Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers.

1. Losartan (DuP 753, MK-954) is a novel, potent and highly selective AT1 angiotensin II receptor antagonist. The effect of multiple oral doses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2. In a double-blind and randomized fashion, subjects received 50 mg losartan or placebo once daily for 15 days in each period. At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively. 3. Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the study, no laboratory abnormalities were noted. 4. Multiple oral doses of losartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0.48h) of immunoreactive digoxin during losartan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml-1 h during placebo; not significant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 vs 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5. Multiple oral doses of losartan did not affect the pharmacokinetic parameters of oral digoxin AUC(0.48 h) during losartan 23.6 +/- 3.7 ng ml-1 h vs 22.4 +/- 2.6 ng ml-1 h during placebo; not significant, Cmax 3.5 +/- 0.7 ng ml-1 with vs 3.1 +/- 0.5 ng ml-1 without losartan; not significant and tmax 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 51.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6. We conclude that multiple oral doses of losartan (50 mg daily) do not alter the pharmacokinetics of immunoreactive digoxin, following either intravenous or oral digoxin. Furthermore, the co-administration of digoxin with losartan is well tolerated by healthy male volunteers.

Single dose pharmacokinetics, safety and tolerability of MK-0476, a new leukotriene D4-receptor antagonist, in healthy volunteers.

MK-4076 or sodium 1-(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl) 3-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cycloproprane) acetate is a novel, potent, and specific LTD4-receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK-0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9-subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK-0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK-0476 (20 to 800 mg) the median value of tmax ranged from 2 to 4 h, while the apparent t1/2 value averaged 4 to 5 h. The median tmax value of the 200 mg capsule dose was not significantly different from the median tmax of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate-limiting step for the absorption of MK-0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in Cmax (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK-0476 was given together with a breakfast, suggesting an increase in bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)

Tuberculous pleural effusion following coronary artery bypass graft.

We present two patients with moderate left ventricular dysfunction, who developed a pleural effusion after coronary artery bypass grafting (CABG). The effusion was proven to be an exsudate of tuberculous origin. This illustrates that not all pleural exsudates developing after CABG are due to a post-pericardiotomy syndrome. Therefore microbiological examination of pleural fluid and if necessary pleural biopsy should be performed in all patients with an unresolving pleural effusion following CABG.

Influences of the calcium antagonists nicardipine and nifedipine, and the calcium agonist BAY-K-8644, on the pharmacokinetics of propranolol in rats.

To determine the effect of dihydropyridines on the metabolism of propranolol, we studied the effects of a single oral dose of nicardipine, nifedipine, and BAY-K-8644 on the pharmacokinetics of propranolol in male Wistar rats fitted with a catheter in the jugularis vein. Oral propranolol (15 mg/kg and 1.5 mg/kg) and intravenous propranolol (1.5 mg/kg) were administered either alone or together with oral nicardipine (2.5 mg/kg). Oral propranolol (15 mg/kg) was administered with oral nifedipine (1.5 mg/kg) and with oral BAY-K-8644 (1.5 mg/kg). Nicardipine increased significantly the AUC and Cmax of oral propranolol (1.5 mg/kg and 15 mg/kg). However, the plasma concentration time curve of intravenous propranolol (1.5 mg/kg) was unaffected. Nifedipine also significantly increased the AUC and Cmax of oral propranolol (15 mg/kg), whereas with BAY-K-8644 there was only a slight increase in the bioavailability of oral propranolol (15 mg/kg). The results indicate that the dihydropyridine calcium antagonists decrease the metabolism of propranolol as a result of a decrease in first-pass clearance. Although an interaction at the level of cytochrome P450 may also be involved, the results of the present study suggest that the inhibitory effect can be largely attributed to changes in liver blood flow.

Early complications of radioiodine treatment for hyperthyroidism.

Three patients were described with undesirable early complications of low dose radioiodine treatment for hyperthyroidism. The first patient with Graves' disease developed an extreme and permanent hypothyroidism within only few months after receiving this therapy. The second patient with a hyperactive nodular goiter and mild hyperthyroidism had an immediate important exacerbation of the symptoms of hyperthyroidism shortly after a low dose treatment. In the third patient with Graves' disease but without preexisting eye disease a therapy-resistant endocrine ophthalmopathy occurred two months after radioiodine administration.

Splenic abscess: a diagnostic challenge.

Splenic abscess is uncommon and remains a diagnostic challenge. We present two cases. Both patients had predisposing factors that may have led to the splenic abscess. At admission, both patients presented clinical and roentgenographic signs, suggestive but nonspecific for splenic suppuration. Of particular interest was the isolation of Salmonella typhimurium in our first patient. The literature on splenic abscess is reviewed.

Hypotensive and regional hemodynamic effects of the dopamine receptor agonist SK & F 85174 in the anesthetized rat.

