood pressure (mmHg) in the untreated group was 253 +/- 9 (n = 10), in the captopril group 156 +/- 9 (n = 7, p less than 0.05), in the benidipine group 197 +/- 9 (n = 7, p less than 0.05), in the nilvadipine group 146 +/- 9 (n = 7, p less than 0.05) and in the indapamide group 206 +/- 5 (n = 7, p less than 0.05). Serum creatinine (mg/100 ml) was lower in the captopril group (0.58 +/- 0.02, n = 7, p less than 0.05) and in the benidipine group (0.50 +/- 0.03, n = 7, p less than 0.05) but not in the nilvadipine group and in the indapamide group 3 weeks after 5/6 nephrectomy compared to the untreated group. Blood urea nitrogen was also lower in the captopril group and in the benidipine group but not in the nilvadipine group and in the indapamide group. Plasma ANP concentration was significantly reduced by the treatment with captopril and benidipine but not with nilvadipine and indapamide. These results suggest that the reduction of blood pressure by the inhibition of angiotensin converting enzyme with captopril has the potential to ameliorate renal function of the SHR with remnant kidney, a model of chronic renal failure with hypertension, associated with the decreased concentration of plasma ANP. However, it remains to be determined whether the reduction of blood pressure by calcium channel blockers may be involved in the delayed progression of renal failure in this model since there were disparate effects on renal function and plasma ANP concentration with these two calcium channel blockers.

Animals↗
PubMed1989

[Cicletanine tolerance in hypertensive patients with metabolic disorders].

In this double-blind trial, the clinical and biochemical side-effects of cicletanine 150-200 mg/day were compared with those of indapamide 2.5 mg/day in a population of hypertensive with such metabolic disorders as diabetes mellitus, obesity, hyperlipidaemia or hyperuricaemia. Sixteen patients received cicletanine and 15 indapamide; 2 patients in the indapamide group were excluded, one for undesirable effect, the other for unexpected effect. The two treatments did not produce any significant change in natremia, glycaemia, uricemia, creatininemia or blood lipid level. Kalemia remained stable under cicletanine but was significantly reduced under indapamide, requiring supplementation with potassium salts in 5 patients. Both cicletanine and indapamide proved to be effective as antihypertensive drugs, although blood pressure levels at inclusion were different in each of the two groups.

Antihypertensive Agents↗
PubMed1994

Alteration of renal receptors for atrial natriuretic peptide and vasopressin in spontaneously hypertensive rats treated with antihypertensive diuretics.

To investigate the alteration of the renal atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) receptors in the controlled hypertensive state of spontaneously hypertensive rat (SHR) treated with antihypertensive diuretics, 12 weeks old SHRs were administered an antihypertensive diuretic, furosemide, trichloromethiazide, or indapamide, daily for 10 days and investigated by radiolabeled receptor assay (RRA) of ANP and AVP. The urine volume was significantly increased in all groups treated with antihypertensive diuretics as compared with the untreated control group on day 3. Systolic blood pressure was significantly decreased in groups treated with both trichloromethiazide and indapamide. The number of renal ANP receptors decreased; affinity was increased only in the SHR administered indapamide. The affinity of the renal AVP receptor was also decreased in that group. Alteration of ANP and AVP receptors was observed only in the group treated with indapamide. This indicates that the ANP and AVP receptor in the kidney of SHR was changed not only by diuresis or reduction of blood pressure, but by the pharmacological action of indapamide.

Animals↗
PubMed1999

Reversal of impaired calcium homeostasis in the rat diaphragm subjected to Monocrotaline-induced pulmonary hypertension.

Monocrotaline (MCT) pneumotoxicity is known to alter the structure of pulmonary vascular wall and impairs endothelial cell function resulting in pulmonary hypertension. Its effect on the diaphragm muscle has not yet been elucidated. This study examines the effect of MCT pneumotoxicity on calcium transport in the rat diaphragm. Pulmonary hypertension induced by MCT pneumotoxicity caused a significant increase (P < 0.001) in calcium accumulation in strips isolated from rat diaphragms. Treatment of rats having received MCT with Indapamide reduced calcium uptake by diaphragmatic strips to levels that are not significantly different from the control (P > 0.05). Treatment with Indapamide alone did not elicit any change in calcium accumulation in the diaphragmatic strips. Treatment of the animals with MCT, Indapamide or both did not produce any significant change (P > 0.05) in the cell volume of the diaphragmatic strips. Pulmonary hypertension increased calcium uptake by the muscle cells in the rat diaphragm which may alter diaphragmatic contractility; an effect that was prevented by Indapamide.

