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.     

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     

Magnesium pyridoxal 5-phosphate glutamate reduces hyperlipidaemia in patients with chronic renal insufficiency

Summary Chronic renal insufficiency is often accompanied by hyperlipidaemia and subsequent coronary heart disease.Two groups of 15 patients with serum creatinine >2 mg/100 ml and serum cholesterol >250 mg/100 ml were given 3×50 mg magnesium pyridoxal 5-phosphate glutamate (MPPG) or placebo for 12 weeks in a double-blind, randomised study.Total cholesterol in the MPPG group (282.4 mg·100 ml^–1) was lower than in the placebo group (354.3 mg·100 ml^–1) after 12 weeks of treatment. Triglycerides in the MPPG group were 265.1 mg·100 ml^–1 compared to 361.9 mg·100 ml^–1. After 12 weeks on MPPG the LDL/HDL ratio of 3.56 was lower than in the placebo group — 6.83. Side effects in the MPPG group were similar to those in the placebo group. Thus, MPPG was an effective antihyperlipidaemic agent in patients with renal insufficiency.     

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state

Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study.The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes.Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography.Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P<0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml^–1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml^–1.Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h.In general the two routes were significantly different from placebo but not from each other.     

Pharmacokinetics of nocloprost in human volunteers and its relation to dose

Summary The pharmacokinetics and absolute bioavailability of nocloprost, a synthetic PGE₂-analogue with cytoprotective properties, was investigated in human volunteers as a function of the dose. Ten young male volunteers received nocloprost 5 g i. v. and 100, 200 and 400 g p.o. in random order at weekly intervals. Serum nocloprost levels were monitored for up to 12 h after each dose, using a specific, validated assay.After nocloprost 5 g i. v. the highest serum level of 373 pg·ml^–1 was found in the first sample 5 min after injection, and the subsequent decline showed one or two phases, with half-lives of 4 and 49 min. The AUC was 89 pg·h·ml^–1, the total plasma clearance was 13.2 ml·min^–1·kg^–1, and the volume of distribution at steady state was 0.16 l·kg^–1.After oral administration the maximum serum level and AUC increased in proportion to the dose. t_max showed a wide scatter, with an average value of about 30 min independent of the dose. Although not detectable in every subject, post maximum serum levels declined biphasically, with half-lives of ca 10 and 35–40 min.The absolute bioavailability after oral administration averaged about 2% and was independent of the dose.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.     

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients

Summary We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred.Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA).Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration.After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng · ml^–1 following the first dose to 5.5 ng · ml^–1 after one month.     

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide level and intracardiac pressure in cardiac transplant recipients

Summary Blood pressures and plasma atrial natriuretic peptide (ANP) concentrations have been measured in venous and intracardiac sites in 11 patients (10 men and 1 woman) given cardiac transplants.The mean plasma ANP level was 214.4 pg·ml^–1 in the superior veina cava and 281 pg·ml^–1 in the right atrium. This significantly higher level was maintained in the right ventricle (269) and in the pulmonary artery (295). The level in controls was 25 pg·ml^–1. Intra cardiac and mean arterial pressures were in normal range in all patients, and there was no correlation between plasma ANP level and intracardiac pressure.The data suggest that in cardiac transplant patients right atrial pressure does not have a primary role in releasing ANP. The transplanted heart is denervated and remains so for many months after operation, thus suggesting that innervation is not obligatory for ANP secretion. Further studies are required to determine the relative contribution of donor and recipient atrial tissues to ANP secretion.     

Effect of 6-hourly intermittent intravenous boluses of oxmetidine and ranitidine on gastric acidity and serum prolactin

Summary We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function.The mean peak plasma concentration of captopril was 2.5 times higher (0.447 µg·ml^–1 vs 0.181 µg·ml^–1) and the concentrations of the disulfides 4 times higher (3.62 µg·ml^–1 vs 0.924 µg·ml^–1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46±19 h. Only 15% of these conjugates were removed by dialysis.This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37±7 mmHg and 24±9 mmHg respectively, occurring 6 h after the dose, compared with 8±7 and 8±1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.     

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     

The tolerability,pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability,in healthy volunteers

447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC₅₀ of 10.2 ng·ml^–1 (23 nM). It is poorly absorbed but 5 mg·kg^–1·day^–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean C_max and AUC were 1.8 ng·ml^–1 and 9.0 ng·ml^–1·h after 200 mg rising to 5.4 ng·ml^–1 and 23.8 ng·ml^–1·h respectively after 800 mg; t_1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.     

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.     

