Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure.

BACKGROUND: Arginine vasopressin may contribute to abnormalities in hemodynamics and fluid balance in heart failure through its actions on V(1A) (vascular and myocardial effects) and V(2) receptors (renal effects). Inhibiting the action of vasopressin may be beneficial in patients with heart failure. METHODS AND RESULTS: A total of 142 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind, short-term treatment with conivaptan, a dual V(1a)/V(2) vasopressin receptor antagonist, at a single intravenous dose (10, 20, or 40 mg) or placebo. Compared with placebo, conivaptan at 20 and 40 mg significantly reduced pulmonary capillary wedge pressure (-2.6+/-0.7, -5.4+/-0.7, and -4.6+/-0.7 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) and right atrial pressure (-2.0+/-0.4, -3.7+/-0.4, and -3.5+/-0.4 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) during the 3- to 6-hour interval after intravenous administration. Conivaptan significantly increased urine output in a dose-dependent manner (-11+/-17, 68+/-17, 152+/-19, and 176+/-18 mL/hour for placebo and 10, 20, and 40 mg groups, respectively; P<0.001) during the first 4 hours after the dose. Changes in cardiac index, systemic and pulmonary vascular resistance, blood pressure, and heart rate did not significantly differ from placebo. CONCLUSIONS: In patients with advanced heart failure, vasopressin receptor antagonism with conivaptan resulted in favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate. These data suggest that vasopressin is functionally significant in advanced heart failure and that further investigations are warranted to examine the effects of conivaptan on symptom relief and natural history in such patients.

Pharmacokinetics of butixocort 21-propionate, budesonide, and beclomethasone dipropionate in the rat after intratracheal, intravenous, and oral treatments.

The disposition of butixocort 21-propionate (JO 1222) in the rat after intratracheal treatment with a pulmonary aerosol was compared to that of budesonide (BUD) and beclomethasone dipropionate (BDP) using tritium-labeled aerosols. Each aerosol canister delivered 50 micrograms of 3H-labeled steroid through an intratracheal catheter directly into the lung. Rats were sacrificed at different times after treatment. Lung and plasma concentrations of unchanged drug and active metabolites were measured by HPLC using a radioactivity detector. Tritium-labeled drugs (1.5 mg/kg) also were administered by the iv and oral routes for the purpose of comparing their systemic availability. The extent of biotransformation of all three steroids in the lung was very limited. JO 1222 was metabolized to the active compounds butixocort (JO 1717) and butixocort 21-methyl (JO 1605). BDP was transformed primarily to beclomethasone monopropionate (BMP); BUD was not metabolized in the lung. In contrast to these results, large differences were observed between plasma concentrations and systemic availability of the three drugs. BUD was rapidly absorbed from the lung, and its plasma elimination half-life was about 3 hr. BDP was hydrolyzed rapidly into its active metabolite BMP after intratracheal and iv treatments; BDP was not observed in plasma after oral treatment. Additionally, plasma concentrations of BMP were higher than those of BUD administered at the same doses. Assuming that BDP was transformed entirely into BMP, the oral bioavailability of BMP at 1.5 mg/kg was around 72%, while that of BUD was 15%. JO 1222 has a distinct pharmacokinetic profile due to the extensive metabolic clearance of both the unchanged drug and its active metabolites JO 1717 and JO 1605.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fedotozine on gastrointestinal motility in dogs: mechanism of action and related pharmacokinetics.

The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N-dim eth yl- n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg-1 stimulated and at 5 mg kg-1 inhibited antral motility. Between 1 to 5 mg kg-1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2.5 and 5 mg kg-1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg-1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg-1 i.v.) and naloxone methylbromide (2 mg kg-1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the mu-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg-1 (and in all dogs except one at 5 mg kg-1) were below the detection limit (less than 20 ng g-1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 microgram g-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaplastic small cell (oat cell) carcinoma of the tonsils: report of two cases.