Animals↗
PubMed1993

Diuretic effects on cardiac hypertrophy in the stroke prone spontaneously hypertensive rat.

OBJECTIVE: The aim was to compare the effects of two diuretics, indapamide and hydrochlorothiazide, on cardiac hypertrophy in stroke prone spontaneously hypertensive rats (SHR-SP). METHODS: Six week old SHR-SP, on a 1% sodium chloride water intake, were treated with oral indapamide (3 mg.kg-1 x d-1) or hydrochlorothiazide (20 mg.kg-1 x d-1) over a 44 d period. The hypertrophic process was evaluated by classical indices and by the morphological analysis of myocyte cross sectional area, coronary artery thickness, and immunohistochemical analysis of interstitial fibrosis. RESULTS: In the untreated SHR-SP on 1% sodium chloride, all animals developed severe hypertension and cardiac hypertrophy when compared to normotensive salt loaded WKY by 13 weeks of age. In salt loaded SHR-SP treated with indapamide or hydrochlorothiazide, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP, at 259(7) and 245(7) mm Hg respectively, v 300(11) mm Hg, p < or = 0.05. Myocyte enlargement appears to be the main feature involved in the development of cardiac hypertrophy in the SHR-SP. By the end of treatment both indapamide and hydrochlorothiazide prevented the development of cardiac hypertrophy evaluated by heart weight to body weight ratio [4.69(0.07) and 4.61(0.08) respectively, v 5.39(0.13), p < or = 0.001] and myocyte hypertrophy (-33% and -21% of the SHR-SP values, p < or = 0.001). Myocardial interstitial fibrosis and perivascular fibrosis were practically absent in the two treated groups. CONCLUSIONS: Our results allow the characterisation of SHR-SP cardiac hypertrophy and indicate that the two types of chronic diuretic treatment prevent SHR-SP cardiac hypertrophy with a drug specific efficiency.

Animals↗
PubMed1997

Sodium, survival, and the mechanical properties of the carotid artery in stroke-prone hypertensive rats.

BACKGROUND: Reduction in sodium intake improves the survival of stroke-prone spontaneously hypertensive rats (SHR-SP) without causing any change in their blood pressure. OBJECTIVE: To investigate whether the diuretic indapamide improves survival of SHR-SP and whether changes in the structure and the function of large arteries are associated with survival. EXPERIMENTAL DESIGN: Forty-eight hypertensive rats aged 6 weeks were divided into three groups: a control SHR-SP group (n = 24) and a control spontaneously hypertensive rat (SHR) group (n = 12), with 1% saline drinking water; and an indapamide-treated SHR-SP group (n = 12) with 1% saline drinking water administered 1 mg/kg per day indapamide via their food. At the end of a 12-week follow-up period, pulsatile changes in blood pressure and common carotid artery diameter (measured by high-resolution echo-tracking techniques) were determined and aortic histomorphometry was performed. RESULTS: By the end of the study 58% of the SHR-SP control group rats had died. There were no deaths in the other two groups. In these two groups the mean blood pressure (217+/-10 and 212+/-7 mmHg), carotid diameter and distensibility (0.48+/-0.09 and 0.61+/-0.22 mmHg[-1]), arterial thickness (116+/-4 and 116+/-3 microm), and collagen content of the arterial wall were identical. In the SHR-SP control group the mean blood pressure was significantly lower (168+/-9 mmHg), the carotid distensibility was higher (1.47+/-0.35 mmHg[-1]), and the arterial thickness (138+/-5 microm) and collagen content were substantially higher than those in the other two groups. In the study population as a whole, for a given mean arterial pressure the carotid distensibility was identical in the three groups, although the arterial thickness was substantially greater in the SHR-SP control group rats. CONCLUSIONS: The study provides evidence that the diuretic compound indapamide improved the survival of SRH-SP even though their blood pressure was higher than that of untreated animals, and that genetic sensitivity to sodium, rather than blood pressure, influences the changes in arterial structure.