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction.The mean t_1/2, C_max, t_max, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml^–1, 4.8 h, and 3.19 g·h·ml^–1, respectively. Values for 1 CAPD patient with liver dysfunction were t_1/2 of 65.4 h, C_max of 182 ng·ml^–1, t_max of 9 h, and AUC of 18.1 g·h·ml^–1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min^–1.Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.These studies were supported in part by the Bristol-Myers Squibb Pharmaceutical Research Institute and by NIH grant M01-RR00065     

Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension

Summary Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nif and Cod alone and in combination to 18 patients with a diastolic blood pressure > 105 mm Hg in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nif and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 min during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, 1 h after the first dose and 90 min after the second treatment.Blood pressure was significantly lower (P < 0.05) where Cod preceded Nif. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg · ml^–1 and in epinephrine from 67 to 55 pg · ml^–1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg · ml^–1 with preceding Cod to 331 pg · ml^–1 was much less than the increase with placebo as premedication, from 284 to 440 pg · ml^–1. Nif caused an increase in renin activity but no increase in aldosterone.Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication. Due to the stabilizing action of Cod on catecholamines and on the side effects of Nif, Cod may be preferable to other antihypertensives in augmenting the antihypertensive action of Nif.     

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.     

Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects

In a single-blind, randomized, two-way crossover study with 12 healthy male volunteers, 60 g of prostaglandin E₁ (PGE₁) or placebo was administered by intravenous infusion during a 120-min period. PGE₁, 13,14-dihydro-PGE₁ (PGE₀) and 15-keto-PGE₀ plasma concentrations were measured by a highly specific and sensitive GC-MS/MS method.Endogenous PGE₁ plasma concentrations ranged between 1.2 and 1.8 pg·ml^–1. Endogenous PGE₀ and 15-keto-PGE₀ plasma concentrations varied from 0.8 to 1.3 pg·ml^–1 and from 4.2 to 6.0 pg/ml respectively. During intravenous infusion of PGE₁, plasma PGE₁ concentrations rose to a level twice as high as during the placebo infusion. In contrast, PGE₀ plasma concentrations were 8 times higher during PGE₁ infusion than during placebo infusion, and 15-keto-PGE₀ plasma concentrations were 20 times higher.The new analytical method has thus been useful to describe the pharmacokinetics of PGE₁ and its metabolites PGE₀ and 15-keto-PGE₀, during and after intravenous infusion of PGE₁.     

Modulation of allergen-induced nasal symptoms and mediator release by treatment with N-acetyl-aspartyl-glutamate (ZY15106)

The aim of this study was to evaluate the effects of the new anti-allergic drug, N-acetyl-aspartyl-glutamate (ZY15106), on allergen-induced nasal symptoms and mediator release. Fifteen outpatients suffering from seasonal allergic rhinitis due to grass pollen were included in the study. A nasal antigen challenge followed by evaluation of symptoms was performed in basal conditions. Ten of the 15 patients underwent sequential nasal lavages in order to evaluate allergen-induced mediator release. The study was performed in winter, when the patients were symptom free, and was a randomized single-blind crossover trial of a 6 % solution of ZY15106 (daily dosage: 48 mg) versus placebo (lactose). The drug and the placebo were administered intranasally q.i.d. for 1 week, with a 2-week interval between the two treatments. Treatment with ZY15106, but not with placebo, caused a significant reduction in nasal obstruction in the first 30 min after challenge and at 60 min and itching in the first 10 min after challenge, but did not reduce sneezing and rhinorrhoea. Moreover, ZY15106 significantly reduced the histamine release in 5 min postchallenge lavage (4.5 ng·ml^–1 after placebo administration vs 2.5 ng·ml^–1, after treatment with ZY15106). A reduction in immunoreactive LTC₄ release in the 5 and 10 min post-challenge lavages was observed after ZY15106 administration (placebo vs active treatment: at 5 min 2.9 ng·ml^–1 vs 1.4 ng·ml^–1; at 10 min: 2.25 ng·ml^–1 vs 0.9 ng·ml^–1). These results indicate that 1-week treatment with ZY15106 can reduce antigen-induced nasal obstruction and itching, and mediator release in human nasal airways. The clinical activity of ZY15106 in the treatment of allergic rhinitis may be related to its ability to inhibit mediator release.     

Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393)

Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg·kg^–1·h^–1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD_0–24 (APTT) came to 913 s·h·kg^–1 under placebo and it was slightly increased to 1,017 s·h·kg^–1 after piroxicam; the 95%-confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal E_max-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam. Maximal APTT-prolongation (E_max; i.e. peak APTT minus the baseline value) was 53 s after placebo and 52 s after piroxicam. The EC₅₀ was 34 nmol·l^–1 after placebo and 40 nmol·h·l^–1 after piroxicam. The AUC₀ of hirudin was to 539 nmol·h·l^–1·kg^–1 under placebo and 557 nmol·h·l^–1·kg^–1 after piroxicam coadministration; the 95%- confidence interval according to MOSES ranged from 0.95 to 1.14, and the point estimator was 1.03. No period effect was detected. There were no significant differences between the other pharmacokinetic parameters except V_ss, which was increased slightly from 0.23 l to 0.27 l under piroxicam. The results do not show a clinically relevant pharmacodynamic and/or pharmacokinetic interaction between hirudin and piroxicam.     

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.