Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension

Summary To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients.We measured the insulin sensitivity index (S_I), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg·m^–2] had been on prior treatment with a thiazide diuretic in low dosage and/or a -adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg·m^–2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage.At entry (before placebo), S_I was slightly but not significantly lower in group A than B [2.7 vs. 3.6×10^–4 ml·U^–4·min^–1]; fasting plasma insulin was 13.6 vs. 12.9 U·ml^–1. After 6 weeks on placebo, S_I averaged 3.7 in group A and 4.4×10^–4 U·ml^–1·min^–1 in group B; fasting plasma insulin was 14.6 vs. 15.1 U·ml^–1, and glucose 5.5 vs. 5.5 mmol·l^–1. After 6 months on amlodipine there were no differences in S_I [group A vs. group B, 5.2 vs. 3.8×10^–4 ml·U^–1·min^–1], fasting insulin [13.0 vs. 12.7 U·ml^–1], glucose [5.4 vs. 5.5 mmol·l^–1], serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions. Compared with placebo, amlodipine significantly reduced systolic and diastolic blood pressures. Heart rate, body weight, and 24 h urinary sodium excretion were unaltered.Long-term treatment with amlodipine does not affect insulin sensitivity, circulating insulin or glucose, or lipoprotein metabolism in obese, non-diabetic patients with essential hypertension.     

Insulin sensitivity in normotensive subjects during angiotensin converting enzyme inhibition with fosinopril

Summary The effect of the new ACE-inhibitor, fosinopril, on insulin sensitivity (S_I), glucose homoeostasis and lipid profile has been examined in 24 young, healthy, normotensive men. S_I, fasting plasma glucose and insulin, serum total triglycerides (Tg) and lipoprotein cholesterol (C) fractions, and ACE activity were assessed after subjects had taken placebo for 1 week and after 3 further weeks either on placebo (12 subjects) or fosinopril 20 mg daily (12 subjects), administered in a doubleblind, randomized order. Measurements were made after 3 days on a standard diet (2500 kcal/d, 45% carbohydrates, 40% fat and 15% proteins) and after an over-night fast.Compared with control values at the end of the runin placebo phase, fosinopril reduced plasma ACE activity (from 106 to 24 nmol·ml^–1·min^–1), Significantly increased plasma potassium and lowered upright systolic blood pressure. It also improved the k-value of the glucose disappearance rate after glucose load (from –1.70 to –1.88%·min^–1) and tended to increase S_I slightly although not significantly (from 10.2 to 12.0·10^–4·min^–1·U^–1·ml^–1). Fasting plasma glucose, insulin, serum total, high-, low-, and very-low density lipoprotein cholesterol fractions and total triglycerides were unchanged following fosinopril and placebo.The findings indicate that in healthy lean humans, ACE inhibition with fosinopril is neutral with regard to lipoprotein and carbohydrate metabolism, and that it may slightly enhance cellular glucose disposal. This calls for further evaluation in individuals at high risk of developing insulin resistance and in patients with impaired insulin sensitivity related to hypertension, obesity, decreased glucose tolerance and diabetes mellitus.This work was supported in part by the Swiss National Science Foundation     

Plasma insulin during physiological and pathophysiological changes in atrial natriuretic factor

Summary Changes in plasma insulin in response to a physiological or pathophysiological elevation in circulating atrial natriuretic factor (ANF) have been investigated.Plasma insulin, glucose, immunoreactive (ir) ANF, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), absolute and fractional excretion of sodium (FENa), have been measured in 14 volunteers before and during infusion of low doses of ANF or vehicle (V). Each subject received single-blind in a randomized sequence at 2 week-intervals: V alone, or ANF 4, 8 and 16 ng·kg^–1·min^–1, indused over 90 min.Plasma irANF was increased 2.5- to 11-fold during the ANF infusion as compared to the test with the vehicle. Plasma insulin did not change during V administration (baseline vs V: 22 vs 21 U·ml^–1) and was unchanged during ANF at 4, 8 and 16 ng·kg^–1·min^–1 (19, 19, 21 U·ml^–1, respectively). Blood pressure, ERPF and GFR were not affected, and diuresis, FENa and urinary Na excretion were increased significantly and dose-dependently during ANF, but not V infusion. Compared to baseline, ANF 4, 8 and 16 ng·kg^–1·min^–1 increased urinary Na excretion by 147, 241 and 446 mol·min^–1, respectively.The findings indicate that, in normal humans, an acute increase in irANF within or slightly above the physiological range, which modified natriuresis and diuresis, did not alter circulating plasma insulin.The work was supported in part by the Swiss National Science Foundation     