Animals↗
PubMed1994

Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries.

We examined the role of K+ channels in mediating the acute vascular actions of hydrochlorothiazide, indapamide, cicletanine, and cromakalim, studying the effect of K+ channel blockers on drug-induced relaxation and drug-induced 86Rb efflux in guinea pig mesenteric arteries. Cromakalim-induced relaxation was unaffected by charybdotoxin, apamin, or phencyclidine (PCP) but was reduced by 75% (with 30 microM cromakalim) by glibenclamide (p < 0.001). Cromakalim increased 86Rb efflux from guinea pig vessels, an effect that was abolished by glibenclamide. Hydrochlorothiazide and cicletanine-induced relaxations have been shown to be inhibited by charybdotoxin by unaffected by glibenclamide, apamin, or PCP. Hydrochlorothiazide and cicletanine increased 86Rb efflux from guinea pig mesenteric arteries. These increases were abolished by charybdotoxin. Indapamide-induced relaxation was not affected by incubation with any of the K+ channel blockers. Indapamide did not alter basal 86Rb efflux. The results suggest that in guinea pig mesenteric arteries indapamide-induced relaxation is not mediated by an action on K+ channels. Cromakalim-induced effects are mediated by KATP. Large conductance KCa mediates the hydrochlorothiazide and cicletanine-induced vascular effects in part.

Animals↗
PubMed2005

C-reactive protein elevation predicts pulse pressure reduction in hypertensive subjects.

Cross-sectional studies have shown a positive association between increased pulse pressure (PP) and an increased likelihood of a C-reactive protein (CRP) level >3 mg/L. In a retrospective subgroup analysis of the hypertensive subjects of the multicenter double-blind study, REASON (PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd), in which fixed first-line antihypertensive combination therapy with an angiotensin converting enzyme (ACE) inhibitor, perindopril (2 mg), and a diuretic, indapamide (0.625 mg), proved significantly more effective than atenolol in normalizing PP, we sought to determine whether perindopril plus indapamide was also more effective than atenolol in lowering CRP levels and, if so, whether this effect correlated with a preferential reduction in PP. At the final visit (12 months) in the 269 patients studied, the decrease in PP was greater, and the proportion of patients with CRP >3 mg/L lower (17.9% versus 28. 9%, P=0.03; adjusted odds ratio, 1.02 to 4.08, P=0.01), in the perindopril plus indapamide group than in the atenolol group. After adjustment for confounders, patients with a baseline CRP >3 mg/L displaying the greatest decrease in PP were more likely (P=0.04) to have a CRP < or =3 mg/L at 12 months. No such relationship was found with systolic or diastolic blood pressure. Perindopril-indapamide combination therapy is more effective than beta-blockade in lowering elevated CRP in hypertensive subjects. This effect is significantly associated with a more effective PP reduction in patients with baseline CRP >3 mg/L.

Adrenergic beta-Antagonists↗
PubMed1999

[Renaissance of diuretics in the treatment of hypertension].

Diuretics and beta-blockers are the only antihypertensives known for their significant reduction of cardiovascular morbidity and mortality, particularly in the elderly. The use of low-dose diuretics can improve the efficacy-safety ratio. Hypokalemia, hypomagnesemia as well as disturbances of carbohydrate and lipid metabolism are dose-dependent side effects of diuretics but only minimal during the low-dose therapy. A novel low-dose formulation of indapamide was developed as a sustained-release (SR) coated tablet (1.5 mg/day) and compared to the immediate release (IR) formulation of indapamide (2.5 mg/day). A > 50% reduction in the number of patients with serum potassium levels < 3.4 mmol/l among hypertensive patients treated with indapamide SR as compared to IR was observed. Indapamide SR has also been shown to be effective (more than 20 mg enalapril) in the reduction of left ventricular mass index (LVMI) in hypertensive patients treated for one year (LIVE study). Therefore, low-dose diuretics are, in accordance with international recommendations for the low-dose antihypertensive drugs, a first line therapy of hypertension.

