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.     

Plasma glucose lowering effect of spartein sulphate infusion in non-insulin dependent (Type 2) diabetic subjects

Summary Sparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2±2.8 to 26.4±4.2 mg · kg^–1 · min^–1 (p<0.01), and it was potentiated by simultaneous infusion of arginine.No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1±0.8 vs 2.6±1.2 mg · kg^–1 · min^–1) was not statistically significant different in the last 60 min of the experiment.It is concluded that sparteine sulphate enhances -cell secretion, causing a fall in the plasma glucose concentration.     

Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients

Summary The effect of doxazosin, an a,-adrenoceptor blocking drug, on blood pressure, sensitivity to insulin and serum lipids has been evaluated in 14 hypertensive, non-insulin dependent diabetic patients. The dose was titrated individually upwards from 1 mg until the diastolic blood pressure was below 90 mm Hg, side-effects precluded further dosage increase or the maximum daily dose of 16 mg was achieved.After 12 weeks of treatment (mean doxazosin dose 5.6 ± 5.1 mg daily), the supine and standing diastolic blood pressure of the patients had declined by about 7 mmHg, whereas their systolic blood pressure and heart rate were not significantly changed. The metabolic clearance rate of glucose increased from 2.35 to 3.37 ml - min^–1 - kg^–1 during treatment, suggesting improved sensitivity to insulin. Fasting plasma glucose was 11.9 mmol·1^–1 before and 10.9 mmol·l^–1 after doxazosin therapy (NS). Serum electrolytes and lipids did not change significantly but serum uric acid decreased from 305 to 281 mol · 1^–1 Doxazosin may be a useful alternative for the treatment of hypertension in NIDDM patients.     

The effect of cardiopulmonary bypass on plasma protein binding of alfentanil

Summary The effect of cardiopulmonary bypass (CPB) on plasma concentration and protein binding of alfentanil was studied during continuous infusions in five cardiac surgical patients. Patients were given a loading infusion of 10 µg·min^–1·kg^–1 lean body mass (LBM) over 30 s followed by a fixed rate maintenance infusion of 1 µg·min^–1·kg^–1 LBM for the duration of surgery.Prior to the commencement of CPB the total plasma alfentanil concentration was 177 µg·l^–1. This fell to 92 µg·l^–1 2 min after commencement of CPB and rose to 155 µg·l^–1 at the end of CPB 2.01 h later. During the same period the unbound fraction of alfentanil rose from 0.16 to 0.35 two min after the start of CPB and fell gradually to 0.22 at the end of CPB. The unbound concentration prior to CPB was 29 µg·l^–1 and was essentially unchanged by the onset of CPB, being 35 µg·l^–1 at two min and then 31 µg·l^–1 at the end of CPB. There was a good correlation between alfentanil bound/unbound concentration ratio and plasma albumin concentration (r=0.57) and plasma ₁-acid glycoprotein concentration (r=0.80), indicating that the decrease in binding during CPB was due primarily to haemodilution.In assessing the effects of CPB on plasma drug concentrations, it is therefore necessary to monitor unbound as well as total concentrations because the effects on these differ greatly.     

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.     

Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia

Summary Sixteen patients with primary hypercholesterolaemia received double-blind either fenofibrate (n=8; 200 mg bid) or the HMG-CoA reductase inhibitor simvastatin (n=8; 20 mg qid or 40 mg qid if LDL-cholesterol did not fall below 3.6 mmol·l^–1 after 4 weeks of treatment).Simvastatin reduced total cholesterol from 9.7 to 7.0 mmol·l^–1 after 10 weeks (–28%), and fenofibrate reduced it from 9.2 to 7.7 mmol·l^–1 (–15%). The decrease was less during fenofibrate than during simvastatin treatment (time × drug:p=0.02).Serum LDL-cholesterol fell from 8.3 to 5.3 mmol·l^–1 (–36%) during simvastatin and from 7.2 to 6.0 mmol·l^–1 (–16%) during fenofibrate administration. Again, the effect of simvastatin was more pronounced than that of fenofibrate (time × drug:p=0.03).HDL-cholesterol increased significantly from 1.1 to 1.2 mmol·l^–1 (+13%) during fenofibrate administration and it did not change significantly during simvastatin.Serum triglycerides fell from 1.3 to 1.1 mmol·l^–1 (–16%) during simvastatin, and even more significantly from 2.2 to 1.1 mmol·l^–1 (–51%) during fenofibrate (time × drug:p=0.002).Apolipoprotein B fell on simvastatin from 1.9 to 1.4 g·l^–1 (–24%) and from 1.8 to 1.4 g·l^–1 (–22%) during fenofibrate.Both drugs were well tolerated and had no significant adverse effects.Simvastatin lowered total and LDL-cholesterol concentrations more than fenofibrate, while the latter had more effect on triglycerides, suggesting specific indications for the two drugs in the treatment of hyperlipoproteinaemias.     

Absorption of zidovudine in patients with diarrhoea

Summary Many patients with AIDS have gastrointestinal complaints, including the major clinical disorder of chronic diarrhoea. The pharmacokinetics of zidovudine was studied in 9 male patients with HIV infection and diarrhoea to establish whether drug absorption was impaired in them.The peak plasma concentration and AUC after a single oral dose of 200 mg, were the same as those reported in 6 healthy male volunteers (3.1 vs 4.0 mol·l^–1 and 7.2 vs 5.2 mol·h·l^–1, respectively).Since the bioavailability of zidovudine is not particularly impaired, oral zidovudine therapy can be maintained in patients with diarrhoea.     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

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.     

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     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Kinetics of human and porcine insulins in normal and Type I diabetic subjects

Summary Human and porcine insulin were infused intravenously at various rates into 4 normal and 6 Type I diabetic subjects, using a double-blind cross-over design and a euglycaemic glucose clamp, to study the relationship between the steady state plasma free insulin concentration and its plasma disappearance rate. By mathematical model validation procedures both human and porcine insulin were found to obey saturation kinetics in normal subjects and first order kinetics in diabetic subjects in the insulin concentration range studied (0–2 nmol/l).No differences in parameters were observed between the two types of insulin in the study groups. The median clearance rate of insulin in normal subjects was 31 ml·kg^–1·min^–1 at infinitestinal plasma insulin concentrations versus 21 ml·kg^–1·min^–1 in the diabetic subjects.Thus, at physiological plasma concentrations both human and porcine insulin disappear faster via the saturable mechanism(s) found in normal subjects than via the apparently linear mechanism(s) found in diabetic subjects.     

Cardiovascular effects of clonidine in an avian species,Larus argentatus

Summary Blood pressure and heart rate were recorded in the sea gull, Larus argentatus, under light pentobarbitone anaesthesia. Clonidine 10^–7 and 10^–8 mol·kg^–1 (27 and 2.7 g·kg^–1) i.v. produced a biphasic effect on blood pressure, a brief initial increase being followed by a prolonged hypotensive response. There was an immediate reduction in heart rate which persisted throughout the hypotensive phase. After spinal transection at the level of C 4, clonidine administration elicited hypertension and bradycardia.Bilateral vagotomy abolished the effect of clonidine on heart rate but did not alter the blood pressure response.Vagotomy in combination with spinal transection abolished the effect of clonidine on heart rate but the hypertensive response was accentuated.Yohimbine 10^–7 or 10^–6 mol·kg^–1 (0.039 or 0.39 mg·kg^–1) given 5 min after clonidine 10^–7 mol·kg^–1 (27 g·kg^–1) effectively antagonized the cardiovascular effects of clonidine, while prazosin 10^–7 or 10^–6 mol·kg^–1 (0.042 or 0.42 mg·kg^–1) had no such effect.We conclude that clonidine acts in the central nervous system of the sea gull to produce a lowering of blood pressure and heart rate. These effects are mediated by central inhibition of sympathetic activity and, in the case of the heart rate, mostly by central activation of vagal activity to the heart. This central action of clonidine involves activation of -adrenoceptors which are blocked by yohimbine but not by prazosin and therefore may belong to the ₂ subtype.     