The effects of the D1/D2 dopamine receptor agonist SK & F 85174, an N-allyl derivative of fenoldopam, on blood pressure and regional hemodynamics were studied in anesthetized normotensive rats. SK & F 85174 reduced blood pressure and enhanced blood flow in the renal, superior mesenteric and the hindquarters vascular beds. Calculated vascular resistances were reduced. The nonselective dopamine receptor antagonist RS-sulpiride abolished, while SCH 23390 (D1 antagonist), domperidone (D2 antagonist) and hexamethonium (ganglion blocker) each partly blocked the hypotensive effect. SCH 23390 antagonized the vasodilator effect more in the renal and superior mesenteric vascular beds, whereas domperidone antagonized the response more in the hindquarters vascular bed. RS-sulpiride antagonized vasodilatation in the three vascular beds. Hexamethonium abolished vasodilatation in the hindquarters vascular bed only. These results indicate that the hypotensive effect of SK & F 85174 is due to stimulation of both postsynaptic D1 and neuronal D2 receptors. The vasodilator effect in the renal and superior mesenteric vascular beds is mediated by D1 receptor stimulation, the vasodilator response in the hindquarters vascular bed is due to neuronal D2 receptor stimulation.

Twenty-four hour ambulatory blood pressure profile of a new slow-release formulation of diltiazem in mild to moderate hypertension.

Twelve patients with a mild to moderate essential hypertension were included in a double-blind, balanced, randomized placebo-controlled cross-over study to assess the efficacy and duration of action of a new slow-release formulation of diltiazem (300 mg) given once daily for 3 weeks. All office blood pressure measurements were done 24 hours after drug intake. In order to improve the accuracy of the trial, 24-hours non-invasive ambulatory blood pressure monitoring (Spacelabs 90207 system) were performed as well. Diltiazem significantly lowered supine and standing systolic and diastolic office blood pressure (by 16.9/12.7 mmHg and by 17.3/13.8 mmHg, respectively), without changing office heart rate. Diltiazem also significantly lowered ambulatory blood pressure measured over 24 hours, as well as ambulatory heart rate. The blood pressure lowering effect was most pronounced during the daytime period and did not reach statistical significance during the sleeping hours. The treatment was well tolerated, and there were no significant side effects. The results confirm the antihypertensive efficacy of diltiazem LP 300 mg once daily during the daytime and during the early morning blood pressure rise, without inducing nocturnal hypotension.

Identification of a D1 dopamine receptor, not linked to adenylate cyclase, on lactotroph cells.

1. We studied the lactotroph cells of the rat by both in vivo and in vitro pharmacological techniques for the presence of D1-receptors. Both approaches revealed the presence of D2-receptor, stimulated by quinpirole (resulting in an inhibition of prolactin secretion) and blocked by domperidone. 2. Administration of fenoldopam, the most selective D1-receptor agonist currently available, resulted in a dose-dependent decrease of prolactin secretion in vivo (after pretreatment with alpha-methyl-p-tyrosine) and in vitro (cultured pituitary cells). This increase was dose-dependently blocked by the selective D1-receptor antagonist, SCH 23390, and although the effect of fenoldopam was less than that obtained by D2-receptor stimulation, these data suggest that a D1-receptor also controls prolactin secretion. 3. In order to detect the location of these dopamine receptors, autoradiographic studies were performed by use of [3H]-SCH 23390 and [3H]-spiperone as markers for D1- and D2-receptors, respectively. Specific binding sites for [3H]-SCH 23390 were demonstrated. Fenoldopam dose-dependently reduced [3H]-SCH 23390 binding, but had no effect on [3H]-spiperone binding. Immunocytochemical labelling of prolactin cells after incubation with [3H]-SCH 23390 revealed that the granulae and hence, D1 binding sites were present on the lactotroph cells. 4. Radioligand binding studies performed on membranes from anterior pituitary cells revealed the presence of the D2-receptor (54 fmol mg-1 protein) with a Kd of 0.58 nM for [3H]-spiperone, but failed to detect D1-receptors. 5. Finally, we studied the effect of dopamine and of fenoldopam on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content of anterior pituitary cells. Although cyclic AMP increased upon prostacyclin administration, indicating an intact adenylate cyclase system, fenoldopam failed to increase the cyclic AMP production. 6. It is tempting to speculate that fenoldopam reduces prolactin secretion through interaction with a non-cyclase-linked D1-receptor on the lactotroph cells.

Increased dopamine-induced nephrogenous cAMP formation in hypertension.