Antihypertensive Agents↗
PubMed1993

Ion channel involvement in the acute vascular effects of thiazide diuretics and related compounds.

The involvement of calcium and potassium channels in mediating the vascular actions of hydrochlorothiazide, indapamide and cicletanine were investigated in guinea pig small vessels mounted on the Mulvany myograph. Hydrochlorothiazide (10 microM) and cicletanine (10 microM) were weak calcium antagonists shifting the calcium dose-response curve half a log unit to the right. Indapamide was a far more potent inhibitor, a 10 microM concentration shifting the calcium dose-response curve 3 log units to the right and reducing maximal calcium contraction by 72% (P < .001). Relaxations to hydrochlorothiazide and cicletanine were reduced in the presence of charybdotoxin, a blocker of calcium-activated potassium channels (KCa). Maximal relaxation induced by hydrochlorothiazide (30 microM) was reduced by 91% and cicletanine-induced relaxation by 63%. In the presence of iberiotoxin, a more selective KCa inhibitor, maximal hydrochlorothiazide and cicletanine-induced relaxations were reduced by 73 and 60%, respectively. Neither drug's action was affected by incubation with glibenclamide, which inhibits ATP-sensitive K+ channels. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no effect on the indapamide-induced relaxation. These results show differences in the involvement of ion channels in the acute vasorelaxation produced by these drugs. Hydrochlorothiazide and cicletanine-induced relaxations appear to be mediated via KCa, whereas indapamide is a potent calcium antagonist.

Animals↗
PubMed1996

Use of antidiabetic and antihypertensive drugs in hospital and outpatient settings in Hong Kong.

OBJECTIVE: To investigate the usage patterns of antidiabetic and antihypertensive drugs and to identify any discordance between recommended management guidelines and clinical practice in two study locations. DESIGN: Prescription survey. SETTING: A government- operated general outpatient clinic (GOPC) and a medical/geriatric specialist clinic (SC) affiliated with a regional hospital in the same district. PATIENTS: Patients presenting with a prescription during the study period at the respective pharmacy were classified as having diabetes if at least one antidiabetic agent was prescribed and as having hypertension if a cardiovascular drug was prescribed in a hypotensive dosage. MAIN OUTCOME MEASURE: The pattern of use of antidiabetic and antihypertensive drugs. RESULTS: One thousand one hundred forty-four consecutive prescriptions were collected in the GOPC, and 1523 in the SC. Of 9.4% (n = 107) of patients were classified as having diabetes in the GOPC and 20.4% (n = 310) in the SC (p<0.001). Most patients with diabetes were taking oral hypoglycemic agents (98.1% in GOPC vs. 84.5% in SC). Glibenclamide was the sufonylurea used most often as monotherapy in both settings (50.5% in GOPC vs. 40.6% in SC). The combined use of a sulfonylurea with metformin was common in both settings (22.4% in GOPC vs. 28.4% in SC). Metformin monotherapy (1.9% in GOPC vs. 2.6% in SC) and combination treatment of insulin with an oral agent (0% in GOPC vs. 2.6% in SC) were rarely prescribed. In the GOPC, 24.5% (n = 280) of patients were prescribed an antihypertensive drug compared with 47.1% (n = 717) in the SC (p< 0.001). In the GOPC, the use of antihypertensive drugs was more prevalent in those with diabetes (53.5%) than in the remaining patients without diabetes (21.5%, p<0.001). In the SC, 51% of patients with diabetes were receiving antihypertensive drugs, but 40% of patients without diabetes were also receiving three treatments. In the GOPC, diuretics (indapamide 14.3% other 59%) and methyldopa (9.5%) were the most frequent choices of antihypertensive drugs when used as monotherapy in subjects without diabetes. In the SC, apart from diuretics (indapamide 12.9%, other 20.3%), beta-blockers (29%) also were prescribed frequently. If treated with only one antihypertensive drug, most patients with diabetes in the GOPC were prescribed indapamide (72.7%), and patients in the SC were treated mainly with angiotensin-converting enzyme inhibitors (35%) indapamide (22.5%), or calcium-channel blockers (13.8%). CONCLUSIONS: In this prescription-based survey, diabetes mellitus and hypertension were found to be common diseases in general practice and in a hospital SC. Oral hypoglycemic agents were the main from of antidiabetic therapy in both settings, with glibenclamide being the most commonly prescribed sulfonylurea. The types of antihypertensive drugs used were different in the two locations and varied according to the coexistence of type II diabetes mellitus. Despite some potential limitations, prescription-based surveys are an easy and economical method for surveying the occurrence of some common medical problems and the pattern of drug use in a fairly large number of patients in health institutions.

