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.     

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.     

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.     

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.     

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     

Intravenous infusion of iloprost in arterial occlusive disease: dose-dependent effects on skin microcirculation

Summary Transcutaneous oxygen pressure (tcPo₂), laser Doppler flux and capillary microscopy have been used to examine the forefoot skin in 5 healthy men and 8 patients with severe peripheral arterial occlusive disease in order to evaluate the dose dependent effects of iloprost on skin microcirculation. Iloprost was infused IV starting at 0.0625 ng·kg^–1·min^–1 and doubling the dose every 15 min up to 2 ng·kg^–1·min^–1.While tcPo₂ at an electrode core temperature of 44°C decreased in both patients and controls, there was a significant dose dependent increase in tcPo₂ (37°C) in the controls from 0.25 ng·kg^–1·min^–1. In the patients the reaction was variable: it was decreased in two and increased in 6, with a maximum either at 0.25–0.5 ng·kg^–1·min^–1 (n=3) or at the highest dose (1.0 or 2.0 ng·kg^–1·min^–1; n=3). Mean laser Doppler flux in both groups was increased, although the reaction was not consistent in the patients. Density of forefoot skin capillaries was reduced in 3 patients, and in the others the flow velocity was very low. During infusion of iloprost, both an increase in capillary density and blood cell velocity were observed. The effects were of variable intensity and occurred at varying doses, some appeared early and diminished as the dose was increased, and others were found only at 2 ng·kg^–1·min^–1.Adverse effects were numerous, extending from harmless skin flushing to mental changes and a quickly reversible attack of angina pectoris. It may be possible to divide patients into those with early effects on the microcirculation, at doses of 0.25–0.5 ng·kg^–1·min^–1, and those in whom the microcirculatory response is preceded and counteracted by the adverse effects.     

The effect of a low dose of quinidine on the disposition of flecainide in healthy volunteers

Summary We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min.Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg^–1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min^–1·kg^–1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min^–1·kg^–1). The excretion of the metabolites of flecainide over 48 h was significantly reduced.These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min^–1·kg^–1).The effects of flecainide on ECG intervals were not altered by quinidine.Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.     

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.     

Bioavailability and pharmacokinetics of oxazepam

Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t_1/2) 6.7 h, total clearance (CL) 1.07 ml·min^–1·kg^–1, volume of distribution (V_c) 0.27 l·kg^–1 (0.21–0.49) and volume of distribution at steady-state (V_ss) 0.59 l·kg^–1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min^–1·kg^–1 and a distribution volume of 12.3 l·kg^–1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t_1/2 at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CL_R) of the glucuronide metabolite was 1.10 ml·min^–1·kg^–1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.     

Effects of altitude (4300 M) on the pharmacokinetics of caffeine and cardio-green in humans

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg^–1) was administered as an intravenous bolus and caffeine (4 mg · kg^–1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t_1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1^–1 · min^–1), and increased clearance (117 vs 86 ml · min^–1 · 70 kg^–1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1^–1 · min^–1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min^–1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.     

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.     

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.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

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.     

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.     

Renal effects of atrial natriuretic peptide during dopa-decarboxylase inhibition in patients with essential hypertension

Summary To assess whether intrarenal dopamine synthesis could contribute to the renal response to ANP in essential hypertension, the effects of -human ANP influsion (50 ng·min^–1·kg^–1 b.w. for 30 min) on the urinary excretion of dopamine and sodium, urine flow rate and arterial pressure were evaluated in 7 patients with mild-moderate essential hypertension before (control period) and during DOPA-decarboxylase inhibition with carbidopa (carbidopa period).In the control period, urinary dopamine excretion was 400 pg·min^–1 in baseline conditions and 340 pg·min^–1 during ANP infusion. Carbidopa significantly decreased urinary dopamine excretion both before (210 pg·min^–1) and during ANP (99 pg·min^–1). In contrast, carbidopa did not affect sodium excretion (control from 184 to 460 Eq·min^–1; carbidopa period from 140 to 390 Eq·min^–1) or urine flow rate (control from 5.35 to 11.21 ml·min^–1; carbidopa period from 4.29 to 11.54 ml·min^–1).Arterial pressure fell significantly during ANP infusion in both periods, and no significant difference was observed between the two study days, i.e. in the absence of and during carbidopa administration.We conclude that DOPA-decarboxylase inhibition does not influence the diuretic and natriuretic response to -human ANP infusion in patients with essential hypertension.     

Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.     

Nicorandil-induced changes in the distribution of cardiac output and coronary blood flow in pigs

Summary The present investigation was conducted to study systemic and regional haemodynamic effects of nicorandil, a potent coronary vasodilator, after intravenous or local intracoronary administration in anaesthetized or conscious pigs. Intravenous infusions of nicorandil for 10 min in both anaesthetized (15, 30, 75 and 150 g · kg^–1 · min^–1) and conscious (20, 40 and 80 g · kg^–1 · min^–1) pigs reduced arterial blood pressure, stroke volume, left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance, but increased heart rate and maxLVdP/dt. Since nicorandil decreased LVEDP at doses which did not affect arterial blood pressure, the drug may be considered as a more potent venodilator than arterial dilator. Nicorandil increased cardiac output only in conscious animals due to a more marked tachycardia (85% after 80 g · kg^–1 · min^–1) than in anaesthetized animals (30% after 75 g · kg^–1 · min^–1). The nicorandil-induced increase in heart rate and maxLVdP/dt, being substantially attenuated in conscious pigs after treatment with propranolol, can be ascribed to a reflex activation of the sympathetic nervous system following the fall in arterial pressure. Although cardiac output did not change in anaesthetized animals, intravenous infusions of nicorandil did cause a redistribution of blood flow in favour of organs such as the heart, adrenals, spleen, small intestine and brain at the expense of that to the stomach and kidneys; hepatic artery and skeletal muscle blood flow did not change. The increase in myocardial blood flow, primarily to the subepicardial layers, was associated with an enhancement in coronary venous oxygen content and was also noticed after intracoronary infusions of nicorandil (0.6, 1.5, 3 and 6 g · kg^–1 · min^–1). The above cardiovascular profile suggests a possible usefulness of nicorandil in angina pectoris as well as congestive heart failure. However, caution is needed because the strong hypotensive action and reflex-mediated tachycardia may under certain conditions aggravate myocardial ischaemia, particularly in the subendocardial layers. Send offprint requests to P. D. Verdouw     

Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine

It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 g · kg^–1·min^–1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1(H₁)-receptor blocker mepyramine (0.5 mg · kg^–1) and once without pretreatment. This mepyramine dose is known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0–10 scale with and without mepyramine pretreatment. The arterial responses, evaluated with transcranial Doppler, were also unaffected by the mepyramine pretreatment. Our results demonstrate that neither headache nor arterial dilatation due to GTN infusion is caused by histamine release. In all likelihood the common mediator of migraine induction by GTN and histamine is nitric oxide.     

The pharmacokinetics of theβ 2-adrenoceptor agonist fenoterol in healthy women

Summary We have studied the pharmacokinetics of fenoterol in healthy women during and after a 3 h intravenous infusion of different doses within the therapeutic range for tocolysis (0.5 g·min^–1, 1.0 g·min^–1, and 2.0 g·min^–1). A specific and sensitive radioimmuno-assay was used for the determination of fenoterol. For compartmental analysis the plasma concentration time data were fitted with the TOPFIT program, assuming two exponentials.The total clearance of fenoterol increased with dose (1299 ml·min^–1 at 0.5 g·min^–1, 1483 ml·min^–1 at 1.0 g·min^–1, and 1924 ml·min^–1 at 2.0 g·min^–1), as did the apparent volume of distribution (from 491 at the lowest to 851 at the highest dose).In contrast, the apparent half-lives were not dose-dependent, with t_{1/2· 1} 4.8 min and t_{1/2· 2} 52 min.This paper is dedicated to Prof. Dr. Ellen Weber, Heidelberg, FRG