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.     

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     

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.     

Pharmacokinetic study of methotrexate,folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue

Summary The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m^–2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL).The median steady-state concentration of MTX was 66 mol·l^–1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m^–2·min^–1.The 7-OHMTX level increased during each infusion and a C_max of 19 mol·l^–1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8.The MTX metabolite APA was detected in concentrations less than 0.06 mol·l^–1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mol·l^–1 and 18 h following the last dose of LCV it was 0.44 mol·l^–1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mol·l^–1 with a median ratio of 5-MTHF to MTX of 2.Twenty infusions with 48 h MTX levels of less than 0.5 mol·l^–1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mol·l^–1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.     

Unaltered insulin sensitivity during calcium channel blockade with amlodipine

Summary The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (S_I). To evaluate the effects of calcium channel blokkade on S_I, glucose homoeostasis and lipid profiles, studies were made of S_I (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal · day^–1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P<0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol·1^–1, respectively) and insulin levels (7.7 vs 7.9 U·ml^–1), S_I (10.5 vs 9.6·10^–4 × min^–1 pro U·ml^–1), serum total Tg, C and lipoprotein C fractions.The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.This work was supported in part by the Swiss National Science Foundation     

Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects

2082 hypercholesterolemic subjects were treated with simvastatin for 12 weeks. In 530 patients the dose was increased after 6 weeks from 10 to 20 mg because of persistently high cholesterol concentrations.Total cholesterol (TC) in the 1552 patients taking 10 mg fell by 1.61 mmol·l^–1 (18.4%), LDL cholesterol (LDLC) by 1.53 mmol·l^–1 (25.2%), and triglycerides (TG) by 0.13 mmol·l^–1 (5.5%); HDL cholesterol (HDLC) significantly increased by 0.05 mmol·l^–1 (3.6%).In the 530 patients taking 20 mg TC fell by 1.89 mmol·l^–1 (19.9%), LDLC by 1.78 mmol·l^–1 (26.0%), and TG by 0.13 mmol·l^–1 (5.5%); HDLC increased by 0.05 mmol·l^–1 (3.7%).The reductions in TC, LDLC, and TG were positively correlated and the increase in HDLC negatively correlated with their respective baseline values.There were independent significant correlations of the fall in LDLC with sex (MANOVA), baseline TG, and adherence to a lipid-lowering diet. The falls in TG significantly correlated with baseline fructosamine concentrations and dietary adherence.There were 571 adverse events in 16.6% of the patients but no case of myopathy.These results show that simvastatin is usually well tolerated and that its effects on TC and LDLC depend on their baseline concentrations.     

Effect of loperamide on jejunal electrolyte and water transport,prostaglandin E 2-induced secretion and intestinal transit time in man

Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit.In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l^–1). The volunteers were pretreated with 1 mg·l^–1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l^–1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT).Loperamide 2 mg·l^–1 converted the minor secretion after perfusion with the standard solution (water –1.45 ml·min^–1, Na –0.09 and Cl –0.04 mmol·min^–1) to absorption (water 0.93 ml·min^–1, Na 0.23, Cl 0.25 mmol·min^–1) within 15 min. Higher doses of loperamide did not increase absorption.The addition of PgE2 induced net secretion of water (–4.48 ml·min^–1) and electrolytes (Na –0.57, Cl –0.51 mmol·min^–1). Loperamide 4 mg·l^–1 significantly diminished the PgE2-induced net secretion by approximately 50%.Loperamide dose dependently increased the MTT from 6 (2 mg·l^–1) to 13.3 min (8 mg·l^–1). MTT was still delayed 60 min after a wash out period (10.5 min).It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.