Adult↗
PubMed1999

Concomitant Block of the Rapid (I(Kr)) and Slow (I(Ks)) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization.

BACKGROUND: The delayed rectifier potassium current, which comprises both a rapid (I(Kr)) and as slow (I(Ks)) component, is a major outward current involved in repolarization of cardiac myocytes. I(Kr) is the target of most drugs that prolong repolarization, whereas electrophysiological effects resulting from combined block of I(Kr) and I(Ks) still need to be characterized. METHODS AND RESULTS: Studies in isolated, buffer-perfused guinea pig hearts were undertaken to compare lengthening of cardiac repolarization under conditions of I(Kr) block alone, I(Ks) Block alone, or combined block of I(Kr) and I(Ks). In protocol A, isolated perfusion with N-acetylprocainamide (NAPA) (I(Kr) block), indapamide (I(Ks) block), or combined NAPA/indapamide was performed at a pacing cycle length of 250 msec. Increases in monophasic action potential duration measured at 90% polarization (MAPD(90)) from baseline after perfusion with NAPA 100 µmol/L (IC(50) for block of I(Kr)) was 19 +/- 6 msed (P <.05), after indapamide 100 µmol/L (EC(50) for block of I(Ks)) 13 +/- 2 msec (P <.05), but 42 +/- 5 msec after combined NAPA 100 µmol/L and indapamide 100 µmol/L (P <.05 vs. baseline and isolated administrations), suggesting the possibility of excessive lengthening of cardiac repolarization by blocking both I(Kr) and I(Ks). As well, in protocol B where sequential perfusions with dofetilide (I(Kr) blocker), dofetilide/indapamide, and indapamide in the same hearts were used, combined dofetilide/indapamide infusion showed a greater increase in MAPD(90) during all pacing cycles studied (250 to 150 msec). CONCLUSIONS: Combined I(Kr) and I(Ks) block may lead to excessive lengthening of cardiac repolarization. This may predispose patients to proarrhythmia during coadministration of drugs.

Journal Article↗
PubMed1988

Formal comparison of the antihypertensive effects of torasemide and other diuretics by the Montevideo mathematical model.

A formal comparison is carried out of the antihypertensive effect of torasemide (1-isopropyl-3- ([4-(3-methylphenylamino)pyridine]-3-sulfonyl)urea) and various other diuretics used as monotherapy. The analyzed data are the results of various independent studies. The time (t) courses of the mean values of supine or sitting systolic (S) and diastolic (D) arterial blood pressure (P) during treatment are analyzed by fitting the "Montevideo mathematical model", described here, to the clinical (experimental) data. Clinically-important values of P and t evaluated from the fitted functions permit the formal comparisons. Decays in P were evaluated by the reductions in SP and DP occurred at 1.17 and 7.54 weeks of treatment, by the times at which the fitted functions showed diminutions of 10, 15 and 20 mmHg and of 10%, 15% and 20% with respect to pretreatment SP and DP mean values, and by the time at which DP attained a value of 90 mmHg. In studies in which the pretreatment mean value of DP ranged between 105.6 and 110.5 mmHg, standard-dose indapamide (2.5 to 5 mg/d), and low-dose torasemide (2.5 to 5 mg/d) elicited similar decays in SP and DP; the antihypertensive effects of etozoline (200 to 400 mg/d) and of hydrochlorothiazide (25 to 50 mg/d) were slower than those of torasemide and indapamide. Cyclothiazide (5 mg/d) and a coprescribed sodium-restricted diet reduced DP, from a pretreatment mean value of 114 mmHg, slower than torasemide and indapamide but quicker than etozoline and hydrochlorothiazide. Torasemide and indapamide should be consequently preferred for the chronic treatment of uncomplicated essential hypertension in terms of efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