Two cases of anaplastic small cell (oat cell) carcinoma of the tonsils are presented. In the first, cervical metastases preceded the manifestation of the primary tumour by 2 years. In case 2 the tonsillar carcinoma was accompanied by a bronchial tumour of the same histological type and by cervical and axillary metastases. Positive Grimelius stain, positive immunohistochemical staining for chromogranin A and neurone-specific enolase and the presence, in case 1, of membrane-bound granules indicate that these tumours display many similarities with neuroendocrine carcinomas even if they originate from pluripotential ductal cells of tonsillar minor salivary glands and not from Kulchitsky-like cells.

Isolation and identification of major metabolites of tixocortol pivalate in human urine.

The metabolism of tixocortol pivalate (PIVALONE), an anti-inflammatory steroid without systemic glucocorticoid effects, has been investigated in man. The analysis was conducted using urine samples collected from two volunteers who had received a 2-g oral dose of 14C-tixocortol pivalate as an oral suspension. Metabolites were purified and isolated from urine by normal phase HPLC, and structural identification was achieved by desorption chemical ionization/NH3 and electron impact/direct line introduction mass spectrometry. Unchanged tixocortol pivalate was not detected in urine; all metabolites were sulfo- and glucurono-conjugates. Metabolites were identified in the neutral steroid fraction obtained after hydrolysis of conjugates. Metabolic transformations in common with cortisol were reduction of the 3-keto, delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol, and cleavage of the side chain at C-17. Specific metabolic pathways involving the C-21 thiol ester function were transformations into methylthio, methylsulfinyl and methylsulfonyl derivatives, and a reductive cleavage of the C-21-S bond leading to 21-methyl structures. Since none of these metabolites had binding affinity for glucocorticoid receptors in vitro, fast and extensive transformation of tixocortol pivalate into inactive metabolites provides an explanation for the large dissociation between the topical and systemic activities of this drug.

[Familial hypocalciuric hypercalcemia. A new family]. / Hypercalcémie hypocalciurique familiale. Nouvelle famille.

A new example of familial hypocalciuric hypercalcaemia is reported. The family studied consists of 19 members over four generations. The first patient described in this study had already undergone a classical surgical operation for "primary hyperparathyroidism" before the correct diagnosis was established: that of a new syndrome described for the first time by Foley in 1972 and subsequently studied by Marx since 1977. The features of this syndrome are: hypercalcaemia accompanied by hypocalciuria, autosomal dominant transmission with strong penetrance, with early appearance of hypercalcaemia, absence of signs of familial multiple endocrine neoplasia, benign course and persistence of the hypercalcaemia despite classical sub-total parathyroidectomy. Following a family survey, the authors discovered eight other members of the family who also presented this syndrome.

Comparative pharmacokinetic studies of tixocortol pivalate and cortisol in the rat.

Comparative pharmacokinetic studies of [14C]tixocortol pivalate ([14C]TP) and [14C]cortisol were carried out in rats. A 2.5 mg/kg i.v. dose (TP and cortisol) and oral doses of 1 and 25 mg/kg (cortisol), 25-250 and 1500 mg/kg (TP) were given separately to male and female rats. 14C-Radioactivity, [14C]cortisol, [14C]TP and [14C]T were determined in plasma samples, using TLC determinations and HPLC analysis. The results showed that plasma clearance and volume of distribution values of TP were respectively 6 and 10 times larger than those of cortisol (ClC = 4.7 l/h/kg and ClTP = 33.3 l/h/kg; VdC = 1.9 l/kg and VdTP = 21.7 l/kg). TP was rapidly converted into T whose plasma concentrations were close to those of TP. By the oral route, the bioavailability of cortisol was complete, whereas that of TP and T was 0.10-0.20. For the same 25 mg/kg p.o. dose, plasma Cmax values of TP and T were 100 times less than those of cortisol. It is concluded that a faster rate of metabolism combined with a larger volume of distribution and a low oral bioavailability all contribute to the lack of systemic activity of TP compared with cortisol.

Bioavailability of Theodel, a new theophylline tablet, in humans.