Lisinopril is neutral to insulin sensitivity and serum lipoproteins in essential hypertensive patients

To investigate the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor lisinopril on insulin sensitivity and related metabolic variables, the insulin sensitivity index (SI), determined with the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure were assessed in 24 lean, non-diabetic patients with essential hypertension. Following a double-blind, randomised crossover design, these parameters were measured after a 4-week run-in period, after 8 weeks of lisinopril or placebo, and after an additional 8 weeks on placebo or lisinopril, respectively. Furthermore, the level of physical fitness was estimated using the Conconi bicycle ergometer test. SI was low in this study population (5.6 vs 13.3 · 10^–4·min^–1·mU^–1·1^–1 in normal lean control subjects). It did not differ between the placebo run-in phase, the lisinopril phase, and the placebo crossover phase (5.8, 5.5, and 5.4·10^–4·min^–1·mU^–1·1^–1, respectively). Moreover, during the administration of lisinopril, no significant changes occurred in fasting plasma insulin and glucose, areas under the glucose and insulin curves, glucose disappearance rate, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions. Heart rate at rest, body weight, and anaerobic threshold remained stable throughout the study. Compliance assessed by pill-counting exceeded 90% at all visits. These findings demonstrate that the ACE inhibitor lisinopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in patients with essential hypertension.     

Simvastatin reduces plasma lipid levels and improves insulin action in elderly,non-insulin dependent diabetics

Summary Twelve elderly non-insulin dependent diabetic patients took part in a double-blind, cross-over, randomized study comparing simvastatin 30 mg/day and placebo. Each treatment period lasted 3 weeks and was separated by a 3 week wash-out period. At the end of each treatment period all subjects underwent in randomized order an oral glucose tolerance test (OGTT; 75 g) and an euglycaemic hyperinsulinaemic (50 mU/kg·h) glucose clamp.Simvastatin compared to placebo significantly reduced plasma total cholesterol (7.9 vs 5.3 mmol·l^–1), LDL-cholesterol (7.2 vs 4.3 mmol·l^–1), triglycerides (2.9 vs 2.1 mmol·l^–1), free fatty acids (1106 vs 818 mmol^–1) and glucose (7.4 vs 6.6 mmol·l^–1) levels.After simvastatin, and in the last 60 min of the glucose clamp, there was an improvement in the action of insulin as demonstrated by stronger inhibition of hepatic glucose output (2.7 vs 5.2 mol·kg^–1·min^–1) and stimulation both of the glucose disappearance rate (26.3 vs 19.5 mol·kg^–1·min^–1) and glucose metabolic clearance rate (4.3 vs 3.6 ml·kg^–1·min^–1).The changes in glucose turnover parameters were significantly correlated with basal plasma free fatty acids and were independent of plasma glucoregulatory hormones. In conclusion, simvastatin seems to exert beneficial effects both on lipid and glucose metabolism.     

Flow resistance and its components in hypertensive men treated with the calcium antagonist isradipine

Summary The components of blood flow resistance were investigated in 14 men with essential hypertension (diastolic blood pressure higher or equal to 100 mmHg) before and after treatment with the dihydropyridine calcium antagonist-isradipine.Isradipine reduced intraarterial blood pressure by decreasing the total (placebo 5.1 U · mPa^–1·s^–1; isradipine 3.9 U·mPa^–1·s^–1), and renal (placebo 48.9 U·mPa^–1· s^–1, isradipine 35.4 U·mPa^–1·s^–1) vascular hindrance, the blood viscosity being unchanged. Arterial compliance was increased by isradipine (placebo 1.03 ml·mm Hg^–1; isradipine 1,25 ml·mm Hg^–1). The pressor response to adrenergic alpha stimulation with phenylephrine was decreased during treatment with the calcium antagonist. The compliance of the venous system was not changed by the treatment with isradipine. Haemorheological parameters were stable throughout the study but some changes in the correlations between the different rheological parameters were observed.The present study indicates that the antihypertensive effect of the dihydropyridine calcium antagonist isradipine was the result of functional modulation of the small and large arteries, the venous system and the flow properties of blood being unaffected.     