Low doses of exogenous dopamine (3 micrograms/kg/min) were administered intravenously to nine patients with essential hypertension and to six age-matched healthy volunteers. During infusion with dopamine, mean arterial blood pressure decreased in hypertensive patients whereas it did not change in normotensive subjects. Basal levels of sodium excretion were comparable in hypertensive and normotensive subjects. The natriuretic response to dopamine was significantly greater in hypertensive patients. Urinary and nephrogenous cAMP significantly increased in both normotensive and hypertensive subjects. The increase of nephrogenous cAMP was more pronounced in hypertensive patients than in normotensive controls. A significant correlation was found between nephrogenous cAMP and sodium excretion. The enhanced natriuretic response to dopamine in hypertensive patients may be due to increased cAMP formation in response to tubular dopamine receptor stimulation. This is in agreement with the hypothesis of either up-regulation or affinity changes of renal dopamine receptors in patients with essential hypertension, secondary to a decreased endogenous production of intrarenal dopamine.

Age- and sex-related differences for the urinary excretion of norepinephrine, epinephrine, and dopamine in adults.

Using a specific high-performance liquid-chromatographic method, we measured norepinephrine, epinephrine, and dopamine in 24-h urine collections from 459 men and 497 women, ages 17 to 88 years. We found a significant negative correlation between age and the 24-h excretion of dopamine in men and women (P less than 0.001). Epinephrine excretion decreased with age in men (P less than 0.001). No age dependence was observed for norepinephrine (P greater than 0.2). The excretion of all three catecholamines, expressed in nmol/24 h, was significantly greater in men than in women. The differences, however, were small. With data expressed in nmol/g of creatinine, only epinephrine excretion was greater in men; norepinephrine and dopamine excretions were slightly greater in women. Also, expressed in these units, urinary excretion of norepinephrine in both sexes and of epinephrine in women was significantly positively related with age; urinary excretion of dopamine was significantly inversely related to age in women, but not in men. Reference values are provided for age-independent variables in both sexes.

Protective effects of felodipine and verapamil against imipramine-induced lethal cardiac conduction disturbances in the anaesthetized rat.

The effect of verapamil and felodipine on imipramine-induced cardiac toxicity was assessed in anaesthetized rats. Rats received either infusion of saline (n = 13), or non-hypotensive doses of felodipine (n = 36) or verapamil (n = 36) over 40 minutes. In saline-pretreated rats IV bolus injection of imipramine (10 mg/kg) resulted in severe hypotension, bradycardia, electromechanical dissociation, and death within 3 minutes. Rats pretreated with nonhypotensive doses of felodipine (1, 3, 6, and 10 micrograms/kg/min) or verapamil (10, 30, 100, and 300 micrograms/kg/min) survived throughout the experiment, despite an initial fall in blood pressure within the first 5 minutes after imipramine administration. Blood pressure returned to baseline levels within 15 minutes. Intermittent ECG monitoring showed significant prolongation of QRS duration after imipramine in both saline (by 138%) and verapamil-pretreated rats (by 63%), whereas in the rats pretreated with felodipine no prolongation was observed (+3%). We conclude that, in our experimental model, felodipine, more than verapamil, protects against the cardiac effects of imipramine intoxication.

Systemic mast cell disease: a review of the literature with special focus on the gastrointestinal manifestations.

Mastocytosis is a chronic disease accompanied by specific infiltration of mast cells into the skin and other tissues. In 90% of cases only the skin is involved. In systemic mastocytosis there is an abnormal proliferation of mast cells in various organs including the gastrointestinal tract and liver. Release of various mediators and infiltrative growth of the mast cells lead to the symptoms of the disease. Therefore, many patients present with abdominal symptoms. The clinical manifestations are reviewed with special focus on the gastrointestinal and hepatic involvement. The prognosis of the disease is variable but most often benign. The treatment is based on H1 and H2-blockers and disodium cromoglycate.

Further studies on the mechanism of the natriuretic response to low-dose dopamine in man: effect on lithium clearance and nephrogenic cAMP formation.

The effect of intravenous infusion of low-dose dopamine on electrolyte excretion, lithium clearance, nephrogenous cAMP formation and renal haemodynamics was investigated in healthy volunteers. Dopamine significantly increased the urine flow rate by 70.6% and urinary sodium excretion by 72%, but did not change creatinine clearance, PRA or plasma levels of AVP, ANP and cAMP. Renal plasma flow significantly increased by 48.6%; the glomerular filtration rate was not changed. Lithium per se increased basal PRA, but had no effect on the increments of urine flow rate, sodium excretion and renal blood flow induced by dopamine. Dopamine significantly increased the fractional excretion of lithium (representing fractional excretion of sodium at the proximal level). The increase in urinary sodium excretion during dopamine infusion, significantly correlated with the increase in fractional excretion of lithium (r = 0.94; P less than 0.01) and the increase in nephrogenous cAMP formation (r = 0.96; P less than 0.01). No correlation was found between the increase in urinary sodium excretion and the increase in renal blood flow. In conclusion, this study confirms that low-dose dopamine increases renal blood flow and urinary sodium excretion in healthy volunteers. This natriuretic response appears to be due to interaction with proximal tubular dopamine receptors, which are positively coupled to adenylate cyclase.