The bioavailability of Theodel, a new scored tablet of theophylline, was investigated in eight healthy adult volunteers. Rate of absorption and AUC infinity were compared after single oral doses of Theodel (250 mg), of an aqueous solution (250 mg), and of two Theolair tablets (2 X 125 mg). Theophylline was rapidly absorbed from the Theodel tablet, with a t1/2abs of 0.44 +/- 0.37 h; maximum plasma concentrations of 8.0 +/- 2.3 mg/l were reached after 1.8 +/- 0.8 h. Almost the entire dose was recovered from urine as theophylline and its major metabolites, 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine. Theophylline was, therefore, efficiently absorbed from this formulation. The plasma elimination half-life ranged from 5.9 to 10.4 h. Based on the assumption that absorption is complete, the plasma clearance ranged from 0.028 to 0.048 1 X h-1 X kg-1, and the apparent volume of distribution from 0.38 to 0.57 1/kg. No significant difference between the rate and the extent of theophylline absorption was observed for the three preparations, which are thus bioequivalent. Simulations of plasma levels after repeated administration of Theodel tablets showed that plasma theophylline concentrations remain in the therapeutic range with three doses per day.

Plasma protein binding of the reversible type A MAO inhibitor cimoxatone (MD 780515).

Binding of a new selective reversible type A MAO inhibitor cimoxatone (MD 780515) to plasma proteins was studied in vitro by equilibrium dialysis. Binding to 580 microM human serum albumin (HSA) and to total plasma proteins was 93-96% and independent of cimoxatone concentration (0.15-207 microM). The drug was mainly bound to HSA with two binding sites and a moderate association constant (K = 2.9 X 10(4) M-1). Free fatty acids did not modify cimoxatone binding to HSA. Cimoxatone was also moderately bound to isolated lipoprotein fractions; alpha 1-acid glycoprotein and gamma-globulins did not play an important role in the binding of cimoxatone. MD 770222, the O-demethyl metabolite, appeared to be bound to HSA at the same binding sites as cimoxatone. However, no interaction occurred between the two compounds for 580 microM HSA. L-Tryptophan, bilirubin, the benzodiazepines flunitrazepam and oxazepam, imipramine and aspirin, did not displace cimoxatone from its binding sites. On the other hand, warfarin and phenylbutazone decreased cimoxatone binding to 29 microM HSA but no interaction occurred with 580 microM HSA.

Pharmacokinetics of theophylline: a dose-range study.

1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg).

Symptomatic hypopituitarism revealing a primary empty sella turcica.

A 64-year-old nulliparous woman presented with clinical signs of thyroid and adrenocortical insufficiency. Subsequent hormonal investigations demonstrated a failure of all anterior pituitary functions. Pneumotomo-encephalography revealed a large arachnoid herniation, leading to the diagnosis of primary empty sella turcica syndrome with secondary panhypopituitarism. This unusual observation emphasizes the necessity of ruling out an empty sella turcica syndrome in patients with pituitary insufficiency.

Absorption, distribution, elimination and metabolism of 14C-heptaminol hydrochloride in rat.

Absorption, distribution, excretion and metabolism studies with 14C-labelled 6-amino-2-methyl-2-heptanol hydrochloride (14C-heptaminol hydrochloride, Hept-amyl) were carried out in rat. After a 10 mg/kg p.o. dose heptaminol was rapidly and entirely absorbed. Following the administration of 8 mg/kg i.v. or 12 mg/kg p.o., all tissues studied, except brain, contained higher levels of radioactivity than did plasma. No evidence of accumulation of the drug was seen in any tissue. Whole-body autoradiography revealed a preferential localisation in salivary glands, hypophysis and adrenal medulla 1 h after a 10 mg/kg i.v. or p.o. dose. Brain autoradiography showed radioactivity localised only in highly vascularised areas (choroid plexus and pia mater). Excretion occurred mainly by kidney, 68% of the radioactivity being excreted in urine 4 h after a dose of 10 mg/kg i.v. Biliary and faecal elimination accounted for less than 1% of the radioactivity administered. Heptaminol was metabolized to a hydroxylated metabolite, 6-amino-2-methyl-1,2-heptanediol, which was excreted unconjugated in urine. As doses increased from 10 to 200 mg/kg p.o., the amount of metabolite excreted in the 24-h urines decreased from 7.05% to 4.24% of the urinary radioactivity, indicating a saturation of the metabolism at high doses. Pretreatment of rats with phenobarbital increased the percentage of metabolite excreted in urine, but was unable to prevent the saturation of the metabolism at high doses of heptaminol.