OACE inhibition does not interfere with acute extrarenal or renal potassium disposal in chronic renal failure

The influence of angiotensin converting enzyme (ACE) inhibition on acute extrarenal and renal potassium elimination in stable chronic renal failure has been examined in 10 male patients median age 44 y; mean CL_CR 42 ml·min^–1·1.73 m^–2. In a double blind, placebo-controlled cross-over study, K⁺ 0.3 or 0.4 mmol·kg^–1 body weight was infused IV on two occasions while the patients also received an infusion either of placebo or 0.5 mg of the ACE inhibitor perindoprilat in random order. Plasma K⁺ levels and urinary K⁺ excretion were measured at regular intervals. During the study patients adhered to an isocaloric diet providing a standardised daily intake of potassium and sodium (50 mmol K⁺ and 40 mmol Na⁺).The median rise in plasma K⁺ was not significantly different after placebo ( K 0.66 mmol·1^–1) compared with to the infusion of perindoprilat ( K 0.66 mmol·1^–1). The median baseline urinary K⁺ excretion rate was 6.5 mmol·3 h^–1 before the placebo infusion and 5.9 mmol·3 h^–1 before infusion of perindoprilat. During the potassium load, the urinary excretion rate rose to 16.1 mmol·3 h^–1 (after placebo) and 15.1 mmol·3 h^–1 after perindoprilat in the first 3 h, and it returned almost to the baseline value within the next 3 h (5.6 mmol·3 h^–1 after placebo and 5.7 mmol·3 h^–1 after perindoprilat); the differences were not statistically significant.With perindoprilat a decrease in mean arterial blood pressure and ACE activity, an increase in renin plasma activity and a decrease in aldosterone concentrations were observed compared to the placebo infusion. There was no significant differences plasma in adrenaline or insulin levels after either infusion.Thus, ACE inhibition did not interfere either with the extrarenal or the renal disposal of an acute potassium load in patients with chronic renal failure.     

Low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients

Fourteen hypertensive (174.3/98.3 mmHg) non-diabetic patients were given a euglyceamic glucose clamp along with infusion of 0.9% NaCl and the prostacyclin (PGI₂) analogue Iloporst (0.7 ng · kg · min^–1). Substrate oxidation was also determined by indirect calorimetry. Over the last 60 min of the clamp, Iloprost vs saline improved whole body glucose disposal (WBGD) (35 vs 28.3 mol · kg^–1 LBM) and non-oxidative glucose metabolism (24.7 vs 18.1 mol · kg^–1 LBM · min^–1). Iloprost delivery was associated with a significant decrease in membrane microviscosity (0.253 vs 0.205), but did not affect arterial blood pressure and heart rate. In nine patients, skeletal muscle blood flow (SMBF) and insulin-stimulated glucose uptake (GU) were also studied. At the end of the study, despite a similar SMBF (37 vs 38 ml · min^–1 · kg^–1), GU (0.55 vs 0.46 mmol · 1^–1) was significantly increased by Iloprost infusion. Percentage decrease in membrane microviscosity was correlated with percentage increase in WBGD (r=0.65) and non-oxidative glucose metabolism (r=0.68). In conclusion, low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Effect of acitretin on the response to an intravenous glucose tolerance test in healthy volunteers

Summary The effect of the synthetic retinoid acitretin (A) on the disposition of blood glucose and on the serum insulin response following the IV infusion of 139 mmol glucose over 10 min (IGTT) has been investigated in six healthy subjects. The IGTT was performed on Days 1, 10 and 24. On Days 3 to 10 A 50 mg/d was administered. Several parameters of glucose disposition and insulin response (K-values, AUC) were assessed. As a methodological variant, the profiles over time of blood glucose and serum insulin were evaluated by model calculations using the minimal model. Acitretin did not influence any parameter of glucose disposition. The area under the insulin-time curve (baseline corrected) was significantly decreased from 1.20 mU·min·l^–1 on Day 1 to 0.89 mU·min·l^–1 on Day 10, and was 0.91 mU·min·l^–1 on Day 24. The model-derived insulin sensitivity increased from 13·10^–4 l·mU^–1·min^–1 on Day 1 to 20·10^–4 l·mU^–1·min^–1 on Day 10 and was 18·10^–4 l·mU^–1·min^–1 on Day 24. The results suggest that A increased sensitivity to endogenous insulin. It supports a recent report showing greater insulin sensitivity in patients treated with the synthetic retinoid etretinate.     

A lack of pharmacokinetic interaction between ranitidine and piroxicam

Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects.In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (C_max) was 467 ng·ml^–1 for ranitidine alone and 466 ng·ml^–1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml^–1 and 2551 h·ng ml^–1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively.In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean C_max was 2.1 ·ml^–1 in the presence of placebo and 2.0 g·ml^–1 in the presence of ranitidine respectively; mean AUC was 133 h·g ml^–1 and 137 h·g ml^–1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

A double-blind comparison of the effects of carvedilol and captopril on serum lipid concentrations in patients with mild to moderate essential hypertension and dyslipidaemia

Summary We have studied 250 patients with mild to moderate essential hypertension (diastolic blood pressure 95 – 114 mmHg) and dyslipidaemia (high-density lipoprotein cholesterol (HDL-C) below 1.03 mmol·l^–1, total cholesterol 5.17–9.05 mmol·l^–1, and triglycerides 2.26–5.64 mmol·l^–1) in a controlled double-blind, multicentre, parallel group trial.The patients took a fat-modified diet. After a 4-week placebo period, patients who continued to fulfil the selection criteria were randomly allocated to treatment with either carvedilol (a vasodilating -blocker) 25–50 mg o.d. (n=116) or captopril (an ACE inhibitor) 25–50 mg o.d. (n=117) for 6 months.In both groups there were favourable effects on the serum lipids. The relative changes (medians) in the carvedilol and captopril group were respectively: increase in HDL-C by 11% and 8%, decrease in total cholesterol by 11% and 10%, in low-density lipoprotein cholesterol by 16% and 12%, and in triglycerides by 13% and 14%. Equivalence of the two treatments was confirmed for the target variable change in HDL-C at a significance level of 5%.Reductions in supine systolic/diastolic blood pressures were comparable in the two groups (carvedilol: 23/19 mmHg, captopril: 20/18 mmHg).The improvement in lipid metabolism in patients treated with carvedilol is probably due to its ₁-blocking properties.     

The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers

Summary We have studied the pharmacokinetics and haemodynamic effects of nicorandil after a 12-h infusion. Nicorandil is a mixed vasodilator combining the actions of a nitrate and a potassium channel opener.Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 g·kg^–1·min^–1 using a placebo controlled, crossover design. Systemic blood pressure, heart rate, electrocardiographic (ECG) intervals, and cardiac output (impedance cardiography) were measured supine and standing.Dose-related, steady-state plasma nicorandil concentrations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose.Four 0.20 g·kg^–1·min^–1 nicorandil infusions were terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays).Blood pressure fell versus placebo only in the standing position and heart rate increased slightly (not significant). That is, standing blood pressure in the 6 to 12 h interval fell from baseline 8.0*/6.8, 1.6/5.1, and 9.8*/7.9* mmHg (systolic/diastolic, *=P<0.05 versus placebo) at 0.05, 0.10, and 0.20 g·kg^–1·min^–1 respectively. Cardiac output increased slightly above placebo at lower doses. Haemodynamic changes correlated poorly with plasma nicorandil concentrations. Similar total doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.     

Venous plasma levels of endothelin-1 are not altered immediately after nitroglycerin infusion in healthy subjects

Endothelin-1 and nitric oxide play an important regulatory role in the control of vascular smooth muscle tone. Nitroglycerin (NTG), a nitric oxide donating drug, may inhibit endothelin production. In this double-blind placebo-controlled crossover study, plasma levels of endothelin-1 were measured before and immediately (5–30 s) after 80 min infusion of NTG (glyceryl trinitrate) or saline in 12 healthy subjects. On two different days separated by at least 1 week, NTG in four different doses, 0.015, 0.25, 1.0, and 2.0 g·kg^–1·min^–1, or placebo (isotonic saline) was infused successively for 20 min each dose. During the infusion blood pressure and heart rate were measured. NTG infusion significantly decreased systolic blood pressure from 112.4 to 103.4 mmHg and pulse pressure from 39.3 to 29.5 mmHg. Heart rate increased from 62.7 to 73.1 beats·min^–1. No changes in endothelin-1 plasma levels were induced by NTG infusion (2.4 pg·ml^–1 before NTG vs. 2.7 pg·ml^–1 after NTG) and placebo infusion also did not affect plasma endothelin-1. It is concluded that venous plasma levels of endothelin-1 are not altered immediately after NTG infusion.     

Metamizole-furosemide interaction study in healthy volunteers

Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min^–1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml^–1 · h^–1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F₂ (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.Parts of the results have been presented at the Ninty-first Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21–23, 1990, San Francisco     

Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring

The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug.Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC_{0–4 h} for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC_{0–4 h} was significantly increased (5.6 g · ml^–1 · h vs 4.5 g · ml^–1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC_{0–4 h} ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65).These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.     

Humoral and haemodynamic effects of idrapril calcium,the prototype of a new class of ACE-inhibitors,in essential hypertensive patients

Idrapril is the prototype of a new class of ACE inhibitors, characterised by the presence of a hydroxdmic group. Six untreated in-patients with essential hypertension were given single oral doses of the calcium salt of idrapril, idrapril calcium (200 mg) and placebo according to a double blind, randomised experimental design. Supine and upright blood pressure, heart rate, plasma idrapril serum ACE, active renin and angiotensin II were measured at timed intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours (3.01 ·ml^–1), and by 12 hours the compound had al most disappeared (67 ng·ml^–1). Derived t_1/2 was 1.4–2.2 h. ACE activity was suppressed [from 77.9 to 3.3 after 2 hours and 11.8 after 12 hours nmol^–1·min^–1·ml] and angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5 (after 12 hours) pg·ml^–1] for up to 12 h, while active renin rose up to 24 h [from 12.3 to 20.1 (after 8 hours) and 17.5 (after 24 hours) pg·ml^–1]. Compared to placebo, idrapril calcium significantly lowered both supine blood pressure starting at 4 hours (idrapril calcium 140/93 mmHg; placebo 157/101 mmHg) up to 24 hours (idrapril calcium 142/91 mmHg; placebo: 155/97 mmHg), and upright blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100 mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg). Idrapril calcium appears to be an effective ACE inhibitor in essential hypertension, with a hypotensive action for up to 24 h.     

Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency

Ten haemodialysis (HD) patients with a median residual creatinine clearance (CL_CR) of 1.9 ml·min^–1·1.73 m^–2 (range 0.6–5.3) were treated with oral furosemide (F) 2.0 g. Overall-efficiency (O-E, daily sodium excretion/total urinary F) and total-efficiency (-E, increase in daily sodium excretion/total urinary F) were measured on the last 24 hours of each interdialysis interval. In addition, O-E was measured during the complete interdialysis interval in 10 HD patients with a median CL_CR of 5.6 ml·min^–1·1.73 m^–2 (range 0.7–6.8) treated for 1 year with a fixed oral dose of F between 250–1000 mg (median 625 mg).In the short study the median O-E was 10.6 mmol·mg^–1 (range 1.9–22.0) and -E 6.2 mmol·mg^–1 (range 1.3–11.2). The fractional excretion of sodium FE_Na was significantly increased from 9.6% (range 4.1–22.9) to 27% (range 14.6–56.2) during F treatment. A positive correlation was found between the basal FE_Na and -E. In the long-term study median O-E was 6.4 mmol·mg^–1. O-E and FE_Na showed no change over time although median RCC decreased from 5.6 to 1.9 ml·min^–1·1.73 m^–2 and median F excretion from 11.8 to 7.5 mg per day.It can be concluded that diuretic efficiency in haemodialysis patients is dependent on FE_Na and the state of hydration during the interdialysis interval.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.